Recent insights into the evolution of mutation rates in yeast

Melde, Robert H.; Bao, Kevin; Sharp, Nathaniel P.

doi:10.1016/j.gde.2022.101953

Cited by 9 publications

(3 citation statements)

References 99 publications

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“…Our experimental context was, of course, artificial, and the comparatively low mutation rate of the parental strain with intact error-free repair indicates that in the BY strain background error-free repair predominates. Mutation rate in different species, and even in different strains of the same species, can vary by at least an order of magnitude (Fijarczyk et al 2021;Jiang et al 2021;Melde et al 2022), and in most cases the mechanism for the variation is not understood. RAD5 was identified as the main causal locus for the mutation rate variation between the RM11-1a strain and the BY strain (Gou et al 2019), and we found that the rad5 allele in RM11-1a confers increased mutagenesis catalyzed by both Rad5-and PCNA-Ub-mediated error-prone repair.…”

Section: Mutagenic Repair Pathways Can Cause Natural Variation In Mut...mentioning

confidence: 99%

Two independent DNA repair pathways cause mutagenesis in template switching deficientSaccharomyces cerevisiae

Jiang

Medley

Brown

2023

Preprint

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Upon DNA replication stress, cells utilize the post-replication repair pathway to repair single-stranded DNA and maintain genome integrity. Post-replication repair is divided into two branches: error-prone translesion synthesis, signaled by PCNA mono-ubiquitination, and error-free template switching, signaled by PCNA poly-ubiquitination. In Saccharomyces cerevisiae, Rad5 is involved in both branches of repair during DNA replication stress. When the PCNA poly-ubiquitination function of Rad5 is disrupted, Rad5 recruits translesion synthesis polymerases to stalled replication forks, resulting in mutagenic repair. Details of how mutagenic repair is carried out, as well as the relationship between Rad5-mediated mutagenic repair and the canonical PCNA-mediated mutagenic repair, remain to be understood. We find that Rad5-mediated mutagenic repair requires the translesion synthesis polymerase ζ but does not require other yeast translesion polymerase activities. Furthermore, we show that Rad5-mediated mutagenic repair is independent of PCNA binding by Rev1 and so is separable from canonical mutagenic repair. In the absence of error-free template switching, both modes of mutagenic repair contribute additively to replication stress response in a replication timing-independent manner. Cellular contexts where error-free template switching is compromised are not simply laboratory phenomena, as we find that a natural variant in RAD5 is defective in PCNA poly-ubiquitination and therefore defective in error-free repair, resulting in Rad5- and PCNA-mediated mutagenic repair. Our results highlight the importance of Rad5 in regulating spontaneous mutagenesis and genetic diversity in S. cerevisiae through different modes of post-replication repair.

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Section: Mutagenic Repair Pathways Can Cause Natural Variation In Mut...mentioning

confidence: 99%

Two independent DNA repair pathways cause mutagenesis in template switching deficientSaccharomyces cerevisiae

Jiang

Medley

Brown

2023

Preprint

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“…Extensions of Fisher's model assuming a Gaussian fitness landscape predict that the current "adaptedness" of a genotype influences the variance of mutational fitness effects but not the average effect; this is because while relatively more beneficial mutations are available to a maladapted genotype, this is offset by an increase in the severity of deleterious mutations (17). Experimental tests of these predictions have yielded somewhat mixed results (21,22), which we review briefly below (see also (12,23)).…”

Section: Introductionmentioning

confidence: 99%

Mutations in yeast are deleterious on average regardless of the degree of adaptation to the testing environment

Bao,

Strayer,

Braker

et al. 2024

Preprint

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The role of spontaneous mutations in evolution depends on the distribution of their effects on fitness. Despite a general consensus that new mutations are deleterious on average, a handful of mutation accumulation experiments in diverse organisms instead suggest that of beneficial and deleterious mutations can have comparable fitness impacts, i.e., the product of their respective rates and effects can be roughly equal. We currently lack a general framework for predicting when such a pattern will occur. One idea is that beneficial mutations will be more evident in genotypes that are not well adapted to the testing environment. We tested this prediction experimentally in the laboratory yeast Saccharomyces cerevisiae by allowing nine replicate populations to adapt to novel environments with complex sets of stressors. After >1000 asexual generations interspersed with 41 rounds of sexual reproduction, we assessed the mean effect of induced mutations on yeast growth in both the environment to which they had been adapting and the alternative novel environment. The mutations were deleterious on average, with the severity depending on the testing environment. However, we find no evidence that the adaptive match between genotype and environment is predictive of mutational fitness effects.

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“…However, caution must be taken in transferring mutation rate estimates between different MA experiments. There is ample evidence that mutation rate is highly experiment-dependent even within a species, with substitution rates differing with strain ploidy, genetic background, and even the environmental conditions in which the mutation accumulation occurred [13][14][15][16]. Recent work using either direct measurement of accumulated mutation number in phenotyped MA lines in Chlamydomonas reinhardtii [17], Drosophila melanogaster [18], mice [19], and Escherichia coli [20] or measuring mutation number and phenotype in parallel MA experiments in a mismatch repair-deficient strain of E. coli [21] has provided more precise estimates of the distribution of mutational effect size in these species.…”

Section: Introductionmentioning

confidence: 99%

Spontaneous single-nucleotide substitutions and microsatellite mutations have distinct distributions of fitness effects

Plavskin

Biase

Ziv

et al. 2023

Preprint

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The fitness effects of new mutations determine key properties of evolutionary processes. Beneficial mutations drive evolution, yet selection is also shaped by the frequency of small-effect deleterious mutations, whose combined effect can burden otherwise adaptive lineages and alter evolutionary trajectories and outcomes in clonally evolving organisms such as viruses, microbes, and tumors. The small effect sizes of these important mutations have made accurate measurements of their rates difficult. In microbes, assessing the effect of mutations on growth can be especially instructive, as this complex phenotype is closely linked to fitness in clonally evolving organisms. Here, we perform high-throughput time-lapse microscopy on cells from mutation-accumulation strains to precisely infer the distribution of mutational effects on growth rate in the budding yeast, Saccharomyces cerevisiae. We show that mutational effects on growth rate are overwhelmingly negative, highly skewed towards very small effect sizes, and frequent enough to suggest that deleterious hitchhikers may impose a significant burden on evolving lineages. By using lines that accumulated mutations in either wild-type or slippage repair-defective backgrounds, we further disentangle the effects of two common types of mutations, single-nucleotide substitutions and simple sequence repeat indels, and show that they have distinct effects on yeast growth rate. Although the average effect of a simple sequence repeat mutation is very small (~0.3%), many do alter growth rate, implying that this class of frequent mutations has an important evolutionary impact.

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Recent insights into the evolution of mutation rates in yeast

Cited by 9 publications

References 99 publications

Two independent DNA repair pathways cause mutagenesis in template switching deficientSaccharomyces cerevisiae

Two independent DNA repair pathways cause mutagenesis in template switching deficientSaccharomyces cerevisiae

Mutations in yeast are deleterious on average regardless of the degree of adaptation to the testing environment

Spontaneous single-nucleotide substitutions and microsatellite mutations have distinct distributions of fitness effects

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