HOW did it happen? Over millions of years, our ancestors evolved the human traits we so pride ourselves on, such as our upright gait and complex language. It is easy to list the main physical changes that mark human evolution, but harder to uncover the driving forces behind them. But now, researchers working on the genomes of our ape cousins, such as the chimp, gorilla and orang-utan, think they have uncovered a clue. It seems that our genome possesses an intriguing talent that could help explain how humans came to be so different.
This feature has given our genome an exceptional freedom to change and evolve, allowing evolution to tinker with our genes and the switches that control them on a scale far more ambitious than is possible with most other mammals – even our closest relatives, the great apes. This left our ancestors poised to adapt quickly to changing environments, exploit new opportunities and evolve new characteristics. It may be that we owe many of our human traits, such as intelligence, language and creativity, to the entrepreneurship of our genome.
Humans are unusual primates in many respects, but everyone agrees the real story of human evolution is what happened between our ears. Yet the genetic roots of this brain power are mysterious. There are no glaring differences in our genome that provide an easy explanation of where it came from. We have roughly the same number of genes and make about as many proteins as a mouse. “If you didn’t tell me that humans were special biologically, I would not have predicted it looking at the human genome,” says Bruce Lahn, a geneticist at the University of Chicago who studies the genetic basis of human uniqueness. Of course, we know so little about how genomes work that we could easily be overlooking subtle differences. Lahn and other researchers are trying to track down the genetic changes that are unique to humans, and have already had some success (see “Spotting the difference”).
Advertisement
Evan Eichler, a geneticist at Case Western Reserve University in Cleveland, Ohio, thinks he’s found one important driving force behind these genetic changes and one that primed our ancestors for success. The human genome, he says, is riddled with duplications – extra copies of segments of DNA a few thousands to tens of thousands of letters long. While every genome has such duplications, humans – and probably other great apes as well – appear to have an especially rich collection. Eichler estimates that about 5 per cent of the human genome consists of relatively recent duplications. That’s equivalent to a whole human chromosome’s worth of DNA. In mice and rats, the figure is only about 1 or 2 per cent, and in fruit flies and worms just 0.1 to 0.01 per cent.
Duplications are the engines of evolution, providing raw material for mutations and natural selection to work on. They give organisms a free roll of the evolutionary dice: random mutations can modify one copy of the duplicated gene without messing up existing biochemical pathways, because the second, intact copy is still around to perform its original function. “This provides you with more opportunities to tinker more often,” says Eichler. “Most of these are dead ends, but occasionally a gene can be born in this matrix of duplications that is beneficial.”
Indeed, the evolutionary history of mammals is full of examples where duplications have proved useful in just this way. A single gene originally coded for the globin portion of the haemoglobin molecule. But duplications allowed the evolution of several different globin proteins, each adapted to a different stage of development from embryo to adult. Red and green cone pigments of the eye – essential parts for colour vision – arose from a single duplicated gene.
Even the mere act of duplicating a gene is likely to change the way the copy works. Because it sits in a different genomic environment from the original gene, the regulatory switches that determine when and where the copy is active may affect it differently, so that it may turn on or off at different times or in different tissues. Such regulatory changes, many think, may have been far more important in the transformation from ape ancestor to human than the protein-coding genes themselves.
Could duplications really be behind the burst of evolutionary inventiveness that brought humans into being? To find out more, Eichler and his team investigated whether the appearance of the duplications coincided with important steps in human evolution. By seeing how many mutations have accumulated in the duplicated regions, Eichler’s team came up with a rough estimate for how old each duplication must be. Most, they found, clustered around 25 million years ago – about the time the ancestor of old world monkeys and apes diverged from new world monkeys – and again 7 or 8 million years ago – about when the human lineage branched off from the great apes (see Diagram).
Eichler suggests that the timing of the duplications is consistent with them providing the genetic raw material for evolving new proteins or patterns of gene expression that helped fuel the evolution of characteristics in great ape and human. Research from Svante Pääbo’s lab at the Max Planck Institute for Evolutionary Anthropology in Leipzig provides convincing support for this idea. Pääbo’s team found that since humans split off from chimps, gene activity in the human brain has changed almost four times as fast as it has in the chimp brain. In contrast, gene expression in the liver had changed equally fast in both species. That would be interesting enough in itself, but the genes whose activity had changed in human brains also tend to be found in duplicated stretches of chromosomes. In other words, the smoking guns of evolution are pointing squarely at Eichler’s targets.
The link is not yet solid. A similar analysis by Morris Goodman’s team at Wayne State University in Detroit produced similar results. But when they reanalysed their data asking whether the activity of whole biochemical pathways, rather than individual genes, had altered, they found the same number of changes in both chimps and humans.
Another recent study sounds a similar note of caution. Michele Cargill of Celera Diagnostics in Alameda, California, and her colleagues compared the human and chimp sequences for 7645 genes to see how many bear the mark of recent evolution. This mark takes the form of an unusually high proportion of mutations that cause changes in the gene’s protein product, as compared to “silent” mutations in which changes in DNA do not result in an altered protein. In the genes they analysed, Cargill’s team found that duplicated genes were no more likely than non-duplicated ones to show signs of evolution. However, Eichler notes that for technical reasons Cargill’s analysis excluded many of the recently duplicated genes, including some of the candidates most likely to have played a role in human evolution.
One big question remains: where did our genome get its talent for duplication? Part of the answer may lie with a genetic parasite called Alu. Alu is a transposon, a “jumping gene” whose main function is simply, and selfishly, to make more copies of itself and scatter them about the genome. About 55 million years ago, Alu started jumping around the genome of our ancestral primate, priming it for making duplications.
It works like this: all primates inherit their chromosomes in pairs; one from mother, the other from father. During the production of eggs and sperm, each chromosome lines up with its pair and swaps stretches of DNA, a process called recombination. Accurate recombination relies on aligning DNA sequences exactly between the pair of chromosomes, so that only matching segments of the chromosomes are swapped. However, Alu dotted the primate genome with many identical stretches of DNA, providing many opportunities for the chromosomes to misalign. Non-matching parts of the chromosomes get swapped, resulting in duplicated segments of DNA (see diagram).
If duplications are important, their effect is likely to snowball. More duplications mean more chances for mis-pairings and hence still more duplications. It’s a tendency that is further enhanced by another quirk of the human genome, Eichler has found. In most animals, duplicated stretches of DNA lie adjacent to their parent gene, but in the human genome duplicated segments tend to accumulate near specific points on the chromosomes dubbed “collector regions”. No one knows why. “They’re kind of like magnets – they draw duplications, and stuff them all together in this one area,” says Eichler. This ghettoising of duplications further increases the odds of more mis-pairing.
Like any entrepreneur, our innovative genome risks failure. Mis-pairings can produce deletions (see Diagram) as well as duplications, and many genetic diseases – including several forms of mental retardation – spring from exactly that cause. Another apparent mistake is the gene Tre2. Unique to humans, this gene appears to have formed from a recombination error that brought together parts of two ape genes. Tre2’s only known function is to promote cancers of the bladder. Still, Eichler thinks that on balance, our genomic creativity must pay off. The fact that our genomes tolerate so much duplication means that the benefits must greatly outweigh the disadvantages – or that duplications happened so often in our recent past that our genomes simply couldn’t get rid of them all.
Other geneticists find Eichler’s ideas intriguing. “I think he’s putting his finger on something rather interesting,” says Goodman. Others argue that while duplications clearly provide fodder for evolution in some cases, they haven’t actually been proved to be important for human evolution. “The question is, have the spare parts actually made a contribution to the biological evolution of humans, and if so, how much?” asks Lahn. Plenty of other duplications have not led to great evolutionary leaps, he notes. Much of the maize genome consists of duplications and similar “junk” that has played no obvious evolutionary role. And the African clawed frog, Xenopus laevis, has duplicated its entire genome, to little obvious effect.
Even Eichler agrees that duplications can’t be the whole story. “This has been going on both before and after the divergence of humans from great apes,” he says. “So it’s not a question of how much was duplicated, but maybe what genes were duplicated.” In essence, the duplications allowed the great apes to buy extra tickets in the genetic lottery. Our ancestors were the ones who just happened to strike it lucky.
Spotting the difference
Tempting as it is to search for a handful of genes that raise people above the apes, it won’t be that simple. There are some 40 million differences in the DNA sequence between the human and chimpanzee genomes, and finding the important changes will not be easy. Still, researchers have already made some intriguing discoveries.
Understanding brain evolution is a key goal. Bruce Lahn of the University of Chicago has been sifting through the human genome looking for genes whose coding regions have changed so rapidly that the changes couldn’t be due to chance alone. Sure enough, many genes active in the brain bear this mark of adaptation. One of them is ASPM. In fruit flies a related gene is active in brain development, and people who carry two mutant copies of the ASPM gene have an abnormally small cerebral cortex. “Obviously, that would be a good candidate for involvement in making the human brain larger during evolution,” says Lahn.
This bigger brain would need more fuel. Morris Goodman of Wayne State University in Detroit points the finger at cytochrome oxidase, a complex of 13 different proteins that plays a crucial role in producing energy. At least 9 of the 13 component proteins show marked evolutionary changes in the primate lineage. Other factors could have influenced brain size too. Ajit Varki of the University of California at San Diego has found that hydroxylase, an enzyme that produces a cell-surface molecule called sialic acid, is missing from humans. In most mammals, hydroxylase is very active throughout the body except in the brain, where very little is produced. Humans lost the gene completely about 3 million years ago, just before our ancestors’ brain size increased dramatically.
Size isn’t the only issue, of course; there is the question of function too. Wolfgang Enard of the Max Planck Institute for Evolutionary Anthropology in Leipzig and his team have found changes in a gene called FOXP2, the first single gene to be linked to speech and language. People carrying a mutant form of the gene have difficulty articulating speech. Clearly, the gene also has other functions, because it is found in all mammals and is present throughout the body. However, the human form of the gene differs from most mammals in two places, and there are signs that natural selection was operating on it no more than 200,000 years ago. This is about the same time that anatomically modern humans emerged, hinting that speech was the trait being selected. But other researchers point out that other factors, such as inbreeding, may mimic the signs of natural selection.
Then there is the mysterious gene called morpheus. Humans and chimps carry between 25 and 35 copies of the gene, which suddenly began to change rapidly in humans just after we diverged from chimps. “It is the most rapidly evolving gene in the human genome to date,” says Evan Eichler of Case Western Reserve University in Cleveland, Ohio. The only problem is, no one knows yet what the gene does, or why it has become so important in evolution.