Effect of mutation mechanisms on variant composition and distribution in Caenorhabditis elegans

Genetic diversity is maintained by continuing generation and removal of variants. While examining over 800,000 DNA variants in wild isolates of Caenorhabditis elegans, we made a discovery that the proportions of variant types are not constant across the C. elegans genome. The variant proportion is defined as the fraction of a specific variant type (e.g. single nucleotide polymorphism (SNP) or indel) within a broader set of variants (e.g. all variants or all non-SNPs). The proportions of most variant types show a correlation with the recombination rate. These correlations can be explained as a result of a concerted action of two mutation mechanisms, which we named Morgan and Sanger mechanisms. The two proposed mechanisms act according to the distinct components of the recombination rate, specifically the genetic and physical distance. Regression analysis was used to explore the characteristics and contributions of the two mutation mechanisms. According to our model, ~20–40% of all mutations in C. elegans wild populations are derived from programmed meiotic double strand breaks, which precede chromosomal crossovers and thus may be the point of origin for the Morgan mechanism. A substantial part of the known correlation between the recombination rate and variant distribution appears to be caused by the mutations generated by the Morgan mechanism. Mathematically integrating the mutation model with background selection model gives a more complete depiction of how the variant landscape is shaped in C. elegans. Similar analysis should be possible in other species by examining the correlation between the recombination rate and variant landscape within the context of our mutation model.Author Summary: DNA variants in the world population of a species reflect the genetic diversity of the species. While examining variants in whole-genome sequenced wild isolates of the nematode worm Caenorhabditis elegans, we discovered apparent correlations between the recombination rate and the proportion of many variant types. To explain this correlation, we present a model of a concerted action of two groups of mutation mechanisms, which act according to different components of the recombination rate. This model can also explain how mutation mechanisms as a whole can affect the genomic landscape of the variant distribution. Using this mutation model, we systemically and holistically estimate the probabilities of generating specific mutation types by distinct groups of mutation mechanisms in C. elegans. Since this mutation model can be mathematically combined with existing natural selection models, such as background selection, a more comprehensive analysis of genetic diversity is now possible. We expect that the mathematical equations we present here can be used for refining computer simulations of evolution and coalescent modeling. Within the context of this mutation model, the correlation between the recombination rate and the proportion of variant types may serve as a useful new metric for analysis of genetic diversity in other species.