Human deleterious mutation rate implies high fitness variance, with declining mean fitness compensated by rarer beneficial mutations of larger effect

Abstract

Each new human has an expected Ud = 2-10 new deleterious mutations. Using a novel approach to capture complex linkage disequilibria from high Ud using genome-wide simulations, we confirm that fitness decline due to the fixation of many slightly deleterious mutations can be compensated by rarer beneficial mutations of larger effect. The evolution of increased genome size and complexity have previously been attributed to a similarly asymmetric pattern of fixations, but we propose that the cause might be high Ud rather than the small population size posited as causal by drift barrier theory. High within-population variance in relative fitness is an inevitable consequence of high Ud[~]2-10 combined with inferred human deleterious effect sizes; two individuals will typically differ in fitness by 15-40%. The need to compensate for the deluge of deleterious mutations slows net adaptation (i.e. to the external environment) by [~]13%-55%. The rate of beneficial fixations is more sensitive to changes in the mutation rate than the rate of deleterious fixations is. As a surprising consequence of this, an increase (e.g. 10%) in overall mutation rate leads to faster adaptation; this puts to rest dysgenic fears about increasing mutation rates due to rising paternal age.