Damage Control

Natural Selection Against Disease-Causing Mutations in Humans is Ongoing
Large crowd fading into distance, representing concept of population over time
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The survival of the human species in the face of a high number of incoming genetic mutations has remained an important problem in evolutionary biology. A newborn human is estimated to receive about 70 new mutations that the parents did not have. While these provide a source of novelty for the species, a large fraction of them can also be damaging, or likely to interfere with the biological function that a gene has for the organism. So how do we not mutate into oblivion?

A study published today in Science by Shamil Sunyaev and colleagues reports that as a species, humans get around this mutation problem thanks to certain interdependencies within the genome. Basically, if a new mutation occurs in a genome that already contains many damaging mutations, it has a stronger effect than if it occurred in a genome with just a few other damaging mutations. Thus, when a genome carries beyond a particular number of damaging mutations, it is significantly less likely to contribute progeny to the next generation.

Researchers including lead author Mashaal Sohail, PhD candidate in Systems Biology at HMS and member of the Sunyaev lab, studied population samples from Europe, Asia and Africa and found a significant depletion of individuals carrying a large number of highly damaging mutations overall. Their results suggests that natural selection against highly damaging genetic mutations is ongoing in humans, and that it is aided by synergistic interactions between different parts of the human genome, a form of epistasis. As selection due to pre-reproductive mortality is deeply relaxed in industrialized humans, it is likely that the observed signal comes from selection due to differential fertility, or pre-natal selection (only ~30% of human conceptions result in live births). This observation is general and is not limited to our own species. The same effect was independently observed in fruit flies.

The findings also help solve another long-standing riddle in evolutionary biology, that of the sustainability of sexual reproduction. Because sex shuffles two genomes together, it creates genomes with both very few and very many mutations every generation. If damaging mutations in a genome behave synergistically, genomes with a high number of damaging mutations are then very unlikely to leave progeny. Evolutionary theory, thus, holds that sexual reproducers may be more successful than asexual reproducers because they are able to purge multiple damaging mutations from the population with single genetic deaths post sex-induced genetic remixing. This is precisely what was observed in this study. By showing that sexual reproducers such as humans and fruit flies have a significant depletion of individuals with a large number of highly damaging mutations, the study provides support to theories that suggest that sex has an evolutionary advantage in a deterministic sense. That is to say, sex had to come about in a species such as our own to allow for more effective natural selection because the mutation rate is too high to sustain otherwise.

Sunyaev is both professor of biomedical informatics at HMS and professor of medicine at Brigham and Women’s Hospital. Collaborators included University of Michigan professor Alexey Kondrashov, the Institute for Information Transmission Problems (Kharkevich Institute) of the Russian Academy of Sciences in Russia, and the Department of Neurology and Neurosurgery at the University Medical Center Utrecht in the Netherlands.

Also see: The Making of an Evolutionary Geneticist