Contamination of the genome by very slightly deleterious mutations: why have we not died 100 times over?

It is well known that whens,the selection coefficient against a deleterious mutation, is below ≈ 1/4Ne, whereNeis the effective population size, the expected frequency of this mutation is ≈ 0.5, if forward and backward mutation rates are similar. Thus, if the genome size,G,in nucleotides substantially exceeds theNeof the whole species, there is a dangerous range of selection coefficients, 1/G< s<//E2>< 1/4Ne. Mutations withswithin this range are neutral enough to accumulate almost freely, but are still deleterious enough to make an impact at the level of the whole genome. In many vertebratesNe≈ 104, whileG≈ 109, so that the dangerous range includes more than four orders of magnitude. If substitutions at 10% of all nucleotide sites have selection coefficients within this range with the mean 10−6, an average individual carries ≈ 100 lethal equivalents. Some data suggest that a substantial fraction of nucleotides typical to a species may, indeed, be suboptimal. When selection acts on different mutations independently, this implies to high a mutation load. This paradox cannot be resolved by invoking beneficial mutations or environmental fluctuations. Several possible resolutions are considered, including soft selection and synergistic epistasis among very slightly deleterious mutations.