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Synonymous and nonsynonymous polymorphisms versus divergences in bacterial genomes.

ABSTRACT: Comparison of the ratio of nonsynonymous to synonymous polymorphisms within species with the ratio of nonsynonymous to synonymous substitutions between species has been widely used as a supposed indicator of positive Darwinian selection, with the ratio of these 2 ratios being designated as a neutrality index (NI). Comparison of genome-wide polymorphism within 12 species of bacteria with divergence from an outgroup species showed substantial differences in NI among taxa. A low level of nonsynonymous polymorphism at a locus was the best predictor of NI < 1, rather than a high level of nonsynonymous substitution between species. Moreover, genes with NI < 1 showed a strong tendency toward the occurrence of rare nonsynonymous polymorphisms, as expected under the action of ongoing purifying selection. Thus, our results are more consistent with the hypothesis that a high relative rate of between-species nonsynonymous substitution reflects mainly the action of purifying selection within species to eliminate slightly deleterious mutations rather than positive selection between species. This conclusion is consistent with previous results highlighting an important role of slightly deleterious variants in bacterial evolution and suggests caution in the use of the McDonald-Kreitman test and related statistics as tests of positive selection.

SUBMITTER: Hughes AL

PROVIDER: S-EPMC2734133 | biostudies-literature | 2008 Oct

REPOSITORIES: biostudies-literature

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Synonymous and nonsynonymous polymorphisms versus divergences in bacterial genomes.

Hughes Austin L AL Friedman Robert R Rivailler Pierre P French Jeffrey O JO

Molecular biology and evolution 20080730 10

Comparison of the ratio of nonsynonymous to synonymous polymorphisms within species with the ratio of nonsynonymous to synonymous substitutions between species has been widely used as a supposed indicator of positive Darwinian selection, with the ratio of these 2 ratios being designated as a neutrality index (NI). Comparison of genome-wide polymorphism within 12 species of bacteria with divergence from an outgroup species showed substantial differences in NI among taxa. A low level of nonsynonym ...[more]

PMID: 18667439

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Project description:Genomic data reveal single-nucleotide polymorphisms (SNPs) that may carry information about the evolutionary history of bacteria. However, it remains unclear what inferences about selection can be made from genomic SNP data. Bacterial species are often sampled during epidemic outbreaks or within hosts during the course of chronic infections. SNPs obtained from genomic analysis of these data are not necessarily fixed. Treating them as fixed during analysis by using measures such as the ratio of nonsynonymous to synonymous evolutionary changes (dN/dS) may lead to incorrect inferences about the strength and direction of selection. In this study, we consider data from a range of whole-genome sequencing studies of bacterial pathogens and explore patterns of nonsynonymous variation to assess whether evidence of selection can be identified by investigating SNP counts alone across multiple WGS studies. We visualize these SNP data in ways that highlight their relationship to neutral baseline expectations. These neutral expectations are based on a simple model of mutation, from which we simulate SNP accumulation to investigate how SNP counts are distributed under alternative assumptions about positive and negative selection. We compare these patterns with empirical SNP data and illustrate the general difficulty of detecting positive selection from SNP data. Finally, we consider whether SNP counts observed at the between-host population level diﬀer from those observed at the within-host level and find some evidence that suggests that dynamics across these two scales are driven by diﬀerent underlying processes.IMPORTANCE Identifying selection from SNP data obtained from whole-genome sequencing studies is challenging. Some current measures used to identify and quantify selection acting on genomes rely on fixed diﬀerences; thus, these are inappropriate for SNP data where variants are not fixed. With the increase in whole-genome sequencing studies, it is important to consider SNP data in the context of evolutionary processes. How SNPs are counted and analyzed can help in understanding mutation accumulation and trajectories of strains. We developed a tool for identifying possible evidence of selection and for comparative analysis with other SNP data. We propose a model that provides a rule-of-thumb guideline and two new visualization techniques that can be used to interpret and compare SNP data. We quantify the expected proportion of nonsynonymous SNPs in coding regions under neutrality and demonstrate its use in identifying evidence of positive and negative selection from simulations and empirical data.

Project description:Gene duplication leads to the formation of gene families, wherein purifying or neutral selection maintains the original gene function, while diversifying selection confers new functions onto duplicated genes. The B56 gene family is highly conserved; it is encoded by one gene in protists and fungi, and five genes in vertebrates. B56 regulates protein phosphatase 2A (PP2A), an abundant heterotrimeric serine/threonine phosphatase that functions as a tumor suppressor and consists of a scaffolding "A" and catalytic "C" subunit heterodimer bound to a regulatory "B" subunit. Individual regulatory B56 subunits confer disparate functions onto PP2A in various cell-cell signaling pathways. B56 proteins share a conserved central core domain, but have divergent N- and C-termini which play a role in isoform specificity. We carried out a nonsynonymous/synonymous substitution analysis to better understand the divergence of vertebrate B56 genes. When five B56 paralogs from ten vertebrate species were analyzed, the gene family displayed purifying selection; stronger purifying selection was revealed when individual B56 isoforms were analyzed separately. The B56 core experienced stronger purifying selection than the N- and C-termini, which correlates with the presence of several contacts between the core and the AC heterodimer. Indeed, the majority of the contact points that we analyzed between B56 and the AC heterodimer experienced strong purifying selection. B56 subfamilies showed distinct patterns of selection in their N- and C-termini. The C-terminus of the B56-1 subfamily and the N-terminus of the B56-2 subfamily exhibited strong purifying selection, suggesting that these termini carry out subfamily-specific functions, while the opposite termini exhibited diversifying selection and likely carry out isoform-specific functions. We also found reduced synonymous substitutions at the N- and C-termini when grouping B56 genes by species but not by isoform, suggesting species-specific codon bias may have a role in regulating B56 gene expression.

Dataset Information

Synonymous and nonsynonymous polymorphisms versus divergences in bacterial genomes.

Publications

Synonymous and nonsynonymous polymorphisms versus divergences in bacterial genomes.

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