A MOLECULAR APPROACH TO ESTIMATING THE HUMAN DELETERIOUS MUTATION-RATE

We propose a method of measuring the human genomic deleterious mutatio n rate based on comparison of the rate of evolution per nucleotide per generation of neutral sequences, mu(N), with the overall rate of evol ution of unique sequence DNA, mu(O). Data on mu(N), which are based on pseudogenes, permit an estimate of the total zygotic (twice the genom ic) mutation rate, U(T) = 2mu(N)n = 2(2 x 10(-8))(3 x 10(9)) almost-eq ual-to 10(2), where n is the number of nucleotides per genome. Data on mu(O), can be obtained by comparison of representative samples of rel atively short homologous sequences from the genomes of Homo and a rela ted species. The fraction of the genome that is controlled by negative selection is f(S) = (mu(N) -mu(O))/mu(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 biolo gy. (C) 1993 Wiley-Liss, Inc.