--- !signs/object:Article attributes: title: "When Genes Go Retro" source: The New York Times author: summary: "
DNA
©Alfred Pasieka
DNA
Pssst! I'm going on a tour of the genome - want to come? I'm going to walk among the coiled spirals of DNA, and ponder the different histories of the different segments. For one of the most remarkable discoveries of recent decades is that genomes are not static, fixed entities that evolve as one; instead, they are highly dynamic. From one generation to the next, stretches of DNA may appear or disappear, or move from one location to another. From time to time, entire new genes appear and become established, thus expanding the organisms' genetic repertoire." text: "But where do new genes come from? It turns out that they can come from a wide variety of sources (I have written about some of them before). This week, I want to consider a particularly intriguing type of new gene: the retrogene. Retrogenes have been an important source of new genes in a number of species, including us humans. The story of the retrogene is the story of three molecules: DNA, RNA and something called reverse transcriptase. If they were characters in a cartoon, they'd be the celebrity, the drudge and the joker. And, for reasons I shall reveal in a moment, if the cartoon had a title, it would be "X-odus." The celebrity, naturally enough, is DNA. And what a celebrity it is! Its double helix structure is an icon of our times. I've seen double helix coins, stamps, necklaces, ear-rings and doorhandles; I've even spotted it in a modern stained glass window. Yet like many celebrities, DNA mostly sits about looking pretty. Much of the grunt work of running the cell is done by its less famous cousin, RNA. RNA is chemically similar to DNA, but where DNA is usually double-stranded - hence, the double helix - RNA is usually single-stranded. As a result, its physical appearance is not generally considered so beautiful as DNA's, and it is far from being an icon. (It has, however, once appeared on a necktie. In the early days of molecular biology, a theoretical physicist called George Gamow, better known for his work on the Big Bang, founded a biology discussion club called the RNA Tie Club. Its members included Jim Watson and Francis Crick, co-discoverers of the structure of DNA.) RNA has many roles in the cell, and more keep being discovered. But the one that's relevant to this story is its role as a messenger. Messenger RNA is a genetic intermediary in the process of making proteins. To recap: a gene is a stretch of DNA that contains the instructions to make a protein. In order to make a given protein, the relevant stretch of DNA is first copied into RNA. The cell then makes the protein from this RNA template - the messenger. In the early days of molecular biology, the assumption was that DNA could be copied into RNA, but not the reverse. But then, reverse transcriptase was discovered. This mischief-making molecule does what no one expected: it copies RNA into DNA. Most of the time, this is for a nefarious purpose. Many viruses - among them, HIV - store their genes not as DNA, but as RNA, and use reverse transcriptase to copy themselves into DNA. They then insert themselves into the genomes of their hosts, where they may remain dormant for some period of time. Such viruses are known as retroviruses. Reverse transcriptase makes trouble in other ways as well. The genomes of most organisms are littered with entities known as retroelements. These are a type of genetic parasite - stretches of DNA that (usually) do nothing useful for the cell, and exist simply to make more copies of themselves. (There are many different kinds of genetic parasite: as much as half of the DNA in the human genome is thought to have originated from them.) The way that retroelements proliferate is complicated, and depends on the element in question, for there are many sorts; but one thing they all have in common is that they, too, depend on the activity of reverse transcriptase. Sometimes, by accident, reverse transcriptase goes to work on a regular piece of messenger RNA, and copies that into DNA. This new piece of DNA may then be incorporated into the genome, giving rise to a new gene - a retrogene. What's interesting about this is that the original gene - the one from which the messenger RNA was generated - will still be present in the genome. In other words, the retrogene is a copy of a gene that already exists. However, the retrogene need not end up anywhere near its original. A retrogene may, for example, be inserted into a different chromosome from its "parent." It also need not have the same activities as its parent. Because a retrogene is made from messenger RNA, it lacks a control region - the part of the gene that acts as a switch, and determines whether the gene is "on" (and the protein is being made) or "off." So in order for a retrogene to be functional and actually make proteins, it has to be inserted into the genome in such a way that it can capture the control region of another gene. As a consequence, whether a newly created retrogene will appear and immediately vanish - or whether it will confer some kind of advantage on the organism and thus spread through the population - depends on where in the genome it gets inserted. If it arrives in the "wrong" place, it may not be able to be switched on; or worse, it may destroy the workings of an existing gene and harm the organism in some way. Hence, only a fraction of the retrogenes that are created will succeed in becoming established. Which brings me to the X-odus. In mammals and in fruit flies, the genetic difference between males and females is that females have two X chromosomes whereas males have an X and a Y. Studies of successful retrogenes in a number of species, including fruit flies, humans, mice and opossums, have all shown the same, striking pattern. The parents of retrogenes are disproportionately likely to be found on the X chromosome. But the retrogenes themselves are typically located elsewhere. In other words, there's a weird kind of genetic migration going on: successful retrogenes are fugitives from the X. And here's something else. These new genes are almost all involved in various aspects of sperm production. The parent genes, in contrast, have a broad range of activities in many different parts of the body. So what is going on? In mammals and fruit flies, the X chromosome gets switched off during the making of sperm. Exactly why this should happen is unclear; but when it gets switched off, the genes on the X become unavailable. Yet - apparently - the proteins made by some of those genes are still needed. When a retrogene appears that furnishes a missing protein, it thus confers an advantage, and becomes established. New retrogenes, it seems, are readily recruited to a seXy cause. NOTES: For general discussions of the origin of new genes, see Betrán, E. and Long, M. 2002. "Expansion of genome coding regions by acquisition of new genes." Genetica 115: 65-80; and Long, M., Betrán, E., Thornton, K., and Wang, W. 2003. "The origin of new genes: glimpses from the young and the old." Nature Reviews Genetics 4: 865-875. For retrogenes as an important source of new genes in humans, see Marques, A. C., Dupanloup, I., Vinckenbosch, N., Reymond, A. and Kaessmann, H. 2005. "Emergence of young human genes after a burst of retroposition in primates." PLOS Biology 3: e357. For a discussion of genetic parasites including retroelements, and for their contribution to building genomes, see chapter seven of Burt, A. and Trivers, R. 2006. "Genes in Conflict: the Biology of Selfish Genetic Elements", Harvard University Press; see also Brosius J. 1999. "Genomes were forged by massive bombardments with retroelements and retrosequences." Genetica 107: 209-238. For the mechanics of how retrogenes are generated, see Esnault, C., Maestre, J., and Heidmann, T. 2000. "Human LINE retrotransposons generate processed pseudogenes." Nature Genetics 24: 363-367. For the successful establishment of retrogenes in the genome (including the acquisition of regulatory elements, and their sometimes deleterious nature), see Vinckenbosch, N., Dupanloup, I., and Kaessmann, H. 2006. "Evolutionary fate of retroposed gene copies in the human genome." Proceedings of the National Academy of Sciences, USA 103: 3220-3225. For evidence of the X-odus among retrogenes in fruit flies, see Betrán, E., Thornton, K., and Long, M. 2002. "Retroposed new genes out of the X in Drosophila." Genome Research 12: 1854-1859; and Bai, Y., Casola, C., Feschotte, C., and Betrán, E. 2007. "Comparative genomics reveals a constant rate of origination and convergent acquisition of functional retrogenes in Drosophila." Genome Biology 8: R11; in mammals, see Emerson, J. J., Kaessman, H., Betrán, E., and Long, M. 2004. "Extensive gene traffic on the mammalian X chromosome." Science 303: 537-540; see also Shiao, M.-S., Khil, P., Camerini-Otero, R. D., Shiroishi, T., Moriwaki, K., Yu, H.-T., Long, M. 2007. "Origins of new male germ-line functions from X-derived autosomal retrogenes in the mouse." Molecular Biology and Evolution 24: 2242-2253; and Potrzebowski, L., Vinckenbosch, N., Marques, A. C., Chalmel, F., Jégou, B., Kaessmann, H. 2008. "Chromosomal gene movements reflect the recent origin and biology of therian sex chromosomes." PLOS Biology 6: e80. Many thanks to Dan Haydon, Henrik Kaessmann, Manyuan Long, Dmitri Petrov and Jonathan Swire for comments, insights and suggestions." comment: "" date: Tue May 06 00:10:00 -0400 2008 type: Article id: "155891" votes: "15" link: "http://judson.blogs.nytimes.com/2008/05/06/when-genes-go-retro/?ref=3Dopini=on" classification_id: "14"