Locating protein-coding sequences under selection for additional, overlapping functions in 29 mammalian genomes
Locating protein-coding sequences under selection for additional, overlapping functions in 29 mammalian genomes
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DOI：
10.1101/gr.108753.110
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发表时间：
2011-11-01
期刊：
影响因子：
7
通讯作者：
Kellis, Manolis
中科院分区：
文献类型：
--
作者：
Lin, Michael F.;Kheradpour, Pouya;Kellis, Manolis
遗传密码的退化允许编码蛋白质的DNA和RNA序列同时编码额外的，重叠的功能元件。与典型的蛋白质编码基因（特别是在同义位点）相比，在纯化选择下进化的蛋白质编码和附加重叠功能序列应该显示出更高的进化保守性。在这项研究中，我们使用29种胎盘哺乳动物的基因组比对来系统地定位人类orf中的短区域，这些区域在这些物种中显示出明显较低的同义替代估计率。29个物种的比对提供了统计能力，可以定位超过10,000个这样的区域，分辨率低至9个密码子窗口，这些密码子窗口存在于超过四分之一的人类蛋白质编码基因中，并且包含相似的2%的同义位点。我们收集了大量的证据，表明在这些区域观察到的同义约束反映了对重叠功能元件的选择，包括剪接调节元件、双编码基因、RNA二级结构、microRNA靶位点和发育增强子。我们的研究结果表明，重叠的功能元件在哺乳动物基因中是常见的，尽管基因组景观广阔。
The degeneracy of the genetic code allows protein-coding DNA and RNA sequences to simultaneously encode additional, overlapping functional elements. A sequence in which both protein-coding and additional overlapping functions have evolved under purifying selection should show increased evolutionary conservation compared to typical protein-coding genes-especially at synonymous sites. In this study, we use genome alignments of 29 placental mammals to systematically locate short regions within human ORFs that show conspicuously low estimated rates of synonymous substitution across these species. The 29-species alignment provides statistical power to locate more than 10,000 such regions with resolution down to nine-codon windows, which are found within more than a quarter of all human protein-coding genes and contain similar to 2% of their synonymous sites. We collect numerous lines of evidence that the observed synonymous constraint in these regions reflects selection on overlapping functional elements including splicing regulatory elements, dual-coding genes, RNA secondary structures, microRNA target sites, and developmental enhancers. Our results show that overlapping functional elements are common in mammalian genes, despite the vast genomic landscape.