Strong purifying selection at synonymous sites in D. melanogaster.
Strong purifying selection at synonymous sites in D. melanogaster.
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DOI：
10.1371/journal.pgen.1003527
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发表时间：
2013-05
期刊：
影响因子：
4.5
通讯作者：
Petrov DA
中科院分区：
文献类型：
--
作者：
Lawrie DS;Messer PW;Hershberg R;Petrov DA
Synonymous sites are generally assumed to be subject to weak selective constraint. For this reason, they are often neglected as a possible source of important functional variation. We use site frequency spectra from deep population sequencing data to show that, contrary to this expectation, 22% of four-fold synonymous (4D) sites in Drosophila melanogaster evolve under very strong selective constraint while few, if any, appear to be under weak constraint. Linking polymorphism with divergence data, we further find that the fraction of synonymous sites exposed to strong purifying selection is higher for those positions that show slower evolution on the Drosophila phylogeny. The function underlying the inferred strong constraint appears to be separate from splicing enhancers, nucleosome positioning, and the translational optimization generating canonical codon bias. The fraction of synonymous sites under strong constraint within a gene correlates well with gene expression, particularly in the mid-late embryo, pupae, and adult developmental stages. Genes enriched in strongly constrained synonymous sites tend to be particularly functionally important and are often involved in key developmental pathways. Given that the observed widespread constraint acting on synonymous sites is likely not limited to Drosophila, the role of synonymous sites in genetic disease and adaptation should be reevaluated. Synonymous mutations do not alter the sequence of amino acids encoded by the gene in which they occur. These synonymous mutations were thus long thought to have no effect on the function of the ensuing protein or the fitness of the organism. At four-fold degenerate sites, every possible mutation is synonymous. For this reason, they are often neglected as a possible source of important functional changes. Using a deep sampling of the variation within a population of the fruit fly Drosophila melanogaster, we show that, contrary to this expectation, 22% of synonymous mutations at four-fold degenerate sites are strongly deleterious to the point of absence in the Drosophila population. The underlying biological function disrupted by these mutations is unknown, but is not related to the forces generally believed to be the principal actors shaping the evolution of synonymous sites. Genes with many such possible deleterious synonymous mutations tend to be particularly functionally important, highly expressed, and often involved in key developmental pathways. Given that the observed functional importance of synonymous sites is likely not limited to Drosophila, the role of synonymous sites in genetic disease and adaptation should be reevaluated.
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影响因子：
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核小体抑制真核生物中碱基特异性自发突变
影响因子：
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通讯作者：
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