The trouble with sliding windows and the selective pressure in BRCA1.
The trouble with sliding windows and the selective pressure in BRCA1.
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DOI：
10.1371/journal.pone.0003746
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发表时间：
2008
期刊：
影响因子：
3.7
通讯作者：
Yang Z
中科院分区：
文献类型：
--
作者：
Schmid K;Yang Z
滑动窗口分析已被广泛用于揭示沿着蛋白质序列的同义（沉默，dS）和非同义（替换，dN）速率变化，以及检测在选择性约束（由dN<dS表示）或正选择（由dN>dS表示）下的蛋白质区域。该方法比较了两个或多个蛋白质编码基因，并绘制了沿序列沿着每个滑动窗口的估计d λ S和d λ N。在这里，我们表明，该方法产生的人为趋势的同义和非同义的速率变化，更大的变化在d S比d N。即使真实的dS和dN沿整个蛋白质沿着是恒定的，并且不同的密码子独立地进化，也会产生这样的趋势。许多已发表的使用滑动窗口的阴性和阳性选择的测试似乎是无效的，因为它们无法纠正多重测试。相反，似然比检验为检测影响蛋白质进化的自然选择信号提供了一个更严格的框架。我们证明，之前的发现即BRCA 1基因的特定区域在纯化选择的驱动下经历了同义率降低，这很可能是滑动窗口分析的假象。我们评估了分子进化，群体遗传学和比较基因组学中的各种滑动窗口分析，并认为如果不事先知道存在趋势，并且如果没有对多重测试进行校正，则该方法通常无效。
Sliding-window analysis has widely been used to uncover synonymous (silent, dS) and nonsynonymous (replacement, dN) rate variation along the protein sequence and to detect regions of a protein under selective constraint (indicated by dN<dS) or positive selection (indicated by dN>dS). The approach compares two or more protein-coding genes and plots estimates dˆ S and dˆ N from each sliding window along the sequence. Here we demonstrate that the approach produces artifactual trends of synonymous and nonsynonymous rate variation, with greater variation in dˆ S than in dˆ N. Such trends are generated even if the true dS and dN are constant along the whole protein and different codons are evolving independently. Many published tests of negative and positive selection using sliding windows that we have examined appear to be invalid because they fail to correct for multiple testing. Instead, likelihood ratio tests provide a more rigorous framework for detecting signals of natural selection affecting protein evolution. We demonstrate that a previous finding that a particular region of the BRCA1 gene experienced a synonymous rate reduction driven by purifying selection is likely an artifact of the sliding window analysis. We evaluate various sliding-window analyses in molecular evolution, population genetics, and comparative genomics, and argue that the approach is not generally valid if it is not known a priori that a trend exists and if no correction for multiple testing is applied.
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