YOU’VE been spammed. You get back from holiday to find your inbox bursting with hundreds of messages with subject lines such as XXX Pics Included, Special Gift For You, and 75% Discount on Viagra. All useless, irritating junk. But consider this: living organisms are infested with enough of the biological equivalent of spam email to make the internet’s flood of junk pale into insignificance.
It is a little shocking to discover that every cell nucleus in your body is crammed with millions of years’ worth of genetic junk mail. It takes up the vast majority of the genome. Much of this junk is in the form of pieces of DNA called jumping genes, or transposons, that can move around genomes, copying and pasting themselves into our genetic inboxes and mailing themselves on to the next generation. They are so good at this that at least half of our genome comprises dead or barely suppressed transposons – some 4 million of them. Most of the remaining genome is a jumble of unrecognisable detritus that is probably the decayed remains of ancient transposons. Only around 2 per cent actually codes for the proteins we need. Biologists have long regarded the rest as garbage.
But is it? A growing number of geneticists now say it may not be junk after all. It seems some transposons have served useful functions, such as fine-tuning our sophisticated immune system. Some biologists claim transposons have given genomes the ability to engineer themselves, allowing evolution to proceed faster than would have been possible by random mutation and natural selection alone. Sceptics insist that the net effect of all this genetic spam is negative. Transposons can cause mutations when they move around and force their hosts to waste energy copying or suppressing them. But good or bad, transposons could hold the key to one of the most intriguing questions in biology: why sex ever caught on.
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We have known for more than 50 years that certain genetic sequences can move around. Some “cut and paste” themselves from one part of the genome to another. Others stay put but make thousands of RNA replicas of themselves. Then an enzyme called reverse transcriptase converts the RNA back into DNA, which is then spliced back into the genome. It’s a sobering thought, but more of the human genome codes for reverse transcriptase than for all other proteins put together.
In the 1940s, a geneticist called Barbara McClintock at the Carnegie Institution of Washington at Cold Spring Harbor, New York, deduced that transposons existed from her studies of maize. By the late 1970s, most scientists had written them off as bits of “selfish” DNA that had only avoided annihilation through their ability to replicate faster than their hosts. In 1980, Francis Crick summed up the zeitgeist when he described them as “the ultimate parasites”.
Their slow rehabilitation began a decade later with the discovery that two genes vital for the functioning of the vertebrate immune system behave in a way strongly reminiscent of a transposon. RAG1 and RAG2 code for an enzyme that cuts DNA at specific sites in the gene for immune-cell receptors. The cut ends are then spliced together. This process generates the huge diversity of differently shaped receptors that allow antibodies and T-cells to recognise and tackle just about any foreign invader. In 1998, David Schatz at Yale University and his colleagues showed that, in a test tube at least, the RAG proteins could also cut out a piece of DNA and paste it somewhere else – just like a transposon. “That provided pretty dramatic support for the notion that they evolved as components of a transposable element,” says Schatz. He speculated that we have a transposon to thank for jumping into the genome of an early vertebrate ancestor and upgrading our immune system.
If transposons did play a pivotal role in the evolution of the immune system, could they have had a hand in developing other vital functions? With the sequences of so many genomes now deciphered, including mouse, human and chimp, geneticists can scour databases for ancient footprints made by transposons as they jumped about in their hosts’ DNA thousands or millions of years ago. These footprints take the form of characteristic repeated sections of DNA that flank transposons and are generated whenever they insert themselves into a new location. Researchers studying these trails claim they show transposons might have played a vital role in evolution.
One theory has it that since we hold so many of our genes in common with other creatures, most of the differences between species can be attributed to changes in the expression of genes rather than the genes themselves (91av, 21 February, p 41). The differences in expression are partly down to short sequences of DNA called promoters that sit in or near genes and control their activity. Active transposons contain their own promoters to fool the cell into producing proteins from them. Because an active transposon is forever hopping around its host’s genome, it is quite possible that its promoter could land next to a host gene and so alter its activity. The question is: has this happened often enough to influence evolution?
To find out, King Jordan of the National Institutes of Health in Bethesda, Maryland, and his colleagues searched a database of human gene promoter sequences, looking for the telltale traces of transposons. Last year they announced that almost a quarter contained sequences derived from transposons. “They could be an important engine for driving change,” suggests Jordan.
In October 2003, a team focusing on the mouse and human genomes added weight to this idea (Trends in Genetics, vol 19, p 68). Of more than 12,000 human genes analysed by researchers at the Terry Fox Laboratory in Vancouver, Canada, 27 per cent were found to be associated with transposons. Significantly, they found that rapidly evolving genes, such as those involved in immunity or response to environmental stimuli, contain more transposons than those evolving more slowly.
Principal researcher Dixie Mager explains that transposons occasionally “donate” their promoters to genes, allowing those genes to be expressed differently in particular tissues depending on which promoter is used. Up to a quarter of our genes have more than one promoter. “This allows the genome to experiment with different patterns of regulation, and transposons are a great way to provide that diversity,” she says.
Her team pinpointed several instances of transposons donating promoters to genes, including one that gave primates the ability to regulate oestrogen levels during pregnancy (Trends in Genetics, vol 19, p 530). The gene in question codes for a key enzyme needed to synthesise oestrogen, and is mainly expressed in the gonads and brain of most mammals. But thanks to an alternative promoter only found in the primate version of the gene, it is also expressed in the placenta of apes and monkeys. In their paper, Mager and her colleagues reveal that this promoter is actually a transposon. “Certainly, most transposons are parasitic DNA,” she says. “But it’s indisputable that some have been recruited to have a role.”
So transposons can change the course of evolution by altering the expression of genes, but what if they change the structure of proteins? Last year, Wojciech Makalowski and Anna Lorenc of Pennsylvania State University in University Park identified transposon sequences when they looked at proteins themselves (Genetica, vol 18, p 183). If a transposon jumps into a protein-coding region, the consequences are likely to be disastrous for both host and parasite, so it is not surprising that only 0.4 per cent of the vertebrate proteins they screened contained a recognisable transposon sequence. But they found evidence that, where this has happened without killing the host, an alternative, unaffected version of the protein is often produced in parallel, through a mechanism called “alternative splicing”. This means a cell can produce either the altered protein or a normal back-up.
Makalowski believes alternative splicing may allow organisms to conduct evolutionary experiments with their proteins using the “ready-to-use motifs” donated by transposons as they hop about the genome. James Shapiro of the University of Chicago goes further. “When a mobile element moves from one place to another, that’s not an accident,” he says. “It’s the turning on of a machine whose job is to move DNA around.”
According to this view, transposons have been tamed and put to work. They are no longer parasites moving about randomly – they’re the tools that genomes use to engineer themselves. Shapiro believes the RAG proteins are just one example of this ability to explore new possibilities. “Once you have mobile elements the organism has a way to evolve much more rapidly. It’s natural genetic engineering.” He cites the way bacteria rapidly evolve antibiotic resistance by moving mobile scraps of DNA around in their genome and from cell to cell. “It’s like any kind of engineering – you take proven modules and rearrange them.”
He points out that when you compare the sequence of amino acids in equivalent proteins in flies, worms and humans, it looks as though the same building blocks have been shuffled around and new ones added during the course of evolution. “This is something totally different from chromosome evolution by changing one nucleotide at a time,” says Shapiro. “It’s more of a cut-and-splice genetic engineering process.” And of course, cutting and splicing are what transposons do best.
So is it time we saw our genetic spam as friend rather than foe? No way, says Timothy Bestor at Columbia University in New York. He believes its net effect is negative. “That doesn’t mean a beneficial function can’t arise from a transposon. But the host does not maintain its transposons for that purpose.” He cites a mathematical model published in 1982 by Donal Hickey of the University of Ottawa in Ontario, which showed that provided an organism reproduces sexually, transposons can spread through its population even if they harm their hosts (Genetics, vol 101, p 519).
Hickey based his sums on the simple fact that when the host organism mates, only half of its genes get passed to the offspring because each sperm or egg has only half the usual complement of chromosomes. But when a DNA parasite hitches a ride into the next generation it can splice a copy of itself into the partner’s chromosomes too, after fertilisation, ensuring that all subsequent offspring will contain a copy. This means its reproductive “fitness” is twice that of its host, so it can harm the host and still spread through the population. To an extent, it can cheat natural selection.
Bestor points out that the genomes of organisms that can only reproduce sexually have the highest number of transposons and asexual organisms have the least. Those that use both methods fall somewhere in between. “The more sex, the more transposons,” he says. According to this view, there’s no need to evoke any helpful functions to explain their presence. The benefit of sexual reproduction for an organism is that it generates lots of variety for natural selection to work on. Asexual species don’t have that advantage, says Bestor, so if the “helpful transposon” hypothesis were true you’d expect them to compensate by having loads of transposons to generate genetic variety. But the exact opposite is true.
“The fashion now is to think of transposons as being good for you and the reason is quite understandable,” he says. “It’s just so revolting to think that the genome is packed full of parasites. It’s just disgusting – and you inherit these parasites and pass them on to your children. People find that unpleasant so they cast around for a more palatable explanation.”
Beneficial spin-offs
There is another way of looking at transposons, though. Some geneticists argue the damage transposons cause is actually a bonus, because it forces the host genome to evolve measures to combat them. These measures can then form the raw material for the evolution of new adaptations. “It’s an arms race going on in the genome that drives increasing complexity,” says John McDonald at the University of Georgia, Athens. “Just like an arms race in human society, the inventions get spun off into non-military purposes.” He says the complex systems used by higher organisms would never have evolved without this internal battle. Random mutation and natural selection would simply have been too slow, he argues.
One process that may have been a spin-off from this arms race is DNA methylation, which cells use not only to suppress transposons but also to silence their own genes. DNA methylation has become an essential feature of sexual reproduction, because it allows either maternal or paternal genes to be turned off in the developing embryo in a process known as imprinting. It also ensures that only one of the two X chromosomes in females is active.
Not everybody is convinced. DNA methylation is Bestor’s specialist area, but for him it is not so much a successful spin-off as a sign that transposons continue to exact a heavy toll on their hosts – a toll that asexual species have avoided by allowing natural selection to weed them out.
“But you can turn that on its head and say that maybe transposons were involved in the evolution of sexual reproduction itself,” says Jordan. If sex helps to spread them from genome to genome in a population at twice the rate of the hosts’ own genes, then it is in the interests of transposons to force their hosts to use this as their mode of reproduction. Supposing an ancient transposon caused a mutation or activated genes that made reproduction possible only by combining the genetic information from two individuals?
This could help explain one of the deepest mysteries in evolutionary biology: how sexual reproduction ever got started. In the long term, sex is beneficial, because it creates new combinations of genes that make adapting to a changing environment easier. But in the short term, it is expensive and time-consuming. Not only does it involve finding a mate, it also means discarding half of your own genes and mixing them with someone else’s. Worse still, parasites of all kinds can get in on the act. By contrast, asexual reproduction is quick and simple, and every one of your genes will be passed to the next generation.
Natural selection penalises traits that have a short-term disadvantage, even if they would have proved beneficial further down the line. So biologists have struggled to explain how evolution ever overcame the immediate disadvantages of sex. But Jordan points out that sex benefits transposons right from the start, and as Hickey’s model shows, they can spread like wildfire through a population even if they temporarily reduce their hosts’ fitness. So perhaps transposons, for their own “selfish” reasons, helped sex to evolve.
The debate will not be solved until more evidence is in. But for those like Shapiro and Jordan, transposons have already given us a glimpse of a new kind of evolutionary race where there don’t always have to be winners and losers. It’s a much more subtle conflict, where the battle with parasites has led to extraordinary innovations. So will electronic spam email ever give us anything that’s useful? In a few million years, perhaps.
