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

Each new human has an expected U(d) = 2 – 10 new deleterious mutations. This deluge of deleterious mutations cannot all be purged, and therefore accumulate in a declining fitness ratchet. Using a novel simulation framework designed to efficiently handle genome-wide linkage disequilibria across many segregating sites, we find that rarer, beneficial mutations of larger effect are sufficient to compensate fitness declines due to the fixation of many slightly deleterious mutations. Drift barrier theory posits a similar asymmetric pattern of fixations to explain ratcheting genome size and complexity, but in our theory, the cause is U(d) > 1 rather than small population size. In our simulations, U(d) ~2 – 10 generates high within-population variance in relative fitness; two individuals will typically differ in fitness by 15–40%. U(d) ~2 – 10 also slows net adaptation by ~13%−39%. Surprisingly, fixation rates are more sensitive to changes in the beneficial than the deleterious mutation rate, e.g. a 10% increase in overall mutation rate leads to faster adaptation; this puts to rest dysgenic fears about increasing mutation rates due to rising paternal age.