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Us and Them
Natural History, November 2001

The February 15, 2001, issue of Nature was a peculiar one. Lodged in the middle of the journal was a kind of scientists’ centerfold: a multipage foldout covered in long trains of tiny hatch marks, alphanumeric codes, and squiggly graph lines. Here, for the first time in print, was a rough draft of the human genome-what Francis Collins, head of the US. Human Genome Project (HGP), called “the first glimpses of our instruction book, previously known only to God.”

It certainly gives one pause to look at this sprawling map and think about what it represents. It’s even tempting to imagine we are peering at a biological version of the soul, the unique essence that determines us both as a species and as individuals. But be careful when you turn to your genome to search for your soul. Where you expect to find your true inner self, you will come face-to— face with a mob of strangers.

Researchers now estimate that the human genome contains roughly 40,000 genes-those stretches of DNA that make the proteins that a cell needs to survive. That’s up from the figure of 30,000 published last February, but these 40,000 genes still constitute only about 2 percent of the full human genome. What’s the other 98 percent? In the 1970s, when geneticists first began to look at it, they dubbed this extra material “junk DNA.”

The implication of the nickname was that there was nothing interesting or important about the stuff. It is true that a sizable portion of the DNA that isn’t part of a gene fits this definition. Known as “pseudogenes,” these segments of DNA are the mutated relics of genes that once encoded proteins. But a large portion of the junk DNA-mounting to about 40 percent of the human genome, in fact, according to an HGP estimate-actually has a life of its own.

An ordinary gene can duplicate itself only when a cell divides and makes a new copy of the entire genome. Certain kinds of junk DNA don’t have to wait that long. Instead they may, for example, harness the cell to copy them in the form of a segment of RNA, the single-stranded version of the genetic code. Normally, RNA is used by the cell during the production of proteins. But in the case of some junk DNA, the cell uses this RNA to create another DNA copy of the junk segment, which it then inserts somewhere else in the genome. Researchers call such self— replicating pieces of junk DNA “transposable elements” because of the way they transpose copies of themselves into new places in the genome.

The more researchers have studied transposable elements, the more these bits of DNA have come to seem like a collection of parasites that use the genome as their host. We tend to think of parasites as autonomous organisms-hookworms or lice, for instance-not as our “own” genetic material. But during the 1980s and 1990s, the metaphor of genetic parasites turned out to be very powerful. Parasites tend to follow certain evolutionary paths, and these genetic parasites are no exception.

Like other parasites, transposable elements can cause a lot of harm to their host-such as by pasting a copy of themselves smack in the middle of a gene. When it comes time for the cell to build a protein based on that gene, it may be unable to do so because the inserted DNA has turned the gene’s code to gibberish. Researchers are discovering more and more forms of human genetic disorders-ranging from hemophilia to breast cancer— that have come about because a transposable element has hopped into an unfortunate place in the genome.

Another hallmark of parasites is that hosts often evolve defenses against them. Transposable elements appear to be no exception to this rule. In certain regions of our genome, for example, our DNA is capped with hydrocarbon molecules. This capping (called methylation) prevents the cell’s DNA-copying machinery from locking onto the genetic material in those parts of the chromosomes. Researchers suspect that in many cases, methylation is the genome’s way of fighting against the damage caused by transposable elements-by stopping them from reproducing.

In the May 10, 2001, issue of Nature, for instance, a group of Japanese researchers described their study of methylation in the genome of the thale cress plant (Arabidopsis thaliana). They found that if a certain gene mutated, the plant could no longer methylate its DNA. Freed from their prisons, the transposable elements in these mutants started replicating themselves and inserting these new copies into the genome. The resultant plants were nothing more than shriveled clumps. Thanks only to methylation, it seems, can the thale cress withstand its genetic parasites.

This discovery points up a conundrum that arises as much in connection with transposable elements as with conventional parasites: if they can be so harmful to their hosts, why haven’t they driven their hosts extinct-and made themselves extinct in the process? Part of the answer comes from their evolutionary history. Transposable elements can spread gradually through a genome over millions of years, but eventually their success at self-replication wanes. Copying errors creep in and undermine their ability to replicate themselves; in addition, the host genome evolves an ability to suppress them. Most of the transposable elements in the human genome, it now seems, are already dead or about to give up the ghost.

The only way a transposable element can escape this fate is to leave its host and find a fresh genome to invade. By comparing transposable elements found in an array of hosts, researchers have discovered that these genetic parasites can make astonishing leaps-from marine flatworms to beetles, for example, or from salmon to frogs-although no one knows for sure how they manage these migrations. Perhaps certain mutations turn the transposable elements into full-fledged viruses-nucleic acid molecules covered in protective protein shells. They can then exit their host, find a new one, and snuggle into its genome. Some of today’s transposable elements might have once been free-ranging viruses, and some contemporary viruses may have had transposable elements as ancestors.

Through migration and proliferation, transposable elements have become inordinately successful, and that is how they have come to constitute 40 percent of our DNA, either as active copies or dead ones. Much of the remaining junk DNA in our genome may also turn out to be former transposable elements that have mutated beyond recognition. In certain species the proportions are even more staggering: 99 percent of the lily genome consists of transposable elements.

Despite what we know about transposable elements, can’t we still salvage the notion of the genome as the biological soul? When I look at the map of the human genome, don’t I still see “myself” in the genes that code for useful proteins-albeit a self that is besieged on all sides by these annoying parasites? The answer, it increasingly seems, is no. You can’t draw a line in the genome between us and them.

One of the best places to see this fuzziness is in the and canyons of Israel. The wild barley plants that grow there carry many copies of one family of transposable elements, called BARE-1. Alan Schulman, of the University of Helsinki, and his colleagues recently studied a single population of barley plants in one of these canyons. They found that the plants growing at the top of the canyon carried three times more BARE-1 copies than did the plants of the same species growing at the bottom, where conditions are less harsh. Similar patterns have emerged throughout Israel and surrounding countries. In other words, having a lot of BARE-1 copies somehow seems to allow barley to survive under and conditions.

One possible explanation is that transposable elements make the genome physically big, which is sometimes a good thing. In 1978 Thomas Cavalier-Smith, then at the University of British Columbia, proposed that the sheer size of a genome can sometimes be an adaptation. Since then, this idea has been generating much controversy as it floats around the scientific community. Its main attraction is that it addresses a fundamental puzzle about DNA: Why do some species have lean, mean genomes with hardly any junk, while others are overwhelmed by it?

A species with a sizable genome may simply have had the bad luck to be attacked by a particularly nasty transposable element. But it’s also possible that genomes of certain sizes may be favored under certain circumstances. Big genomes tend to be found in big, slow-dividing cells. As genomes expand, the cells they inhabit may have to expand with them to accommodate a larger crew of proteins employed in keeping the genome in good working order. Getting these bigger cells to divide may also be a bigger undertaking, and this would make them multiply more slowly.

Large, slow-dividing cells may outperform small, quick-dividing ones in some situations. If a plant can grow to a good size, it can capture more sunlight and make more seeds. But plants also need water to grow, and in Israel and the rest of the eastern Mediterranean region, winter is when the most water is available. Since the relatively cold temperatures slow down the chemical reactions involved in cell division, plants may grow by developing fewer, bigger cells instead of a lot of small ones. In the case of the barley plants, the climate at the top of the canyon is much harsher than the climate at the bottom, favoring bigger genomes and the bigger cells they bring. It’s possible that similar tradeoffs have driven the evolution of different-sized genomes not just among plants but maybe among animals, fungi, and amoebas as well. So while transposable elements may indeed be genetic parasites, they may end up helping their hosts.

Transposable elements also appear to play a crucial role in the evolution of the cell’s “legitimate” genes. Genes can evolve only if they first mutate, and transposable elements create a significant fraction of a genome’s mutations. Like other kinds of mutations, most of those caused by transposable elements are neutral or harmful, but some of them can do an organism good. Sometimes, for instance, these mobile genetic parasites drag a piece of a neighboring gene with them to their new home. In the process, they link two preexisting chunks of genes into a new combination that may quickly take on a new function.

Transposable elements themselves have even become vital parts of genes. About 500 million years ago, for example, a transposable element in the genome of early vertebrates was incorporated into a gene that became part of our immune system. This ex-parasite stopped using its DNA-splicing skills to replicate itself and instead began rearranging the genes that encode pathogen-recognizing proteins. Thanks to this transposable element, our immune cells can quickly generate millions of different-shaped proteins. Through a process much like natural selection, the cells with proteins that allow them to identify pathogens will survive and can then be made to alter their genes again to do an even better job. In other words, it is only thanks to an erstwhile parasite that we can fight off other parasites.

This example of an adopted transposable element is just one of hundreds that geneticists have uncovered, and the list keeps growing. These discoveries have left biologists groping for new kinds of metaphors to describe the genome. In a review article concerning transposable elements, published in the January 2001 issue of Evolution, biologists Margaret G. Kidwell and Damon

R. Lisch sounded downright Zen. “Who are we and who are they, who is host, and who is parasite can be seen as a function of how selection is operating at any given time,” they wrote, adding that in specific cases “these distinctions can become meaningless.”

I highly recommend mulling over riddles like that one while you gaze at the map of the human genome. The self can be found everywhere and nowhere on that chart. Your genome is an ancient ecosystem, a jungle, a tangled bank of a river, in which hundreds of thousands of mysterious life-forms compete, cooperate, co-opt one another, and coevolve. In the words of the immortal Pogo, “We have met the enemy and he is us.”

Copyright 2001, Carl Zimmer. Reproduction or distribution is prohibited without permission from the author.

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