A molecular approach to estimating the human deleterious mutation rate

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 N n = 2(2 × 10 −8 )(3 × 10 9 ) ≈ 10 2 , 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 T f s . If f s > 0.01, U S > 1, which would have important implications for human genetics and evolutionary biology. © 1993 Wiley‐Liss, Inc.