Rates and Fitness Consequences of New Mutations in Humans

Abstract

Abstract The human mutation rate per nucleotide site per generation (μ) can be estimated from data on mutation rates at loci causing Mendelian genetic disease, by comparing putatively neutrally evolving nucleotide sequences between humans and chimpanzees and by comparing the genome sequences of relatives. Direct estimates from genome sequencing of relatives suggest that μ is about 1.1 × 10−8, which is about twofold lower than estimates based on the human–chimp divergence. This implies that an average of ∼70 new mutations arise in the human diploid genome per generation. Most of these mutations are paternal in origin, but the male:female mutation rate ratio is currently uncertain and might vary even among individuals within a population. On the basis of a method proposed by Kondrashov and Crow, the genome-wide deleterious mutation rate (U) can be estimated from the product of the number of nucleotide sites in the genome, μ, and the mean selective constraint per site. Although the presence of many weakly selected mutations in human noncoding DNA makes this approach somewhat problematic, estimates are U ≈ 2.2 for the whole diploid genome per generation and ∼0.35 for mutations that change an amino acid of a protein-coding gene. A genome-wide deleterious mutation rate of 2.2 seems higher than humans could tolerate if natural selection is “hard,” but could be tolerated if selection acts on relative fitness differences between individuals or if there is synergistic epistasis. I argue that in the foreseeable future, an accumulation of new deleterious mutations is unlikely to lead to a detectable decline in fitness of human populations.