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Polymorphism Data Assist Estimation of the Nonsynonymous over Synonymous Fixation Rate Ratio ? for Closely Related Species.

ABSTRACT: The ratio of nonsynonymous over synonymous sequence divergence, dN/dS, is a widely used estimate of the nonsynonymous over synonymous fixation rate ratio ?, which measures the extent to which natural selection modulates protein sequence evolution. Its computation is based on a phylogenetic approach and computes sequence divergence of protein-coding DNA between species, traditionally using a single representative DNA sequence per species. This approach ignores the presence of polymorphisms and relies on the indirect assumption that new mutations fix instantaneously, an assumption which is generally violated and reasonable only for distantly related species. The violation of the underlying assumption leads to a time-dependence of sequence divergence, and biased estimates of ? in particular for closely related species, where the contribution of ancestral and lineage-specific polymorphisms to sequence divergence is substantial. We here use a time-dependent Poisson random field model to derive an analytical expression of dN/dS as a function of divergence time and sample size. We then extend our framework to the estimation of the proportion of adaptive protein evolution ?. This mathematical treatment enables us to show that the joint usage of polymorphism and divergence data can assist the inference of selection for closely related species. Moreover, our analytical results provide the basis for a protocol for the estimation of ? and ? for closely related species. We illustrate the performance of this protocol by studying a population data set of four corvid species, which involves the estimation of ? and ? at different time-scales and for several choices of sample sizes.

SUBMITTER: Mugal CF

PROVIDER: S-EPMC6984366 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Polymorphism Data Assist Estimation of the Nonsynonymous over Synonymous Fixation Rate Ratio ω for Closely Related Species.

Mugal Carina F CF Kutschera Verena E VE Botero-Castro Fidel F Wolf Jochen B W JBW Kaj Ingemar I

Molecular biology and evolution 20200101 1

The ratio of nonsynonymous over synonymous sequence divergence, dN/dS, is a widely used estimate of the nonsynonymous over synonymous fixation rate ratio ω, which measures the extent to which natural selection modulates protein sequence evolution. Its computation is based on a phylogenetic approach and computes sequence divergence of protein-coding DNA between species, traditionally using a single representative DNA sequence per species. This approach ignores the presence of polymorphisms and re ...[more]

PMID: 31504782

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Project description:BackgroundNonsynonymous mutations change the protein sequences and are frequently subjected to natural selection. The same goes for nonsense mutations that introduce pre-mature stop codons into CDSs (coding sequences). Synonymous mutations, however, are intuitively thought to be functionally silent and evolutionarily neutral. Now researchers know that the optimized synonymous codon usage is advantageous in the speedy mRNA translation process. With the advent of NGS technique, the explosion of NGS data generated from the tumor tissues help researchers identify driver mutations in cancer-related genes, but relatively less attention is paid to the SNP data in healthy human populations when studying cancer.MethodsHere, we analyzed the publically available human SNPs. We classified these SNPs according to their functional and evolutionary categories. By simply dividing the human genes into cancer-related genes and other genes, we compared the features of nonsynonymous, synonymous and nonsense mutations in these two gene sets from multiple aspects.ResultsWe provided lines of evidence that the nonsynonymous, synonymous and nonsense mutations in cancer-related genes undergo stronger purifying selection when compared to the expected pattern in other genes. The lower nonsynonymous to synonymous ratio observed in cancer-related genes suggests the suppression of amino acid substitutions in these genes. The synonymous SNPs, after excluding those in splicing regions, exhibit preferred changes in codon usage and higher codon frequencies in cancer-related genes compared to other genes, indicating the constraint exerted on these mutations. Nonsense mutations are less frequent and located closer to stop codons in cancer-related genes than in other genes, which putatively minimize their deleterious effects.ConclusionOur study demonstrated the evolutionary constraint on mutations in CDS of cancer-related genes without the requirement of data from cancer tissues or patients. Our work provides novel perspectives on interpreting the constraint on mutations in cancer-related genes. We reveal extra constraint on synonymous mutations in cancer-related genes which is related to codon usage bias and is in addition to the splicing effect.

Dataset Information

Polymorphism Data Assist Estimation of the Nonsynonymous over Synonymous Fixation Rate Ratio ? for Closely Related Species.

Publications

Polymorphism Data Assist Estimation of the Nonsynonymous over Synonymous Fixation Rate Ratio ω for Closely Related Species.

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