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Mother's little helper New Scientist 24 Feb 2001

Viruses may cause disease, but would we be here without them?

GENES from ancient viruses may be an essential component of mammalian reproduction, helping the placenta to establish itself in the womb, suggest biologists in California. Their research supports the idea that viruses' talents for ferrying DNA and genes into cells has played a key role in the evolution of humans cells as well as those of other higher organisms.

"Viruses are known primarily for causing disease," said Luis Villarreal of the University of California at Irvine at the meeting. "But I think that's a bum rap- 11

While many of the viruses that cause disease survive for only a short time in the body during a brief burst of infection, other less virulent varieties stay around for a long time, causing no symptoms and making it easy for the virus to evolve along with its host. One group of viruses called endogenous retroviruses, or ERVS, has dev-. eloped an especially intimate relationship with mammalian cells.

These ERVs are the remains of viruses that worked their way into mammalian chromosomes a long time ago. Some biolo- gists, including Villarreal, have suggested that ERV genes may help the placenta function properly, because they are switched on at high levels in this tissue (New Scientist, 12 June 1999, p 26). To test this idea, Villarreal used another virus that suppresses ERV genes in mouse cells. When he and his colleagues put this virus into the cells of an embryo, normal mice were born. But when they put the virus into cells that form the placenta, these cells would not implant in the mouse uterus, derailing the reproductive process right at the start. This suggests that the ERV genes are either essential for implantation itself or for preventing the mother's immune system rejecting the fetus. Villarreal thinks that a viral transport system may also explain why vertebrates seem to have inherited more than a hun- dred genes directly from bacteria. Viruses could easily have shuttled those genes into our cells, he says. The most recent work from his lab suggests that even the system of enzymes that copies our DNA may have come from a virus Uournal of Virology, vol 74, p 7079). Villarreal points out that viruses have the ability to change rapidly. So when it comes to inventing complex new biology, viruses may provide higher cells with a quick fix. Even ERVS, which are now permanent fixtures in mammalian chromo- somes, evolve Viuch faster than the surrounding genes. "Viruses can be a great creative force in the evolution of their host," says Villarreal. Philip Cohen

NZ Herald 5th June 2001

One in five parents can now expect a multiple birth as a result of IVF.

Frequent Human Genomic DNA Translocation Driven by LINE-1 Retrotransposition

Oxana K. Pickeral, Wojciech Makatowski, Mark S. Boguski, and jef D. Boeke

Genome Research 10:411-415 2000 www.genome.org

Human L1 retrotransposons can produce DNA transduction events in which unique DNA segments downstream of L1 elements are mobilized as part of aberrant retrotransposition events. That L1s are capable of carrying out such a reaction in tissue culture cells was elegantly demonstrated. Using bioinformatic approaclies to analyze the structures of Li1 element target site duplications flanking sequence features, we provide evidence suggesting that -15% of full-length L1 elements bear evidence of flanking DNA segment transduction. Extrapolating these findings to the 600,000 copies of L1 in the genome, we predict that tihe amount of DNA transduced by L1 represents -1% of the genome, a fraction comparable with that occupied by exons.

Exon Shuffling by L1 Retrotransposition

John V. Moran, Ralph J. DeBerardinis, Haig H. Kazazian jr.

Science 283:1530 5 Mar 1999 www.sciencemag.org

Long interspersed nuclear elements (LINE-ls or Lls) are the most abundant retrotransposons in the human genome, and they serve as major sources of reverse transcriptase activity. Engineered Lls retrotranspose at high frequency in cultured human cel[s. Here it is shown that Lls insert into transcribed genes and retrotranspose sequences derived from their 3' flanks to new genomic locations. Thus, retrotransposition-competent Lls provide a vehicle to mob!Llze non-Ll sequences, such as exons or promoters, into existing genes and may represent a general mechanism for the evolution of new genes.

The impact of L1 retrotransposons on the human genome

Haig H. Kazazian, Jr & John V. Moran
Nature Genetics 19:19 19 May 1998

The'master' human mobile element, the Ll retrotransposon, has come of age as a biological entity. Knowledge of how it retrotransposes in vivo, how its proteins act to retrotranspose other poly A elements and the extent of its role in shaping the human genome should emerge rapidly over the next few years. We review the impact of retrotransposons and how new insight is likely to lead to important practical applications for these intriguing mobile elements.

Evolutionary biologists hypothesize that the earliest life forms contained self-replicating RNA genomes. The advent of poly- merases that make DNA copies of RNA teniplates allowed the conversion of information from unstable ribose-based polymers to more stable deoxyribose-based polymers through the process of reverse transcription. In this way, reverse transcription appears to have played a pivotal role in the formation of the first DNA genomes. Although reverse transcription has been ongoing during genome evolution, its impact is only just being realized. lt is now apparent that reiterative rounds of reverse transcription served to expand both the size and complexity of the human genome. The chief perpetrators in this process seem to have been a small number of autonomously mobile DNA sequences known as long interspersed nuclear elements (LINEs or L1s). At least one-quarter of the human genome consists of sequences which either are derived directly from retrotransposition-competent L1 s or likely resulted from the promiscuous action of L1 encoded reverse transcriptase on other transcripts, including Alu elements and cellular mRNAs. Although other autonomous mobile sequences likely exist in the human genome, their coiitribution to its total mass is far less dramatic than that of L1 elements.

Does SINE evolution preclude Alu function?

Carl W. Schmid*
Section of Molecular and Cellular Biology and Department of Chemistry, University of California at Davis, Davis, CA 95616, USA

Nucleic Acids Research 26:4541-4550 1998
Received May 6, 1998; Revised and Accepted July 1, 1998

ABSTRACT

The evolution, mobility and deleterious genetic effects of human Alus are fairly well understood. The complexity of regulated transcriptional expression of Alus is becoming apparent and insight Into the mechanism of retrotrans- position is emerging. Unresolved questions concern why mobile, highly repetitive short interspersed elements (SINES) have been tolerated throughout evolution and why and how families of such sequences are periodically replaced. Either certain SINEs are more successful genomic parasites or positive selection drives their relative success and genomic maintenance. A complete understanding of the evolutionary dynamics and significance of SINEs requires determining whether or not they have a function(s). Recent evidence suggests two possibilities, one concerning DNA and the other RNA. Dispersed Alus exhibit remarkable tissue-specific differences in the level of their 5-methyl- cytosine content. Differences in Alu methylation in the male and female germlines suggest that Alu DNA may be involved in either the unique chromatin organization of sperm or signaling events in the early embryo. Alu RNA is increased by cellular insults and stimulates protein synthesis by inhibiting PKR, the eIF2 kinase that is regulated by double-stranded RNA. PKR serves other roles potentially linking Alu RNA to a variety of vital cell functions. Since Alus have appeared only recently within the primate lineage, this proposal provokes the challenging question of how Alu RNA could have possibly assumed a significant role in cell physiology.

Telomerase Catalytic Subunit Homologs from Fission Yeast and Human

Toru M. Nakamura, Gregg B. Morin, Karen B. Chapman, Scott L. Weinrich, William H. Andrews, Joachim Lingner,* Calvin B. Harley, Thomas R. Cecht

Science 277:955 15 Aug 1997

Catalytic protein subunits of telomerase from the ciliate Euplotes aediculatus and the yeast Saccharomyces cerevisiae contain reverse transcriptase motifs. Here the homol- ogous genes from the fission yeast Schizosaccharomyces pombe and human are identified. Disruption of the S. pombe gene resulted in telomere shortening and senescence, and expression of MRNA from the human gene correlated with telomerase activity in cell lines. Sequence comparisons placed the telomerase proteins in the reverse transcriptase family but revealed hallmarks that distinguish them from retroviral and retrotransposon relatives. Thus, the proposed telomerase catalytic subunits are phylogenetically conserved and represent a deep branch in the evolution of reverse transcriptases.

Developmental and Cell-type specificity of LINE-1 Expression in Mouse Testis: Implications for Transposition

Dan Branciforte and Sandra Martin

Molecular and Cellular Biology Apr 1994 14/4:2584-92

The L1 family constitutes roughly 10% of the mammalian genome. Its abundance is due to duplicative transposition via and RNSA intermediate, L1 encoded proteins and reverse transcription. Although in principle trnsposition may occur in any cell type, exprssion andtransposition of a functional element in the germ line are necessary to explain the evolutionary genentic of L1. We have found differential expression of L1 protein and RNA in germ and somatic cells of the mouse testis during development. Od particular interest is the co-expression of full-lenght sense-strand L1 RNA and L1-encoded protein in leptotene and zygotene spermatocytes at postnatalday 14 of developmen. Expression inmeiotic prophase precedes the strand breakage that occurs during chromosomal recombination this offers an avenue for L1 insertion into new locations in a cell type that ensure L1 propagation in future generations.

Tightly regulated developmentally specific expression of the first open reading frame from LINE-1 during mouse embryogenesis

Stephanie Trelogan and Sandra Martin

Proc Nat Acad Sci 92:1520 1995

Line-1 L1 has achieved its status as a middle repetitive DNA family in mammalian genomes by duplicative transposition. Although transposition may occur in any cell type, expfression and transposition of a full length functional element in the germ line are necessary for evolutionarily significant propagation of L1. An immuno-chemical analysis of adult mouse ovaries and mouse postimplantation embryos revealed expression of L1 open reading frame 1 in the germ line as well as in steroidogenic tissues. These results demonstrate that L1 expression is controlled by a tightly regulated temporal and spatial program of events during developments and imply that multiple loci of L1 in the mouse genome are active for expression [since expression of different types of transcript occurred under differing contexts].

Free for all NS 17 Feb 2001

Who will be the winners and losers in the genome game?

SO we have it at last, or most of it anyway. Laid out in Nature and Science this week are two versions of the human genome, replete with 30,000 or so genes. For now, these charts are symbolic rather than informative. Here, for all to see, is the basic information needed to create a human. A few years from now schoolchildren will be as familiar with annotated versions of the genome as we are with the periodic table of elements.

As if to stress that we are at the start of an era, the genome has given us plenty of mysteries to solve. Why do we have so few genes? And if we share so many genes with our evolutionary cousins, what really sets us apart? How did we get a gene for depression from a bacterium? There are medical opportunities too. Existing drugs home in on about 480 targets in the body. The genome will bring tens of thousands more for pharmacologists to study. The prospects of it all are mind-blowing. Yet much of the attention on the genome this week has focused on a more prosaic issue-the dispute between scientists working within the publicly funded ' Human Genome Project and Celera Genomics, the American company that makes its money selling genetic information to subscribers. The HGP scientists published their results in Nature rather than alongside Celera's findings in Science because the company has restricted what researchers can do with its information.

Academic scientists can download small parts of Celera's genome, but only under strict conditions: their intentions must not be commercial, and they must not try to supplement the company's information or redistribute it. There are extra rules for academics who want to see Celera's entire genome, and tighter restrictions still on researchers working in industry. Despite Celera's protestations, this puts academic research at risk. Academic freedom isn't an empty slogan: it's essential if we are to improve our understanding of the world. It's through open publication and discussion with colleagues that researchers develop and hone ideas. Now, some will constantly have to consider whether sharing information will break the terms of their agreement with the company. Restricting researchers in this way may be good for Celera's business, but it does nothing to foster open discussion. Science has been criticised for colluding with Celera. Its defence is that if it had not agreed to the company's terms, Celera's version of the genome would have remained secret to all but its subscribers, and it's true that we can now compare the public and private versions of the genome (see p 4). But Science has set a horrendous precedent. What will the restrictions be on access to other important genomes: mouse, chimp, wheat and the rest? How will a mouse genome researcher know what information can be shared with an expert on human genomics or a rice researcher, without breaching confidentiality? We could be heading for a legal minefield.

And then there is the question of applying information from a genome that is held in private hands. Last month, for example, two companies announced completion of the rice genome, one of the most important for the developing world. That information will not be made public. The companies are limiting access to researchers and want first refusal on patenting any inventions that come from collaborations. Companies that own such information have a powerful monopoly that governments-and other companies-must challenge. Food and healthcare will become increasingly costly if these genomes stay in the hands of individual companies. The human genome has been described as a resource for everyone-just like the periodic table. The same must be true of other genomes that could bring big benefits, such as those from the primates, rice and other major crops. To ensure that everyone benefits from them, more collaborative sequencing ventures must be set up, funded by industry and governments. That goes too for sequencing human proteins, which Celera is now doing. There is already a model for such ventures. The SNP Consortium, which is mapping single DNA base changes within the genome, has both academic and commercial partners. The same is true of the Mouse Sequencing Consortium, set up last year. Such projects need to be widened and supported. If you doubt this, think about what would have happened if the Human Genome Project had been shut down, as some suggested when Celera began its sequencing effort in 1998. Celera would now have absolute power over the human genome. Ask yourself whether the company would now be offering anyone free access to its data.

Less is more Our genes are subtler than we ever guessed NS 17 Feb 2001 6

ITS not how many genes you've got, it's what you do with them that counts. 'rhat's one of the key revelations about the human genome announced this week.

The first look at our genetic panorania, the result of a massive effort by both public and private groups, fills more than 100 pages in Nature and Science.. "It's the first time we've stood back to look at the landscape of our own human biology," says Francis Collins, head of genome research at the National Institutes of Health near Washington DC. "It's a milestone of the highest order."

The nuggets that scientists are eager to find in this new territory are our genes, regions of DNA that are copied to make RNA templates for producing proteins. The most surprising revelation of the two reports is that our genes are rarer treasures than nearly anyone guessed. Ten years ago, most researchers predicted that our cells harboured about 100,000 genes.

But the two independent genome groups, using different strategies to sift through the sequence, discovered a mere 27,000 to 40,000 human genes. The small number of genes has tremendous implications," says Craig Venter of Celera. "The fruit fly genome has only 13,000 or so genes, and we're so much larger and smarter that we thought we should have a lot more genes."

Also humbling is the discovery of 223 genes that our ancestors appear to have acquired directly from bacteria. This must have occurred when wayward bacterial DNA became integrated into the DNA inside the sperm or egg of a distant vertebrate. Many of these genes appear to play a crucial tole in our biology.

About 22 per cent of vertebrate genes aren't found in worms or flies. In fact, vertebrates can lay claim to a certain amount of innovation when it comes to protein design, such as the invention of new structural elements that many proteins share. Our proteins also tend to have more coniplex arrangements of these elements.

But the secret of out complexity may lie not in the numbers of our genes, but how we use them, says Richard Myers of Stanford University. "A fine sports car and a junker may have the same number of pieces," he says. "The difference is tile quality of parts and the sophistication with which we put them together."

For exainple, genes usually come in segments. By "splicing out" some segments of the RNA templates for proteins, or using one segment rather than another, a single gene can yield many different proteins. The same gene can be used to make one protein in, say, muscle and another in the brain. Up to 60 per cent of our genes produce these "splice variants".

Another key finding from both public and private genome efforts is that many human "transcription factors" are unique and a cut above those of the fly and the worm. Transcription factors and other reg- ulatory proteins dictate which genes are switched on at vital stages of development, as embryos form and organs take shape. lt is they that orchestrate such amazing complexity from so few genes.

Venter thinks all higher vertebrates have roughly the same genes. What's important is when they are switched on and off, he says. "We have the same number of genes as cats and dogs, but differently regulated."

If we don't have as many genes as some hoped, no one can be disappointed by our vast collection of clutter. It turns out that the coding regions of genes fill a scant 1.5 per cent of our genome, while repetitive copies of "jumping genes", or transposons, claim about half our DNA real estate.

While transposons appear to be just junk, they may have helped us to evolve. Most are now inactive, but when they first arrived they were able to hop from place to place in out genome. This helped to rearrange the I)NA in chromosomes, creating new genes.

Indeed, one newly discovered transposon, MER85, appears to contain an active gene that is switched on in the brains of fetuses. Our chromosomes also turn out to be remarkably variable. Genetic oases are often surrounded by vast geneless deserts. And Rogier Versteeg at the University of Amsterdam in the Netherlands and his colleagues report that highly active genes are often grouped together in what he calls regions of increased gene expression, or RIDGES, where the transcription of genes zooms along at 200 times the rate found elsewhere. "These are like factories just churning out RNA," says Versteeg. Another property that is unevenly distributed through the genome is recombination -
the exchange of DNA segments between pairs of chromosomes during the formation of sperm and eggs. James Weber of the Marshfield Medical Research Foundation in Wisconsin and his colleagues found that there are dead spots for recombination, as well as "jungles", where chromosomes switch pieces 100 times as often.

Nothing that has been found so far in the DNA sequence predicts where recombination is likely to occur. Another twist is that the preferred sites of recombination differ substantially between men and women.

A final enigma is how cavalier we are about where we keep genes. Most biologists had bet that the ends of chromosomes, or telomeres, would be gene-free zones because telomeres shorten throughout our lifetime. But when Robert Moyzis of the University of California, Irvine, searched for genes near telomeres, he found 500 candidates. Putting precious genes in telomeres is like building homes on an earthquake zone. "I frankly can't come up with a good reason to do that," he says. Intriguingly, this suggests that some aspects of ageing could be caused by genetic changes triggered by telomere shrinkage. The work is only just starting. "The important thing to realise is that some of us are already using this sequence every day to solve problems in biology," Myers adds. 'And people will be doing that for decades, if not millennia." Philip Cohen and Andy Coghlan

Privatising your proteins
A trio of companies plans to go way beyond the human genome project NS 14 Apr 2001 5

WITH the ink barely dry on the first draft of the human genome, three companies want to go one stage further. They have announced a $185 million plan to map the identity and function of every protein in the human body-the human 'proteome'.

'It's our goal to complete the human proteome map in three years,' says Peter Meldrum, president of Myriad Genetics in Salt Lake City, Utah, the company leading the project. Hitachi of Tokyo will provide computing hardware for the task, while software will come from Oracle, the Californian computer giant. There are worries about a private consortium controlling so much vital information. Sudhir Saharabudhe, the research chief at Myriad, says the company's database of interactions will only be available on subscription, although there will be a cheaper rate for academics. But the proteome is much too open-ended for one company to bag the whole lot, says Ewan Birney of the European Bioinformatics Institute in Cambridge. "As long as the data gets out there in the,,,end, that's what's important," says Ian Tomlinson of the Laboratory of Molecular Biology in Cambridge, a founder member of the Human Proteome Organization, an alliance of institutes and companies that hopes to identify all human proteins. "The aim is to get drugs and cure people. So in the end, companies have to be involved." There are also doubts about whether the feat can be pulled off technologically. Tackling the proteome is much harder than the genome. Many genes code for multiple variants of the same protein. And many proteins are modified by adding sugar molecules, which play a big role in determining where proteins go and what they do. What's more, different proteins can join together to carry out completely new functions. Myriad is confident that a new subsidiary, Myriad Proteomics, has the technology to crack these mysteries. lt will be relying on two techniques. The first, 'ProNet", is an automated version of the so-called yeast twohybrid system. A yeast cell engineered to produce a human protein is mated with asecond yeast cell that makes a different human protein. The cells turn blue if the two human proteins interact. The second technique, "ProSpec" enables the company to extract interacting proteins from human cells and identify them using mass spectrometry.

Last year, however, Stan Fields of Washington University in Seattle showed that many interactions identified by the yeast system don't occur naturally. 'This means there could be lots of red herrings," says Tomlinson. Saharabudhe says the company has found a way to screen out all but 1 per cent of these false positives. But he admits that the yeast system is not good for analysing human proteins that have sugars added, or for proteins that straddle cell membranes. Yet such proteins carry out many vital functions. Andy Coghtan