A molecular approach to estimating the human deleterious mutation rate

Abstract

We propose a method of measuring the human genomic deleterious mutation rate based on comparison of the rate of evolution per nucleotide per generation of neutral sequences, μ_N, with the overall rate of evolution of unique sequence DNA, μ_o. Data on μ_N, which are based on pseudogenes, permit an estimate of the total zygotic (twice the genomic) mutation rate, U_T = 2μ_Nn = 2(2 × 10⁻⁸)(3 × 10⁹) ≈ 10², where n is the number of nucleotides per genome. Data on μ_O can be obtained by comparison of representative samples of relatively short homologous sequences from the genomes of Homo and a related species. The fraction of the genome that is controlled by negative selection is f_s = (μ_N -μ_o)/μ_N and the deleterious zygotic mutation rate, the expected number of new deleterious alleles carried by a zygote, is U_s = U_Tf_s. If f_s > 0.01, U_S > 1, which would have important implications for human genetics and evolutionary biology.