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Sasani, TA, BS Pedersen, Z Gao, L Baird, M Przeworski, LB Jordo, AR Quinlan. 2019. Large, three-generation human families reveal post-zygotic mosaicism and variability in germline mutation accumulation. eLife 2019:8:e46922; DOI: https://doi.org/10.7554/eLife.46922.
Summary. Parental and offspring genotypes were compared over three generations in 33 large families, consisting of 4-16 children each. DNA differences between parents and offspring were attributed to inheritance of mutations that occurred in the parental gametes. Results showed that the average number of genetic changes per person is 70, but varies in different families and for different parental ages. The greatest number of mutations were inherited from the fathers, and the numbers of mutations increased with parental age in both sexes. The effect of parental age on mutation rate varied from 0.19 to 3.24 mutations per year, causing mutations to accumulate faster in some families than in others. About 10% of the mutations occurred after the egg was fertilized, and sometimes resulted in tissue mosaicism, where some tissues do not have the mutation and others do, sometimes including the reproductive organs.
Comment. Mutations play a central role in evolutionary theory, but are increasingly seen as problematic. First, the rate of mutation is far too slow to allow for the observed rapid changes in living species. This rapid adaptation to local environments is due to other mechanisms, such as environmentally induced epigenetic changes and perhaps even the influence of diet and the gut microbiome on the genes. A second problem is that the mutations that are observed do not seem capable of producing new organs and body plans as demanded by evolutionary theory. Instead, they modify existing features, generally by “breaking” them. Third, it is well known that beneficial mutations are very rare compared to mutations with minor negative effects. Thus, over many generations negative mutations accumulate much more rapidly than beneficial mutations, which will eventually lead to genetic meltdown through error catastrophe. The study reported here sheds important light on the rates of mutation and some of the factors that cause variation in the rate, and show that the measured rate of mutation is high enough to produce degeneration of the species.