CONTAMINATION OF THE GENOME BY VERY SLIGHTLY DELETERIOUS MUTATIONS - WHY HAVE WE NOT DIED 100 TIMES OVER

It is well known that when s, the selection coefficient against a dele terious mutation, is below similar to 1/4N(e), where N-e is the effect ive population size, the expected frequency of this mutation is simila r to 0.5, if forward and backward mutation rates are similar. Thus, if the genome size, G, in nucleotides substantially exceeds the N-e of t he whole species, there is a dangerous range of selection coefficients , 1/G < s < 1/4N(e). Mutations with s within this range are neutral en ough to accumulate almost freely, but are still deleterious enough to make an impact at the level of the whole genome. In many vertebrates N -e approximate to 10(4), while G approximate to 10(9), so that the dan gerous range includes more than four orders of magnitude. If substitut ions at 10% of all nucleotide sites have selection coefficients within this range with the mean 10(-6), an average individual carries simila r to 100 lethal equivalents. Some data suggest that a substantial frac tion of nucleotides typical to a species may, indeed, be suboptimal. W hen selection acts on different mutations independently, this implies too high a mutation load. This paradox cannot be resolved by invoking beneficial mutations or environmental fluctuations. Several possible r esolutions are considered, including soft selection and synergistic ep istasis among very slightly deleterious mutations. (C) 1995 Academic P ress Limited