deleterious mutation

Charlesworth B, Borthwick H, Bartolomé C & Pignatelli P 2004 Estimates of the genomic mutation rate for detrimental alleles in Drosophila melanogaster. Genetics 167:815-826.

  • there is a detectable decline in mean viability associated with the accumulation of detrimental mutations on chromosome 3 of D. melanogaster
  • there are likely to be at least 0.12 new detrimental mutations arising per diploid genome per generation
  • the results do not confirm the very high estimates of the genomic deleterious mutation rate reported by Mukai and co-workers (Mukai 1964; Mukai et al. 1972)
  • but are substantially higher than some more recent estimates (García-Dorado 1997; Avilá and García-Dorado 2002)
  • it seems reasonable to accept a U* of 12–30% as an estimate for the diploid genome of D. melanogaster, on the basis of these results and those of Fry (2001) and Fry and Heinsohn (2002)
  • the true diploid mutation rate to detrimental alleles, U, will be much higher than this, if there is a wide distribution of fitness effects of mutations (Mukai et al. 1972; García-Dorado and Gallego 2003)
  • especially since only viability mutations have been accounted for in these experiments
  • with an exponential distribution of mutational effects, the true value of U would be twice our estimate, and the mean value of the selection coefficient would be one-half our estimate
  • there is thus still considerable uncertainty concerning the value of the per genome deleterious mutation rate, U, for detrimental alleles in D. melanogaster
  • it seems clear that suggestions that it is of the order of only 2–3% (Caballero and Keightley 1998; Avilá and García-Dorado 2002) are inconsistent with the more recent reappraisals of the data on balancer-based experiments, as well as with the present study
  • estimates based on amino acid sequence comparisons between species indicate that U cannot be <6–8% for D. melanogaster (Keightley and Eyre-Walker 2000)
  • the values of s* for the quasi-normal lines in our experiment are poorly estimated by the regression method (Table 4)
  • except for experiment 2, which yields a value of ~2%
  • these are in any case upper bounds to the mean selection coefficients
  • much higher values (of the order of 10%) are obtained from the revised order method (Table 2), but these are likely to be even more upwardly biased
  • as has been pointed out before (Keightley and Eyre-Walker 1999), mutations with small effects on fitness, such as are likely to be caused by most amino acid substitutions or nucleotide substitutions in regulatory sequences, will not contribute significantly do DM or DV in mutation-accumulation experiments
  • this suggests that transposable element (TE) insertions and insertion/deletion mutations, which are more likely than point mutations to severely disrupt the function of coding and regulatory sequences, may contribute many of the deleterious mutations detected by D. melanogaster MA experiments
  • no evidence for any significant quadratic terms was obtained
  • the high level of synergism estimated by Mukai (1969) cannot easily be reconciled with evidence from measurements of inbreeding load (Charlesworth 1998)
  • there is only weak evidence for widespread synergistic effects of detrimental mutations (Rivero et al. 2003; Szafraniec et al. 2003)