Quantifying the mutational process

• Main Author: Halligan, Daniel L.
• Published: University of Edinburgh 2004
• Subjects: 572.8
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.651982

A novel DAN-based method was used to infer levels of evolutionary constraints in the <i>Drosophila</i> genome by comparing rates of nucleotide substitution in non-coding and putatively neutrally evolving DNA. Introns were found to have a significantly higher rate of substitution than synonymous sites, and, when introns were used as a neutrally evolving standard, constraint in the 500bp of intergenic DNA upstream and downstream of coding regions was found to be about 44%. Selection against mutations in intergenic DNA should therefore make a substantial contribution to the mutational load in <i>Drosophila</i>. Secondly, a fitness- based approach was used to estimate mutational parameters in lines of <i>Caenorhabditis elegans</i> containing large numbers of deleterious homozygous EMS-induced mutations. Replicated inbred sublines were produced for eight mutant lines, and the performance of the sublines, the mutant lines and the wild-type strain was measured for three fitness-related traits. The number of mutations per line was then estimated for each trait by applying a modified version of the Castle-Wright estimator and a maximum likelihood (ML) method. Both the Castle-Wright and the ML analyses suggest that most of the variation among sublines was due to a small number (~1.5-2.5) of large-effect mutations, given that each line is expected to have a large number of mutations, this supports the hypothesis that many have very small (but still deleterious) effects. The average dominance coefficient of mildly deleterious mutations was estimated from a selection of 19 relatively high fitness mutant lines by comparing the performance of heterozygotes and homozygotes to the wild-type for three fitness-related traits (viability, productivity, and relative fitness). There was very little effect of mutations on viability, but for productivity and relative fitness was found to be ~0.1. Combined with the conclusion that most homozygous mutations have very mild effects, this suggests that many newly arising deleterious mutations may have very small heterozygous effects indeed.