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)