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More effective purifying selection on RNA viruses than in DNA viruses.

ABSTRACT: Analysis of the pattern of nucleotide diversity in 222 independent viral sequence datasets showed the prevalence of purifying selection. In spite of the higher mutation rate of RNA viruses, our analyses revealed stronger evidence of the action of purifying selection in RNA viruses than in DNA viruses. The ratio of nonsynonymous to synonymous nucleotide diversity was significantly lower in RNA viruses than in DNA viruses, indicating that nonsynonymous mutations have been removed at a greater rate (relative to the mutation rate) in the former than in the latter. Moreover, statistics that measure the occurrence of rare polymorphisms revealed significantly a greater excess of rare nonsynonymous polymorphisms in RNA viruses than in DNA viruses but no difference with respect to synonymous polymorphisms. Since rare nonsynonymous polymorphisms are likely to be undergoing the effects of purifying selection acting to eliminate them, this result implies a stronger signature of ongoing purifying selection in RNA viruses than in DNA viruses. Across datasets from both DNA viruses and RNA viruses, we found a negatively allometric relationship between nonsynonymous and synonymous nucleotide diversity; in other words, nonsynonymous nucleotide diversity increased with synonymous nucleotide diversity at a less than linear rate. These findings are most easily explained by the occurrence of slightly deleterious mutations. The fact that the negative allometry was more pronounced in RNA viruses than in DNA viruses provided additional evidence that purifying selection is more effective in the former than in the latter.

SUBMITTER: Hughes AL

PROVIDER: S-EPMC2756238 | biostudies-literature | 2007 Dec

REPOSITORIES: biostudies-literature

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More effective purifying selection on RNA viruses than in DNA viruses.

Hughes Austin L AL Hughes Mary Ann K MA

Gene 20070920 1-2

Analysis of the pattern of nucleotide diversity in 222 independent viral sequence datasets showed the prevalence of purifying selection. In spite of the higher mutation rate of RNA viruses, our analyses revealed stronger evidence of the action of purifying selection in RNA viruses than in DNA viruses. The ratio of nonsynonymous to synonymous nucleotide diversity was significantly lower in RNA viruses than in DNA viruses, indicating that nonsynonymous mutations have been removed at a greater rate ...[more]

PMID: 17928171

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Project description:Comparison of polymorphism at synonymous and non-synonymous sites in protein-coding DNA can provide evidence for selective constraint. Non-coding DNA that forms part of the regulatory landscape presents more of a challenge since there is not such a clear-cut distinction between sites under stronger and weaker selective constraint. Here, we consider putative regulatory elements termed Conserved Non-coding Elements (CNEs) defined by their high level of sequence identity across all vertebrates. Some mutations in these regions have been implicated in developmental disorders; we analyse CNE polymorphism data to investigate whether such deleterious effects are widespread in humans. Single nucleotide variants from the HapMap and 1000 Genomes Projects were mapped across nearly 2000 CNEs. In the 1000 Genomes data we find a significant excess of rare derived alleles in CNEs relative to coding sequences; this pattern is absent in HapMap data, apparently obscured by ascertainment bias. The distribution of polymorphism within CNEs is not uniform; we could identify two categories of sites by exploiting deep vertebrate alignments: stretches that are non-variant, and those that have at least one substitution. The conserved category has fewer polymorphic sites and a greater excess of rare derived alleles, which can be explained by a large proportion of sites under strong purifying selection within humans--higher than that for non-synonymous sites in most protein coding regions, and comparable to that at the strongly conserved trans-dev genes. Conversely, the more evolutionarily labile CNE sites have an allele frequency distribution not significantly different from non-synonymous sites. Future studies should exploit genome-wide re-sequencing to obtain better coverage in selected non-coding regions, given the likelihood that mutations in evolutionarily conserved enhancer sequences are deleterious. Discovery pipelines should validate non-coding variants to aid in identifying causal and risk-enhancing variants in complex disorders, in contrast to the current focus on exome sequencing.

Project description:Study questionDoes selection for mtDNA mutations occur in human oocytes?Summary answerWe provide statistical evidence in favor of the existence of purifying selection for mtDNA mutations in human oocytes acting between the expulsion of the first and second polar bodies (PBs).What is known alreadySeveral lines of evidence in Metazoa, including humans, indicate that variation within the germline of mitochondrial genomes is under purifying selection. The presence of this internal selection filter in the germline has important consequences for the evolutionary trajectory of mtDNA. However, the nature and localization of this internal filter are still unclear while several hypotheses are proposed in the literature.Study design, size, durationIn this study, 60 mitochondrial genomes were sequenced from 17 sets of oocytes, first and second PBs, and peripheral blood taken from nine women between 38 and 43 years of age.Participants/materials, setting, methodsWhole genome amplification was performed only on the single cell samples and Sanger sequencing was performed on amplicons. The comparison of variant profiles between first and second PB sequences showed no difference in substitution rates but displayed instead a sharp difference in pathogenicity scores of protein-coding sequences using three different metrics (MutPred, Polyphen and SNPs&GO).Main results and the role of chanceUnlike the first, second PBs showed no significant differences in pathogenic scores with blood and oocyte sequences. This suggests that a filtering mechanism for disadvantageous variants operates during oocyte development between the expulsion of the first and second PB.Large scale dataN/A.Limitations, reasons for cautionThe sample size is small and further studies are needed before this approach can be used in clinical practice. Studies on a model organism would allow the sample size to be increased.Wider implications of the findingsThis work opens the way to the study of the correlation between mtDNA mutations, mitochondrial capacity and viability of oocytes.Study funding/competing interest(s)This work was supported by a SISMER grant. Laboratory facilities and skills were freely provided by SISMER, and by the Alma Mater Studiorum, University of Bologna. The authors have no conflict of interest to disclose.

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More effective purifying selection on RNA viruses than in DNA viruses.

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More effective purifying selection on RNA viruses than in DNA viruses.

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