Detection of Regional Variation in Selection Intensity within Protein-Coding Genes Using DNA Sequence Polymorphism and Divergence.
Detection of Regional Variation in Selection Intensity within Protein-Coding Genes Using DNA Sequence Polymorphism and Divergence.
复制标题
使用 DNA 序列多态性和分歧检测蛋白质编码基因内选择强度的区域变异。
DOI：
10.1093/molbev/msx213
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发表时间：
2017
影响因子：
10.7
通讯作者：
Townsend,JeffreyP
中科院分区：
文献类型：
--
作者：
Zhao,Zi-Ming;Campbell,MichaelC;Li,Ning;Lee,DanielSW;Zhang,Zhang;Townsend,JeffreyP
基于物种内多态性和物种间差异的比较，已经开发了许多方法来推断自然选择。这些方法对于检测跨基因的均匀选择尤其有效。然而，经验分析表明，与同一基因的其他区域相比，蛋白质编码基因中表现出氨基酸取代簇的区域受到不同程度的选择。为了量化编码序列中选择的异质性，我们通过apoissonrandomfield （MASS-PRF）开发了modelaveragedsitesselection。MASS-PRF识别了多态性位点和发散位点的基因内聚类模型的集合。该模型集合在泊松随机场框架内使用，以逐点估计选择强度。通过模拟，我们证明MASS-PRF在检测小基因区域的氨基酸变异簇方面具有很高的能力，可以可靠地估计序列数据中每个核苷酸位点发生变异的概率，并且对历史人口统计趋势和重组具有鲁棒性。我们将MASS-PRF应用于从千人基因组计划中获得的人类基因多态性和来自普通黑猩猩的分化数据。在此分析的基础上，我们发现了选择强度的显著区域差异，表明了积极或消极的选择，在之前与神经处理、免疫和生殖相关的明确定义的基因域中。我们认为，这些区域内的氨基酸改变取代可能在人类谱系中具有选择性优势，在蛋白质功能中起着重要作用。
Numerous approaches have been developed to infer natural selection based on the comparison of polymorphism within species and divergence between species. These methods are especially powerful for the detection of uniform selection operating across a gene. However, empirical analyses have demonstrated that regions of protein-coding genes exhibiting clusters of amino acid substitutions are subject to different levels of selection relative to other regions of the same gene. To quantify this heterogeneity of selection within coding sequences, we developedModelAveragedSiteSelection viaPoissonRandomField (MASS-PRF). MASS-PRF identifies an ensemble of intragenic clustering models for polymorphic and divergent sites. This ensemble of models is used within the Poisson Random Field framework to estimate selection intensity on a site-by-site basis. Using simulations, we demonstrate that MASS-PRF has high power to detect clusters of amino acid variants in small genic regions, can reliably estimate the probability of a variant occurring at each nucleotide site in sequence data and is robust to historical demographic trends and recombination. We applied MASS-PRF to human gene polymorphism derived from the 1,000 Genomes Project and divergence data from the common chimpanzee. On the basis of this analysis, we discovered striking regional variation in selection intensity, indicative of positive or negative selection, in well-defined domains of genes that have previously been associated with neurological processing, immunity, and reproduction. We suggest that amino acid-altering substitutions within these regions likely are or have been selectively advantageous in the human lineage, playing important roles in protein function.