Department of Genetics, Stanford University, Stanford, CA, USA.
PLoS Genet. 2013 May;9(5):e1003527. doi: 10.1371/journal.pgen.1003527. Epub 2013 May 30.
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.
同义位点通常被认为受到较弱的选择约束。出于这个原因，它们通常被忽视，而不是作为一个可能的重要功能变异的来源。我们使用来自深度群体测序数据的位点频率谱来表明，与这种预期相反，在黑腹果蝇中，四联体同义（4D）位点中有 22%受到非常强的选择约束，而很少（如果有的话）受到弱选择约束。将多态性与分歧数据联系起来，我们进一步发现，在果蝇系统发育上进化较慢的那些位置，暴露于强纯化选择下的同义位点比例更高。推断出的强约束的功能似乎与剪接增强子、核小体定位以及产生典型密码子偏好的翻译优化不同。一个基因内受强约束的同义位点比例与基因表达密切相关，特别是在中晚期胚胎、蛹和成虫发育阶段。在受强约束的同义位点中富集的基因往往特别具有功能重要性，并且通常参与关键的发育途径。鉴于观察到的广泛作用于同义位点的约束可能不仅限于果蝇，因此应该重新评估同义位点在遗传疾病和适应中的作用。
