Accelerating Mutational Load Is Not Due to Synergistic Epistasis or Mutator Alleles in Mutation Accumulation Lines of Yeast

Jasmin, Jean-Nicolas; Lenormand, Thomas

doi:10.1534/genetics.115.182774

Cited by 11 publications

(5 citation statements)

References 78 publications

(81 reference statements)

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“…We further suppose that the “dark matter” represented by the (assumed) missing fraction of indels in the low-fitness lines would amplify the difference in average selective effects. These results represent some of the first direct evidence that spontaneous mutations interact synergistically, on average (see also Jasmin and Lenormand 2016).…”

Section: Discussionsupporting

confidence: 64%

Evolution of the mutational process under relaxed selection inCaenorhabditis elegans

Saxena

Salomon

Matsuba

et al. 2018

Preprint

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The mutational process varies at many levels, from within genomes to among taxa. Many mechanisms have been linked to variation in mutation, but understanding of the evolution of the mutational process is rudimentary. Physiological condition is often implicated as a source of variation in microbial mutation rate and may contribute to mutation rate variation in multicellular organisms.Deleterious mutations are a ubiquitous source of variation in condition. We test the hypothesis that the mutational process depends on the underlying mutation load in two groups of Caenorhabditis elegans mutation accumulation (MA) lines that differ in their starting mutation loads. “First-Order MA” (O1MA) lines maintained under minimal selection for ∼250 generations were divided into high-fitness and low-fitness groups and sets of “second-order MA” (O2MA) lines derived from each O1MA line were maintained for ∼150 additional generations. Genomes of 48 O2MA lines and their progenitors were sequenced. There is significant variation among O2MA lines in base-substitution rate (µbs), but no effect of initial fitness, whereas the indel rate is greater in high-fitness O2MA lines. Overall, µbs is positively correlated with recombination and proximity to short tandem repeats and negatively correlated with 10 bp and 1 Kb GC content. However, probability of mutation is well-predicted by the three-nucleotide motif. ∼90% of the variance in standing nucleotide variation is explained by mutability. Total mutation rate increased in the O2MA lines, as predicted by the “drift barrier” model of mutation rate evolution. These data, combined with experimental estimates of fitness, suggest that epistasis is synergistic.

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Section: Discussionsupporting

confidence: 64%

Evolution of the mutational process under relaxed selection inCaenorhabditis elegans

Saxena

Salomon

Matsuba

et al. 2018

Preprint

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“…Mutational bias occurs when the distribution of phenotypic effects depends on genetic background and thus when there are non-additive and epistatic effects between the de novo MA and the fixed genetic background ( Halligan and Keightley 2009 ; Jones et al 2014 ; Saxena et al 2018 ; Schweizer and Wagner 2020 ). In our case, however, one should be cautious in interpreting the presence of epistasis because the phenotypic effect distribution of new mutations was barely sampled ( Keightley et al 2000 ; Peters and Keightley 2000 ; Jasmin and Lenormand 2016 ). Given the number of generations in any MA experiment and the small number of lines assayed here, each MA line carries an idiosyncratic number of mutations that do not comprehensibly target the QTL underlying presumed polygenic traits such as locomotion behavioral traits.…”

Section: Discussionmentioning

confidence: 86%

Variation in mutational (co)variances

Mallard

Noble

Baer

et al. 2022

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Because of pleiotropy, mutations affect the expression and inheritance of multiple traits and, together with selection, are expected to shape standing genetic covariances between traits and eventual phenotypic divergence between populations. It is therefore important to find if the M matrix, describing mutational variances of each trait and covariances between traits, varies between genotypes. We here estimate theMmatrix for six locomotion behavior traits in lines of two genotypes of the nematode Caenorhabditis elegans that accumulated mutations in a nearly-neutral manner for 250 generations. We find significant mutational variance along at least one phenotypic dimension of the M matrices, but neither their size nor their orientation had detectable differences between genotypes. The number of generations of mutation accumulation, or the number of MA lines measured, was likely insufficient to sample enough mutations and detect potentially small differences between the two M matrices. We then tested if the M matrices were similar to one G matrix describing the standing genetic (co)variances of a population derived by the hybridization of several genotypes, including the two measured for M, and domesticated to a lab-defined environment for 140 generations. We found that the M and G were different because the genetic covariances caused by mutational pleiotropy in the two genotypes are smaller than those caused by linkage disequilibrium in the lab population. We further show that M matrices differed in their alignment with the lab population G matrix. If generalized to other founder genotypes of the lab population, these observations indicate that selection does not shape the evolution of the M matrix for locomotion behavior in the short-term of a few tens to hundreds of generations and suggests that the hybridization of C. elegans genotypes allows selection on new phenotypic dimensions of locomotion behavior.

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“…Mutation load can be purged with reduced effects on population growth rate if mutations interact epistatically, although there is little empirical evidence for this (Agrawal and Whitlock ; Jasmin and Lenormand ). We suggest that our results are consistent with synergistic epistasis where selective death occurs in individuals with a mutation load above a threshold, or that selective death increases with mutation load.…”

Section: Resultsmentioning

confidence: 99%

Do slower movers have lower reproductive success and higher mutation load?

Walsh

McGuigan

2018

Evolution Letters

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Deleterious mutations occur frequently in eukaryotes, resulting in individuals carrying multiple alleles that decrease their fitness. At a population level, if unchecked, accumulation of this mutation load can ultimately lead to extinction. How selection counters the accumulation of mutation load, limiting declines in population fitness, is not well understood. Here, we use manipulative experiments in zebrafish (Danio rerio) to investigate the opportunities for selection on mutation load. Inducing high mutation load through mutagenesis, we applied one generation of within‐family selection on locomotor performance and characterized both the direct response to this selection and the indirect response of reproductive success. Offspring of slow swimming parents exhibited age‐dependent declines in swimming speed, whereas their cousins, with faster swimming parents, did not. This pattern mimics previously documented differences between high and low mutation load populations of zebrafish, suggesting that slow swimming siblings inherited (and transmitted) more mutations than their faster swimming siblings. Crosses among offspring of slow swimming fish had, on average, <75% of the reproductive success of crosses among offspring of fast swimming parents, or crosses of offspring of slow swimmers with offspring of fast swimmers. This evidence of mutationally correlated swimming speed and reproductive success reveals the potential for concordant selection on mutation load through different fitness components. There was no evidence that crosses within families (where parents potentially shared the same mutations inherited from their common ancestor) had lower reproductive success than crosses among families, suggesting that viability selection was not acting predominantly through lethal recessive homozygotes. Rather, patterns of reproductive success are suggestive of effects of mutation number per se on embryo viability. Overall, our results highlight the potential for early life mortality to remove deleterious mutations, and the need to account for this mortality when investigating the evolutionary dynamics of mutation load.

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Accelerating Mutational Load Is Not Due to Synergistic Epistasis or Mutator Alleles in Mutation Accumulation Lines of Yeast

Cited by 11 publications

References 78 publications

Evolution of the mutational process under relaxed selection inCaenorhabditis elegans

Evolution of the mutational process under relaxed selection inCaenorhabditis elegans

Variation in mutational (co)variances

Do slower movers have lower reproductive success and higher mutation load?

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