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Natural selection against genetic damage is ongoing

The survival of the human species in the face of high rates of genetic mutation is a real problem. While mutations provide our species with the ability to adapt quickly to enviornmental changes, a large fraction of these genetic adjustments are, or become, damaged.

A newborn human is estimated to have about 70 new mutations that its parents do not have. In a project conducted by Brigham and Women's Hospital research geneticist Shamil Sunyaev PhD, and University of Michigan professor Alexey Kondrashov PhD, scientists studied natural selection in humans. Their findings are published in Science. In the work, they report that humans keep damaged mutations in check as each new mutation causes larger consequences, thereby decreasing an individual's ability to pass on genetic material.

A damaging mutation will likely interfere with the original biological function that gene was supposed to assist. The researchers studied population samples from Europe, Asia and Africa and found overall, very few individuals carry large numbers of highly damaging mutations. From this fact, they inferred if an individual carries a heavy dose of damaging mutations, the less likely that person will be able to contribute children into the next generation.

"Our study suggests that natural selection against highly damaging genetic mutations is ongoing in humans, and is aided by synergistic [cooperative] interactions between different parts of the human genome."

Shamil R. Sunyaev PhD, Professor and Distinguished Chair of Computational Genomics, Division of Genetics, Brigham & Women’s Hospital; Department of Biomedical Informatics, Harvard Medical School, Boston, Massachusetts, USA.

This observation is not limited to humans. The same effect was independently observed in fruit flies. This observation helps explain another puzzle in evolutionary biology — the maintenance of sexual reproduction.

Because sex shuffles two genomes together, it tends to generate some genomes with very few mutations, but a few with lots, repeating every generation. If damaging mutations in a genome behave synergistically where the affects are united, a high number of damaging mutations are unlikely to leave progeny.

Evolutionary theory holds that sexual reproduction may be more successful than asexual reproduction because sex purges damaged mutations from the population. Precisely what researchers observed.

"By showing that sexual reproducers — such as humans and fruit flies — have a much lower rate of individuals with a large number of highly damaging mutations, our study provides support to theories that suggest sex has an evolutionary advantage in a deterministic sense," Mashaal Sohail, PhD candidate in systems biology at Harvard University  and lead author.

"That is, sex had to come about in a species such as our own to allow for effective natural selection — as mutations can be too high to sustain."

Mashaal Sohail, PhD candidate, Department of Systems Biology, Harvard University, and lead author.

Negative selection against deleterious alleles produced by mutation influences within-population variation as the most pervasive form of natural selection. However, it is not known whether deleterious alleles affect fitness independently, so that cumulative fitness loss depends exponentially on the number of deleterious alleles, or synergistically, so that each additional deleterious allele results in a larger decrease in relative fitness. Negative selection with synergistic epistasis should produce negative linkage disequilibrium between deleterious alleles and, therefore, an underdispersed distribution of the number of deleterious alleles in the genome. Indeed, we detected underdispersion of the number of rare loss-of-function alleles in eight independent data sets from human and fly populations. Thus, selection against rare protein-disrupting alleles is characterized by synergistic epistasis, which may explain how human and fly populations persist despite high genomic mutation rates.

This work was conducted at Harvard Medical School's Department of Biomedical Informatics and Brigham and Women's Hospital's Division of Genetics in collaboration with 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.

This project was supported by the National Institutes of Health and by the Russian Science Foundation.
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May 16, 2017   Fetal Timeline   Maternal Timeline   News   News Archive   

People and fruit flies are surprisingly alike, genetically speaking. "About 61% of known human disease genes have a recognizable match in the genetic code of fruit flies, and 50% of fly protein sequences have mammalian analogues," explains Sharmila Bhattacharya PhD, head of the Biomodel Performance and Behavior laboratory at NASA Ames Research Center.
Image Credit:NASA Ames Research Center


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