Detection of nonneutral substitution rates on mammalian phylogenies
Detection of nonneutral substitution rates on mammalian phylogenies
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DOI：
10.1101/gr.097857.109
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发表时间：
2010-01-01
期刊：
影响因子：
7
通讯作者：
Siepel, Adam
中科院分区：
文献类型：
--
作者：
Pollard, Katherine S.;Hubisz, Melissa J.;Siepel, Adam
用于检测在中性漂移下比预期更快或更慢的核苷酸取代速率的方法被广泛用于鉴定基因组序列中的候选功能元件。然而，大多数现有的方法考虑减少（保护）或增加（加速）的速度，但不是两者兼而有之，或假设选择行为均匀跨越分支的一个同源性。在这里，我们研究了更普遍的问题，检测偏离中性替代率在任何一个方向，可能在一个分支特定的方式。我们考虑四个统计，系统发育测试来解决这个问题：似然比测试，得分测试，测试的基础上的确切分布的取代数量，和基因组进化速率分析（GERP）测试。所有四个测试都已在一个名为CNOMP的免费程序中实现。基于大量的模拟实验，这些测试在统计功效上非常相似。与36个哺乳动物物种，他们似乎都能够相当好的灵敏度与低假阳性率在检测强选择在个别核苷酸，中等选择在3-bp的元素，和较弱的或进化枝特异性选择在较长的元素。通过应用CNOP从ENCODE项目的哺乳动物多重比对，我们揭示了模式的保护/加速已知和预测的功能元件，近似分数的网站受到限制，并在灵长类动物和glires进化枝的分支特异性选择的差异。我们还描述了UCSC基因组浏览器中的新“保护”轨迹，该轨迹显示44种脊椎动物物种全基因组比对的phyloP和phastCons评分。
Methods for detecting nucleotide substitution rates that are faster or slower than expected under neutral drift are widely used to identify candidate functional elements in genomic sequences. However, most existing methods consider either reductions (conservation) or increases (acceleration) in rate but not both, or assume that selection acts uniformly across the branches of a phylogeny. Here we examine the more general problem of detecting departures from the neutral rate of substitution in either direction, possibly in a clade-specific manner. We consider four statistical, phylogenetic tests for addressing this problem: a likelihood ratio test, a score test, a test based on exact distributions of numbers of substitutions, and the genomic evolutionary rate profiling (GERP) test. All four tests have been implemented in a freely available program called phyloP. Based on extensive simulation experiments, these tests are remarkably similar in statistical power. With 36 mammalian species, they all appear to be capable of fairly good sensitivity with low false-positive rates in detecting strong selection at individual nucleotides, moderate selection in 3-bp elements, and weaker or clade-specific selection in longer elements. By applying phyloP to mammalian multiple alignments from the ENCODE project, we shed light on patterns of conservation/acceleration in known and predicted functional elements, approximate fractions of sites subject to constraint, and differences in clade-specific selection in the primate and glires clades. We also describe new "Conservation" tracks in the UCSC Genome Browser that display both phyloP and phastCons scores for genome-wide alignments of 44 vertebrate species.