Thursday 8 October 2015

Rate of deleterious mutations per generation, expected decline in fitness per generation - estimates from Michael Lynch

From Michael Lynch. Rate, molecular spectrum and consequences of human mutation. PNAS 2010; 107: 961-8. 

What is the likely magnitude of the per-generation loss in human fitness caused by recurrent introduction of deleterious mutations? From the present results, we infer that an average human gamete acquires approximately 38 de novo base-substitution mutations, approximately three small insertion/deletions in complex sequence, and approximately one splicing mutation. Transposable-element insertions, microsatellite instabilities, and segmental duplications and deletions of total or partial gene sequences will almost certainly sum to several additional events per gamete, so it is likely that an average newborn acquires a total of 50 to 100 new mutations at the diploid level, a small subset of which must be deleterious.

The net fitness consequences of human mutations remain unclear and will likely continue to be a major challenge, but some general arguments allow an order-of-magnitude assessment of the situation. Using rather different approaches, Yampolsky et al. and Eyre-Walker et al. have derived similar estimates of the distribution of fitness effects of new amino acid altering base-substitution mutations: approximately 11% cause fractional reductions in heterozygote fitness with s < 10−5, 12% with 10−5 < s < 10−4, 50% with 10−4 < s < 10−2, and 27% with s > 10−2, with an overall average selective disadvantage of approximately 0.04. Only approximately 1.5% of the human genome consists of coding DNA and approximately 25% of coding sites are silent, so we expect approximately 0.86 novel amino acid altering mutations per newborn. Approximately 5% of such mutations will lead to nonsense mutations, many of which will likely be in the category of s > 10−2, but the remaining 95% will be missense in nature, with deleterious fitness effects averaging approximately 4% or less according to these results. Thus, with a complete relaxation of natural selection, the expected decline in fitness associated with mutations in coding DNA alone appears to be on the order of 1% to 3% per generation.

Less clear is the added contribution from other forms of mutations. The vast majority of point mutations reside outside of coding regions (on the order of 40 per gamete), and it is likely that most of these will have very minor fitness effects, with average s almost certainly << 10−2. Nevertheless, Eöry et al. make a compelling case that approximately 4% of intergenic, 15% of UTR, and 22% of silent sites are under weak purifying selection in humans, which is consistent with the arguments presented above for base-composition selection. Most major deletions and splicing mutations are probably highly deleterious, as they will generally render their host genes nonfunctional. Most transposable-element insertions and gene duplications appear to be at least weakly deleterious; the average deleterious effects of such mutations are likely to be at least 1% per event, and as noted earlier, at least one such event is likely to arise per zygote per generation. Thus, although there is considerable uncertainty in the preceding numbers, it is difficult to escape the conclusion that the per-generation reduction in fitness due to recurrent mutation is at least 1% in humans and quite possibly as high as 5%.

Although such a mutational buildup would be unnoticeable on a generation timescale, over the course of a couple of centuries (approximately six generations), the consequences are likely to become serious, particularly if human activities cause an increase in the mutation rate itself (by increasing levels of environmental mutagens). A doubling in the mutation rate would imply a 2% to 10% decline in fitness per generation, and by extension, a 12% to 60% decline in 200 years... 

Unfortunately, it has become increasingly clear that most of the mutation load is associated with mutations with very small effects distributed at unpredictable locations over the entire genome, rendering the prospects for long-term management of the human gene pool by genetic counseling highly unlikely for all but perhaps a few hundred key loci underlying debilitating monogenic genetic disorders (such as those focused on in the present study)…