Mutability of mononucleotide repeats, not oxidative stress, explains the discrepancy between laboratory-accumulated mutations and the natural allele-frequency spectrum inC. elegans

Abstract

Important clues about natural selection can be gleaned from discrepancies between the properties of segregating genetic variants and of mutations accumulated experimentally under minimal selection, provided the mutational process is the same in the laboratory as in nature. The base-substitution spectrum differs between C. elegans laboratory mutation accumulation (MA) experiments and the standing site-frequency spectrum, which has been argued to be in part owing to increased oxidative stress in the laboratory environment. Using genome sequence data from C. elegans MA lines carrying a mutation (mev-1) that increases the cellular titer of reactive oxygen species (ROS), leading to increased oxidative stress, we find the base-substitution spectrum is similar between mev-1, its wild-type progenitor (N2), and another set of MA lines derived from a different wild strain (PB306). Conversely, the rate of short insertions is greater in mev-1, consistent with studies in other organisms in which environmental stress increased the rate of insertion–deletion mutations. Further, the mutational properties of mononucleotide repeats in all strains are different from those of nonmononucleotide sequence, both for indels and base-substitutions, and whereas the nonmononucleotide spectra are fairly similar between MA lines and wild isolates, the mononucleotide spectra are very different, with a greater frequency of A:T → T:A transversions and an increased proportion of ±1-bp indels. The discrepancy in mutational spectra between laboratory MA experiments and natural variation is likely owing to a consistent (but unknown) effect of the laboratory environment that manifests itself via different modes of mutability and/or repair at mononucleotide loci.

Whole-Genome Sequencing Reveals Germ Cell Mutagenicity of α-Endosulfan in Caenorhabditis elegans

“…Further analysis of mutation spectra revealed that G:C → A:T transitions (24.68%) and A:T → T:A transversions (22.08%) are two kinds of dominant mutations in the control group. These results are generally in line with previous findings in C. elegans, 36,37 indicating a consistency of MA in worms under normal culture conditions. Treatment of parental worms with α-endosulfan increased the MF (5.07 mutations per genome) of progeny, unveiling the mutagenic effects of α-endosulfan on germ cells.…”

“…Further analysis of mutation spectra revealed that G:C → A:T transitions (24.68%) and A:T → T:A transversions (22.08%) are two kinds of dominant mutations in the control group. These results are generally in line with previous findings in C. elegans , , indicating a consistency of MA in worms under normal culture conditions.…”

Variation in mutational (co)variances

“…Our first finding is that the two M matrices of the N2 and PB306 genotypes are similar in size and orientation, though the N2 M matrix tends to be larger and more eccentric than the one from PB306. This result is in itself not too surprising given that both genotypes showed similar mutation rates and molecular spectra, except perhaps for the X chromosome, when a subset of MA lines from the two genotypes were whole-genome sequenced (Denver et al, 2012; Rajaei et al, 2021). Another study using the same two sets of MA lines used here showed that the mutational correlations between vulval and fitness-related traits, when significant, was similar in sign and magnitude among genotypes (Braendle et al, 2010).…”

How Sequence Context-Dependent Mutability Drives Mutation Rate Variation in the Genome

“…Even though our model is based on human mutations, similar variation is seen in other species. In addition to the 75-fold trinucleotide mutability variation found in mismatch-repair-deficient Bacillus subtilis ( Sung et al 2015 ), we calculated similar trinucleotide mutability models for other organisms with sufficiently large mutation accumulation data sets and found 20-fold global mutability variation in Chlamydomonas reinhardtii ( Ness et al 2015 , n = 6,843), 12-fold in Saccharomyces cerevisiae ( Zhu et al 2014 , n = 867), 9–21-fold in Caenorhabditis elegans ( Rajaei et al 2021 , n = 770–3,434), and 55-fold in Mus musculus ( Lindsay et al 2019 , n = 764). Therefore, although the results we present here are focused on a human model, it seems reasonable that similar processes could apply across a broad range of organisms.…”