Mutation rates are astonishingly high, and most mutations damage an organism. Evolutionary theory suggests that human mutations appear faster than natural selection can purge them, meaning that there is currently no satisfactory explanation for why the buildup of deleterious mutations has not already led to the extinction of humans. We hypothesize that many slightly deleterious mutations are not purged, but are instead compensated for by larger-effect beneficial mutations at a different level of organization. This hypothesis would not only solve the long-standing puzzle of how human populations persist, but could also cause a ratchet of biological innovation and complexity. By combining three technical innovations, we have devised the first computational strategy capable of simulating evolution for realistically high population size and mutation rate for humans. We will conduct simulations to prove the viability of the compensation hypothesis; preliminary results suggest that it will be the first to explain population persistence. We will also develop a superior variant of the main (currently inadequate) alternative hypothesis of synergistic epistasis, to compare and synthesize. Our new model will also allow us to make inferences about the variation in mutation load among humans, to forecast the future of human mutation load under different scenarios, and to better understand the evolution of the high human mutation rate that underlies these findings. The primary deliverables of this proposal will be the publication of peer-reviewed scientific papers. The work will be further disseminated to its primary scientific audience through talks and twitter threads, and to a general audience through edits to relevant Wikipedia pages.
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