To the untrained eye, it looks like the work of a very bored chimpanzee sitting at a half-broken typewriter. But the 2.8 billion As, Ts, Cs and Gs published by an international consortium of sequencing labs is far from a random string of letters. The chimp genome sequence will tell us much about how our closest evolutionary cousins are put together – and teach us a great deal about ourselves.
“The major accomplishment is that we now have a catalogue of the genetic differences between humans and chimps,” says lead author Tarjei Mikkelsen of the Broad Institute in Cambridge, Massachusetts. Having that, adds co-author LaDeana Hillier of Washington University in St Louis, “gives us the ability to look at evolution at work”.
In keeping with previous studies comparing much smaller portions of the chimp and human genomes, the first thing that jumps out is how incredibly similar they are. While 29 per cent of our genes are absolutely identical, the average number of protein-changing mutations per gene in each species is just two (see “Genome in Numbers”). These changes could have happened on the chimp lineage or our own.
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We already know from looking at other species that the degree of genome similarity alone is far from the whole story. The mouse species Mus musculus and Mus spretus have genomes that differ to a similar degree and yet they look far more similar than chimps and humans. Domestic dogs on the other hand vary wildly in appearance, yet their genomes are 99.85 per cent similar.
Most of the changes will turn out to be neither beneficial nor detrimental in evolutionary terms, so the real challenge will be finding the changes that played a major role in the evolution of chimps and humans since the two lineages split 5 to 8 million years ago. Predictably, nothing obvious has leapt out of the initial analysis (Nature, vol 437, p 69). “From this study, there’s no silver bullet of what makes chimps chimps and humans humans,” says Evan Eichler of the University of Washington in Seattle.
Even so, comparing the two genomes has thrown up numerous candidates for what makes us different. One such set came by searching through 13,454 genes for those showing signs of rapid evolution. For each gene, the researchers compared the number of single-letter mutations that alter the protein the gene codes for versus silent mutations that have no effect. These mutations are possible because most amino acids are encoded by more than one three-letter DNA “word” – for example, proline is coded by CCU, CCC, CCA and CCG, so a mutation at the third position makes no difference to the protein.
Comparing the two types of mutations allowed the team to spot genes with mutations favoured by natural selection while taking into account the background mutation rate. And 585 of the genes, many involved in immunity and reproduction, had more protein-altering mutations than silent ones.
The important differences may not be in the genes themselves though. Some researchers believe that only changes in how genes are regulated could have sufficiently far-reaching effects (żěè¶ĚĘÓƵ, 21 February 2004, p 37). This is because mutations in the regulatory sequences that surround genes or in the “transcription factors” that bind to these sequences and switch on genes can alter the timing and location of several genes’ expression in one fell swoop. These changes, particularly if they happen early on in development, can have profound effects.
“Comparing genome sequences can only reveal so much. Now begins the job of zeroing in on the promising parts”
Using a similar method of comparing protein-changing mutations with silent changes in human, chimp and mouse genes, the team looked for general categories of genes that make us different. Only seven out of 809 categories of functionally related genes had accumulated slightly more changes in humans relative to chimps, indicating accelerated evolution in the human lineage. While this is only three more than would be expected by chance, the group with the greatest difference between humans and chimps is, intriguingly, the “transcription factor activity” category.
Another way to find significant bits of our genome is to look for regions that have undergone recent “selective sweeps”, say in the last 250,000 years. This phenomenon occurs when a rare mutation confers a strong selective advantage and spreads rapidly throughout a population, dragging neighbouring sequences along with it. The chimp genome sequence helps to distinguish this “hitchhiking effect” from regions which simply experience few mutations.
Of particular interest is a selective sweep region on chromosome 4 that contains no genes but has been linked with obesity in humans. Team member Robert Waterston of the University of Washington in Seattle speculates that the mutation responsible for the selective sweep may be in a regulatory region there that acts on genes elsewhere in the chromosome. Another selective sweep region contains the FOXP2 gene, which seems to play an important role in language.
Comparing genome sequences can only reveal so much. Now begins the methodical job of zeroing in on the promising parts of the sequence and, one by one, identifying the differences that count. “This really marks a beginning rather than an ending,” says team member Richard Wilson of Washington University in St Louis.
But for now, Waterston finds the human-chimp comparisons inspiration enough. “Coming face to face with the details of evolution is really spectacular,” he says.
And a Fossil too…
As a fitting complement to the chimp genome, the first convincing chimp fossils have been found – where they were least expected.
Unlike our human ancestors, whose fossil remains are relatively plentiful, chimps have been conspicuously absent from the fossil record. Many experts doubted such specimens could exist because most chimps live in the forests of west and central Africa where acid soil and high rainfall hamper fossil preservation.
Early humans lived in more arid regions, such as the east African rift valley, which were good for preserving fossils but hostile to chimp survival. “It’s the last place you’d expect to find chimps,” says anthropologist Jay Kelley of the University of Illinois, Chicago.
Nevertheless, that is what has happened. Sally McBrearty of the University of Connecticut and Nina Jablonski of the California Academy of Sciences discovered three fossilised chimp teeth in the Tugen Hills near Lake Baringo in Kenya. The two incisors and a molar, probably all from the same individual, are around 500,000 years old. They were found in a layer that includes fossils of two early humans – Homo erectus or Homo rhodesiensis – suggesting that chimp and human ancestors were contemporaries. A possible fourth tooth is has yet to be analysed.
On their own, the fossils won’t tell us much because so little has been preserved, says palaeontologist Tim White of the University of California, Berkeley. What the find does prove is that chimp ancestors were capable of adapting to a broader range of environments than previously thought. “There is no logical necessity why chimps had to remain in the forest,” says McBrearty.
She believes her discovery will encourage others to look for chimp fossils in unexpected places. It might even be possible to find much older chimp fossils from a time near the split in human and chimp lineages. White believes this is not only possible, it’s probable. “It is only a matter of time,” he predicts.
Robin Orwant
