LONDON - The human race is rapidly accumulating new mutations that are mild but which could nevertheless be harmful to health, a study of human DNA has concluded. Researchers in the U.K. estimated that at least 1.6 harmful mutations have occurred per individual per generation, ever since chimpanzees and humans diverged from their common ancestor 6 million years ago.
Adam Eyre-Walker, a biologist at the Centre for the Study of Evolution & School of Biological Sciences at the University of Sussex in Brighton, U.K., told BioWorld International: "This is an incredibly striking result. No one has ever observed this level of degeneration of the genome before."
Eyre-Walker and his co-author, Peter Keightley, of the Institute of Cell, Animal and Population Biology at the University of Edinburgh in the U.K., published their results in the Jan. 29 issue of Nature, in a paper titled: "High genomic deleterious mutation rates in hominids."
The two scientists set out to determine the rate of harmful mutations after recent published estimates suggested that individuals could inherit up to 100 new mutations every generation. Eyre-Walker said, "Even if a small fraction of those are harmful, then it could have consequences for human health." Such work would also have implications for those studying the conservation of small populations of animals, such as tigers or rhinoceroses. If they, too, suffered many harmful mutations this would increase the risk of their becoming extinct.
To carry out the study, Eyre-Walker and Keightley obtained data on the DNA sequences of regions of the genome which code for proteins. They concentrated on protein-coding regions for two reasons. First, efforts directed at sequencing DNA have concentrated on these regions, and homologous copies of the same sequences from humans and other primates were therefore more likely to be available. Second, deleterious mutations are more likely to occur in the protein-coding regions than in the rest of the genome.
Common Ailments Caused By Mutations?
The rate of mutation for the non-coding regions was already known. Eyre-Walker and Keightley set out to compare the rates of mutation in the coding and non-coding regions. Because individuals who experienced deleterious mutations (which would mainly have been in the coding regions) probably succumbed to natural selection and died before they reproduced, these mutations would be lost to the gene pool. A comparison of the mutation rates of the coding and non-coding regions therefore makes it possible to estimate the rate at which deleterious mutations occur.
The researchers estimated that, out of the 100 new mutations that occurred in the genome each generation, about four changed the amino-acid sequence of a protein. They also estimated that about 40 percent of these mutations were removed by natural selection, which indicates that there have been more than 1.6 new deleterious mutations per person per generation.
Eyre-Walker told BioWorld International that the findings offer two puzzles. "One is why the deleterious mutation rate, at 1.6, is so high," he said. "If these mutations were eliminated independently, then most of the population would die or fail to reproduce. We could have only escaped this fate if deleterious mutations interacted synergistically." According to this theory - known as synergistic epistasis - having two mutations is more than twice as harmful as the independent effects of the two mutations put together. "Our survival is therefore evidence that there is synergistic epistasis between deleterious mutations," he said.
The second puzzle, Eyre-Walker said, is why only 40 percent of the new mutations were removed by natural selection. In similar studies of other organisms, this figure is often as high as 70 or 80 percent. He said: "We presume that these mutations are only slightly deleterious, and this study shows that these mutations are entering the human population and becoming fixed in our genome." However, while our genome appears to be degenerating generally, it is clear that there have been a number of advantageous mutations which have led to some key adaptations, like our intelligence, he said.
What does all this mean for the future health of the human race? Eyre-Walker and Keightley said this is difficult to predict. Improvements in living conditions and health care in some human populations may have greatly reduced the effect of natural selection, they suggested. "The selective elimination of mildly deleterious mutations may therefore have slowed down, and our populations could be accumulating deleterious mutations," they added. "It has been postulated that if conditions worsen, then populations may pay the penalty for this accumulation at some future time. However, this theory critically depends on how large the effects of the mutations are. If the mutations have very small effects, then the current relaxation of selection may not matter, unless it goes on for a very long time."
James Crow, a geneticist at the University of Wisconsin in Madison, commenting on the paper in the same issue of Nature, asked whether some of the headaches, stomach upsets, weak eyesight and other ailments that we suffer could be the result of mutation accumulation. At present, we can only speculate, he concluded in a "News and Views" article titled "The odds of losing at genetic roulette."
Steven Rose, director of the Brain and Behaviour Research Group at the Open University, in Milton Keynes, U.K., said it was difficult to define what constitutes a deleterious mutation, because mutations that would be deleterious in one context would not be in another. "For example," he said, "insofar as having short sight is heritable, having short sight would have been a deleterious mutation in the context of a less technologically driven past, but it is now routinely rectified by spectacles and is no longer deleterious. In addition, our society has changed so that the ability to see things sharply in the distance is no longer a crucial aspect of human survival. If we had a nuclear war and were taken back into Stone Age conditions, those of us unfortunate enough to be carrying these mutations would no longer be protected and would rapidly die out and not reproduce."
Next, Eyre-Walker and Keightley aim to carry out similar analyses of other organisms, including other mammalian groups, fruit flies and nematodes. "We also need to know a lot more about what effects these mutations have," Eyre-Walker said. "Are most mutations slightly deleterious or very deleterious, or do most mutations have no effect?"