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

Oman, Madeleine; Alam, Aqsa; Ness, Rob W.

doi:10.1093/gbe/evac032

Cited by 16 publications

(10 citation statements)

References 24 publications

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“…Moreover, adaptive dynamics have been evoked to explain the differences in the recombination landscape between populations of D. pseudoobscura, (Samuk et al, 2020). It will be interesting to test whether mutation events follow similar patterns, now that the impact of various sequence motifs on local μ is being more thoroughly investigated (DeWitt et al, 2021;Kim et al, 2021;Oman et al, 2022). Unraveling the factors that shape the mutation landscape at different genomic scales will likely provide important insight.…”

Section: Discussionmentioning

confidence: 99%

The landscape of nucleotide diversity in Drosophila melanogaster is shaped by mutation rate variation

Barroso¹,

Dutheil²

2023

Peer Community Journal

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What shapes the distribution of nucleotide diversity along the genome? Attempts to answer this question have sparked debate about the roles of neutral stochastic processes and natural selection in molecular evolution. However, the mechanisms of evolution do not act in isolation, and integrative models that simultaneously consider the influence of multiple factors on diversity are lacking; without them, confounding factors lurk in the estimates. Here we present a new statistical method that jointly infers the genomic landscapes of genealogies, recombination rates and mutation rates. In doing so, our model captures the effects of genetic drift, linked selection and local mutation rates on patterns of genomic variation. We then formalize a causal model of how these microevolutionary mechanisms interact, and cast it as a linear regression to estimate their individual contributions to levels of diversity along the genome. Our analyses reclaim the well-established signature of linked selection in Drosophila melanogaster, but we estimate that the mutation landscape is the major driver of the genome-wide distribution of diversity in this species. Furthermore, our simulation results suggest that in many evolutionary scenarios the mutation landscape will be a crucial factor shaping diversity, depending notably on the genomic window size. We argue that incorporating mutation rate variation into the null model of molecular evolution will lead to more realistic inferences in population genomics.

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Section: Discussionmentioning

confidence: 99%

The landscape of nucleotide diversity in Drosophila melanogaster is shaped by mutation rate variation

Barroso¹,

Dutheil²

2023

Peer Community Journal

View full text Add to dashboard Cite

show abstract

“…5 of Stoltzfus 2021), to ideas about “directed” or “smart” mutation systems (Roth et al, 2006). New thinking continues to emerge on these and related topics, e.g., Oman et al (2022) explore the issue of what happens to the mutation rate and pattern as a genome evolves under context-dependent mutation. In adaptive walks, simply reversing mutation biases partway through the walk appears to improve adaptation by shifting the de novo distribution in favor of previously low rate beneficial mutations that have not yet had the chance to fix (Sane et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

Mutation and selection induce correlations between selection coefficients and mutation rates

Gitschlag

Cano

Payne

et al. 2023

Preprint

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The joint distribution of selection coefficients and mutation rates is a key determinant of the genetic architecture of molecular adaptation. Three different distributions are of immediate interest: (1) thenominaldistribution of possible changes, prior to mutation or selection, (2) thede novodistribution of realized mutations, and (3) thefixeddistribution of selectively established mutations. Here, we formally characterize the relationships between these joint distributions under the strong selection, weak mutation (SSWM) regime. Thede novodistribution is enriched relative to the nominal distribution for the highest rate mutations, and the fixed distribution is further enriched for the most highly beneficial mutations. Whereas mutation rates and selection coefficients are often assumed to be uncorrelated, we show that even with no correlation in the nominal distribution, the resultingde novoand fixed distributions can have correlations with any combination of signs. Nonetheless, we suggest that natural systems with a finite number of beneficial mutations will frequently have the kind of nominal distribution that induces negative correlations in the fixed distribution. We apply our mathematical framework, along with population simulations, to explore joint distributions of selection coefficients and mutation rates from deep mutational scanning and cancer informatics. Finally, we consider the evolutionary implications of these joint distributions together with two additional joint distributions relevant to parallelism and the rate of adaptation.

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“…Moreover, adaptive dynamics have been evoked to explain the differences in the recombination landscape between populations of Drosophila pseudoobscura , (Samuk et al, 2020). It will be interesting to test whether mutation events follow similar patterns, now that the impact of various sequence motifs on local μ is being more thoroughly investigated (DeWitt et al, 2021; Kim et al, 2021; Oman et al, 2022). Unraveling the factors that shape the mutation landscape at different genomic scales will likely provide important insight.…”

Section: Discussionmentioning

confidence: 99%

The landscape of nucleotide diversity inDrosophila melanogasteris shaped by mutation rate variation

Barroso

Dutheil

2021

Preprint

View full text Add to dashboard Cite

What shapes the distribution of nucleotide diversity along the genome? Attempts to answer this question have sparked debate about the roles of neutral stochastic processes and natural selection in molecular evolution. However, the mechanisms of evolution do not act in isolation, and integrative models that simultaneously consider the influence of multiple factors on diversity are lacking; without them, confounding factors lurk in the estimates. Here we present a new statistical method that jointly infers the genomic landscapes of genealogies, recombination rates and mutation rates. In doing so, our model captures the effects of genetic drift, linked selection and local mutation rates on patterns of genomic variation. Guided by our causal model, we use linear regression to estimate the individual contributions of these micro-evolutionary forces to levels of nucleotide diversity. Our analyses reveal the signature of selection in Drosophila melanogaster, but we estimate that the mutation landscape is the major driver of the distribution of diversity in this species. Furthermore, our simulation study suggests that in many evolutionary scenarios the mutation landscape will be a crucial force shaping diversity, depending notably on the genomic window size used in the analysis. We argue that incorporating mutation rate variation into the null model of molecular evolution will lead to more realistic inference in population genomics.

show abstract

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

Cited by 16 publications

References 24 publications

The landscape of nucleotide diversity in Drosophila melanogaster is shaped by mutation rate variation

The landscape of nucleotide diversity in Drosophila melanogaster is shaped by mutation rate variation

Mutation and selection induce correlations between selection coefficients and mutation rates

The landscape of nucleotide diversity inDrosophila melanogasteris shaped by mutation rate variation

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