deleterious mutation
Agrawal AF & Whitlock MC 2011 Inferences about the distribution of dominance drawn from yeast gene knockout data. Genetics 187:553-566.
- our approach allows us to quantify, for the first time, the substantial variance and skew in the distribution of dominance coefficients
- this heterogeneity is so great that many population genetic processes analyses based on the mean dominance coefficient alone will be in substantial error
- for deleterious mutations, the mean selection is E[s] = 0.045
- we find E[hdel] = 0.77
- it may be more useful to calculate an s-weighted average dominance
- Es[hdel] = Σhs / Σs
- we then find Es[hdel] = 0.205
- the mean is not very informative because of the variation in h
- even the mean value of h for a given s interval is not very informative because of the considerable variation and skew in the distribution
- our analysis provides strong evidence for a negative relationship between h and s
- alleles are more likely to be recessive if they have strong homozygous effects
- the mean dominance coefficient over all mutations that have a deleterious effect on fitness from these data is ~0.8
- this high average dominance is due to the estimated high h values for very weakly selected loci
- when the average h value is weighted by s, the mean shrinks to ~0.2
- this latter number is qualitatively similar to the mean values obtained over a larger range of studies
- the typical mutation that affects fitness is moderately, but not completely, recessive
- more novel is the observation of a great deal of variation masked by these averages
- a broad range of dominance coefficients are observed for all values of the selection coefficient
- this is the first study that attempts to quantify higher moments of the h distribution
- one of the surprises of this analysis was the strong positive skew, indicating that the modal value of h is lower than the mean
- Caballero and Keightley (1994) made some inferences about the joint distribution of h and s
- they proposed that h, for a given s, was uniformly distributed between 0 and exp(−Ks)
- our results indicate that, for a given s, values of h are not uniformly distributed but rather strongly skewed
- the Caballero and Keightley model predicts a decline in the variance in h with increasing s
- we found no support for such a decline in the yeast data set
- the observed variance and positive skew in h would result in more inbreeding depression than expected on the basis of average dominance
- it is necessary to use the harmonic mean of h to properly account for the variation in h when predicting the effects of inbreeding across the genome
- our analysis suggests that the harmonic mean of h is ~0.18, thus predicting reasonably strong positive inbreeding depression
- the correlation between h and s is strong enough that the predicted change in mean fitness during purging is ~3.5 times greater than that predicted using approximations based on the mean h and mean s
- the expected change in inbreeding depression is of much larger magnitude and of opposite sign when accounting for the relationship between h and s than would be erroneously predicted using the mean values of these quantities
- in our survey of the yeast data, we find a strong relationship between h and s, as first reported by Phadnis and Fry (2005)
- our estimated relationship between h and s is similar to that inferred by Deng and Lynch (1996)