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A population genetics-phylogenetics approach to inferring natural selection in coding sequences.

ABSTRACT: Through an analysis of polymorphism within and divergence between species, we can hope to learn about the distribution of selective effects of mutations in the genome, changes in the fitness landscape that occur over time, and the location of sites involved in key adaptations that distinguish modern-day species. We introduce a novel method for the analysis of variation in selection pressures within and between species, spatially along the genome and temporally between lineages. We model codon evolution explicitly using a joint population genetics-phylogenetics approach that we developed for the construction of multiallelic models with mutation, selection, and drift. Our approach has the advantage of performing direct inference on coding sequences, inferring ancestral states probabilistically, utilizing allele frequency information, and generalizing to multiple species. We use a Bayesian sliding window model for intragenic variation in selection coefficients that efficiently combines information across sites and captures spatial clustering within the genome. To demonstrate the utility of the method, we infer selective pressures acting in Drosophila melanogaster and D. simulans from polymorphism and divergence data for 100 X-linked coding regions.

SUBMITTER: Wilson DJ

PROVIDER: S-EPMC3228810 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

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A population genetics-phylogenetics approach to inferring natural selection in coding sequences.

Wilson Daniel J DJ Hernandez Ryan D RD Andolfatto Peter P Przeworski Molly M

PLoS genetics 20111201 12

Through an analysis of polymorphism within and divergence between species, we can hope to learn about the distribution of selective effects of mutations in the genome, changes in the fitness landscape that occur over time, and the location of sites involved in key adaptations that distinguish modern-day species. We introduce a novel method for the analysis of variation in selection pressures within and between species, spatially along the genome and temporally between lineages. We model codon ev ...[more]

PMID: 22144911

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Project description:BackgroundCodon usage bias (CUB), the non-uniform usage of synonymous codons, occurs across all domains of life. Adaptive CUB is hypothesized to result from various selective pressures, including selection for efficient ribosome elongation, accurate translation, mRNA secondary structure, and/or protein folding. Given the critical link between protein folding and protein function, numerous studies have analyzed the relationship between codon usage and protein structure. The results from these studies have often been contradictory, likely reflecting the differing methods used for measuring codon usage and the failure to appropriately control for confounding factors, such as differences in amino acid usage between protein structures and changes in the frequency of different structures with gene expression.ResultsHere we take an explicit population genetics approach to quantify codon-specific shifts in natural selection related to protein structure in S. cerevisiae and E. coli. Unlike other metrics of codon usage, our approach explicitly separates the effects of natural selection, scaled by gene expression, and mutation bias while naturally accounting for a region's amino acid usage. Bayesian model comparisons suggest selection on codon usage varies only slightly between helix, sheet, and coil secondary structures and, similarly, between structured and intrinsically-disordered regions. Similarly, in contrast to prevous findings, we find selection on codon usage only varies slightly at the termini of helices in E. coli. Using simulated data, we show this previous work indicating "non-optimal" codons are enriched at the beginning of helices in S. cerevisiae was due to failure to control for various confounding factors (e.g. amino acid biases, gene expression, etc.), and rather than selection to modulate cotranslational folding.ConclusionsOur results reveal a weak relationship between codon usage and protein structure, indicating that differences in selection on codon usage between structures are slight. In addition to the magnitude of differences in selection between protein structures being slight, the observed shifts appear to be idiosyncratic and largely codon-specific rather than systematic reversals in the nature of selection. Overall, our work demonstrates the statistical power and benefits of studying selective shifts on codon usage or other genomic features from an explicitly evolutionary approach. Limitations of this approach and future potential research avenues are discussed.

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Dataset Information

A population genetics-phylogenetics approach to inferring natural selection in coding sequences.

Publications

A population genetics-phylogenetics approach to inferring natural selection in coding sequences.

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