Although we perceive sex as a simple division into male and female rooted in fertilization, sexuality is a complex interwoven relationship with many forms of interaction more subtle and pervasive than the raw sexual urge. To fully understand sex we thus need to appreciate this deep relationship between sex and the warp and weft of entanglement.
Much of this entanglement comes from the long history of biological sex as a prisoners' dilemma relationship from which there is no escape but reproductive fertilization, except for brief periods of parthenogenesis, interrupted by cryptic sexual exchange and adaption.
Central to the dark nature of sexuality is the Edenic notion that sex is central to our downfall into the mortal coil and hence that our sexual desire is at the root of our fallibility, without which we could have become 'as Gods'. We need to understand the source of this fallacy in coming to terms with the redemptive nature of sexuality in the perpetuity of life.
Sex is of course the source of individual organismic mortality because, rather than reproducing clonally or parthenogenetically as bacteria do, when they are not using viral or plasmid promiscuity to exchange DNA, we share only half our genes with a partner, in conceiving new offspring, rather than transmitting all our genes and hence a complete replicon of ourselves in parthenogenesis. None our offspring will thus ever have the same genes as ourselves again in the entire history of the universe, because of sex's endless recombination. This teeming complexity, which is central to Taoistic notions of nature never repeating itself exactly, is one of the most insightful affirmations of the power of sexual exchange in creating almost endless variety from the molecular dance of the primal ooze.
Contrasting and complementing sex's tryst with death is its role in immortal life, for sex is also our salvation in the perpetual passage of the generations. For us to come into existence at all, our living germ-line, or more appropriately germ-web has had to have run in an unbroken chain of ancestors for the entire three and a half billion years back to the first beginnings of life on Earth. While sexuality gives every non-parthenogenetic organism a limited life-span, we thus owe our very existence to the immortal sexual genetic web.
Moreover, sex is the most fundamental nemesis of selfishness, for in transmitting only half our genes, we have entered into a fundamental pact with the 'other' to share our very identity and our reproductive destinies. To do this we must ultimately elicit the cooperation of the other, for defection once mutual becomes our collective nemesis. Thus the unmitigated selfishness of the parthenogenetic gene is compromised, cleaved to a break-even between selfishness and altruism, which remains the founding paradox of all sexual engagement.
Bacteria engage in much more radical forms of pan-sexuality than higher organisms, involving viruses and plasmids, themselves separate mobile genetic elements acting as agents of genetic transfer. This enables the genetic sequences of bacteria, archaea and protists to move around in the genome and to be exchanged between cells, and even between different species. This form of pan-sexuality is a mirror to our own dyadic sexuality. Sexual exchange of material can happen both through viral exchange and through a conjugation plasmid, which can spool DNA from one bacterium into another, resulting in a net donation of genes from one strain or species to another, which ensures a broad exchange of genetic material throughout bacterial ecosystems, resulting in rapid accumulation of advantageous genes exemplified by plasmid borne infectious drug resistance.
Bacterial pan-sexuality. Above: Syringe-like bacteriophages injecting their DNA are capable of transferring genes between bacteria, carrying bacterial genes with them when they multiply and are released. Some phages also integrate with the host chromosome. Below: A positive sex-strain bacterium using plasmid sexual pili to transfer DNA simultaneously to two other bacteria. Sexual plasmids also integrate with the host chromosome during sexual conjugation (Wolfe R757).
Because the genes driving this exchange are from a separate 'organism', a genetic plasmid, carrying its own genes and conferring male doning capacity on bacteria harbouring it, there are no bounds on exchange between the same species. Indeed plasmid sexuality is promiscuous between many bacterial species, resulting in sharing of genetic information on a pan-sexual basis. In addition to plasmid-mediated genetic exchange, bacteria also engage extensive genetic recombination, through viral exchange, which carries genes between bacteria, as temporary additions to a viral genome. Although some of these elements, such as the phages, are parasitic, the sexual conjugation plasmids are essential for bacterial survival and also depend on the bacteria for their existence. The overall relationship is thus a symbiotic one of mutual genetic inter-dependence amid competition. Plasmid sexuality has resulted in major aggregations of antibiotic resistance genes onto a single plasmid in infectious drug resistance.
This view of sexuality as an ecosystemic process of sharing genetic information and providing recombination into new genomic arrangements capable of new forms of survival in new ecological niches is central to the ecosystemic foundation from which sexuality gains its immense variety. It is also important in understanding the deep relationship between sexuality as an interdependent sharing of information and variety and the dyadic form of sexuality we find in higher organisms, to which we shall now return. However this ecosystemic sexual exchange has certain limitations. Notice that this form of sexuality is not directly linked to bacterial reproduction. Basically it is transferring part of a single copy genome from one cell to another. It works very well at sharing key genes among many types of bacteria. It also does well at providing new types of genome, or even new species, with new combinations of existing genes, however it doesn't provide for recombining an existing genome characteristic of a given species in a way which can make new viable varieties of individual which remain viable and interfertile within a given species. Also it is too scrambled and chaotic a process to enable the evolution of complex genomes with many chromosomes and elaborate organismic regulation which needs to be conserved.
The dyadic sex of higher organisms is the enchanted loom of emergence of all living animals, plants and fungi, because the immense genetic variety produced by sexual recombination, virtually all of whose combinations are viable genomes, is what has made evolution into complex organisms possible. If we had to rely on parthenogenetic cloning we would still be single-celled animals of unremitting genetic selfishness. The few higher species which do reproduce by parthenogenesis generally also rely on cryptic sexuality to restore variation, particularly in times of stress. If we had had to rely only on bacterial sex, we would likewise have remained at the stage of single celled single chromosome organisms. Deborah Blum (R66 ) notes that dyadic sex at the most basic level ensures we recombine only with a single genome of the same species and don't have to cope with the chaotic multiple agent mixing of bacterial pan-sexuality. But what is absolutely unique about higher organismic sex is that it enables specific recombination of the variants, or alleles, of a singe gene to be recombined in ways which make for almost endless variety, while still preserving the overall organization of the genome.
This creative bounty comes despite sex's supposedly 'destructive' carnivorous origins (Margulis and Sagan R438). The first eucaryotes seem to have engulfed the typhus-like bacteria which became the mitochondrion, giving us our respirative energy and the cyano-bacteria which became the chloroplasts of plants which provide the energy of photosynthesis. A more controversial suggestion by Margulis has been that the kinetochores at the base of flagella which form the centrioles organizing the spindles which make both mitotic cell division of paired chromosomes and the meiotic recombinations of sex cells possibly originated from spirochaete flagella. Closer analysis may not support this idea because spirochaete flagella now appear to be rotary engines like the bacterial flagellum, rather than flexing. Lynn Margulis suggests merging of two (haploid) genomes, each containing a single copy of each of our genes, doubling our chromosome number to the diploid form, and hence fertilization itself, originates in amoeba which found 'eating one's mate alive was as good as being twins'. Diploid sexuality and possibly the separation of the nucleus and multiple chromosomes as well may thus have originated from beneficent cannibalism.
Eucaryote sexual reproduction: Both normal mitotic cell division in eucaryotes (a) and sexual meiosis involve the spindle apparatus centered on the semi-autonomous centriole (b) which must itself divide before the chromosomes can separate and is also the source of the flagellum. Crossing over requires spooling of the DNA to find homologous points of exchange, mediated by the synaptonemal complex (c) after which the crossed chiasmata can be seen in later stages (d) (R146, R757, R355).
A new form of sexuality emerges, in which there is an alternation between haploid sexual generations, each containing one copy of each gene, which fuse in fertilization to diploid generations containing two copies of every gene which can, before again forming the next sexual generation, recombine this double-headed genome to mix the genetic characteristic of 'father-sperm' and 'mother-egg' into new son and daughter sexual genomes containing a viable serially-ordered mix of each. From this elegant, stunning and still not-fully understood process, whose evolutionary roots remain obscure, comes the immense capacity for variety we find in multi-celled organisms. Pivotal to this is the kinetochore and spindle apparatus that can pull daughter chromosomes apart after every cell division and the sifting and ordering of the genes at the crossover points during generation of sexual gametes in meiosis. The mechanism for homologous crossing-over has recently been clarified.
Eucaryotic sex has a very complex origin. Bacterial cells contain only one chromosome attached to the cell membrane. Eucaryotic cells containing many chromosomes divide mitotically, by replicating each chromosome and pulling them apart using microtubules (a) organized around the centrioles (b). The centriole itself has a cryptic origin, being partially autonomous in the sense that division of the crossed centrioles, which come in pairs at right angles, to form a new pair, precedes separation of the replicated chromosome pairs.
Centrioles are also the source of the flagellum in the sperm and other cells. Lynn Margulis has suggested that, like the mitochondrion and chloroplast, the centrioles arose from symbiosis with motile spirochaetes, which have tubulin-like proteins. However spirochaete flagella appear to be more like the rotatory bacterial flagella (Charon and Goldstein R114), so centrioles may originate internally in the apparatus linking the chromosome to the cell membrane. Studies show that at least some animal cells can generate new centrioles if their centrioles are destroyed by laser microsurgery (Khodjakov et. al. R360). These generate random multiple arrays from a cloud of microtubules, implying that mother-daughter centriole pairs serve to ensure clean bipolar spindles rather than disorganized chromosome division, which centriole-less anastral plant spindles suffer from more than animal cells (Marshall et. al. R445). Series of studies searching for independent cytoplasmic DNA or RNA in centrioles which could form a genetic symbiosis like the mitochondrion have not produced clear evidence for either (Hinchcliffe et. al. R316, Marshall et. al. R446).
Centromeres, the anchor regions where microtubules from the centriole link to the chromosome, essential for chromosome division, have been found to contain selfish DNA that attempts to propagate itself exclusively during meiosis, when the division in females is asymmetric, with three of the four duaghter cells becoming polar bodies rather than an ovum, and thus do not get propagated to the next generation. Centromeres differ in their binding strength and stronger ones can detect their orientation within the dividing cell due to proteins released by the membrane to induce asymmetric division. When they find themselves in the region leading to a polar body, they repeatedly let go, focing the opposing centromere to do likewise, until due to random movements within the cell, they find themselves on the ovum pole and then draw tight ensuring their transmission along with the chromatids that contain them in the ovum. These centromeres appear to be genuinely selfish because centromere-binding proteins have been found to be one of the most rapidly evolving genes in the human genome, implying that they are caught in an arms race of mutually-antagoistic co-evolution (Akera T et al. 2017 Spindle asymmetry drives non-Mendelian chromosome segregation Science 358/6363 668-672 doi:10.1126/science.aan0092).
The 16-unit protein Dmc1, which shows homology with the bacterial recombinase RecA (Watson et. al. R734 319), mediates homologous recombination between DNA of maternal and paternal versions of chromosomes in meiosis, by spooling double-stranded and single stranded DNA vertically and horizontally, as shown, consistent with the scheme at right (Kinebuchi et. al. R362). Intriguingly the tumor suppressor gene p53 seems to have been recruited from a protein essential ot meiotic recombination (Cancer guardian found playing a role in sex New Scientist)
Some primitive eucaryotes still have chromosomes linked to the nuclear membrane. In a scenario in which cell fusion or cannibalism led to a doubling of a single chromosome, to a diploid cell, these could again subdivide to form haploid cells. Mitotic spindles could have begun on one diploid chromosome pair and subsequently developed to separate several chromosomes cleanly into the daughter cells. From here the double division of the tetrad of chromatids arising from replicated diploid chromosomes to regain haploid sex cells during meiosis would follow naturally. However the validity of sex depends on the variety created by sexual exchange and this requires recombination between sister chromosomes through crossing over. This is again a complex and not fully understood process mediated by the synaptonemal complex, requiring the DNA of the pair of chromosomes being crossed over to be carefully spooled to find homologous regions, so that the crossing does not interrupt a gene and retains a perfect complement of genes in each sex cell.
In addition to their selfish gene load, there are also indications of genetic symbiosis between cellular and mobile elements, which may facilitate a variety of regulatory and evolutionary processes. The incidence of genes with associated mobile elements is high. Of 12,000 human genes investigated in one study (Trends in Genetics 19 p 68) 27% were associated with transposable elements. More rapidly evolving genes, such as those in the immune system, had more transposable elements. The huge variety of antibody type in immunity is induced through many factors including large gene libraries and hyper-variable regions prone to mutation and translocation. In turn, the RAG1,2 immune system genes induce editing processes characteristic of transposon activity. 25% of human genes contain multiple promoters, including those of transposed elements, which provide an adaptive basis for complex forms of regulation. Primates have a unique capacity to regulate estrogen in the placenta independently of the gonads because of such an adaption.
This co-evolution is also fraught with the mutual antagonism we have seen between male and female sexes. In the 0.4% of genes which contain transpositional insertions into coding regions there are alternative forms of RNA splicing, which can mask and tolerate what could otherwise be a lethal mutation (for both host and endogenous element). The sexual imprinting of genes through methylation may be an adaption of a defence against genes infected by deleterious mobile elements by rendering a section of DNA inactive. In turn transposable elements may have driven sexuality itself. According to Donal Hickey (R314) transposable elements are at a two-for-one advantage to sexual genomes because they can transfect sex-cells during the reproduction cycle (as LINEs are known to do) thus ensuring all offspring of any host partner are infected, while each of the sexual partners can contribute only half their genes. It is thus possible that sexuality itself was generated as a adaptive response by transposable element evolution rather than the host genome. Species which are highly sexual have large transposable element loads. Those in between have lower loads and asexual species very few. However the transposable elements can neither be considered benign nor entirely selfish. The chromosomal and mobile genomes are in a truly sexual genetic entwinement too, with the benefits to both arising indirectly through the mutual defences each has set up to the strategic onslaught of the other (Kingsland R376). Thus the answer to the selfish gene thus turns out to be a form of sexually antagonistic coevolution (p 16).
Human transposable element evolutionary history of L1-LINEs (cream), Alu elements (lt. blue), retrovirus-like LTR (long-terminal repeat) elements (green) and DNA transposons (dk. brown). Older LINEs and SINEs are in yellow and dk. blue. This history extends back over 200 million years indicating the very ancient basis of this potentially symbiotic relationship (Human Genome Consortium R336).
Coding sequences comprise less than 5% of the human genome, whereas repeat sequences account for at least 50% and probably much more. Transposable LINE or long-intermediate repeat retroelements common to vertebrates, with a history running back to the eucaryote origin are specifically activated in both sperms and eggs during meiosis (R74, R684, R698). These replicate from transcribed RNA copies of themselves thus using RNA to instruct DNA copies, indicating an origin in RNA-based life, as does the active RNA processing of our own eucaryote cells. Their RNA-based reverse transcriptase shows homologies with the telomerase essential for maintaining immortality in our germ line, indicating a common and symbiotic origin. 100,000 partially defective LINEs and their 300,000 dependent smaller fellow traveller Alu SINEs make up a significant portion of the human and mammalian genomes, along with pseudogenes, apparently defective copies of existing genes translocated by elements such as LINEs.
These elements travel passively down the germ line with chromosomal DNA, so their specific activation during meiosis suggests they may perform a role of coordinated regulatory mutation. This suggests that the type of symbiotic sexuality embraced by bacteria and plasmids also continues to function in higher organisms in a form of sexual symbiosis between our chromosomes and transposable genetic elements. This is consistent with the 1.4% point mutation divergence between humans and chimps, being overshadowed by an additional 3.9% divergence to 5.4% overall (Britten R78), when insertions and deletions are accounted (p 98).
SINEs, such as human Alu, a free-rider on the LINE reverse transcriptase derived from the small cellular RNA used to insert nascent proteins through the membrane, are in turn implicated in active functional genes (Reynolds R574, Schmid R615) particularly some involved in cellular stress reactions, again suggesting genetic symbiosis. Humans have about 13 times as many RNA edits as non-primate species, including inosine insertions associated with Alu elements, as well as intron deletions (Holmes R325) and newly inserted exons (Ast R26), which may differentiate humans from other apes through alternative splicing of genes expressed in the brain (p 102). An Alu mobile element derived gene has been found in humans which encodes a neural small cytoplasmic RNA BC200. Conserved features of the active BC200a gene suggests that its RNA product has been "exapted" into a function of the primate brain and provides a selective advantage to the species (Martignetti and Brosius 1993 PNAS 90 11563-7). RNA editing is abundant in brain tissue, where editing defects have been linked to depression, epilepsy and motor neuron disease. There is a new Alu insert about every 100 births. As many as three quarters of all human genes are subject to alternative splice editing.
Recent explosion of the area of interfering miRNAs as regulatory elements in gametogenesis and development (See: Großhans H, Filipowicz W 2008 The expanding world of small RNAs Nature 451 414-6, doi:10.1038/nature06863, 06642, 06908, 07015) has provided an explanation of how pseudogenes, including those retrotransposed via LINE elements, can gain functional regulatory significance even though they do not produce translatable mRNAs.
Left: Pseudogene-mediated production of endogenous small interfering RNAs (endo-siRNAs). Pseudogenes can arise through the copying of a parent gene (by duplication or by retrotransposition). (a) An antisense transcript of the pseudogene and an mRNA transcript of its parent gene can then form a double-stranded RNA. (b) Pseudogenic endo-siRNAs can also arise through copying of the parent gene as in a and then nearby duplication and inversion of this copy. The subsequent transcription of both copies results in a long RNA, which folds into a hairpin, as one half of it is complementary to its other half. In both a and b, the double-stranded RNA is cut by Dicer into 21-nucleotide endo-siRNAs, which are guided by the RISC complex to interact with, and degrade, the parent gene's remaining mRNA transcripts. The mRNA from genes is in red and that from pseudogenes is in blue. Green arrows indicate DNA rearrangements (Sasidharan R, Gerstein M 2008 Protein fossils live on as RNA Nature 453/5 729-32). Right: LINE-1 is essential for progression from the 2-cell embyo to the blastula in mice.
Although the data from the human genome project indicated that human LINEs are becoming less active as a group by comparison with the corresponding elements in the more rapidly evolving mouse genome, there remain about 60 active human LINE elements which are known to be responsible for mutations in humans. More recent investigation (Boissinot et. al. R71) shows that the most recent families are highly active. Around four million years ago shortly after the chimp-human split, a new family Ta-L1 LINE-1 emerged and is still active, with about half the Ta insertions being polymorphic, varying across human populations. Moreover 90% of Ta-1d, the most recent subfamily are polymorphic, showing highly active lines remain present. LINEs are more heavily distributed on the sex chromosomes with X chromosomes containing 3 times as many full length potentially active elements and the Y chromosome 9 times as many! This is consistent with a continuing mutational load on humans which is removed more slowly from the sex chromosomes by crossing over in proportion to the degree to which crossing over is inhibited in each (i.e. totally on the Y and largely in males in the X but not in females). We have noted (p 28) that sexual recombination is a protection from mutational error in a process called Muller's ratchet.
L1 elements have also been found to replicate in neural progenitor cells in both the mouse and human and copy numbers have been found to increase in the hippocampus, and in several regions of adult human brains, when compared to the copy number of endogenous L1s in heart or liver genomic DNAs from the same donor. The authors comment that these data suggest that de novo L1 retrotransposition events may occur in the human brain and, in principle, have the potential to contribute to individual somatic mosaicism (Coufal et. al. 2009 L1 retrotransposition in human neural progenitor cells Nature doi:10.1038/nature08248).
L1 is paradoxically highly expressed during early development and plays essential roles in mouse embryonic stem cells (ESCs) and pre-implantation embryos. In ESCs, LINE-1 acts as a nuclear RNA scaffold that recruits Nucleolin and Kap1/Trim28 to repress Dux, the master activator of a transcriptional program specific to the 2-cell embryo. In parallel, LINE-1 RNA mediates binding of Nucleolin and Kap1 to rDNA, promoting rRNA synthesis and ESC self-renewal. In embryos, LINE-1 RNA is required for Dux silencing, synthesis of rRNA, and exit from the 2-cell stage. The results reveal an essential partnership between LINE-1 RNA, Nucleolin, Kap1, and peri-nucleolar chromatin in the regulation of transcription, developmental potency, and ESC self-renewal (Percharde M et al. 2018 A LINE1-Nucleolin Partnership Regulates Early Development and ESC Identity Cell 174 doi:10.1016/j.cell.2018.05.043).
Evolution of reverse transcriptases from a common ancestor bearing a LINE archetype (Xiong and Eickbush R772 Nakamura et. al. R498). The root of their evolution goes back to the transfer from RNA to DNA at the beginning of life. They form a complementary evolutionary tree to that of cellular life as genetic symbionts of metazoa travelling down the germ line. Their group includes telomerases essential to the reproductive cycle.
LINEs are preferentially expressed in both steriodogenic and germ-line tissues in mice (Branciforte and Martin R74, Trelogan and Martin R698), suggesting stress could interact with meiosis. L1 expression occurs in embryogenesis, at several stages of spermatogenesis including leptotene, and in the primary oocytes of females poised at prophase 1. This could enable somatic stress to have a potential effect on translocation in the germ-line which might enable form of genetic adaption in long-lived species such as humans.Conversely the SRY-group male determining gene SOX has been found to regulate LINE retrotransposition (Tchénio et. al. R684). Similarly LINE elements have been found to be 'boosters' in the inactivation of one X chromosome that happens in female embryogenesis (Lyon R428, Chow et al. doi:10.1016/j.cell.2010.04.042).
Both L1 and Alu elements may be able to self-regulate rates of replication, through the existence of stealth drivers, viable elements which maintain a low transcription rate of active elements, with little genomic impact and hence little negative selection. These occasionally seed daughter master elements, which may replicate actively to form new families when conditions permit. This picture is consistent with long periods of quiescence, punctuated by bursts of 'saltatory' replication leading to large copy numbers (Han et. al. R287).
Endogenous retroviruses, or ERVs, which also travel down the germ line as free-riders, although some may retain infectious capacity, may be essential for placental function, as every mammal tested has placental blooms of endogenous retroviruses which appear to both aid the formation of the syncytium, the super-cellular fused membrane that enables diffusion from the mother to the baby and the immunity suppression which prevents rejection of the embryo, both characteristics of retroviruses such as HIV. Mi and colleagues (R472) found a placental whose sequence was homologous to several viral envelope proteins. The sequence, now called syncytin, is identical to the envelope protein of the HERV-W retrovirus. It is expressed at high levels in the syncytiotrophoblast (and at low levels in the testes) and nowhere else. Most of the other genes of the provirus have been mutated, suggesting that the envelope glycoprotein function was specifically selected. If cultured cells are made to express syncytin, they will fuse together, and this fusion can be blocked with antibodies against syncytin. HERV-W is only found in primates, but mice have similar retroviral blooms. Our ability to form the placenta may thus depend on our harnessing a viral gene somewhere in our evolutionary lineage.
The developing human embryo expresses genes and control sequences from two classes of HERV in large amounts, though their functions are not known (Virology, vol 297, p 220). It also appears that HERVs play important roles in normal cellular physiology. Analysis of gene expression in the brain suggests that many different families of HERV participate in normal brain function. Syncytin-1 and syncytin-2, for example, are extensively expressed in the adult brain, though their functions there have yet to be explored (Ryan Frank I Virus New Scientist 29 Jan 2010).
The 'lampbrush' phase of extended chromosomes during meiosis has also been suggested to enable forms of genetic re-processing. In non-mammals this extended phase involves open transcription of coding and non-coding regions and has been proposed to be a form of genetic processing (Wolfe R757), which probably occurs in a less obvious way in mammals as well. Some of the early radioactive tracer studies of diplotene 'lampbrush' chromosomes in amphibians showed apparent spooling of the DNA during maturation of the ovum, consistent with a gene comparison mechanism (Callan R100, R101). The purpose of such openly transcribing stretches of the whole chromosomes including vast regions which are not coding for any protein remains obscure (Angelier et. al. R17). All transcription units functioning in lampbrush loops synthesize RNA at a maximum rate. In situ hybridization has provided evidence for transcription of both unique coding sequences and highly repetitive sequences. For repetitive sequences, their intense transcription appears to be non-productive, in that RNAs are not translatable and might be useless products of read-through transcription, unless they have a role in genetic modulation as RNAs.
Lampbrush chromosomes in the newt (Gall, Wolfe R757).
The much longer time primary oocytes remain in meiotic stasis before eventual maturation might to give the female a tendency to express stress-induced translocational effects during adult life, 'compensating' for the up to four-fold higher base rate of male point mutation, because the continual mitotic production of sperm cells leads to more cell divisions, by contrast with quiescent immature oocytes (Ellegren R187, Nachmann and Crowell R497, McVean and Hurst R462). X-chromosomes evolve more slowly, presumably because they spend three quarters of their time in the female line.
Sex appears to become a necessity, linked to reproduction as a means of generating genetic variation when the generation to generation reproduction rate slows to the point that mutations occur at too low a rate to provide enough genetic variation for populations to fully adapt. This means a strict reliance upon sex as a means of reproduction is largely a feature of larger and relatively slowly reproducing, multicellular organisms. Many unicellular organisms have no known sexual reproduction, and can be considered to be obligate asexual. No unicellular organism is obligate sexual. Not all multicellular organisms are obligate sexual, but all the obligate sexual organisms are multicellular.
Before there was gender there was symmetrical sex. In many fungi today, and in some simple plants, like spirogyra, any two distinct strains of a species can fertilize one another by passing a nucleus through a conjugation tube. Some 'primitive' single-celled protoctists still use identical isogametes.. All multi-celled animals however depend on the cytoplasm of the egg to differentiate into the tissue layers of the developing embryo, and its organs. Egg and sperm have become symmetry-broken into complementary yin and yang genders, as wave and particle are in physics - exemplified above by a large enveloping egg membrane covered in many particulate sperm endeavouring to fertilize the ovum. This relationship with wave-particle complementarity may be more than just an analogy. It may be an expression of quantum reality at the organismic level.
Here 'sex' means the formation of haploid sexual gametes which fuse their genes again through fertilization. Each haploid sex cell contains one copy of each (non-sex) chromosome - half of the number of 'paired' chromosomes found in the diploid form of the organism, in which there are two of each. Some organisms such as mosses and coelenterates also have active haploid phases. 'Gender' is here the symmetry-breaking of sex cells, and the sexual organisms bearing them, into complementary masculine and feminine morphologies. This is the sense Kim Walen also uses it in describing 'gender predispositions' in sex as a minimum energy genetic solution breaking sexual symmetry in the simplest most efficient way - "The effect of a predisposition is essentially to open up the path of least resistance". He compares the development of gender with the way the visual nervous system responds dynamically to visual input, in stimulating development (Blum R66 18). It is clear the brain is far more complex than the 60% or so of our 30,000 genes could produce by hard wired genetic determinism. Thus the developing brain uses genetic cues to establish a dynamical process conducive to the development of a much more complex organ than the genes themselves can determine. This provides a window on a fascinating complementarity and interactivity between nature and nurture in which nature finds the simplest most efficient route in responsive relationship with the natural and social environment to give rise to engendered sexuality. In this view all the variations in trans-sexual development along with sexual orientation are just results of 'having enough slip' in this predisposing biological pathway.
We contrast 'gender', as symmetry-broken environmentally responsive sexuality with 'cultural engendering' - social or politically acceptable (or indeed transvestite) sex roles which a given society may impose, encourage or seek to exorcise. While acknowledging, especially in the critique of patriarchy, that imposed cultural roles can and do result in cultural variation in cultural engendering, we will argue that the health and viability of a human culture depends on a whole engagement of the 'human animal' in which culture responds to and resonates creatively with our underlying biologically 'engendered' evolutionarily sustainable nature, rather than imposing its values upon it. Thus rather than a confrontation between the conflicting influences of nature and nurture, nature in evoking complexity seeks a constructive and responsive complementation. It is this complementation that a fully abundant society gives expression to in evolutionary time.
Richard Dawkins (R151) mischievously portrays the 'engendering' of sex as the original sin of a sneaky Adam seeking to spread his reproductive investment like wild oats: "In some respects a big isogamete would have an advantage ... because it would get its embryo off to a good start. ... But there was a catch. The evolution of isogametes which were larger then were strictly necessary would have opened the door to selfish exploitation. Individuals who produced smaller than average gametes could cash in provided they could ensure that their smaller than average gametes fused with extra-big ones. ... There was a large-investment, or honest strategy. This automatically opened the way for a small-investment exploitative or 'sneaky' strategy. Each honest one would prefer to fuse with an honest one ... [but] the sneaky one's had more to lose, and they therefore won the evolutionary battle. The honest ones became eggs and the sneaky ones became sperms".
There is an irony of dramatic oversimplification here because this very differentiation may have been caused by killer genes in the female cytoplasm resulting from the selfishness of cytoplasmic genes, not the male. Isogametes frequently display cytoplasmic genetic conflict, sometimes destroying 90% of their cytoplasm in fertilization. The single celled alga Chlamydomonas illustrates this phenomenon. Most of its life cycle it is haploid. It is only diploid when two haploid cells fuse. Fusion can only occur between a 'plus' type and a 'minus' type (which can be regarded as distinct male and female gametes) but both types have cytoplasm and cell organelles such as mitochondria and chloroplasts. When two Chlamydomonas cells undergo sexual reproduction, the haploid nuclei fuse, become diploid, undergo meiosis and become haploid again. Meanwhile, however, a 'war', or better, a genetic conflict breaks out. By means of restriction endonuclease enzymes, the mitochondria of one individual 'kill' the mitochondria of the second, whilst the chloroplasts of the second 'kill' the chloroplasts of the first. The process wipes out 95% of all chloroplasts of both types illustrating how destructive the process is. This damaging cytoplasmic genetic war strongly favours one mating type digesting any cytoplasm in the other, driving the symmetry-breaking into fully-fledged gender - giant sappy egg and a lean sperm with little more than DNA. The prevailing idea has been that all sperm organelles in higher animals are digested are digested, but the story in humans is a little more subtle as we shall see.
Sex becomes gender. The slime mold myxomycota has flagellated isogametes, while apicomplexa although a simple single celled protoctist already has sperms and ova (Margulis and Schwartz R439).
For this reason eucaryotes either have conjugation sex (in which case only nuclear DNA, without the symbiotic organelles are exchanged) or fusion sex, but in that case only one gamete should deliver the endosymbiont organelles. Cytoplasmic incompatibility thus neatly explains why we generally see only two sexes, one contributing the cytoplasm and one not. With conjugation sex there is really no such limitation and we find in mushrooms and ciliated protozoans there are many tens of different genders. In the ciliate hyptotrich which uses both fusion and conjugation, there are but two fusion genders but tens of conjugation ones. Some slime molds have 13 fusion sexes arranged in a hierarchy, contributing organelles strictly in order of precedence (Low R427 41, Ridley R577 97). Physarum polycephalum sexuality is controlled by a system of three interacting genes mat A, B & C (Bailey et al 1999 Arch Microbiol 172 :364-376) with hierarchical mating protocols which are sometimes challenged by a mutant allele. Physarum has 29 variants of sex-controlling genes. To ensure genetic diversity, each slime mold sex cell can only fuse with a sex cell that has completely different variants of genes than its own. The possible combinations of genes and sex cells, give Physarum more than 500 different sexes (Tidwell R691).
In algae, there is indication of a link between sex and stress, with different stress conditions activating related sex inducing genes. Volvox carteri responds to oxidative stress with a sex inducing gene related to the gene family in Chlamydomonas reinhardtii responsibile for sexual response to nitrogen stress (Nedelcu R499), suggesting sex evolved to spawn new genetic variants in response to stress, consistent with the Red Queen hypothesis (p 26), which explains how sexuality can become advantageous in one generation despite a 2:1 loss in gene transmistion , because sexual variation avoids a doomsday epidemic due to a parasite killing the entire parthenogenetic clone.
Bobbi Low (R427) has a more 'dispassionate' description of the symmetry-breaking of gender based on natural selection for two fundamental traits - nurturing - that is ensuring there are sufficient cytoplasmic resources favouring large gametes, and seeking - being able to find a complementary gamete e.g. through motility favouring small ones. Natural selection thus favours a skewing of characteristics because mid-sized isogametes fail to compete at both tasks. This leads to two characteristics which continue into higher organismic behaviour - parenting investment and mating investment (p 29). Broadly speaking females invest in parenting and males in mating, though both do each to varying degrees in a given species.
We have noted the origin of sex in a Red Queen race between parasites and hosts (p 26) and that this extends to a genetic race between the sexes themselves (p 28). This extends to killer genes in one sex which affect the other. Male killer genes are found intermittently in various species because they favour the female. This can happen even with nuclear genes if they spend a selectively advantageous time in the female as is the case for male-killing 'dishonest-X' in fruit flies, but the majority are cytoplasmic in origin, since cytoplasmic organelles are transferred exclusively down the female line. Cytoplasmic genes can originate from plasmids, from DNA in our symbiotic organelles and from endoparasitic bacteria. Sometimes these stunt or kill males or render them infertile, or even incite parthenogenesis. Many hermaphroditic plants from beans to maize harbour sterilizing mitochondria which disable the male parts and promote propagation down the female line.
By far the most diverse and notorious sexual distorters are Wolbachia (Majerus R433). These bacteria are inherited and widespread among insects and other arthropods, infecting more than a fifth of all insect species, the most diverse among all living phyla. They may govern every facet of arthropod lives. Infection produces a catalogue of weird effects on arthropod sex and sexuality. In most cases, infected males only produce viable offspring if mated to a female infected with the same strain of Wolbachia. This has been demonstrated to potentially enable speciation by causing a fertility barrier between populations, so it may even contribute to insect diversity. Such fertility barriers and severe sex imbalances, which in some butterflies will result in clouds of unrequited virgins competing to pounce on the odd remaining male's advances can be cured by antibiotics. Like many parasites, Wolbachia has a small genome. Even high temperatures can cleanse Wolbachia infection, so there are frequent outlets from the cul-de-sac of male 'silencing'. In some crustaceans, gender-bending Wolbachia transforms infected males into females. In colonial insects such as bees, wasps and ants, infection abolishes males altogether, so that females reproduce clonally, without sexual reproduction, creating female-only populations. In other cases, arthropods come to depend on the presence of Wolbachia to perform their most basic functions. Sex determination in most creatures depends on the presence or absence of certain sex chromosomes, but in some populations of the pill wood louse, it depends on the presence or absence of Wolbachia. In two species of ladybirds and butterflies Wolbachia kills all males outright, only half the eggs hatching to maturity. This actually helps the ladybirds, whose hatching larvae can eat the dead males and develop more quickly. It severely distorts the sex ratio, but occasional bacteria-free males which escape vertical transmission, keep the sexual population alive. Some species, such as the parasitic round worms causing elephantiasis, depend on Wolbachia to survive, opening the prospect of using antibiotics to cure the human parasitic disease. Henry Gee quotes in Nature: "Long ago, some male chauvinist wag suggested that a suitable mascot for the feminist movement should be the angler-fish, in which a tiny, insignificant male is dominated by (and dependent on) a gigantic, bloated female. The work on Wolbachia suggests an altogether more sinister alternative."
Engendering causes a symmetry-breaking in the forms and reproductive strategies of male and female organisms, which is particularly pronounced in mammals and even more so in humans. Dawkins (R151) notes: "Sperms and eggs too contribute equal numbers of genes, but eggs contribute far more in the way of food reserves: indeed sperms make no contribution at all, and are simply concerned with transporting their genes as fast as possible to an egg. At the moment of conception therefore, the father has invested less than his fair share (i.e. 50 per cent) of resources in the offspring. Since each sperm is so tiny, a male can afford to make many millions of them every day. This means he is potentially able to beget a very large number of children in a very short period of time, using different females. This is only possible because each new embryo is endowed with adequate food by the mother in each case. This therefore places a limit on the number of children a female can have, but the number of children a male can have is virtually unlimited. Female exploitation begins here".
Fertilization displays amoebic engulfing by the ovum
(King R363 1978 left) in the sea urchin (Sci. Am. right).
Pertinent to the issue of female reproductive choice is the question of whether it is the first sperm which fertilizes the egg by simply pushing its way in, or whether it is the ovum reacting to a sperm's presence, through a coordinated amoebic and electro-chemical response elicited at the time of fusion, during the complex chain-reaction ensuring only one sperm enters the egg. Sarah Hrdy (R330 70) comments "Rather than being penetrated by a sperm, the egg (or oocyte) more nearly engulfs it, quite possibly selecting which sperm to accept and producing the chemicals that are necessary for fertilization to take place." This speaks of fertilization itself as strategic paradox.
Recently evidence has been found for non-Mendelian inheritance, in which it apears that the egg has been actively choosy to avoid being fertilized by a sperm carrying a deleterious gene. Apobec1 and Dnd1 affect risks for testicular cancer, one of the most heritable forms. When the researchers bred female mice carrying one normal and one mutant copy of Dnd1 with heterozygote Apobec1 males, everything appeared to follow Mendel's rules and 75% of the offspring carried one or the other of the affected alleles, but when they reversed the breeding (a female Apobec1 heterozygote mated with a male Dnd1 heterozygote), they found that only 27 percent of the expected offspring carried copies of mutant Apobec1, mutant Dnd1 or both, compared with the 75 percent they expected to see (Nadeau J 2017 Do Gametes Woo? Evidence for Their Nonrandom Union at Fertilization Genetics 207 369-387 doi:10.1534/genetics.117.300109). Usually this is explained by embryonic lethality removing the missing offspring, but in this case the litter sizes were normal.
Outside embryonic lethality, the most prominent exceptions to random segregation are the rare, naturally occurring examples of transmission ratio distortion (TRD), which drives allelic preference in one sex, regardless of the genetics of the mating partner. TRD may arise during chromosome segregation in meiosis (meiotic drive), gametogenesis (gamete competition), or embryonic development (preferential lethality). Many of these "selfish genetic" systems are composed of several closely linked elements that not only lead to preferential transmission of the chromosome on which they are carried, but also confer sterility or lethality on homozygous carriers, thereby preventing fixation at the cost of reduced population fitness. Without these counterbalances, TRD systems would quickly replace their wild-type (WT) alleles in the population, their competitive advantage would be lost, and selective sweeps affecting variation at neighboring loci would be their only legacy. Since then, evidence has emerged for a raft of 12 other genes, providing examples for TRD during fertilization, where genetic variants, acting in both sexes control the combination of gametes that join at fertilization, were found without evidence for dead embryos or reduced litter size. Two explanations have been suggested. The first involves the metabolism of B vitamins such as folic acid, which form important signaling molecules on sperm and egg, so that abnormalities in certain signaling genes may alter how much sperm and egg attract each other. The second builds on the fact that sperm are often present in the female reproductive tract before the final set of cell divisions that produce the egg. Signals from the sperm could influence these cell divisions and bias the identity of the cell that becomes the egg.
The mechanism of fertilization in mammals is complex. An outer follicle cell glycoprotein, ZP3, binds to the sperm heads causing the release of the acrosomal cap which dissolves the eggs jelly-like outer layer. A protein in the exposed sperm head can now bind with a receptor on the egg's membrane precipitating membrane fusion. These receptors go by the names of integrin on the egg and disintegrin disintegrin on the sperm, a domain on a protein called fertilin from the ADAM family convolutedly named after "A Disintegrin And Metalloprotease containing protein". This leads to binding and insertion of the protein into the egg's membrane, bringing the two membranes together; resulting in a pore. The oily membrane-fusing domain from fertilin shares features with viral integration proteins, suggesting viral membrane fusion could have played an early role in sexual fusion (White R740, Bloebel et. al. R65, Wolfsberg et. al. R758). Integration proteins evolve very rapidly in HIV and other viruses and in many species of animal in mutually antagonistic co evolution. Consequently fertilins cannot promote fusion on their own in the way viral integration proteins do (White personal communication). A hair-trigger cortical response of membrane electrical depolarization ensues, as in a neuron reacting to a neurotransmitter (fast block to other sperm). A calcium ion release is set off by a G-protein, a type common to sensory transduction, certain neuroreceptors and hormone amplification. This causes an explosive blowing off of the outer layers by the cortical granules in the sea urchin, or an outer hardening within seconds in mammals (slow block). It is also accompanied by active amoebic engulfing of the sperm by the egg. Once the sperm and egg fuse, the beating of the tail stops immediately, the sperm is drawn into the egg by elongation and fusion of egg's microvilli, forming the fertilization cone. Microvilli grow and surround the sperm, and via actin polymerization draw the sperm into the egg. As a result the entire contents of the sperm, including the nucleus and other organelles, are incorporated into the egg cytoplasm.
At this point the nucleus of the egg, still suspended in meiotic arrest now divides again to form the haploid egg pro-nucleus and a polar body. The condensed sperm DNA now expands and a nuclear envelope also forms. The sperm carries along with its axonene and basal bodies, centrioles, which nucleate new microtubules in the egg cytoplasm. With pushing forces, the male pronucleus migrates to the center of the egg. The female pronucleus uses the same microtubules as a track to meet the male pronucleus in the center of the cell. The two pronuclei fuse to form the diploid nucleus.
Recent evidence confirms another bizarre twist to this for the superficial sex war between the egg and sperm has entered into a deeper state of sexual paradox over time. The mammalian zygote relies on the paternal gamete to provide the centrosome component essential for the first mitotic division. It is the sperm centriolar apparatus that is one which survives to shepherd the chromosomes apart in the embryo. Eggs fertilized by dissected sperms which lack an intact centriolar flagellum base do not undergo correct spindle cleavage. Electron microscope study has traced the paternal centrioles extensively. The sperm proximal centriole is introduced into the oocyte at fertilization and remains attached to the expanding sperm head during sperm nuclear decondensation, as it forms the male pronucleus. A sperm aster is initially formed after the centriole duplicates at the pronuclear stage. At syngamy, centrioles occupy a pivotal position on opposite spindle poles, when the first mitotic figure is formed. Centrioles were traced from fertilization to the hatching blastocyst stage. It is very likely that the paternal centriole is the ancestor of the centrioles in fetal and adult somatic cells (Sathananthan et. al. R612, Moomjy et. al. R481). There are also up to 18,000 RNA transcripts, found in sperms, not present in unfertilized ova, including genes for fertilization, the stress reaction, embryogenesis and implantation (Ostermeier et al. R520).
Fertilized human ovum at the point of nuclear fusion, two and eight-cell embryos (Morris R487).
The passage of the mitochondria is, by contrast, more of a feminine tale. Mitochondria from the sperm remain during early cleavage stages and may play a role in development. One hypothesis is that they set up the embryonic axes. 5-15% of the mitochondrial DNA in the placenta is derived from the sperm, but little or none appears in the embryo (R437). Paternal mtDNA usually comprises only 0.1% of the mtDNA in the gametes at normal conception, minimizing any chances of serious sex war of the organelles. However recombination between paternal and maternal mitochondria has recently been found to take place in a small proportion of cells (Kraytsberg et. al. R393).
Evidence has also been found for inheritance of paternal mitochondria in some organs which has implications for evolutionary genetics (p 103). A 28-year-old man had a normal heart and lungs and his muscles appeared healthy, but absorbed very little oxygen. His mitochondrial DNA had two mutations, one of which was responsible for his extreme fatigue. Muscle biopsies showed that about 90 per cent of his mitochondria came from his father. However, the mitochondria in his blood, hair roots and fibroblasts came entirely from his mother. (Mitochondria can be inherited from both parents 23 August 2002 New Scientist).
Up to 50% of conceptions end in miscarriage due to serious genetic errors in the developing body. Allen Enders of UC Berkeley noted we could consider God the world's greatest abortionist on this basis (Blum R66 20). Twin conceptions form a large proportion of pregnancies but in the majority of cases, one embryo fails to develop. Some researchers suggest the female can assert choice over the sex of the offspring either by her response to X and Y sperm during fertilization, or by differential reaction during or after implantation (Grant R254, King R363). Water voles are known to produce 5 times more male offspring under stress (J. of Applied Ecology, 42, 91). Variations of the sex of offspring suggest that dominant, higher testosterone women who are better fed may give birth to more boys (R254). Children of famous men also appear to be more frequently male (Jones R349).
Men may also be able to modulate sex through differential production of X and Y sperm. Imbalances in the sex of offspring in a given family may arise because the fathers are genetically disposed to producing either boys or girls. Indeed the balance of the sexes may be maintained by feedback between the relative reproductive advantage these two populations of men, with those favouring the rarer sex having a temporary advantage (SPNews 1836).
Fertilization is itself a manifestation of sexual paradox through sexually antagonistic co-evolution. In the shellfish the abalone, for instance, the lysin protein that the sperm uses to bore a hole through the glycoprotein matrix of the egg is encoded by a gene that changes very rapidly (the same is probably true in us), probably because there is an arms race between the lysin and the matrix. Rapid penetration is good for sperm but bad for the egg, because it allows parasites or second sperm through (Ridley R579). The semen of flies is similarly in sexual conflict with the reproductive interests of the female forcing her to devote a disproportionate share of her reproductive energy to the siring from the ejaculate.
While it is facile to blame the male gender for what has now become a biological necessity for virtually every sexual organism, this symmetry-breaking has continued to have a significant impact on the evolution of life and reaches its 'long arm' into human sociobiology, for while the investment of the human female in the egg itself is small, her investment in the fertilized ovum is immense and pivotal to both her own survival and the survival of her offspring. It continues through pregnancy, lactation and some ten to fifteen years of child-rearing. Human pregnancy has a massive effect on the female physiology, which is unique among mammals. Although the human male often does play a significant and sometimes pivotal share of this work, being 'left holding the baby' is not a figure of speech without reason. This very ancient biological motif has become a theme we must respect in our very 'conception' of evolving human society. We fail to do so at our peril.
"One sex has a large investment to protect and looks for quality and stability. The other has little to lose and tends to be far more interested in quantity and variety. So it pays males to be aggressive, hasty, fickle and undiscriminating. They pounce, they generally make the first moves and are more ardent in them. While it is more profitable for females to be coy, to find out as much as possible in advance and to wait and see what happens. They play hard to get and play for time by flirting. All moves with a sound grounding in evolutionary psychology. Genes which allow females to be less inhibited leave fewer copies of themselves than genes which persuade them to remain highly selective. Amongst males, the best strategy is exactly the opposite one. The maximum advantage goes to those males with the fewest inhibitions. "Love 'em and leave 'em" is not so much a nasty piece of male chauvinist piggery as an accurate reflection of biological reality. In a very real sense, each sex still finds it pays to use the other as a vital resource. ... Men are a little like selfish genes, looking for convenient vehicles to carry their inheritance into the next generation. Women are more cautious, like canny investors or developers, seeing men as inconvenient sources of a seminal substance that is nevertheless necessary to realize the potential of their precious nest eggs. These bald descriptions sell both sexes short, but the two who differ so widely in interest and intent are bound to have different agendas and a conflict of interest. The fact that they manage to agree on anything at all is miraculous. Yet they do. (Watson R735).
Even this fairly obvious expression of has been challenged by social constructionists with a feminist political agenda. Anne Fausto-Sterling for example (Campbell R103 16) claimed that an association between low parental investment and promiscuity was just an argument for the male status quo, citing birds called sea snipes or phalaropes, in which it is the females which are promiscuous: "you name your animal species and you make your political point". However the species she has used to make her point confirms the evolutionary argument precisely. The non-political point which she conveniently ignores is that sea snipes are a species in which the male makes the greater parental investment. Male parental investment is also true of the midwife toad and several fish species, such as sea horses, where females inject their eggs into the males pouch through a penis-like appendage.
In lower vertebrates, sex is often determined environmentally by the temperature of the maturing fertilized egg, as in alligators and turtles. Here the warmer the egg the larger, so alligators with larger competing males have hot eggs, becoming male whereas most turtles, which mate peaceably in the ocean have the egg-laying female the warmer sex, except for male-competing snapping turtles which follow the alligator pattern. Snails are hermaphrodites and can form sexual chains of mutual fertilization.
Studies have begun to elucidate the mehanisms of temperature sex determination. In elucidating a pathway in turtles, researchers used viruses with RNA snippets to weaken the effects of the Kdm6b gene in the embryos of red-eared slider turtles (Trachemys scripta elegans) before the gonads formed, then tracked the embryos' development at 26° Celsius. That temperature should have yielded all male turtles. Instead, in two separate experiments done with different gene-silencing viruses, 80 and 87 percent of the surviving embryos became female (doi:10.1126/science.aap8328). Still, something as complex as sex determination can't be boiled down to a single gene. Kdm6b controls a gene called Dmrt1, directing male development but may itself be influenced by an upstream temperature sensor.
Bearded dragon lizards are an unusual case because chromosome combinations and temperature are known to influence sex determination. When eggs are incubated below 32° Celsius, embryonic bearded dragons with two Z chromosomes develop as male, while dragons with a Z and a W chromosome develop as female. But as temperatures creep above 32°, chromosomally male ZZ dragons will reverse course and develop as females instead. Sex-reversed females turned up the activity of several genes, the researchers found (doi:10.1126/sciadv.1700731). Two, JARID2 and JMJD3, are part of a family of genes called the Jumonji family, which are known to influence sex differentiation in other animals. For instance, in mammals, a Jumonji gene interacts with SRY, a gene on the Y chromosome that sets off testes development in males. Another is involved in X chromosome inactivation, which ensures that females don't get a double dose of proteins made by genes housed on their pair of X chromosomes.
Halichoeres chlorocephalus In many species of wrasse,
Sexual dominance is also a determinant. In several wrasse species, including the cleaner fish, the dominant female switches to the male sex when the alpha male dies or is injured, adopting the advantages of the high gain sex. Females are actually hermaphrodites as they all have small amounts of active (but walled-off) testicular material scattered through their ovaries. This again presents as an innovative solution to the sexual prisoners' dilemma, the fittest female becoming the alpha male with no loss of wasted male offspring. In a monogamous variation, the Nemo-like anemone fish Amphiprion bicinctus nestled like a sultan upon a bed of pink-tipped sea anemone tentacles. When a male chances on another male one transforms into a female. and invites the other fish to mate. Nobody gets hurt and in time both get to pass their genes into the next generation. "Perched upon their anemone, the two will live in prim monogamy until death do them part. At which time, the survivor may once again shift gender to secure a mate". This sex shifting goes to dynamic extremes. Hamlets (genus Hypoplectrus) are simultaneous hermaphrodites. Hamlets hold the sex-shifting record, switching from one set of gonads to the other and back in 30 seconds or less, with an average of 14 spawns in one day (Tidwell R691).
Achieving dominance in non-sex-reversing Cichlid fish also brings males to immediate maturity., . Within minutes of the dominant male being removed from an aquarium, a subordinate male turns from grey to flashy blue or yellow, cells in the anterior preoptic area swell to 8 times their previous volume with gonad-stimulating hormones, his testes grew and matured, and sperm production went into overdrive (Burmeister R95). This was due to switching on of a gene, egr-1 also found in humans, which may help us to respond to social cues.
The same sexually paradoxical logic applies again to the recently discovered whale bone worm Osedax frankpressi (Rouse et. al. R594), where any individual gaining a foothold on a rich whale bone becomes female and those who cannot become male. If there is no place for the larva to land except on another female, it does the next best thing and becomes a male, to provide that female with sperm. Whereas female worms are several inches in length, males are little more than microscopic threads, which act as nothing more than sperm factories.
Whether a species is protoandrous, and switches to female, or protogynous, and switches to male, depends on the payoffs in the sexual prisoners' dilemma game. Species where an individual can monopolize resources and become a large egg bearer tend to be protoandrous and have small males. Species where a large male is dominant tend to be protogynous and have small females. Sex changing species are common in highly stratified ecological societies as on reefs where niches are highly defined and mating opportunities which preserve territory are restricted. In free schooling species there is no advantage to the added cost of sex change. So Roughgarden's point about the influence of social factors gains good ground among the coral, even if it is not apparent in the open ocean or among mammals.
Hermaphroditic molluscs such as slugs and snails also ensure the payoff for eac hindividual maintains a prisoners' dilemma realtionship. Sea slugs donate sperm only on the condition that they receive it, so thwarting the male desire to fertilise and run. Each slug inserts its penis into the other and one transfers a small package of sperm. The transfer of further sperm will only proceed if the partner reciprocates, transferring a pack of its sperm (Current Biology 15 92).
Haplodiploidy is a sex-determination system in which males develop from unfertilized eggs and are haploid, and females develop from fertilized eggs and are diploid. It determines the sex in all bees, ants, wasps and thrips. This system helps to explain how social colonies centered around one queen can maintain reproductive stability from genetic rebellion from some of the female workers. The haplodiploid sex-determination system has a number of peculiarities. For example, a male has no father and cannot have sons, but he has a grandfather and can have grandsons. Additionally, if a eusocial-insect colony has only one queen, and she has only mated once, then the relatedness between workers (diploid females) in a hive or nest is 3⁄4. This means the workers in such monogamous single-queen colonies are significantly more closely related than in other sex determination systems where the relatedness of siblings is usually no more than 1⁄2. It is this point which drives the kin selection theory of how eusociality evolved.
Chromosomal sex has become a pervasive and successful sexually defining strategy among many groups of organism, including mammals. Genetic sex determination enables early and precisely programmed sexual differentiation. Temperature sex determination is also unfeasible for warm-blooded internally-fertilizing animals. But there is a deeper reason. Externally fertilizing animals can sustain major fluctuations in the sex ratio that may result from temperature-mediated sex determination because both sexes produce a relatively large number of gametes. By contrast mammals only produce a vanishingly small number of eggs in a lifetime and cannot afford a serious imbalance in the sex ratio towards males. Following Kim Walen's energy-minimizing sexual symmetry-breaking paradigm (Blum R66 18), genetic sexuality provides a strongly fixed complementarity and stable sex ratio with only moderate slippage into transsexual and homosexual variations.
The pattern of uterine gestation and lactation in mammals results in great reproductive success, by passing the vast majority of the child-rearing energy and attention budget to the female. It is thus little wonder that the vast majority of mammals species are polygynous with males often contributing little to child rearing. By contrast birds, being uniquely warm-blooded while still laying eggs have an overweening need to have two partners to hatch the egg and provide sustenance, causing most bird species to become overtly monogamous.
In mammals sexuality is determined by additional X and Y chromosomes, XX being female and XY male. In fact it is the Y which contains the few genes, including SRY (sex-determining region Y) or TDF (testis determining factor) essential for switching the female mammalian form to the male path. SRY in turn activates developmental protein Sox-9, which determines growth into the testis rather than ovary. A small non-coding enhancer region enhancer 13 (Enh13), located over half a million bases away from the Sox9 gene appears to be essential for the correct timing and strength of Sox9 activation. If this region is absent or removed in mice XY males instead develop ovaries (doi:10.1126/science.aas9408). Enh13 is located in part of the mouse genome that maps directly onto a region of the human genome. People with XY chromosomes who are missing a larger DNA fragment in this region of the genome develop female sex organs, and this study could finally explain why this happens.
Ping-pong RNA-cleavage between Fem and Masc in the silk worm.
Birds, some fishes, butterflies and moths have a reverse female-determining chromosome system with ZW being female and ZZ being male. In the silkworm, the W chromosome is almost fully occupied with transposable element sequences and seems to have no protein producing genes at all, while a small PIWI-interacting RNA (piRNA) Fem, which silences an opposing DNA-binding zinc-finger protein of the male gene Masc on the Z by m-RNA cleavage, appears to determine sex (Kiuchi T. et al. 2014 A single female-specific piRNA is the primary determiner of sex in the silkworm Nature doi:10.1038/nature13315). PIWI is a motif in proteins, conserved across plants and animals, that is involved in programmed RNA cleavage.
The competition between the tendency of retroelements to replicate explosively in the germ line and cellular control is maintained through the RNA silencing effects of PIWI-interacting small RNAs (piRNAs) and various nuclear and cytoplasmic accessories using RNA interference (Zamudio & Bourchis 2010). This mechanism appears to have emerged right at the origin of LECA because modular components of the key proteins have been identified as coming from two sources (a) a phage in the early proteobacterial endosymbiont contributing both an RNA dependent RNA polymerase and RNAaseIII and (b) the founding archaeum contributing an argonaute and a helicase (Shabalina & Koonin 2008), leading to the radiation of the composite proteins PIWI, Ago and Dicer. Archaea are also known to contain argonautes related to the eucaryote versions (Swarts et al. 2014). Piwi has been proposed to function with downstream partners, and one of them is the heterochromatin Protein 1a (HP1a), which reportedly enforces transposon silencing in the Drosophila germline and ovarian somatic cells (Teo et al. 2018).
Piwi-interacting RNA (piRNA) is the largest class of small non-coding RNA molecules expressed in animal cells. piRNAs form RNA-protein complexes through interactions with piwi proteins. piRNAs direct the piwi proteins to their transposon targets. These piRNA complexes have been linked to both epigenetic and post-transcriptional gene silencing of retrotransposons and other genetic elements in germ line cells, particularly those in spermatogenesis. The majority of piRNAs are antisense to transposon sequences, suggesting that transposons are the piRNA target. In mammals it appears that the activity of piRNAs in transposon silencing is most important during the development of the embryo, and in both C. elegans and humans, piRNAs are necessary for spermatogenesis. Three piwi subfamily proteins - MIWI, MIWI2 and MILI - have been found to be essential for spermatogenesis in mice. A decrease or absence of PIWI gene expression is correlated with an increased expression of transposons and a reduction in fertility. piRNA and endogenous small interfering RNA (endo-siRNA) may have comparable and even redundant functionality in transposon control in mammalian oocytes..
The biogenesis of piRNAs is not yet fully understood, although possible mechanisms have been proposed. A primary processing pathway is suggested to be the only pathway used to produce pachytene piRNAs; in this mechanism, piRNA precursors are transcribed resulting in piRNAs with a tendency to target 5' uridines. The Ping Pong mechanism wherein primary piRNAs recognise their complementary targets and cause the recruitment of piwi proteins. This results in the cleavage of the transcript at a point ten nucleotides from the 5' end of the primary piRNA, producing the secondary piRNA. These secondary piRNAs are targeted toward sequences that possess an adenine at the tenth position. Since the piRNA involved in the ping pong cycle directs its attacks on transposon transcripts, the ping pong cycle acts only at the level of transcription. In silk worms, PIWI ping-pong amplification is involved in sex determination (Kiuchi et al. 2014). piRNAs can be transmitted maternally, and based on research in D. melanogaster, piRNAs may be involved in maternally derived epigenetic effects. Ping-pong signatures have been identified in very primitive animals such as sponges and cnidarians, pointing to the existence of the ping-pong cycle already in the early branches of metazoans.
The piRNA Ping-Pong pathway was first proposed from studies in Drosophila where the piRNA associated with the two cytoplasmic Piwi proteins, Aubergine (Aub) and Argonaute-3 (Ago3) exhibited a high frequency of sequence complementarity over exactly 10 nucleotides at their 5' ends.This relationship is known as the "ping-pong signature" and is also observed in associated piRNA from Mili and Miwi2 proteins isolated from mouse testes. The proposed function of Ping-Pong in Drosophila or in mouse remains to be understood, but a leading hypothesis is that the interaction between Aub and Ago3 allows for a cyclic refinement of piRNA that are best suited to target active transposon sequences.
Both the ancestral X/Y and Z/W were originally autosomes which became differentiated and lost much of their recombinational capacity when a sex-determining gene arose on one of them. Although mammalian chromosomes, vary in number between species. the 23 pairs in humans come from an original complement of 21 in the common eutherian ancestor of mammals. The Z chromosome in birds appears to originate from the homolog of autosomal chromosome 9 in humans rather than chromosome 23 of the X/Y pair. By contrast, with mammalian XY where in females on X is inactivated in somatic tissues, avian Z chromosomes lack chromosome-wide dosage compensation and dosage compensation has been shown to be regional. Both transcriptional and translational gene-specific dosage compensation have been observed in avian sex chromosomes. Male birds are thus not a somatic chimera unlike female mammals. It appears most likely that sex determination, with the Z-linked gene DMRT1 being male determining in ZZ, rather than through the W, which seems to consist largely of a residue of ancestral Z genes essential for normal function in a double dosage, although female-specific selection does have a significant effect on W chromosome gene-expression patterns (Moghadam et al. 2012 doi:10.1073/pnas.1202721109), also helping to suppress further degradation of the W chromosome (Rutkowska et al. 2012 doi:10.1098/rsbl.2012.0083).
The ZW chromosome inheritance in birds favours Fisher runaway to flashy sexually successful males, because female choice about male characteristics is reinforced because the fathers Z chromosomes are transmitted to their sons, unlike mammals where a father can pass an X-linked gene only to daughters. Left: The Superb Lyre bird not onlyproduces a mesmerizing dsplay, which at peak is a lacy veil completely surrounding the prospective mate, but it can also mimic almost every bird call and any sound including a chain saw. Right: The Golden Bower bird has extremely brightly coloured plumage by contrast with the camouflaged female, has to build a love nest adorned with bright objects, has to call and alternately dilate and contract each of his pupils, perform a crooning dance with gutterall calls, in which he struts and waves his left wing like a bull-fighter's cape, then has to offer her a berry fruit, as in the image, but even then the skittish female may lose interest if any other suitor appears.
There is an intriguing difference between ZW and XY sexual chromosome inheritance that explains why male bird are often more flashy then the females (Albert A & Otto S 2005 Sexual Selection Can Resolve Sex-Linked Sexual Antagonism Science 310 119). With a sexually antagonistic trait on the X chromosome (males XY, females XX), females evolve to prefer mates carrying alleles beneficial to daughters. In contrast, with a Z-linked trait (males ZZ, females ZW), females more often evolve mating preferences for mates carrying alleles beneficial to sons (that is, flashy displays). With sexual antagonism, chromosomal location should strongly affect the evolution of female preferences. Simply put, an X-linked male trait is never passed on from an attractive father to his sons, whereas his daughters suffer the cost of carrying the display trait. Offspring in XY species therefore do not gain a fitness benefit from females preferring males with a more extreme X-linked display trait. In contrast, both males and females contribute a Z chromosome to sons in ZW species. Thus, females preferring a Z-linked display trait receive the fitness benefit of sexy sons, even though their daughters suffer a fitness cost. This cost is lessened by the fact that daughters inherit only one of their father's Z chromosomes.
Their results point to a potentially large effect of the sex-determination mechanism on how female preferences evolve for sexually antagonistic traits. Over long time scales, evolutionary changes in female preferences will lead to the fixation of the trait alleles most fit in females in XY systems and ZW systems when the preference is autosomal, but the trait allele most fit in males in ZW systems with Z-linked preferences. Thus, sexually antagonistic selection is always resolved in favor of females in XY species, but in favor of males in ZW species when the preference is Z-linked. Consistent with this, genes expressed in testis but not in ovary in chickens are highly over-represented among genes that have emerged on the Z-chromosome during avian evolution. Moreover, genes with male-biased expression are similarly over-represented among new Z-chromosomal genes. Interestingly, genes with female-biased expression have more often moved from than to the Z-chromosome (Ellegren H 2017 Emergence of male-biased genes on the chicken Z-chromosome: Sex-chromosome contrasts between male and female heterogametic systems Genome Research 21 2082–86).
In grasshoppers, roaches and some other arthropods, we have an X0 system where the presence of the diploid X is female determining with a single X male. Spiders have a great variety of variations on this theme. Of the 678 spiders whose chromosomes have been analysed, 67.3% have sex chromosomes of the X1X20 type, which is proably the ancestral condition originally deried from an X0 system. Among the others, 15.5% have an X0 system; 8.7% have an X1X2X30 system; 1.5% have X1X2Y type; 0.7% have an X1X2X3X40 system, 0.7% have an XY system like mammals; 0.7% have an X1X2X3Y type; 1 species or 0.1% an X1X2X3X4X5Y type; and 1 species exhibits variations of a multiple XnYn type. The extreme sexual differentiation of some spider species, such as the peacock spider Maranatus, involving a highly coloured male with elaborate courtship dances and vibratory seduction routines, thus poses somewhat of a paradox, as the XY system is less conducive to this form of extreme sexual selection, so it must derive from the exreme pressures driving courtship in the face of potential predation by the female.
The platypus has a bizarre variation to this with no less than five X and five Y with males being (XY)5 and females (XX)5 (DOI 10.1038/nature03021). While the platypus X1 chromosome has 11 genes that are found on all mammalian X chromosomes, the X5 carries a gene called DMRT1, also found on the Z chromosome in birds.
The white-throated sparrow (right) has undergone a major inversion in chromosome 2 which has generated a situation in which there are effectively four sexes and helps explain how sex chromosomes evolved in the first place. Because the inverted section cannot corssover with the original version, it has mutated and diverged in function. Both males and females come in two forms - white stripes and tan stripes, with divergent genetic and behavioral characteristics, however white striped individuals mate almost exclusively with tan and vice versa in a phenomenon called disassortive mating. On average half the offspring inherit the inverted version, producing half tan and half white-striped offspring (Nature doi:10.1038/539482a).
Finally in social bees and ants, the diploid condition is female, with fertilized eggs becoming female queens and workers andunfertilized eggs becoming male drones. The queen also courts many drones thus forming several superfamilies in the hive adding adaptive resistance. Workers in the same superfamily are supersisters, sharing more genes (100% from father and 50% from mother=75%) than their own offspring (50%). Social stability is thus underpinned by the haploid-diploid sexual determination.
In another dimension to sexual antagonism and sexual selection, unlike the female ZW sex pairing of birds (male ZZ) where female selection favours male genes and hence showy sons, the XY male (XX female) mammals have female selection skewed to favour alleles advantageous in daughters, (R4) a discovery which may explain why women appear to be a step ahead of men in evolution, being more neotonous (child-like), less hairy, and explain pronounced female sexual characteristics in breasts, buttocks, concealed estrus and ecstatic clitoris.
X-linked tortoise-shell gene variation demonstrates X-mosacism in a female cat (King). The confinement of this phenomenon to female felines combined with an elusive contracted genetic element in female somatic cells, the Baar body, was the trigger for Mary Lyon, the discoverer of mosaic X-inactivation to make the discovery (Jegalian and Lahn R339).
Mammals have an ingenious sexual genetic scheme to align sexual selection with the effects of the honest egg and the cheating sperm. The female XX and male XY means that the male is haploid X and the female diploid XX. The haploid state provides for maximal selective advantage, because there is just one 'pure' copy of each gene on this entire chromosome, not two interacting copies. When the female embryo begins to divide about the 10 to 20 cell stage, in each somatic cell i.e. apart from the germ-line sex cells, one or other X randomly collapses. So a female brain is single X, like the male, but with a difference - it is a mosaic of cells of two genetic X-identities, those of her father and mother, as in the picture of the tortoise-shelled cat. The male by contrast is endowed with one pure maternal X-dose. When he is good he is very very good - but when he is bad he is singularly retarded.
There are at least 8 forms of X-linked male mental retardation because the X chromosome, the hemizygous 'haploid' X is carrying several key genes for brain development at the spearhead of human evolution (Turner G 1996 Intelligence and the X chromosome Lancet 347 1814-5).
According to one analysis, there are 221 known human genetic defects that can cause mental impairment, some 10% of which reside on the X chromosome, even though it carries less than 4% of known human genes and the complete sequence of the X chromosome (Ross et al. 2005 The DNA sequence of the human X chromosome Nature 434 325−337), confirms that an unusually large number of its genes code for proteins important to brain function. Researchers have also found that in some traits linked to intelligence, such as verbal skills and good social behaviour, male twins were more alike than female twins indicating X-linked genes in which the females are chimeric (Loatet al. 2004 Twin Res. 7 54−61).
In our own species, where intelligence and social skills are thought to be central to success, genes on the X chromosome seem to have evolved rapidly to provide us with the necessary brain power (Check, Erica 2005 Genetics: The X factor Nature 434, 266-7). An explanation goes as follows. As the X and Y diverged from a common autosome pair they each began to accumulate autosomal genes. Ultimately the X and Ydiverged to the point where most X genes cannot recombine with Y and become recombined only in female oogenesis. This makes the X one of the most stable in the mammalian genome, for two reasons. Firstly because the genes are expressed in almost exclusively haploid form in males, who have lost the corresponding Y genes, they need to be more strongly conserved according to Muller's theory. Secondly, mutation rates are much lower in females producing a relatively small number of primordial eggs only early in embryogenesis, as opposed to males, which produce vast numbers of sperm throughout life.
Nevertheless mouse and human X chromosomes have both generated and received an excess of genes through retrotransposition that began before humans and mice diverged and has continued after that divergence in both lineages. Mammalian X chromosomes have also gained genes through the duplication of existing X-linked genes. The human X chromosome is enriched for amplicons that contain testis-expressed genes, including the cancer-testis antigen (CTA) genes, which are expressed in the male germ line but also appear in many cancers and are a target for immunotherapy. . Some CTA gene families, including the MAGE genes, the most abundant gene family on the human X chromosome, have independently expanded in both rodent and primate lineages (Bellott and Page 2010 Reconstructing the Evolution of Vertebrate Sex Chromosomes Cold Spring Harb Symp Quant Biol doi:10.1101/sqb.2009.74.048). This shows the X can contain some of the same multiple gene batteries we will see on the Y, and paradixocally reinforcing a male-oriented function. However there has been extensive traffic of male-biased genes out of both mammalian and Drosophila X-chromosomes, and there are also reports of an under-representation of male-biased genes on the X, consistent with X-linked genes being biased overall by female-oriented selection, due to female reproductive choice favouring fathers who pass their successful X-linked genes exclusively to their daughters although, again paradoxically, there do not appear to be any female-benefit amplicons on X chromosomes, where they might be expected to arise because the X chromosome is exposed to more frequent selection in females than in males.
The stability and inheritance of the X may have paradoxicallyexposed X genes to more intense pressure to evolve. As genes became transferred between chromosomes, those involving intelligence that became transferred to the X become exposed to acute sexual selection by females because in males, the X chromosome genes get a chance to shine, or to fail miserably, each time they pass through the male line. Because a male carries only one copy, any new mutations are revealed in all their glory.
Many of the genes on the X chromosome associated with human brain function seem to have distant relatives with different functions in other vertebrates, such as chickens and fish (Kohn et al. 2004 Trends Genet. 20 598−603). So in boosting our cognitive abilities, the X chromosome seems to have co-opted a diverse range of existing genes, rather than evolving a new set of genetic sequences for the purpose, posing a paradox of conservatism amid rapid change.
In some instances, geneticists have pinpointed genes on the X chromosome that still seem to be in the process of adopting new roles in the brain. For instance, a gene called JARID1C seems to be evolving from a similar gene called JARID1D, which is found on the Y chromosome. If men inherit a damaged version of the JARID1C gene on their single X chromosome, they develop mental disabilities. The fact that the healthy Y chromosome version cannot compensate for its defective cousin hints that JARID1C is becoming more crucial to the brain as it evolves (Jensen et al. 2005 Am. J. Hum. Genet. 76 227−236).
Darwin Family tree (Turner). His grandfather was the founder of Wedgwood Pottery and his cousin, Galton, was a prolific writer and the founder of the Eugenic movement. The pedigree shown in the figure was said, at the beginning of the century, to indicate that genius is a Y-linked dominant, but it could equally well be explained by X linkage. Charles Darwin received Joshua Wedgwood's X chromosome and therefore his intelligence through his mother (11-3), and Erasmus Darwin's brilliance having reappeared in Francis Galton via his mother (11-7), rather than his father. Mary Howard (1-3), was also related to the Galtons.
When the occasional man gets the pure benefit of a fortuitous X complementing his other good brain genes on the diploid chromosomes he may thus become a genius. The irony is that the male never can transmit this heritage to his sons. It is always the maternal X that goes to the son, because to be a son he must have got the paternal Y. Females are thus the progenitors of male prodigies, but the prodigies are doomed ducks. This is the sacrificial saga of the sex gene. The only hope for a male genius is to have daughters! By contrast, females can fortuitously give direct birth to male geniuses. This doesn't mean only males display creative genius. Neither does it deny the capacity of culture and education to mediate natural differences.
A revolutionary idea is that female genes encouraging female sexual selection for intelligence are strongly linked to genes for high intelligence selected for in the male. Early in human evolution, researchers suggest (Zechner, U. et al. 2001 Trends Genet. 17 697−701), females developed a preference for intelligent males. According to their theory, the genes for super-intelligence and for the preference of intelligent males were closely linked, and so were inherited together. And because superior intelligence also aided survival, the process wasn't kept in check by natural selection — unlike other sexually selected characteristics such as the peacock's tail, which makes its bearers more vulnerable to predators. These X-linked genes then ran away together without any limitation by natural selection, because of the adaptive advantage of intelligence, but there is an irony to this, in the emergence of Machiavellian intelligence, as strategic bluffing, counterposing prisoners' dilemma paradoxes of cooperation and deceit over the positive influences of the "mating mind" model of astute female choice combined with intelligent, resourceful husbanding (Miller G The Mating Mind" 2000 Random House).
Richard Prum in The Evolution of Beauty (2017 Doubleday) amplifies on this point: "I think a very powerful case can be made for the role of female mate choice in the evolution of the human species. ... Less aggressive, more cooperative males living in ongoing relationships with females would have created an environment of grearer social stability for their developing offspring, which in turn would have made possible the longer development times and greater investment in each offspring that were required for the evolution of all the qualities we prize as evidence of our humanness-intelligence, social cognition, language, cooperation, culture, material culture, and ultimately technology. This new view of human evolurion requires much work to test, bur the stakes couldn'r be higher."
It is common to animal species that the reproductive potential of individual females is relatively equivalent to one another, but that of the males varies widely depending on opportunity and reproductive fitness. Females compete only for scarce resources but males directly for impregnation. Mammalian evolution has put the X with its largely haploid single dose gene expression in both males and females into the position where it can be subject to strong sexual selection by the female where the evolutionary selection can have the greatest effect. This has now become a central motif in a theory of human culture as runaway sexual selection.
X-mosaicism has many other subtle effects in human females. Female monozygotic twins are often not genetically identical because X-inactivation occurs differentially between the two twins, more commonly than expected by chance, leading to the conjecture that genetic discord can also promote twinning. Specific organs may display mosaic genetic defects normally seen only in susceptible males, such as colour blindness, muscular dystrophy and autoimmune diseases, which are more common in females may result from the thymus educating t-cells only to recognize tissues with the same X-inactivation type (Bainbridge D. 2003 The double life of women New Scientist May 10 41-5).
The sequence of genes on the X-chromosome is almost entirely conserved across mammal species, possibly as a result of the conservatism of X-inactivation. Long sections on each arm of X are homologous to non-sex chromosomes 1 and 4 in birds, showing X and Y both originated from autosomes. Unlike the Y, the X does not contain female-determining or developmental genes and even encodes among its array of housekeeping and specific functional genes male genes for sperm production. Since the X is also expressed in males, this is logical and consistent. There is a greater probability that a recessive mutation beneficial to males will appear on the X than on an autosome (Ross et al. 2005 The DNA sequence of the human X chromosome Nature 434 325−337). This may give rise to a tug of war, in which X-genes favouring one sex may be selected for, even though they impose a cost on the other sex. The fertile mother effect in homosexuality (p 384) and the skewing of X-inactivation (p 385) are provocative hints of sexually antagonistic coevolution (p 16).
The Y-chromosome (Jones R349) is a genomic enigma. It was originally an X which gained the male sex-determining SRY gene. Consequently it still contains some active and 'fossil genes' showing correspondence to genes on the X. It also contains large stretches of genetic desert as well as 78 genes (Kirsch R380) some involving maleness which have moved to the Y. The Y crosses-over with homologous areas of the X only on 5% of its meagre length, at their very tips, although it has many other relics of homologous genes in other areas, some still active. The X suffers none of this, as it recombines actively in oogenesis, while also being able to express each X gene fully in a haploid manner in males and in female somatic lines. Over time, the SRY gene, which itself cannot logically cross with female-default X, has been the nucleus for four inversions of whole sections of the Y chromosome, leaving these regions unavailable for homologous recombination. Given no serial homology to enable crossing-over, these regions have degraded to a genetic desert and many genes have been eliminated by deletions. At some point, SRY has moved to the short arm of the Y chromosome again close to the tips of the Y that are still able to recombine with the X, thus leaving open the possibility of occasional crossing-overs that cause XX-SRY+ males and XY-SRY– females because an SRY has been transferred from Y to X in the father's spermatogonia.
In 2012 it was discovered that the SRY protein is also expressed in the brain and other organs in the human adult and not merely in early embryogenesis, leading researchers to suggest that not only testosterone, but the SRY protein itself may be involved in stereotypical male behaviors like flight or fight, and a competitive tendency to macho or even violent reactions under pressure. Earlier studies in rodents also saw this expression, specifically in the substantia nigra invoving the dopamine reward system and striatum and was absent in females (Dewing et. al. Curr Biol. 2006;16:415-420). In another twist, mice with a mutation putting the SRY on non-sex chromosome are more sexually active (Hormones and Behaviour, DOI: 10.1016/j.yhbeh.2012.02.003) if they also have a double XX. While these XX male mice had the same level of testosterone as normal XY mice, they displayed more masculine sexual behaviours - mounting females more often and ejaculating more frequently. Human XXY males, although they have a more feminine physique and are infertile, did in one study have more sex on average than normal XY infertile males (Yoshida et. al. Int J Androl. 1997 Apr;20(2):80-5).
Such non-recombining regions along with the nine times higher intermediate repeat LINE incidence and inverted repeats causes the Y to be prone to deletions which can cause male reproductive deficiencies. Over time such deletions continue to reduce the size of the Y. In addition there are the effects of conflicting gene drive. Because females have two X chromosomes while males have an X and a Y, three-quarters of all sex chromosomes are Xs and only one-quarter are Ys. An X chromosome thus spends two-thirds of its time in females, and only one-third in males. Therefore, the X chromosome is three times as likely to evolve the ability to take pot shots at the Y as the Y is to evolve the ability to take pot shots at the X. Any gene on the Y chromosome is vulnerable to attack by a newly evolved driving X gene. Some researchers have sugested that the shrunken state of the Y indicates it is heading for oblivion and that the combined processes of decay are causing the Y to disappear up the fundamental orifice of the very male-determining gene SRY which caused it to diverge in the first place. In some species, such as platypus and kangaroo, the Y is under significant risk of complete deletion being only a shadow of our shrunken size. In some mice and voles, the sex determining role of the Y has already been corrupted, resulting in XY females or a loss of Y determination.
However a detailed study (www.nature.com/news/the-human-y-chromosome-is-here-to-stay-1.10082) of human, chimp and rhesus macaque Y chromosomes shows that the human Y chromosome has lost no further genes in the last 6 million years, and only one compared with the macaque in the last 25 million years, leading to the consclusion that the human Y chromosome is stable, due to gene duplication and shuffling. Promiscuous species such as chimps are likely to generate extra copies of sperm-producing genes and the human Y is longer than that of the rhesus macaque.
The X and the Y laid out on a plate.
In 2014 a team compared the Y chromosomes of human, chimp, rhesus macaque, marmoset, mouse, rat, bull and opossum (Nature 508, p 494). They found bursts of gene loss directly after chromosome inversions which disrupt pairing with the X, but were followed by long periods of stability. Although only 3% of the ancestral autosomal genes giving rise to X and Y still exist in the Y not a single gene has been lost from the oldest part of the human Y in the last 44 million years. Of 18 pivotal genes still existing 97 million years ago in the mammalian radiation 14 still surive in humans. A similar picture holds in marsupials. The remaining genes may simply be too essential to lose, as the genes still in X-Y gene pairs are fundmental to survival, with functions including maintaining central process from DNA to RNA and proteins. Compared to other ancestral genes that survive on the X chromosome, X-Y pair genes are enriched for annotations such as nucleic-acid binding, transcription and translation as well as stem-cell self-renewal (bellott at al 2014 Nature doi:10.1038/nature13206).
The mammalian Y chromosome has long been thought of as a sort of genomic wasteland, bereft of pertinent information and shrinking over the course of evolution, the Y chromosome has now been shown to contain remarkable patterns of repeating sequences that appear dozens to hundreds of times. These make up about 24% of accessible DNA in the human Y, 44% of that of the bull and in the Y of the mouse, which is much larger than that of a human, they make up almost 90% of accessible DNA. The intricate patterns, which often contain palindromes - sequences that read the same in forward and reverse order - carry three families of protein-coding genes whose function and origin remain a mystery. In mice there is evidence for mutually antagonistic evolution between these X and Y genes that have arisen since their divergence. In contrast to theories that Y chromosomes are heterochromatic and gene poor, the mouse MSY is 99.9% euchromatic and contains about 700 protein-coding genes. Only 2% of the mouse Y derives from the ancestral autosomes that gave rise to the mammalian sex chromosomes. Instead, all but 45 of the MSY’s genes belong to three acquired, massively amplified gene families that have no homologs on primate MSYs but do have acquired, amplified homologs on the mouse X chromosome. And in the mouse, human and bull, the repeated genes on Y and X are expressed in the male germ cells that eventually produce sperm. The complete mouse MSY sequence brings to light dramatic forces in sex chromosome evolution: lineage-specific convergent acquisition and amplification of X-Y gene families, possibly fueled by antagonism between acquired X-Y homologs (Soh et al. Cell 10.1016/j.cell.2014.09.052). This suggests that the genes are involved in meiotic drive, a not fully understood biological process that subverts the standard rules of heredity, in which, a particular version of a gene - or a large piece of a chromosome - manages to increase the frequency by which it is transmitted to the next generation. Previous studies lend credence to this idea. A team led by Paul Burgoyne found that mice with a partial deletion of the Y chromosome produce offspring with a female-skewed ratio suggesting they are affecting how successful the X and Y sperms in the male are at fertilizing eggs with the female sersion evolving to compensate in some way. The researchers subsequently shifted offspring sex ratios in both directions by tinkering with the expression of these multicopy genes Maher B 2015 Nature doi:10.1038/nature.2015.17817).
Another team (Nature 508, p 488) surveyed the Y-chromosomes of 15 different mammal species and a bird. They found that a chromosome linked with maleness evolved three times - one in birds, one in the ancestor of the platypus and echidna, and one in the ancestor of all other mammals. The ancestors of the three Ys each started with different kinds of genes, but all ended up with a stable set of the same sorts of regulatory genes vital for controlling many other genes.
Essentially the Y is caught in a wrenching dissonance between sexually-determining genes on the one hand such as SRY which cannot cross over with corresponding genes on the X as they are male determining and can't be expressed in XX females and ancient genes that are still paired with their X homologues and cross over in men with the male X. This allows inversions in the Y to disrupt cross-over pairings in ancient genes paired with the X.
When a gene also on the X is lost from the Y, males are left with one copy of the gene, on their single X chromosome, so only about half of the protein the gene codes for gets made. Evolution can fix this in males through mutations which increase production from the single X, but then their female descendants get a potentially poisonous double dose from their two Xs. Females have evolved to inactivate one of their two copies of most genes on the X but the process is a fraught transition which may explain why key Y genes are retained, even when they may no longer cross over with an X version.
The Y is also important for male long-term survival. Around 8% of elderly men lose the Y chromosome in their bone marrow. They have a higher risk of cancer and die an average of 5.5 years younger than other men.
Humans have the worst sperm count of any mammalian species, with the exception of the gorilla, possibly because of the fragile location of these sperm production genes on the Y chromosome. A recent study suggests that there has been a slight decline in human sperm counts in every year that it has been documented (p 405). Speculation on the reasons for the decline include environmental toxins, estrogen-fed beef, or even statistical bias in studies due to geographic differences in sperm production rates among different populations of men. It is very clear, however, that sperm production is genetically controlled, and that humans are in some ways 'genetically programmed' to have an unstable sperm count (Ridley R579, Jegalian and Lahn R339, Jobling and Tyler-Smith R340).
Even more bizarrely, but logically, the X inactivation that causes X-mosiaicism in female somatic cells happens principally only for the X genes which do not remain active on the Y. This explains why X inactivation occurs in the female. As Y genes became inactive as a result of loss of recombination and mutation, their dosage was firstly halved in men, who were relatively disabled by having only a half dose from the X . Evolutionary selection then tends to double the level of expression of these genes to correct for male disability, and to evolve to inactivate one copy in the XX female, to correct for overdosing her, so one equal dose occurs again in both sexes. However sequencing of the human X has shown that there is significant variability in individual women in 10% of the 'inactivated' X genes (R108), giving females a more varied genetic disposition of these X genes.
Several male fertility genes have converged on the Y, in the non-recombining region near SRY, thus making up to some degree for the relative decay overall. The Y thus harbors specific genes, and protects them from further recombination, providing these genes with a safe place in which to amplify and not be carried in the women. Compensating for the lack of homologous recombination, these genes exist in multiple copies on the Y, active versions becoming seeds of further multiplication as other copies become inactivated by mutation. Associated with this process are huge palindromic regions with reverse reflections like "Madam I'm Adam" up to 3 million bases long. There are 8 palindromes 6 of which carry male determining genes. It has now been established that these palindromic repeats are a fundamental way the Y compensates for not crossing-over by providing instead a gene conversion process in which sections of the palindromes are copied to one anther - about 600 base pairs per newborn male child. Male-specific genes in these regions display 99.97% homology to their counterparts. Six of the palindromes were established before the human-ape divergence confirming a continuing role in maintaining human male specific genes from creeping errors (Rosen et. al. R595, Skaletsky et. al. R645).
Many of these genes, including SRY itself, lack introns, the non-coding inserts punctuating the functional sub-domains of most higher organism genes. This indicates they have been made through reverse transcription from the already processed messenger RNAs that code proteins. They may have been generated by retroviruses or the LINE type retroelements dispersed throughout the genome and in effect jumping retrogenes- mobile DNA in the classic sense of the 'selfish gene'. In a paradoxical reversal, closing the logical loop, the SRY family gene Sox-11 has been found to regulate LINE-transcription, consistent with the coupling we have seen of LINE to the meiotic cycle (Tchénio R684). SRY evolved from a Sox gene on the X - to which it is related but now has a different function (Jegalian and Lahn R339).
LINEs are pivotally expressed in the first stage of activation of the zygote in maternal and paternal genes in a manner consistent with an essential role in initiating epigenetic reprogramming and genome integration.
Moreover LINEs appear to play a key role in X chromosome inactivation (Ross et. al. R591), with the defective LINE elements resulting from the inactivation of the LINEs resulting from natural nuclear resistance to the onslaught of active disruptive mobile elements, functioning to inactivate the receptors of X genes. X-inactivation is a very unusual process in several respects. It is controlled by a gene called Xist, but this gene does not produce a translated protein. It merely produces a messenger RNA which appears to 'paint' the inactivated X chromosome from end to end. An anti-sense complementary version of this mRNA is also produced, appropriately called Tsix. In mice, the active X secretes Tsix to oppose Xist (Sado et. al. R606) however in humans Tsix does not repress Xist and is expressed on the inactive X (Migeon e. al. R473). The original central dogma of Crick and Watson is that DNA makes RNA makes protein which carries out the essential catalytic tasks. However X inactivation smacks of the ancient forms of RNA processing that may have preceded the DNA genome of eucaryote cells, which still appear to be major players in processing mRNAs from the majority of genes containing introns, non-coding inserts between functional sub-domains of genes. The key violation of the central dogma that opened up a major reconceptualization of the field was the discovery of reverse transcription from RNA to DNA, a process shared by retroviruses, LINE elements and the telomerase which adds new telomeres essential to maintaining the immortality of the germ line. There are sequencing homologies between the reverse transcriptases of all of these indicating a viral origin for telomerases. Significantly LINE elements, which are concentrated in specific regions of other chromosomes are also spread over the X-chromosome and concentrated around the inactivation centre where Xist lies (Lyon R428). LINE expression requires the specific heterochromatic state induced by Xist. These LINEs often lie within escape-prone regions of the X chromosome, but close to genes that are subject to XCI, and are associated with puta- tive endo-siRNAs. LINEs may thus facilitate XCI at different levels, with silent LINEs participating in assembly of a heterochromatic nuclear compartment induced by Xist, and active LINEs participating in local propagation of XCI into regions that would otherwise be prone to escape Chow et al. doi:10.1016/j.cell.2010.04.042.). This suggests a very ancient symbiotic relationship between cellular RNA processing and retroelements. What is more, disrupting the action of LINE retrotransposons by administration of the drug nevirapine causes an irreversible arrest in development in mouse embryos, suggesting that LINEs are somehow critical to early development in mammals (Systems Biology in Reproductive Medicine, vol 54, p 11).
The introns that punctuate eucaryote genes may also have originated as transposable elements in the founding eucarote cell line in which the endo-symbiosis of the mitochondrion first occurred, as there are putative relationships with transposable elements infecting delta-proteobacteria related to the mitochondrial ancestor. It has been estimated that up to 75% of the nuclear genes whose ancestry has been determined, including the majority of metabolic genes have putative delta-proteobacterial origin, as opposed to the amoebiod orgin of the information processing nuclear genes permitting splicing and other RNA-dependent activities in eucaryote cells. It is thus likely that recombinant sexuality arose from the selective advantage of sexuality promoting genes, in the high variation and mutational loads of the founding eucaryote lineage, during absorption of the mitochondrial genome into the nucleus, which facilitated genomes containing advantageous alleles of multiple genes, rather than the 'frozen' genomes of parthenogenic clones, where an advantageous allele in one gene is obligately entrapped with average or inferior alleles of other genes (See: p 28, King 2009, Lane 2009).
The SRY gene sequence is very strongly conserved among men: there are virtually no point mutations in the human race. It is a variation-free gene that has changed hardly at all since the last common ancestor of all people around 200,000 years ago. Yet our SRY is very different from that of a chimpanzee, and different again from that of a gorilla. There is, between species, ten times as much variation in this gene as is typical for other genes. Compared with other active genes, SRY is one of the fastest evolving. The answer appears to lie in selective sweeps. From time to time, a driving gene appears on the X chromosome that attacks the Y chromosome by recognizing the protein made by SRY. At once there is a selective advantage for any rare SRY mutant that is sufficiently different to be unrecognized. This mutant begins to spread at the expense of other males. The driving X chromosome distorts the sex ratio in favour of females but the spread of the new mutant SRY restores the balance. The end result is a new SRY gene sequence shared by all members of the species, with little variation. The effect of this sudden burst of evolution would be to produce SRYs that were very different between species, but very similar within species (Ridley R579, Jones R349).
There are several genes related to SRY in the genome, the closest neighbour of which is a gene on the X chromosome involved in early brain development (R349). A cluster of Y genes involved in sex characteristics include ones for sperm manufacture, growth rate, formation of teeth, left-handedness, aggression (in mice) and a gene for a protein active in the brain, adding to the logical entanglement of the sexuality of brain function and consciousness. Certain genetic anomalies can be explained by an aberrant crossing over between the X and the Y in the father, in regions neighbouring the SRY, transferring it to the X, resulting in an X containing SRY and a Y failing to do so. This leads to both XX individuals who may develop somatic characteristics of males and XY individuals who turn out female.
A man's genetic make-up may play a role in whether he has sons or daughters, a study of hundreds of years of family trees suggests. Newcastle University researchers found men were more likely to have sons if they had more brothers and vice versa if they had more sisters. They looked at 927 family trees, with details on 556,387 people from North America and Europe, going back to 1600. The same link between sibling sex and offspring sex was not found for women. Dr Gellatly said it was likely that a genetic difference affected the relative numbers of X and Y sperm within those produced by the man. He said that the effect was to actually balance out the proportion of men and women in the population. "If there there are too many males in the population, for example, females will more easily find a mate, so men who have more daughters will pass on more of their genes, causing more females to be born in later generations."
The XY signature is a source indicator of the divergence between reptiles and internally fertilizing, lactating and gestating mammals. The first of four Y inversions happens around the time of the platypus and echidna, the next close to the divergence between marsupials and true mammals, the next at the main mammalian radiation and the fourth around the time apes differentiated from other primates. The fact that birds have a mirror-complementary female-determining ZW sex-chromosome arrangement suggests this chromosomal form of sexual differentiation has specific evolutionary advantages.
Non-sex chromosomes (autosomes) are also sexually-imprinted in a way which may give the mother's genes a key developmental role in the cerebral cortex, striatum and hippocampus with the father's being more significantly expressed in the mid-brain emotional centres - the hypothalamus, amygdala and pre-optic area. (Keverne et. al. R357, R358, R313, Gibbons R237). This would mean children tend to inherit their father's personalities, but they inherit their mother's astuteness, intellect and memory. Eric Keverne sees this as being evidence of evolution of executive areas of the cortex in a context of prolonged association between female relatives, consistent with the matrilocal pattern of most mammals and primates but not apes (Hrdy R330 143). This also suggests an early arms race in which competition for a male drive for emotion was countered by a major growth of controlling factors in the cortex including the frontal areas maintaining overall integration (Campbell R103 239).
Sexually imprinted genes and their locations in the brain. Maternally-imprinted genes red in the cortex and paternally in emotional centres green (New Scientist 3 May 1997)
Chris Badcock (R32) claims the conflict between the male-imprinted limbic system and the female cortex may reflect a parallel with a paternal id making egocentric, infantile and constant demands on the mother while the maternally-controlled cortex represses them. This reflects Haig's (R278, R279) theory of an arms race between paternal genes favouring growth promotion in the hypothalamus and the invasive placenta and maternal genes spreading the effort among offspring. Notably the insulin growth factor IGF II is paternally expressed while the IGF IIR receptor is maternally expressed and seems to have a role in inhibiting excessive growth in the embryo. However the evolution of these genes is not accelerated as in active arms races so the process may have stratified.
Genes for telomere length and hence long-levity also appear to be peternally imprinted, correlating only with the father's pattern, rather than the mother's (Nordfjäll R505). There is evidence that telomere length in sperm increases with age, so "it is possible that children with older fathers would inherit longer telomeres", Nordfjäll says. This shows an ultimate sexual paradox at work - female reproductive choice applied to older successful men causes successful genomes to become even more long-lived.
The small minority of about 50 genes (Hrdy R330 432) which are sexually imprinted by paternal or maternal descent display some stunning examples of a genetic 'tug-of-war' between the sexes, although some are more difficult to interpret. Daughters inheriting a mutant form of a male imprinted mouse gene called Mest display, in addition to a slight reduction in body size, failure to eat the placenta on birth and deficiencies in mothering (R330 433). The key theory about 'fatherly' imprinting of genes is interpreted in a conflict model to favour the selective replication of paternal genes, by encouraging the female to devote more energy to the current offspring of the father than consistent with her overall reproductive commitment to all her potential offspring, favouring for example larger babies which consume more of the mother's resources. David Haig has suggested this sexual 'tug of war' may have become an essential feature and that disruption of the counterbalances on either side could compromise fertility (ibid). Haig's predictions have been confirmed in experiments where specific genes were modified to have only maternally imprinted versions of vice versa The female imprinted offspring were only 60% of normal size and the male imprinted 130% (R330). However paternally imprinted Mest and Peg-3, which affect mothering by affecting oxytocin-related bonding appear to equally favour maternal fortunes.
Children with Turner's syndrome are genetically neuter. They have a single X-chromosome, inherited from either their mother or their father, instead of the usual two X chromosomes of a girl or the X and Y of a boy. Since a female body plan is the default among mammals, they look and act like girls. Turners syndrome females with a single X differ in their symptoms, with the maternally-inherited X displaying more serious problems of social maladjustment and those with a paternal X being better at interpreting body language, reading emotions, recognizing faces, handling words, and getting along with other people. This is consistent with the adaptive imprinting of the maternal X for the social restiveness of males who always have a maternal X to prime them for reproductive competition (Hrdy R330 142).
Methylation of the cytosine bases on DNA is one key mechanism that leads to imprinting, permitting the independent expression of maternal and paternal genomes during early development and after. The female germ line is more highly methylated than the DNA of the male germ line. The methylation of some genes may lead to their silencing into inactive clumped regions, while others may be activated. Imprinting appears to have a sexually-polarized role in the primal development of the embryo. A tumorous uterine growth called a hydatidiform mole is caused by the lack of female imprinted genes, as a result of more than one sperm entering the egg. Either all the genes are paternally inherited, or there is one maternal and two paternal sets. The hydatidiform mole is effectively an exclusively placental pregnancy, supporting Haig's theory of an arms race in which the paternal genes promote invasive growth (p 16) in line with males ensuring the survival of their offspring in 'captive' females.
Sexual imprinting master switch: Key imprinted H19 and Igf2 genes on the same mouse chromosome are oppositely 'imprinted' in normal embryos. On the maternal chromosome, an enhancer-blocking protein CTCF, which recognizes the DNA sequence CCCTC binds to the differentially methylated domain (DMD), blocking the access of enhancers to Igf2 and instead favouring H19 expression. On the paternal chromosome, the DNA of the boundary element is methylated; the blocking protein cannot bind, and Igf2 is expressed (Loebel and Tam R422).
Recent experiments have suggested that the maternal and paternal genomes have different roles during mammalian gastrulation. Mouse zygotes can be created that have only sperm-derived chromosomes or only egg-derived chromosomes. The male-derived embryos (androgenones) die with deficiencies in the embryo proper but form well-developed chorions. Conversely, the female-derived embryos (gynogenones) die with deficiencies in their chorions, even though the actual embryo seems normal. It appears that sperm-derived genes are needed for the proper development of the chorion, while egg-derived genes are necessary for the normal development of the embryo itself (Barton et al., R48; McGrath and Solter, R459; Surani et al., R674). This has been confirmed by making allophenic mice in which blastomeres from a normal 4-cell embryo are aggregated with blastomeres from either androgenetic or gynogenetic embryos. In both cases, cells from both the normal and abnormal embryos were originally seen in all regions of the blastocyst. However, by the end of gastrulation, androgenetic cells are seen almost exclusively in the trophoblast, while gynogenetic cells are hardly ever seen in trophoblast-derived tissues (Thomson and Solter, R687). This strongly suggests that the maternal and paternal genomes serve distinct functions during early mouse embryogenesis.
In 2004 the first successful 'parthenogenetic' mouse pups have been raised by manipulating maternal imprinting to repress it in one maternal haploid genome, and introducing this into an ovum, to mimic the natural imprinting expression above, resulting in two live pups out of 598 oocytes, one of which proved fertile in adulthood (p 412). Kono et. al. (R387) comment "These results suggest that paternal imprinting prevents parthenogenesis, ensuring that the paternal contribution is obligatory for the descendant".
Varieties of sex hormones: The steroid hormones (a) are synthesized sequentially from progesterone through testosterone and androstenedione (which differs from testosterone in the same way estrone differs from estradiol) via aromatase to the estrogens estradiol and estrone. For further details see the complete steroidogenesis map (b) Prostaglandins (c) Polypeptides oxytocin and vasopressin. (R406)
The steroid sex hormones, like neurotransmitters are an ancient feature of evolution. In the turtle which determines its sex by temperature, eggs incubating at the female temperature have a rising estrogen flush which then tapers off once sex determination has taken place. At male-determining temperatures, while estrogen levels still rise, there is a pulse of testosterone at the time sex determination takes place. These patterns echo strongly the patterns of human embryogenesis even up to the time of a brief testosterone burst around the time of birth that is believed to have an engendering effect on the human brain.
The main steroid hormones are in a state of yin-yang complementation. The dominant male hormone testosterone is a metabolic intermediate sandwiched between the two female hormones, progesterone and estradiol, which have an oscillatory nature driving the menstrual cycle and ovulation. Steroids are lipid molecules which can drift through cell membranes, pass the blood brain barrier, and act directly on gene regulation in the nucleus of target cells. This makes them ideal for hormonal signalling from the gonads to the brain and other tissues. Invertebrate species also use steroids as hormone signallers. Ecdysone is the key hormone in the stages of insect molting and metamorphosis and ecdysone variants maintain ovarian function in adult mosquitoes (Hagedorn et. al. R276).
Estradiol level is positively associated with a woman’s self- and other-perceived physical attractiveness and with inclinations to mate outside her current relationship and marginally negatively associated with a woman’s satisfaction with her primary partner and relationship commitment (Durante K & Li N 2008 Oestradiol level and opportunistic mating in women Biol. Lett. doi:10.1098/rsbl.2008.0709).
Progesterone stimulates the implantation of the fertilized embryo and the maintenance of pregnancy. Estrogen is largely secreted by the ripe ovarian follicles as they come to maturity, triggering the bursts of follicle stimulating hormone and lutenizing hormone from the pituitary that cause ovulation to occur. Then in the latter part of the cycle, progesterone from the corpus lutetum, the yellow remains of the follicle prevents the endometrial lining of the uterus from sloughing of for long enough for implantation to occur.
Part of the paradox of this situation for the human female is that estrogen is supplied by the follicles of the germ-line ova rather than maternal tissues. In males testosterone is manufactured in the somatic interstitial cells of the testis, rather than the sperm-producing germ-line cells of the seminiferous tubules. This means that males continue into later life with only about a 1% decline in testosterone a year. However in females, the lioness' share of female sex hormones come directly from the oocytes. Unlike sperms, which are produced continuously from germ-cell primordia, oocytes are not generated afresh during adult life, but remain dormant, since first multiplying prenatally, When their supply runs out in mid-life, menopause occurs. Female chimps remain fertile until too aged to bear pregnancy, so it is unclear whether this is an ironic penalty of human evolution, or an adaption to provide grandmotherly support for the next generation's parents rather than competing with one's own long-lived offspring (Hrdy R330). Estrogen levels fall by about half in menopause and progestogen levels precipitously. In menopausal women, as estradiol levels fall, fat cells and to a certain extent muscle cells begin secreting estrone. A moderately well-endowed menopausal woman may circulate more estrogens than a skinny woman having normal cycles.
Estradiol plays a crucial role in female fertility, sexual motivation and behaviour. In an experimental study, estradiol level was positively associated with a woman's self- and other-perceived physical attractiveness and with inclinations to mate outside her current relationship. Estradiol was marginally negatively associated with a woman's satisfaction with her primary partner and relationship commitment (Estradiol level and opportunistic mating in women Kristina M. Durante and Norman P. Li Biol. Lett. doi:10.1098/rsbl.2008.0709).
Although men have ten times as much circulating testosterone as estrogen and women the reverse, both sexes secrete several steroid sex hormones, including both androgens and estrogens. The formation of breasts depends rather sensitively on the balance and starving prisoners of war were known to grow breasts in their first flush of a good diet. XY males who have androgen receptor intolerance fail to develop as normal males, having no penis, but instead a shallow vagina, with only the outer labia since they also lack the estrogen required for a fully developed female anatomy. Since they appear anatomically as female many have their defunct testicles removed at birth and given estrogen replacement therapy in adolescence. Since the default condition in mammals is female, they identify as women and appear as sometimes beautiful women.
Those madly in love also have converging levels of testosterone, higher in women and lower in men, suggesting nature seeks to mediate the dissonance of differing sex strategies when love is the binding glue (Marazziti Psychoneuroendocrinology to appear, R13). NGF or nerve growth factor has also been cited as an albiet transient accompaniment of falling in love (Truly, madly, deeply in love - but not for very long NZ Herald 28 Nov 2005) Music has been found to have a similar effect, confirming it has a complex role in human bonding (Fukui R228), not only developed as a signal of courtship, as Darwin remarked, but also evolved to influence human love in a complicated way.
However the paradox does not end there. Males have an enzyme called aromatose which converts testosterone to estradiol, just as the ova convert androgens to estrogen. In women testosterone is produced (in much smaller quantities than men) in the adrenals and ovaries as a principal estrogen precursor. In rats, estrogen is essential for masculinizing the brain. In mice, α-fetoprotein binds to estrogen stopping it from masculinizing the brain. This process is different in humans. While human 'males' with androgen receptor intolerance have both feminized external genitalia and feminine brain and behaviour, the corresponding rats have masculine brains because of these paradoxical effects of fetal estrogen. Human males with estrogen receptor intolerance, although they appear to be normal but perhaps oversized men, are infertile because estrogen receptors are essential for full fertility in the male. Rare disturbances in the aromatose pathway result in men who cannot mate. Parts of the testis have higher estrogen concentrations than the ovary and sperm are during their journey in the male subjected to higher estrogen levels than the ovum.
In both men and women aromatose activity increases with age. In men, estrogen production is not confined to the brain. Estrogens are also secreted from the skin, blood and fatty tissue. A man of over 50 may have higher estrogen levels than a menopausal woman (Angier R18, Blum R66). Testosterone levels rise in men with muscular activity partly as a result of its role in energy metabolism so in older men activity promotes hormonal health. Conversely, testosterone is converted into aromatose in fatty tissue which in turn can increase fat gain, resulting in an increase in estrogen in inactive older men. Conversion to estrogen in men has been associated with irritability. It appears essential for maintaining important classes of brain neurons, such as those involved in Parkinson's, and in the maintenance of memory. Women suffering sudden falls in estrogen notice memory impairment. The brains of female rats fluctuate noticeably in the density of their hippocampal synapses during the estrus cycle, coming to a maximum in proestrus as the endometrium and follicles are maturing, driven by estradiol. Progesterone is also present in men, rising in the evening.
The hormones in turn appear to have major effects on gene expression in the sexes. A study (Wang R726, Yang R773) revealed the huge extent of sex differences in the genes of brain, muscle, fat and liver. The team used microarrays to simultaneously assess the expression of more than 23,000 genes in all of the four tissues, looking for differences between the male and female mice. For most genes the expression difference was less than 20%, but for some it was more than 300%. There were more than 25,000 examples of different gene expression. In the liver, where drugs are metabolised, about 70% of expressed genes were different between the sexes. Only 14% of the genes expressed in the brain were found to be different, although the researchers caution that this preliminary result might not mean anything significant about the difference between male and female brains.
The sex hormones are also in feedback with one's sexual charisma, sense of success, libido , sexual arousal and male dominance (Mazur and Booth R451). Men, experience a noticeable rush of 100% increase in testosterone watching pornographic movies. Astrid Jutte also found (New Scientist 22 Aug 98 11) that women also have an 80% rise in testosterone under the same circumstances (albeit from a ten times lower baseline). It is thus no surprise to hear that some women find testosterone also enhances their libido if taken as a drug. Though testosterone levels in men and women do not overlap, variations in level have similar kinds of effects in the two sexes. High-testosterone women smile less often and have more extramarital affairs, a stronger social presence, and even a stronger handshake. In men testosterone is very volatile, rising in single men on the prowl, and before a contest, falling during stress and plummeting when a man is beaten, rising after success. It is also responsible for the growth of a female's genital hair just as it is in the male. However one should note that there is a hundred times more testosterone bound in the blood proteins of a male than available to receptors, so levels are smoothed out over time. Broadly speaking testosterone has a ravaging effect across many species, diverting energy from immunity and repair towards reproduction, and reducing pain sensitivity (Hau R298), suitable for a sex which has to contest risking death and is expendable in the reproductive process. Males tend to age more rapidly and often accrue more parasites. The effects are exaggerated in highly polygynous species. By contrast estradiol promotes immunity and protects women against effects of aging such as heart disease and osteoporosis, suggesting part of its function is to ensure the females of the species retain good health throughout their valuable reproductive years (Blum R66).
"'The rush of a T shot is not unlike the rush of going on a first date or speaking before an audience. I feel braced. After one injection, I almost got in a public brawl for the first time in my life. There is always a lust peak-every time it takes me unaware" (Andrew Sullivan Pinker R544 348).
When estrogen levels are high, women get even better at tasks on which they typically do better than men, such as verbal fluency. When the levels are low, women get better at tasks on which men typically do better, such as mental rotation. A variety of sexual motives, including their taste in men, may vary with the menstrual cycle as well, tending to more hunky male features during ovulation, although a large study in 2017 contradicts this idea (Jones B et al. biorxiv doi:10.1101/136549). Baron Cohen (R43) has found that high testosterone at birth correlates with autism, less curiosity and less eye contact. Valerie Grant (R254) suggests a link between higher testosterone, female dominance and the birth of additional sons, possibly involving selection for Y-sperm by the ovum or differential implantation, something which may be an evolutionary adaption to take advantage of the reproductive opportunities of male offspring. Blum however notes that higher testosterone women in modern society seem to be more interested in careers rather than child-rearing. There is also a correlation between more sons and the aftermath of major wars, like WW1 and WW2. A better diet is also said to favour boys. Girls with excess exposure to androgens show early preferences for male toys and 'tomboyish' behavior even when the condition is treated at birth, indicating pre-natal determination (p 386).
Storey et al. (R668, R484) have also found increased levels of prolactin and decreased levels of testosterone, consistent with findings in other paternal mammals suggests human males are hormonally modulated to promote fatherhood and reduce aggression. Men are reputed to have reduced testosterone levels around the time of the birth of their children, which may facilitate parental bonding and paternal support for the baby, but in men trying for a baby, peaks in testosterone levels coincided far more often with periods of intense sexual activity (Hirschenhauser R319). Rises in testosterone also trigger a hormonal pathway that increases sperm production, making conception more likely. At ovulation in the flush of high estrogen, women will naturally shift their choices in male faces from a preference for androgynous figures towards a classically 'high-testosterone' male archetype for example with thick-set jaws. These features are in turn caused by a very high testosterone peak at puberty. Why should that be attractive? Because - so the argument runs - only men with robust immune systems are able to tolerate such a surge. A firm jaw line, in other words, is an outward sign of hidden biological fitness. Gordon Gallup has also found that semen makes women happier than use of a condom (Persaud R Semen acts as an anti-depressant New Scientist 29 jun 2002). The results aren't a complete surprise because semen does contain several mood-altering hormones, including testosterone, estrogen, follicle-stimulating hormone, lutenizing hormone, prolactin and several different prostaglandins. More recent research has shown that seminal fluid induces expression of a range of genes in the cervix, including ones that affect the immune system, ovulation, the receptivity of the uterus lining to an embryo, and even the growth of the embryo itself (Le Page M 2015 Semen has controlling power over female genes and behaviour New Scientist 25 Jul). More recently it has been found to alter the woman's immune response to aid implantation (Klein A Semen reshapes immune system to boost chances of pregnancy New Scientist26 Aug 2016).
Disturbances of the sex hormones can also lead to genital and social changes. CAH or congenital adrenal hyperplasia (p 386), also called AGS or adrenogenital syndrome, is a group of conditions of similar source: a family of autosomal recessive disorders of steroid hormone production in the adrenal glands leading to a deficiency of cortisol, the stress fighting hormone. The pituitary, sensing the deficiency, secretes massive amounts of the stimulating hormone corticotropin to bring the cortisol levels up to normal. This hormone in turn causes the adrenal glands to overproduce certain intermediary hormones which have testosterone-like effects on the fetus and child, leading to so-called 'virilization.' In females, the clitoris of girls is enlarged, and may resemble the male penis to the point that the sex of the child is questioned or mistaken. Males have enlarged penile size.
The accessory hormone estriol which is produced by the placenta from steroids generated by the embryo's adrenal gland appears to act as an immune suppressor to reduce the chances of the mother rejecting the fetus. Consequently estriol has also been found to alleviate the autoimmune condition multiple sclerosis in women.
Along with the steroid sex hormones are prostaglandins. These are conjugated fatty acids which have a modulating effect on the actions of steroid hormones. They were first discovered in semen, where there are over 40 different prostaglandins. Certain prostaglandins are also agents of uterine contraction. They also function in many tissues, having a role in malaise. Asprin for example inhibits cyclo-oxygenase, which elicits prostaglandin synthesis.
The menstrual cycle, showing variations in follicle stimulating hormone, lutenizing hormone, progesterone and estrogen (R406).
However another class of hormones, polypeptides - small strings of amino acids, and with them glycoproteins - longer strings of amino acids with sugars attached, are major hormonal feedback molecules in both vertebrate and invertebrate species. The hormones which regulate the steroid pathways fall into these categories. During development and in the menstrual cycle, secretory neurons in the hypothalamus, with kisspeptin neurones being pivotal, secrete gonadotropin releasing hormone GnRH, which passes through a portal vein through the pituitary. Too fast or too slow cycling of kisspeptin activity contributes to up to one third of female infertility, which is thus sourced in the brain, rather than the goands or uterus.
GnRH in turn controls the levels of two glycoproteins, follicle-stimulating hormone FSH, and lutenizing hormone LH, named for its role in causing the follicle envelope to form the corpus lutetum or yellow body, after ovulation, which enables the embryo to implant, by releasing progesterone, as shown in the figure above. These two hormones are common to both male and female and also act in complementary ways on disparate testis tissues in the male, FSH directly stimulating spermatogenesis in the tubules and LH stimulating interstitial androgen production and indirectly sperm production. The cyclic behaviour of FSH and LH in the hypothalamus appears to be ablated about the time of birth by androgens in the male. Low levels of a related polypeptide hormone corticotropin-releasing hormone (CRH), is also associated both with the calm of breast feeding mammals, including humans, and with the fearless aggression a mother shows towards males or other predators who may attack her offspring (Behavioral Neuroscience DOI: 10.1037/0735-7044.118.4.000).
The Menstrual cycle starts with low level FSH stimulation of immature egg follicles which at this point are insensitive to LH. One of these becomes predominant and begins to grow, secreting small amounts of estrogen. This responds to the FSH by growing and secreting estrogen. This estrogen holds the process in check, by suppressing FSH over the two weeks that it takes for the follicle to fully ripen, and stimulates growth of the endometrial tissue in the uterine lining. Eventually rapidly rising estrogen levels in the follicle cause a hypothalamic rise of GnRH stimulating both FSH and particularly LH in the pituitary where in addition estrogen increases LH sensitivity to GnRH. By now, the mature ovum has developed LH receptors and the LH now sends the follicle toward ovulation within 48 hours. Subsequently the remains of the follicle, the corpus lutetum continues to excrete estrogen and with it the progesterone necessary for maintaining the lining and permitting implantation. The precipitating factor in ending the cycle may be prostaglandins in the uterus At this point both steroid levels plummet and menstruation sets in as the uterine lining is shed. In many mammals species the uterine linings are absorbed. If implantation occurs, human chorionic gonadotropin causes the corpus lutetum to continue making progesterone. In humans the placenta also makes progesterone after the first two months. See also related primate cycles (p 76).
(New Sci. 19 Jul 2003)
Actually things are by no means as simple as this cyclic picture suggests. Many ovarian follicles mature in a given cycle although only one is released and the others atrophy and die. In recent research 68% of women were found two have two follicular flushes a month and 32% had three (Pierson et. al. R541). This is more consistent with a chaotic dynamical system than a simple periodicity. Even given progesterone masking of later flushes, in some of these cycles, two ova will be released, explaining the 10% incidence of non-identical twins, and possibly why menopause has an earlier onset in some women. Multiple ovulation tends to become more frequent as a woman ages due to FSH overcompensation for declining ovarian fertility (Human Reproduction, DOI: 10.1093/humrep/de1009).
Progesterone is just one of a series of progestins which affect the cycle and maintain pregnancy. In addition estradiol is replaced by placental estriol, with some additional estrone, as well as the progestins. Estradiol is known to boost killer T-cell immune reactions so its suppression in pregnancy may help prevent rejection of the embryo (Blum R66).
Two other hormones secreted by the posterior pituitary are believed to have an important role in sex and bonding, the polypeptides: oxytocin, sometimes romantically called the 'love molecule', and vasopressin. Oxytocin is involved in both uterine contractions in childbirth and, along with another pituitary polypeptide prolactin, in lactation, where it triggers the let down reflex that releases milk for breast feeding and may help both mothers and fathers bond closely to protect young offspring. It also has other effects increasing insulin and the effective assimilation of food. In an experiment with masturbating women, oxytocin levels were found to rise, albeit slightly on orgasm, and to correlate to some degree with the pleasure experienced (Fisher R210 257). Oxytocin was released also in massage in women but not in erotic fantasy (Campbell R103 241).
The fact that oxytocin functions in overcoming avoidance behavior and establishing a trusting bond in men, despite the apparent circumstances has been established in an experiment, where men sniffing oxytocin were unknowingly much more likely to give their money to a trustee in a trustee investment game (p 51). In another study oxytocin made men just as empathetic as women. However it has been claimed that some of these studies have failed to be replicated and that the claims persist due to publishing bias (Oxenham S 2016 Everything you’ve heard about sniffing oxytocin might be wrong New Scientist 16 May).
Oxytocin effects of hugs can be particularly good for women's hearts. In a study, hugs between partners were found to both increase oxytocin levels and reduce blood pressure, particularly if the relationship was loving, but the effects were highest in women, accompanied by a reduction in cortisol (How hugs can aid women's hearts BBC 8 Aug 2005). It has also been found to help the autistic brain and alleviate anorexia.
A small population of interneurons in the prefrontal cortex that express the oxytocin receptor has been found to be necessary for mating behavior in female mice, whose silencing obliterates sexual responsiveness during estrus. Since intranasal administration of the oxytocin activates the frontal cortex in humans, it is likely a similar feedback process is in play in human sexual responses (Nakajima et al. Cell doi: 10.1016/j.cell.2014.09.020).
Vasopressin is essential in water regulation through the kidneys. Those lacking it flush so much urine that they lose glucose and become victims of diabetes insipidus. The relatively neutral comments of humans given vasopressin as a drug which is claimed to have beneficial effects on memory retention give vasopressin a similarly ambiguous status as a bonding agent in humans.
However there is evidence these two chemicals function as female and male bonding neurotransmitters in some species. Experiments injecting them into the nervous systems of voles and sampling the natural secretion of them in rats and simian monkeys suggest that oxytocin functions to elicit maternal child-grooming behaviour, even in animals which have never given birth. Prairie voles (p 33), (p 375) are socially monogamous and there is a strong association between oxytocin in females and vasopressin in males generated by conjugal love-making up to 30 times a day, acting on dopamine pathways in maintaining bonding (Campbell R103 240) through the 'addiction' of partnership. The combined effects of cohabitation and release of these neurotransmitters has been found to induce epigenetic changes associated with long-term bond formation (Cormier, Zoe 2013 Gene switches make prairie voles fall in love doi:10.1038/nature.2013.13112). Aragona et al. (R19) have mapped out two domapine recptors D-1 and D-2 which can unravel or enhance prairie vole fidelity. Aragona's team discovered the D-2 receptors are activated during the first mating encounter, which results in pair-bond formation. After extended cohabitation with the female, however, there was a significant increase in stimulation of D-1 receptors, which led to aggressive behaviour towards other females. Blocking D-1 at this point prevented the aggression. A virgin male adult injected with a D-2 activating chemical formed an instant and lasting pair bond with the nearest female, even if she were not sexually active and no mating took place. The injection also triggered aggressive behaviour towards other females, even ones that offered sex. D-1 activation in virgin males, conversely, prevented them from committing to a female in the first place. Non-monogamous montaine and meadow voles do not show this pair-bonding relationship. However they can be induced to do so simply by altering the promoter region of the V1aR vasopressin receptor gene to that of the prairie vole (Lim et al R418). Prairie voles with variants containing 19 more microsatellites than other strains show greater monogamous attention and better parenting (Hammock and Young R286).
The key region contains micro-satellites which are highly variable and provide for rapid evolutionary adaption. Humans possess a corresponding region, with polymorphisms in the population. The corresponding human region is not as long as that of the prairie vole, and among the polymorphisms have been found promoters of 17 different lengths, suggesting that the population contains individuals with a wide variety of genetic responses to fidelity. Variation in a section of the vasopressin receptor gene called RS3 334 was linked to how men bond with their partners. The higher the number of copies, the worse men scored on a measure of pair bonding (Walum et. al. PNAS DOI: 10.1073pnas.0803081105, SPNews 1727). Divorce rates in fact show a degree of heritability.
A paternally-imprinted gene which affects oxytocin neurons also disrupts mothering in mice (p 346). In plain fin midshipman fish, which like some other species have two types of male, courting males which sing and sneakers which don't (p 33). Sneakers, like the females can only grunt, and vasopressin and oxytocin seem to be associated with singing and grunting in this species, rather than male or female behavior per se. (Campbell R103 241). These differential reactions are characteristic of polypeptides, which may act quite differently as a neurotransmitter to their effect in the blood, since they do not easily cross cell membranes and the blood-brain barrier like steroids do. Interestingly testosterone has been found to stimulate the growth of oxytocin receptors in the brain hinting at a neuronal feedback between reproduction, arousal and bonding (Blum R66).
Several of these results have now been extended to human studies. An association has been found between one of the human AVPR1A repeat polymorphisms (RS3) flanking the arginine vasopressin (AVP) gene and traits reflecting pair-bonding behavior in men, including partner bonding, perceived marital problems, and marital status, which shows that the RS3 genotype of the males also affects marital quality as perceived by their spouses (Walum et al. 2008 PNAS doi:10.1073/pnas.0803081105).
An association has also been found between pair-bonding and dopamine receptors in humans. Selection theory suggests a mechanism for selective pressure for and against the 7R+ genotype that may explain the considerable global allelic variation for this polymorphism. The DRD4 VNTR genotype varies considerably within and among populations and has been subject to relatively recent, local selective pressures. These findings show that genetic variation in the brain's dopaminergic reward pathway appears to be an influential factor in individual differences in motivation to engage in sexual behavior of a risky and uncommitted nature. Individuals genotyped as 7R+ were significantly more likely to report having engaged in promiscuous sex (e.g. a one-night stand). Of those reporting infidelity, 7R+ individuals were cheating on romantic partners more often, which under certain circumstances could result in higher genetic fitness via greater offspring diversity as well as increased total fecundity. This suggests that in local environments where monogamy and sexual fidelity are advantageous, the 7R- genotype would be subject to positive selective pressure. In contrast, in environments where monogamy and fidelity are disadvantageous, the 7R+ genotype would be subject to positive selective pressure (Garcia et al. 2010 PLoS ONE doi:10.1371/journal.pone.0014162).
One also needs to note that social monogamy does not imply sexual fidelity. Paternity tests indicate that the animals touted as paragons of monogamy frequently cheat on their partners. Sue Carter at the University of Illinois at Chicago, says that these findings highlight the importance of social bonding. "Humans want to believe in sexual monogamy. That focus may have distracted people from the relative importance of social monogamy". (A. G. Ophir et al. Anim. Behav. doi:10.1016/j.anbehav.2007.09.022; 2008, SPNews 1344).
Here we flow into the complex question of how neurotransmitters as well as hormones facilitate love and sexual and parental bonding. Falling in love affects not only our hormone levels but neurotransmitters such as serotonin which affect the relaxation and elevation of our mood. Love is by its nature addictive and has to be so in the most healthy of ways for sexual reproduction to remain the mainstay of an increasingly intelligent autonomous organs like humanity. We know opiates, and the dopamine and serotonin affecting drugs exhibit tolerance and severe withdrawal symptoms. 'Falling in love' is by its very name a partially involuntary process beyond our rational control whose energies are wild and completely addictive, with in some ways the most severe withdrawal reactions of all the source of all love's tragedies. The ecstasy and fulfillment of love clearly involves all these neurotransmitters and hormones interacting in a symphonic manner.
This carries us finally to the most subtle and pervasive molecular dance of all, that of the pheromones. The term pheromone means 'excitement bearer' a term appropriate to their 'galvanizing' sexual role. The first to be discovered was the sexual pheromone which attracts a male moth to the female, discovered to be a volatile alcohol, even one molecule of which is said to be capable of eliciting a response from the male. Research on human pheromones has been slower to mature and it is only recently that science has acknowledged that we have specialized pheromonal organs and that human pheromones may play a major part in our hormonal cycles and in our mate choice.
Folk wisdom tells not only that the menstrual rhythm is subtly coupled to the phases of the moon (Cutler et. al. R141), but that women together often become 'mode locked' into phased cycles. This was confirmed experimentally by Martha McClintock in the dormitories of a women's college. Synchronized ovarian cycles have been found to be common to humans, non-human primates, rodents and oppossums (R453, R454). The airborne nature of such phasing indicates it could be mediated through a pheromone. This has been confirmed in a series of experiments by Winnifred Cutler (R141) and George Preti and co-workers (R552) who dabbed under arm sweat from males and females on the upper lips of test women. Female pheromones, possibly volatile fatty acids, called copulins, apparently 'caused' test women to enter phase synchrony with the pheromonal donor, and male pheromones, possibly the steroid androstenone, which is a female sex attractant in pigs, tended to bring long and short cycles towards the optimally fertile 29.5 day length and has been shown to influence female hormone levels. Cortisol levels in the women who smelled androstadienone shot up within roughly 15 minutes and stayed elevated for up to an hour. Consistent with previous research, the women also reported improved mood, higher sexual arousal, and had increased blood pressure, heart rate and breathing (R770). The result has been an explosion of interest in human pheromone attractants which has seen Cutler and Preti part company on critical terms, with Preti questioning the scientific validity of her findings, when Cutler began marketing the supposed 'attractants' for $600 and ounce, becoming overnight a scientist millionairess with advertisements in Esquire.
Women's string-figure depicting "menstrual blood of three women", illustrating the Yolngu people's tribal mythology of menstrual synchrony Arnhem Land R383.
There continues to be controversy over the status of both menstrual synchrony and lunar coupling. Martha McClintock's research methods R453, have been questioned and other researchers have failed to replicate her findings. But both effects could be more predominant in cultures living with the sun and moon and coexisting in tribal bands. Differing evolutionary arguments have been made. One argument is that reproductive synchrony is a relatively common mechanism in animal populations through which co-cycling females can increase the number of males included in the local breeding system. Conversely, if there are too many females cycling together, they would be competing for the highest quality males; forcing female-female competition for high quality mates and thereby lowering fitness disfavoring synchrony. Differences of Neanderthal reproductive strategies from those of modern Homo sapiens have recently been analysed in these terms. Modern human female ancestors, less seasonally constrained, pursued a strategy of cosmeticization of menstrual signals. This Female Cosmetic Coalitions model accounts for the African Middle Stone Age record of pigment use. Among Neanderthals, strategies alternated. Severe seasonality during glacial cycles tied Neanderthal males into pair-bonds, suppressing cosmetic signaling. Only during interglacials when seasonality relaxed would Neanderthal females require blood-red cosmetics (Power C, Sommer V, Watts I 2013 The Seasonality Thermostat: Female Reproductive Synchrony and Male Behavior in Monkeys, Neanderthals, and Modern Humans PaleoAnthropology doi:10.4207/PA.2013.ART79) .
Androstadienone and estratetraenol are metabolites of testosterone and extradiolmproduced by men and women which have no steroidal activity and little or no odour but appear to act as sexual attractants of the opposite sex according to research in (Zhou et al., Chemosensory Communication of Gender through Two Human Steroids in a Sexually Dimorphic Manner, Current Biology (2014), http://dx.doi.org/10.1016/j.cub.2014.03.035). Androstenone is present in the sweat and urine of both men and women. It has a sexual pheromonal function on female pigs. As a result of polymorphisms in the receptor, a person with two functioning alelles smells it strongly like stale urine and with one weakly vanilla like.
Astrid Jutte (New Scientist 7 sep 1996) has found that men's testosterone levels increase by half when they inhaled synthetic copulins linked to ovulation however from the study it is not clear they were more attracted. Neither is this necessarily a pheronmonal effect but an odor which men may naturally associate with having sex with women. One should be warned that all is not necessarily wine and roses for male pheromones either. Many studies show no consistent effects or even a filtering one promoting female choice but not mindless attraction, although in one study it seemed to make women feel 'submissive' (Benton R58). In a rating study, 289 women rated the smell of androstenone (Grammer R253). Subjects rated the main component of male body odor 'unattractive'. This changed only to a 'neutral' emotional response at the conceptive optimum around ovulation. Karl Grammer notes: "The finding has direct consequences for hypotheses concerning the evolutionary loss of estrus. The cyclic-dependent emotional rating of androstenone might facilitate active female choice of sex partners and may be a proximate cue for female mate-choice".
There is a natural logic to ovarian synchrony. It provides a way to ensure the costly investments of reproduction are coordinated with an appropriate social and physical environment. Although this is common to many mammalian species, Chris Knight (R383) has suggested lunar and pheromonal ovarian synchrony may have favoured female reproductive choice in a monthly 'sex strike' to motivate the men to hunt for meat (p 77). Mild coupling to the lunar cycle may occur through the light-responsive melatonin cycle in the pineal (p 76).
Mammals have been discovered to have not one nasal organ of smell, but two - the usual one for the smells we experience in the everyday world and the other for a variety of body chemicals which affect our feelings of intimacy, not because of their particular smell, but rather the people and connotations they invoke. Like the G-spot, the human vomero-nasal organ or VNO is only a recent item on the list of accepted human discoveries, but it plays a pivotal role, not only in influencing who we feel has the 'right body chemistry' but the entire sexual development of the male. A defective X-linked gene called KAL-1 encoding the cell-adhesion protein anosmin, causes lack of smell because olfactory axons from the nose fail to receive the correct signals to fan out in the olfactory bulb. But it also has another bizarre effect in men who, having only one X are more exposed to this defect. In males, cells in the embryonic VNO actually migrate into the brain along the fascicles - the rail-like paths made by the olfactory axons taking up residence in the brain to become gonadotropin releasing hormone secretors. Hence lutenizing hormone is not released, testosterone is suppressed and the resulting males with Kalman's syndrome have small gonads and penis and no sexual attraction to women. Thus we find an organ we didn't know about may not only be governing our sexual bonding but the entire maturation of male sexuality (Ridley R580 138-9).
However neuroscientist Michael Meredith has no hesitation in dismissing it as a remnant. "If you look at the anatomy of the structure, you don't see any cells that look like the sensory cells in other mammalian VNOs," he says. "You don't see any nerve fibres connecting the organ to the brain." He also points to genetic evidence that the human VNO is non-functional. Virtually all the genes that encode its cell-surface receptors - the molecules that bind incoming chemical signals, triggering an electrical response in the cell - are pseudogenes, and inactive. So what about the puzzling evidence that humans respond to some pheromones? Larry Katz and a team at Duke University, have found that as well as the VNO, the main olfactory system in mice also responds to pheromones. If that is the case in humans too then it is possible that we may still secrete pheromones to influence the behaviour of others without using a VNO to detect them.
However molecules with pheromonal action may also act through the normal nasal pathways. Specific nasal pheromonal trace amine-associated receptors (TAAR) have been discovered in mice and humans and fish share the gene, involving both stress-related and sexual attractant molecules. Nobel prize-winner Linda Buck and Stephen Liberies discovered a new family of 15 TAARs, which respond to urine amines in the mouse. Pregnant mice will abort if they smell the urine of an alien male, demonstrating the potential effect of such receptors. Intriguingly, Buck found that humans have the genes to make at least six of the same pheromone receptors present in mice, so humans appear to be capable of processing pheromones, despite their possibly vestigal VNO (The secrets of animal attraction BBC 31 July 2006).
The plot has been thickened by the discovery of the so-called zeroth cranial nerve, a small nerve pair in front of the pair of olfactory nerves, existing in all vertebrates, with connections running both to the VNO and olfactory receptors and connecting directly to centres in the hypothalamus involved in sexual arousal. It is the embryonic nerve zero on which the gonadotropin-releasing cells discussed above travel to the brain. Cranial nerve zero also directly secretes globules containing gondadotropin relasing hormone and provides a way for pheromonal signals in humans to be relayed to the hypothalamus from nasal receptors, even if the VNO remains vestigal (Fields, R. 2009 Sex and the Secret Nerve. Sci. Am. Mind, Jun 20/3).
In a direct study of the effects of steroidal aromas on the brain study, in 2005, Ivanka Savic found that androstadienone activated the hypothalamus in heterosexual women and homosexual men, but not in heterosexual men or homosexual women. She later found the opposite effect with estratetraenol. In a series of studies, volunteers, particularly women, were also able to detect the scent of fear. In one study nebulized sweat for sky divers reuslted in the stimulation of fear centres (the amygdala and hypothalamus) in volunteerrs given fMRI scans. This doesn't mean that such molecules will reliably elicit fear or attraction unless the actual situation presents danger or an attractive male is present (Williams C 2008 The secret sex signals in human sweat New Scientist 3 Dec).
Vertebrates, with the aid of sexual recombination, have built up comprehensive libraries, not only of immune genes, but of histocompatibility genes, which define compatible tissue types. The major histocompatibility MHC proteins produced by these gene libraries vary significantly between individuals and play a part in giving the person their natural pheromonal body odour, in combination with other glandular substances which give the stimulated vagina and semen their subtly attractive fragrances, referred to in the song of songs as mountains of spices. These contribute to the intrinsically exogamous nature of sexual health - breeding with someone whose genes are different enough to be complementary. Even in cousin marriages the sharing of 1/8 of our genes constitutes a significant load of inbreeding homozygosity, reducing our genetic variety and hence our fitness even when it doesn't result in outright genetic disease, as has been reported in immigrant groups in the UK (SPNews 1336), as indicated in research by Lucas Keller (R167). However a study of Hutterites has found that with each founder carrying an average of 1-2 lethal recessive mutations resulting in a 1.8% increase in a homozygous lethal recessive in first cousin marriages, not a major escalation (doi:10.1038/nature.2015.17304). Marrying distant (third to fourth) cousins has even been found to boost the number of offspring in an Icelandic study (SPNews 1330) and one population of rural Italians with more than its fair share of male nonagerians showed a surname distribution indicating significant inbreeding. This was possibly a result of being homozygous for a gene conferring longlevity (Annals of Human Genetics, doi: 10.1111/j.1469-1809.2007.00405.x). On the other hand an exhaustive 2015 study of homozygosity has found a 10 month decline in educational achievement and a .29 standard deviation decline in cognitive function in the first cousin offspring effect (Nature doi:10.1038/nature14618).
Evolution has served us well in our innate reactions to these histocompatability/immune molecules. A woman responds to ovulation by finding the exotic allure of men with complementary histocompatibility particularly attractive. Men likewise find women of complementary type most attractive. This makes evolutionary sense because the offspring from such liaisons will have increased immunity and natural resistance. With even more focus on reproductively successful genes, ovulating women in long-term relationships found the odor of socially-dominant men more alluring (R299). Infidelity in relationships has also been found to increase with increasing identity in MHC genes, to the extent that 50% of women in a relationship in which there is a 50% similarity engage in sexual infidelity (R233). Men appear to remain indifferent to this effect.
These factors appear to be moderated by other visual and sensory impressions that mediate towards having partners not too different to ourselves. By contrast, when a woman becomes pregnant, she becomes more responsive to the smells of her immediate kin in what would appear to be a protective reaction to seek the safety of kin not inconsistent with a matrilineal scenario. This swing of olfactory affinity is consistent with incest avoidance, suggesting the 'incest taboo' has a biological basis.
The contraceptive hormone pill appears to mimic the pregnant state, running a potential risk of altering long-term mating patterns to favour people of the same compatibility type with lower natural viability. When they asked women to rate the attractiveness of odours from T-shirts previously worn by men, those who were on the pill were more likely to find the "wrong" partner attractive (Proceedings of the Royal Society B, DOI: 10.1098/rspb.2008.0825, SPNews 1732). However another study suggests such selectivity varies across cultures. While American couples are selecting mates, in large part, based on MHC genes, not so for Yoruba couples, who seemed to pick mates with MHC genes no more different than would be expected for any two people picked at random from the population (PLoS Genetics DOI: 10.1371/journal.pgen.1000184.g001, SPNews 1671).
Klaus Wedekind has found that in exclusive religious groups with increased inbreeding and lowered MHC complementarity, pregnancy rates drop and miscarriages increase (Blum R66). Protecting against self-fertilization is a major issue in hermaphroditic plants, where for example, broccoli has no less than 50 genes involved in the process. Human pheromones are coming to be marketed as if they are sure-fire way to a quick sexual fix in ways which are almost certainly fallacious. However there are a whole spectrum of new viagra-like sexual arousal potentiators being developed which are rapidly effective by nasal inhalation, attesting to the power of pheromonal attractants.
Pheromones can also have unpredictable effects. Ironically although male pheromones ususally turn off males, men under the influence of androstenol - a pheromone found in men's underarm sweat - find men's lifestyle magazines to be more attractive and are more likely to purchase them than those not exposed to the pheromone. Women appeared to be completely unaffected by the pheromone. (Kirk-Smith et. al. R379).
In the hours and days that follow fertilization, the genomes of the newly united egg and sperm cells begin to express genes important in early development. Prior to this activation, maternal factors packaged in the oocyte are in charge. But changes to the overall chromatin structure of the paternal and maternal genomes, which are housed in separate pronuclei within the zygote, permit access by transcription factors shortly after fertilization - at about 13 hours in mouse embryos (Akst J 2017 New Techniques Detail Embryos' First Hours and Days The Scientist 1 Dec).
Both the paternal and maternal genomes appeared to have already reestablished local features known as loops and topologically associated domains (TADs). While the paternal genome also contained higher-order formations called compartments, the maternal genome contained only the local structures, but no compartments - global features of chromatin in which transcriptionally active DNA associates more closely with other transcriptionally active regions, while silent stretches associate more closely with one another.
After fertilization, the genomes donated by the sperm and the egg lose many of the organizational features of their chromatin, which must be reestablished in the early embryo. One area of the genome where restructuring appears important for early development is the heterochromatin - highly compacted regions of DNA that are normally silent but that suddenly become active in the zygote.
Retrotransposons, one of the main components of heterochromatin, are highly transcribed at this time. In most of our cells these transposons are silent. Most researchers had considered retrotransposon activation to be a side effect of the overall reprogramming process. But when transcription activator-like effectors (TALEs), were used to prevent LINE-1 activation, decreased rates of development resulted. However, adding LINE-1 mRNAs to make up for the lack of transcription did not rescue the phenotype, so it's not the messenger RNA itself, but just what is happening the DNA loci, suggesting that retrotransposon activation initiates zygotic gene expression, helping open up the chromatin, so that other elements that direct transcription in other genes can function more efficiently.
At the same time that the chromatin of embryonic genomes is restructuring, the vast majority of the epigenetic cytosine methylation marked differently on the paernal and maternal DNA is lost. In the maternal genome, passive dilution of the methylation marks occurs over a few days, while the paternal genome undergoes active and rapid demethylation - often accompanied by replacement with alternative modifications, including hydroxymethylation and carboxylation - shortly after fertilization.
One mechanism at play in the paternal pronucleus involves the excision of the methylated DNA by breaking and repairing the double helix. As those breaks are repaired, nonmethylated cytosines are inserted where methyl marks used to reside. But although this would be very dangerous because it might induce mutations in the founding cells, the cell has a surveillance mechanism to ensure that development does not continue if the breaks go unrepaired, and the zygote does not undergo its first cell division.
DUX4 a protein which is normally epigenetically repressed has been observed to upregulate a suite of genes active during early embryonic development and when excised no development occurs, indicating it is a pivotal link in the first wave of transcription factors.
Although cells of mammalian embryos differ from one another early on, they retain flexibility in cell-type specification until transcription factors such as Sox2 bind to mouse DNA for different periods of time at the four-cell stage. The zygote and the cells of the two-cell embryo, and to some extent the four-cell embryo, are considered totipotent - each cell is capable of giving rise to a whole organism. Over just a few days, however, they lose this ability. Some cells become destined to form the extraembryonic lineage that forms the placenta, while others are fated to become the fetus itself. In mics, those cells with longer Sox2 binding start to express genes, including Sox21, that repress the expression of transcription factors associated with differentiation. As a result, these cells preferentially form the interior population of cells that give rise to the fetus. The length of SOX2 binding is regulated by CARM1, an enzyme that methylates arginine 26 on histone H3 (H3R26). As far as we know for now, everything starts with this particular epigenetic modification - methylation of histones - and this drives cell-fate specification.
The origin of the sex cells is a tortuous tale of migration, enticement and complementarity, of tragedy and success, despite extra-ordinary odds. It is also the immortal story of the single cells which literally pass from generation to generation between diploid primary germ cells to haploid egg and sperm, alongside which the organism is just a multicelled offshoot the germ-line, spawned to ensure fertilization takes place. This is a story of this giddy dance, taking place alongside the doomed organism (p 357), the very cells which tricked us into sexual mortality and yet escape from us to regain immortality.
Testis with seminiferous tubules generating sperm from primordial spermatogonia near the edge, with interstitial spaces lower left (Keaton R355) and Ovary with developing follicles and ovulation (Campbell R106)
Human primordial germ cells first appear in the epiblast which will form the first ectodermal and endodermal layers of the embryo, in the region that will become the extraembryonic mesoderm. While in simpler animals such as insects, a region of the ovum cytoplasm continuing specific RNAs acts an organizing centre, in mammals the determination is more gradual. In the mouse, the germ cell lineage only becomes defined during gastrulation, not during oogenesis or early cleavage as in lower animals. Grafting experiments have shown that many regions of the mouse embryo are capable of forming germ cells when transplanted to the extraembryonic mesoderm of the epiblast prior to gastrulation.
Germ cells are proto-stem cells. Like stem cells they are totipotent, and have the capacity to generate embryonic stem cells, although this totipotentiality is only expressed after meiosis and fertilization. Consistent with this, stem cell factor is expressed throughout the stages of development of the germ line and is coupled to a specific receptor on the germ cells called ckit. Mutations disabling either of these cause infertility. Some germ determining genes particularly the anti-Mullerian male determining hormone AMH are, like the homeotic developmental genes, universal to arthropods and vertebrates. AMH, along with BMP, is a member of the transforming growth factor TGF-b family, highly conserved among animals having members common to humans, frog, fruit-fly and nematodes. These belong to the major class of high-mobility group HMG-box proteins which bind to four-way junctions that arise when self-complimentary single strands of DNA loop out to form twisted hairpins in the regulatory regions 'heading' active genes. SRY is also an HMG-box protein. HMG-box genes are involved in fundamental speciation events. Another universal sex-determining gene is Daz, 'deleted in azoospermia', first discovered in fruit flies which has a human homologue whose mutants also result in male infertility, showing it plays a key factor also in human spermatogenesis. This is one of the several male fertility genes that has moved from the autosomes (chromosome 3) to the Y chromosome around when the great apes began to develop. Oct, a nuclear transcription factor is also critical for the origin of primordial germ cells. It is expressed in cell lineages that give rise to them as well as in the germ cells and oocytes but not in sperm once they are in the testes.
While they cannot properly be called any of the three layers ectoderm, mesoderm nor endoderm, since all these are doomed to become the somatic layers of the organism, primordial germ cells do display certain endodermal characteristics. They produce rich enough amounts of alkaline phosphatase, a key enzyme in bone, to become a key means in their detection. They also appear to use forms of bone morphogenic protein BMP, as mutant mice without this gene lack primordial germ cells. The primordial germ cells move from the epiblast to extra-embryonic mesoderm, then about two weeks after fertilization they migrate into the yolk sac stalk. The reason for this remains obscure, but may be to ensure they do not become imprinted as somatic cells. This does not seem to be to avoid X-inactivation which begins in humans almost immediately after fertilization. Both the tortoise-shell cat's large blotches and the genetic analysis of human blood cells indicates this switch happens at about the 10-20 cell stage and may even appear as soon as the first division (Montiero et. al. R479 , Puck et. al. R557, Brown R84).
At about four weeks, the primordial germ cells migrate again through the hindgut endoderm, up the dorsal mesentery to the genital ridge where the indifferent gonad, a mesodermal structure forms near the embryonic kidneys. They proliferate during the migration, starting with 50-80 cells and becoming 30,000 by the time they reach the ridge. They move by extending filopodia (fine pseudopods), developing long processes, linked to each other in a stream-like fashion. They can pass between cells in tissues. There is evidence the genital ridges secrete a chemo-attractant that guides the primordial germ cells towards them. In addition, they may follow extracellular matrix "roadways" leading to the genital ridges, lined with a protein called fibronectin.
Migration of primordial germ cells into the gonads (www).
Integrins, which act as fibronectin receptors, are involved in the migration. In mutants lacking integrins, primordial germ cells fail to migrate into the gonads. If they do not successfully migrate to the gonad they can become the source of totipotent tumorous growths called teratomas which differentiate as they grow onto organs such as teeth, ears, and bones. The primordial germ cells now enter the gonads and elicit a series of interactive changes with these tissues. Female XX primordial germ cells proliferate in the cortex, the outer layer of the gonad and male XY germ cells proliferate in the medulla or core. Their presence now sets off a series of reactions in the somatic tissue of the indifferent gonad. At about 6 weeks of gestation in humans, a difference in the sexes becomes apparent: in females the genital ridge remains unchanged in morphology, whereas the male gonad develops sex cords. A series of genetic and hormone switches also occur which lead to the sex-determining pathways. If SRY is present, cells of the medullary sex cords will differentiate into Sertoli cells. Once Sertoli cells form, the gonad is committed to becoming a testis. Sertoli cells secrete a glycoprotein called anti-Mullerian hormone or AMH also called MIS. These involve a simple dimeric signalling cell-surface receptor which activates a nuclear transcription factor. AMH is a major switch which represses the female Mullerian developmental pathway. It also stimulates intermediate mesoderm to differentiate into Leydig cells, which secrete testosterone. The medullary sex cords also form the testis cords.
In plants and lower animals such as sponges and corals sex cells are made from somatic cells in the adult, but in complex animals, the sex cells are produced early in the embryo. A theoryfrom Nick Lane and co-workers explaining this (2016 PLoS Biol. 14, e2000410) is that it avoids the mitochondria accumulating too many mutations in complex organisms where the mutational load of high oxidative metabolism is greater. This process, called This requires a balance between allowing a few mutations to provide for selective adaption while not so many as to cause deleterious decline. In that case, the best solution is to have a limited burst of cell division to form the female gamete precursors, giving many more germline cells than are needed, and then to cull most of them to produce a random selection of variants. This process, called atresia, is found in many organisms, including humans. Once a nicely varied population of female gametes is obtained, further division is stopped so as not to risk accumulating too many mitochondrial mutations later in development. Such mutations do accumulate in sperm, which undergo many more rounds of cell division than do eggs. But that doesn't matter, because their mitochondria are jettisoned when an egg is fertilized, and so are not passed on to the next generation.
There are "pro-female" as well as "pro-male" genes, so that sexual differentiation is governed by a delicate balance between the two. The gene r-spondin1 promotes the development of the ovaries, and without it individuals who are genetically female grow up physically and psychologically male, although they have ambiguous external genitalia and are sterile (Parma P. et. al. Nature Genetics, vol 38, p 1304).
In males, the primordial germ cells become diploid spermatogonia. In the genital ridges of the male, mitosis of the diploid spermatogonia continue until puberty. Cell death is minimal, however AMH causes the germ cells to remain in meiotic arrest until puberty, when they undergo spermatogenesis, developing from spermatogonia into spermatozoa. Simultaneously, testosterone induces the testis cords to become the seminiferous tubules. At puberty some of the spermatogonia become committed to meiosis. However, diploid spermatogonia persist throughout life and serve as a continuous stem cell population. The spermatogonia committed to meiosis become primary spermatocytes, and it is in these cells that genetic crossing over occurs. After completion of meiosis, the diploid spermatids develop a tail and a condensed head. During spermiogenesis, the spermatids move toward the lumen of the testicular seminiferous tubule and are released into the lumen. Around 200 million sperm are produced a day, vastly more than the number of eggs a female produces in a lifetime.
This results in manifest differences in the mutation rates of sperm and eggs. The number of mutations in a sperm from a man of 20 is around 25 but this doubles every 16 years, because sperm precursor cells are continually dividing and exposed to mutation, so by 56 there are around 130 mutations on average per sperm. By contrast in a woman there are no more than 15 mutations, no matter what her age because the ova remain sequestered and genetically protected. Consequently the chldren of older men are 3.5 times more likely to have autism and to be less beautiful biologically and do less well in school, although they may live longer because their basic gene complement came from a long-lived father. In a study in Nature adolescent children of men of 40 were consistently rated as 5-10% less attractive than those of a man of 22. Many of these de novo mutations are not necessarily coding for altered proteins, which might result in a lethal mutation, but non-coding regulatory areas. Leading causes of autism appear to be linked to such mutatons. Those born to older fathers had a 13-fold extra risk of ADHD, 24-fold higher risk of bipolar disorder.
Development of the indifferent gonad into testis and ovary involves development of either the Mullerian or Wolffian ducts (Sarawer www).
The testis develops several weeks sooner than the ovary and is larger. Because the right side of the body also tends to develop sooner, this makes it possible for true hermaphrodites to exist who have an ovary on the left side and a testis on the right. Such individuals generally have some Y-related activity on a non-sexual chromosome, although they are generally XX and may have ovarian cycles at puberty and some even bear children. In females, the pattern of differentiation is markedly different. In the genital ridges of the female, cell death of the primordial germ cells will begin and continue; mitosis does not continue. The primordial germ cells associate with the cortical region of the sex cords undergo a few further mitotic divisions. Shortly after arrival in the genital ridge, the female primordial germ cells cease dividing and become primary oocytes or oogonia. Sex cord cells become the granulosa cells supporting and nutrifying the ovum and the medulla gives rise to the layer of thecal cells secreting the androgens which are precursors of the estrogen generated by the follicles. In the absence of SRY and AMH, the medullary sex cords atrophy. Ovaries develop in the presence of the germ cells and the activation of both X chromosomes during gonadal differentiation, so that the germ-line again has a fully active XX complement. The primary oocyte together with a surrounding layer of flat epithelial cells is known as the primordial follicle. These cells replicate their DNA for the first meiotic division and then undergo crossing over. While still in the prophase of the first meiotic division with the points of chromosome synapsis still visible, these cells then become arrested. While eggs may remain in this state until puberty when menarche occurs, the majority resume meiosis I at varying times (in utero, infancy, prepuberty) only to be lost short of ovulation in atresia.
By the fifth month of prenatal development, the total number of germ cells in the ovary is estimated at around 7 million. By the seventh month, many of the oogonia and primary oocytes have atrophied in a programmed cell-death or apostosis. Surviving primary oocytes enter prophase of the first meiotic division, where they arrest until puberty. A tragic mass extinction of oocytes has taken place, with their numbers falling precipitously to about 500,000 by the time puberty begins, leaving the woman throughout her reproductive life with only around 70,000, a mere shadow of her founding endowment, only some 400 of which will ever become ovulated. However recent research chemically destroying ova in pre-pubic in mice suggests ovarian stem cells persist which can regenerate viable oocytes. It remains to be seen whether it is possible in human ovaries (BBC 'Female fertility extension hope' 11 Mar 2004). For a while, it was believed that the female pathway was the default, since in the absence of SRY the gonad becomes an ovary. Recently, genes have been discovered that challenge this view.
The gene Dax-1, when duplicated in the XY individual, results in sex reversal to form an XY female. It is located on the X chromosome and one copy is typically expressed in both males and females, where only one X chromosome is active in somatic lines. In some XY females, Dax-1 is duplicated on the X. Having 2 copies antagonizes SRY, leading to sex reversal to female type despite the presence of Y and SRY. Dax-1 appears to be involved in induction of the ovary and female sex-determination through Wnt-4. This antagonistic relationship between Dax-1 and SRY is a classic case of interlocus contest in sexually-antagonistic co-evolution - so sexual determination is founded on genetic warfare as manifested also in the 'fitful' evolutionary jumps of SRY.
The principal genes and their related hormones and effects in the sex-determination pathway (www).
Originally the female sex organs were believed to be just an inverted version of the male, turned inside out from a lack of the 'heat' ascribed to male generative 'lust' (Jones, Friedman). This 'inverted shadow' of the female perpetuated from another older fallacy - that the female was simply a ripe garden for the planting of the male seed (MacElvaine R457), a complete male sperminal homunculus, which Nicholas Hartsoeker claimed to have actually perceived under the microscope in 1694, and which persisted until the discovery of the ovum by von Baer in 1827.
It is in many ways a fitting epitaph to the patriarchal dominion of the last four millennia that a process which obviously involves both sexes and was at least intuitively understood in animal husbandry and which is predominantly the 'issue' of the female in all externally fertilizing animals, from insects' to fishes and frogs, from whose ova we have quintessential delights such as caviar, were so neglected and repressed in human culture. Of course these ideas were fallacious also in the male, whose penis was believed to become erect by air pressure rather than blood, but it is nevertheless a commentary on the grim confines of sexually antagonistic coevolution that such fantasies could prevail along with dire punishments for women found in adultery or lacking the tokens of virginity. This sets a fertile stage for a discovery process in which the development of the external sex organs is found to be in many ways a homologous inversion, albeit in a context in which the female form is in many ways the default and the male an inversion of the female, via the SRY gene and its sequellae.
The mechanism appears to involve SRY blocking the inhibition of the Dax-1 pair on SF1 which then teams up with Sox-9 and Wt-1 to upregulate AMH production. In the female Dax-1 stimulates the formation of the ovary via Wnt-4. Interestingly some genes in the female pathway, such as Daz, are conserved between human and insects. The system has many more emerging components. TGF-b and LIF regulate further mitosis of PGCs in the gonad. In the male, these are primarily inhibited. Bone morphogenic protein Bmp-8 also seems to be involved in sperm development.
Homunculus in the sperm - Hartsoeker (Welcome library, London)
At the end of the seventh week, the gonads have differentiated to either male or female. However, the rest of the reproductive tract is still bipotential. The mesonephros begins to degenerate, but the mesonephric tubules and mesonephric (Wolffian) ducts remain, connected to each other. A second duct system, the paramesonephric (or Mullerian) ducts form as an invagination of the coelomic epithelium on the lateral side of the gonadal ridge. At the end of the eighth week, there are thus two sets of ducts. In males, with the presence of testosterone, the Wolffian ducts and the mesonephric tubules are maintained. The Wolffian ducts eventually become efferent ductules and the vas deferens. The Mullerian ducts degenerate in the presence of AMH. In females, in the absence of testosterone, the mesonephric tubules and Wolffian ducts degenerate. In the absence of AMH, the Mullerian ducts are retained. These eventually become the uterus, oviducts, and two-thirds of the vagina. These organs are missing in males with androgen insensitivity, resulting in a shortened vagina in an otherwise apparently female external anatomy. A similar condition can arise from hypoplasia of the Leydig cells caused by a failure of pituitary hormones.
Developmental homology between the external sex organs (Keaton R355).
If the ovaries are removed, before the ducts differentiate, Wolffian ducts degenerate, but the Mullerian ducts are retained. When the testes are removed, again the Wolffian ducts degenerate, and the Mullerian ducts are retained. This is due to the absence of testosterone and AMH. Again, the female pathway appears to be the default.
Human Reproductive Tracts (Keaton R355)
Testosterone is converted to dihydrotestosterone (DHT) by the enzyme 5-alpha reductase during fetal life. DHT is the active hormonal key to the differentiation of external genitalia into a penis and scrotum. It also induces prostate formation. If the enzyme is mutated so that it is completely nonfunctional, an apparently female pattern of external genitalia develops. 'With undescended testes and a penis so short and stubby it resembles an oversized clitoris'. However at puberty something very unusual happens. The flush of androgen appears to trigger a late onset maturation of male penis and scrotum. Where these mutations are concentrated in the Dominican Republic, such people are called guevedoces meaning "eggs (testes) at 12." The girl has become a man, who now dates girls in a natural 'sex change'. (Blum R66 34). They are generally raised as girls with a girl's name until puberty when they get a boy's name. They generally feel they are boys and despite being brought up as girls, almost all in a study showed strong heterosexual preferences.
Guevedoces in transition
Research has also come upon a second direct route from cholesterol to DHT that appears to be essential for normal development of the male genitalia (The American Journal of Human Genetics, DOI: 10.1016/j.ajhg.2011.06.009).
In the fifth week, cloacal folds develop on both sides of the cloacal membrane (which breaks down to form the anus). Elongation of the cloacal folds and fusion with the urorectal folds gives rise to the labioscrotal folds, urogenital folds, and genital tubercle. In the male, the urogenital folds becomes the penis shaft, the labioscrotal folds become the scrotum, and the genital tubercle becomes the head of the penis. At the end of the third month, urogenital folds on the caudal end of the cloacal folds fuse to form the penile urethra. In the female, the urogenital folds become the labia minora, the labioscrotal folds the labia majora, and the genital tubercle the clitoris.
Homologous origins of the penis and clitoris: The external sex organs in a human embryo begin a generic androgynous state. In the 12-week old fetus it is difficult to distinguish male penis from female clitoris. (The Human Body BBC)
The sex organs are thus intimately entwined, both homologous in many parts such as the indifferent gonad, the penis and clitoris, labia and scrotum, and complimentary in others such as the Mullerian and Wolffian ducts, cortex and medulla which in turn give rise to inverted paradigms, the testes full of internal tubing and the ovaries externally ovulating to be enveloped by Fallopian motions of the fully developed Mullerian duct. This is an internal inversion of the sex organs as profound as the inversion of the sex organs in the fully developed penis and vagina, despite their homologous origin.
In a fascinating paper in Nature looking for genes, or regulatory sequences, which have been deleted in humans that may make us different from other animals, the authors report that one of the prominent genes essential to the majority of mammals which has been deleted in humans is the androgen regulator for penile spines. Penile spines which are accompanied by basal nerve fibres may have many functions including increasing male sexual sensitivity, reducing the length of female estrus, removing competitors sperm and many others. We have also lost the muscle-controlled baculum or penis bone that is used in most mammals to ensure the male has an erect penis. In the paper and its follow up comments the authors point out that the loss correlates with the evolution of pair bonding in humans and that chimps and bonobos which do have neuro-sensitive spines have a very short copulation time like 5 to 7 seconds. Hardly enough to keep a woman happy with her hubby. So it looks like we have lost our penile spines so that we can make love in a way which makes the women climax and gives both men and women a deep sense of bonding and to give a genuine indicator of reproductive fitness on the aprt of the male. One might also conclude that this selection of male characteristics has been driven by women's preference for males who can really go the mile to make them feel fulfilled and bonded with, suggesting that female choice has driven human sexuality throughout our emergence. So much for the Flintstones Man the Hunter view of sex and the patriarchal notion that women should be obedient and servile! The bumps or papules that can appear on the glans of some human men are not neuro-sensitive spines, and have a different origin and basis. (McLean CY et. al. 2011 Human-specific loss of regulatory DNA and the evolution of human-specific traits. Nature 471/7337 216-9).
Two views of the G-spot, associated Skeine's glands (female equivalent of the prostate) and erectile tissue, which in some women can result in ejaculates of up to 2 cc of fluid containing prostate specific antigen (New Scientist 6 Jul 2002, 'Everything you always wanted to know about female ejaculation' 28 May 2009). The larger amounts of clear fluid women sometimes squirt are urine.
Associated with each sex are differing and complementary types of orgasm. A man has a well defined pattern of spontaneous or stimulated excitement, erection, plateau, and ejaculation necessary to the act of fertilization. A female has a more complex and diverse sexual response. Firstly the female body and tactile sense is very sensually endowed, (e.g. breasts, buttocks and sexual areas), and secondly female orgasm serves a more mysterious function which is not directly connected with fertilization, but appears to be an evolutionary adaption of great significance to the female (p 86). Sexual excitation happens in more than one area. The vagina and/or cervix is a claimed source of major convulsive muscular orgasms which can become multiple, repeated or continual. It is these that some people suggest could cause deferential upsuck of sperm from the desired partner although confirmation is elusive. At another extreme, the clitoris although small carries up to twice as many merge endings as the entire penis. It is thus sensitive sexually in a way not dissimilar to the fovea of the retina - a very focussed organ with knife edge energetics and since it is homologous with the male penis is the focus of the orgasmic climax and release.
Dr Helen O'Connell has pioneered the understanding that there is much more to the clitoris than just the glans at the tip, containing in 'inverted form all the structures of the penis: "There's nothing quite like the shape of a clitoris, the glans are dense with nerve endings and receptors - all the vibration and sensation is there. The bulk of it is shaped like a pyramid. Its base forms the external genitalia or vulva; its triangular 'walls' are wrapped around the urine-carrying tube known as the urethra and the vagina. When aroused, the whole structure becomes engorged" (Mascall S 2006 Time for rethink on the clitoris BBC 11 Jun).
Somewhere in between the bladder and the vagina is claimed to be the G-spot, which includes Skein's glands, the female equivalent of the prostate, and an area of erectile tissue on the front of the vagina which uses nitric oxide in the same way as the penis. There is continuing debate about whether the G-spot is a real anatomical manifestation, or more of a cultural fashion in which the capacity for vaginal orgasm is focused on a mythical construction which gives it cultural acceptability to be discussed in the media, unlike the undeserved swearword connotations of the C-word. It has also been associated with the phenomenon of female ejaculation (Moalem S 2009 Everything you always wanted to know about female ejaculation (but were afraid to ask) New Scientist 28 May). Nevertheless, despite doubts of some researchers, concerns about the negative effects of pursuing an illusory agenda of G-spot augmentation involving cometic surgery, and the anatomical rejection of it outright by others (doi: 10.1002/ca.22471), some commentators of both sexes still insist the phenomenon is real in terms of sexual pleasure .
The breasts are also directly sexual. Female orgasm is not linked directly to ejaculation, although some women do ejaculate up to 2 cc of fluid similar to seminal fluid containing prostate-specific antigen. Although in males ejaculations causes a refractory period so, and strong clitoral orgasms may result in a short period of quiescence, female orgasm is much more like surfing the great wave and can result in repeated climaxes.
Brain regions lit up by se-stimulation in three areas: (Linda Geddes Sex on the brain: What turns women on, mapped out New Scientist 6 Aug 2011, Journal of Sexual Medicine, DOI: 10.1111/j.1743-6109.2011.02388.x)
A 2011 study has finally shown the areas that light up under fMRI when women self stimulate either their inner vagina, the clitoris or the nipples, supporting the case that each of these areas in females have their own erogenous capacity and that vaginal orgasm is not simply clitoral orgasm. Furthermore nipple stimulation lit up genital areas supporting the erotic sensitivity of the nipples in females.
Some people have suggested that female orgasm and with it the clitoris is a kind of 'spandrel' an evolutionary feature of no selective value simply eixsting because of the developmental homology between male and female sex organs and the need for males to ejaculate to fertilize females - along the same lines that male nipples are a non-functional relic. This argument claims a degree of support in the sizeable fraction of women who report that they have few or no orgasms when making love. This leads to an idea that female orgasm is evolutionarily driven by male orgasm. To test this hypothesis researchers investigated 5000 identical twins and non-identical twins of opposite sex. The questionnaire asked about the time to orgasm in men and the frequency and ease of orgasm in women. While the identical twins had correlated orgasmic dynamics, there was no increased correlation between those of male and female non-identical twins over unrelated males and females. This suggests female orgasm, while it may have a common developmental basis with male orgasm, is being driven by independent evolutionary forces and that female orgasm has an evolutionary role in human emergence (Animal Behaviour, DOI: 10.1016/j.anbehav.2011.08.002).
Geoffrey Miller (The Mating Mind" 2000 Random House) notes that the penis and vagina are in an evolutionary race, with the clitoris coquettishly evolving to demand more and more pleasure to be 'satisfied' and the penis evolving to try to deliver it in the paradigm of evolution by female sexual selection. The clitoris is thus not attuned to the monotony of monogamy so much as the thrill of the chase and the novelty and abandon of falling in love.
Richard Prum in "The Evolution of Pleasure" (Doubleday 2017) has made an eloquent case for the diversity of evolutionary processes from the courtship plumage and elaborate songs and reproductive routine of birds, through to human sexual anatomy and sexual pleasure being an aesthetic product of mutual mate selection. He suggests the clitoris and female orgasm is neither an evolutionary "spandrel" or relic simply derived from the deveopmental homology of female and male sexual development, nor is it a directly adaptice process of natural selection as suggested by the "upsuck hypothesis", both of which have manifest flaws, but is rather a product of females finding sex pleasurable and in turn seeking sexual liasons which promote behavior which reinfoces sexual pleasure from their partners, thereby driving evolutionary enhancement of sexual pleasure in both sexes. This perspective transcends the arms race between the penis and clitoris cited by Geoffrey MIller, which also conveys a broadly positive view of sexual selection promoting mutually beneficial relationships between the human sexes.
Sarah Hrdy (R330) suggests that female sexual ecstasy is to aid the survival of offspring and the degree of resourcing from males, but not exclusively to one. In most species, including humans, female sexuality acts to both to seek 'choice' genes and more disquietingly for the males, to reduce paternity certainty. There are extremely valid reasons for this. By inviting 'many possible fathers', females significantly reduce the risk of infanticide by any given male and at the same time encourage one or more of them to act in a broadly supportive manner - thus reducing paternity certainty. In socially monogamous species, females invest both in a resourceful partner and an insurance in good genes in some 'time on the side'. Human society is no exception. In DNA tests, over 10% of children in many Western societies are not sired by their ostensible father. Pair bonding has increased paternity uncertainty by comparison with chimps, from around 50% to about 80%, although in some matrilineal societies it could be lower than 33%, the point where investing in the children of your sister is more worthwhile than those of your partner, which is a common motif in such societies.
"The key biological fact is that boys and girls have different genitalia, and it is this biological difference that leads adults to interact differently with different babies whom we conveniently color-code in pink or blue to make it unnecessary to go peering into their diapers for information about gender."
Pinker (R544 345) notes that the pink-and-blue theory is becoming less and less credible, listing a dozen kinds of evidence that the difference between men and women is more than genitalia-deep.
In all human cultures, men and women are seen as having different natures, divide their labor by sex, with more responsibility for childrearing by women and more control of the public and political realms by men. Men are more aggressive, more prone to stealing, more prone to lethal violence and war, and more likely to woo, seduce, and trade favors for sex. And in all cultures one finds rape, as well as proscriptions against rape .
Many of the psychological differences between the sexes are exactly what an evolutionary biologist who knew only their sexual differences would predict, in particular the greater parental investment of women and the greater mating investment of men. Other physical traits of men, such as later puberty, greater adult strength, and shorter lives, also indicate a history of selection for high-stakes competition, male polygyny.
Many of the sex differences are found widely in other primates, indeed, throughout the mammalian class. Including the above sex differences and the male having a greater range, reflected in men's advantage in using mental maps and performing 3-D mental rotation may not be a coincidence.
Geneticists have found that the diversity of the mitochondrial DNA (which men and women inherit from their mothers) is far greater than the diversity of the DNA in Y chromosomes (which men inherit from their fathers), implying men have had greater variation in their reproductive success than women.
The human body contains a mechanism that causes the brains of boys and the brains of girls to diverge during development. The Y chromosome triggers the growth of testes in a male fetus, which secrete androgens, the characteristically male hormones (including testosterone). Estrogens, the characteristically female sex hormones, also affect the brain throughout life. Receptors for the sex hormones are found in many parts of the brain, as well as in the cerebral cortex.
The brains of men differ visibly from the brains of women in several ways, size (men), proportion of grey matter (women), cerebral commisures and hypothalamic nuclei involved in arousal.
Variation of testosterone levels among different men, and in the same man in different seasons or at different times of day, correlates with libido, self-confidence, and the drive for dominance.
Women's cognitive strengths and weaknesses vary with the phase of their menstrual cycle.
Androgens have permanent effects on the developing brain, not just transient effects on the adult brain. Girls with congenital adrenal hyperplasia, though their hormone levels are brought to normal soon after birth, grow into tomboys.
Attempts to surgically feminize boys with a damaged penis such as that of John Money, below, fail and the individuals though reared as a girl insist on identifying as males and even marrying.
The evidence from girls with Turner's syndrome indicates that the X-chromosomes are differently imprinted from fathers and mothers in ways which have long-lasting effects in adult life.
Contrary to popular belief, parents in contemporary America do not treat their sons and daughters very differently. Nor do differences between boys and girls depend on their observing masculine behavior in their fathers and feminine behavior in their mothers, even when they have two 'mothers' and no father.
Two key predictions of the social construction theory - that boys treated as girls will grow up with girls' minds, and that differences between boys and girls can be traced to differences in how their parents treat them - have gone down in flames.
As to the first Pinker illustrates a poignant example of attempted sex reversal at birth.
"The ultimate fantasy experiment to separate biology from socialization would be to take a baby boy, give him a sex-change operation, and have his parents raise him as a girl and other people treat him as one. If gender is socially constructed, the child should have the mind of a normal girl; if it depends on prenatal hormones, the child should feel like a boy trapped in a girl's body. Remarkably, the experiment has been done in real life-not out of scientific curiosity, of course, but as a result of disease and accidents. One study looked at twenty-five boys who were born without a penis (a birth defect known as cloacal exstrophy) and who were then castrated and raised as girls. All of them showed male patterns of rough-and tumble play and had typically male attitudes and interests. More than half of them spontaneously declared they were boys, one when he was just five years old. .In a famous case study, an eight-month-old boy lost his penis in a botched circumcision (not by a mohel, I was relieved to learn, but by a bungling doctor). His parents consulted the famous sex researcher John Money, who had maintained that "Nature is a political strategy of those committed to maintaining the status quo of sex differences." He advised them to let the doctors castrate the baby and build him an artificial vaginal and they raised him as a girl without telling him what had happened. I learned about the case as an undergraduate in the 1970s, when it was offered as proof that babies are born neuter and acquire a gender from the way they are raised. A New York Times article from the era reported that Brenda (née Bruce) "has been sailing contentedly through childhood as a genuine girl." The facts were suppressed until 1997, when it was revealed that from a young age Brenda felt she was a boy trapped in a girl's body and gender role. She ripped off frilly dresses, rejected dolls in favor of guns, preferred to play with boys, and even insisted on urinating standing up. At fourteen she was so miserable that she decided either to live her life as a mate or to end it, and her father finally told her the truth. She underwent a new set of operations, assumed a male identity, and today is happily married to a woman".
In 2004 David Reimer committed suicide after the departure of his wife and the suicide of his twin brother, cementing this misadventure in history:
As to the second prediction, Pinker quotes the following summary:
"A recent assessment of 172 studies involving 28,000 children found that boys and girls [in the US] are given similar amounts of encouragement, warmth, nurturance, restrictiveness, discipline, and clarity of communication. The only substantial difference was that about two-thirds of the boys were discouraged from playing with dolls, especially by their fathers, out of a fear that they would become gay. (Boys who prefer girls' toys often do turn out gay, but forbidding them the toys does not change the outcome.) Nor do differences between boys and girls depend on their observing masculine behavior in their fathers and feminine behavior in their mothers. When Hunter has two mommies, he acts just as much like a boy as if he had a mommy and a daddy."
Anne Campbell (R103) notes that many sex differences are universal, extend to primates and the developmental onset of behavioural differences in young children predates the ability to name the sex of others, to name one's own sex, to appreciate gender constancy and knowledge of gender stereotypes.g Site