Multinucleotide mutations cause false inferences of lineage-specific positive selection.
Multinucleotide mutations cause false inferences of lineage-specific positive selection.
复制标题
DOI：
10.1038/s41559-018-0584-5
复制
发表时间：
2018-08
影响因子：
16.8
通讯作者：
Thornton JW
中科院分区：
文献类型：
--
作者：
Venkat A;Hahn MW;Thornton JW
适应性进化的系统发育测试，如广泛使用的分支位点测试，假设核苷酸替换是单独和独立发生的。但最近的研究表明，在DNA复制过程中，邻近位点的错误经常发生，由此产生的多核苷酸突变(MNMs)极有可能是非同义的。我们评估了分支点测试(BST)是否可能将MNMS产生的序列模式误解为对正选择的错误支持。我们分析了两个基因组规模的数据集-一个来自哺乳动物，另一个来自苍蝇-发现具有多个差异的密码子几乎解释了BST中对谱系特定的正选择的所有支持。在从这些比对得到的条件下的模拟显示，没有正面选择的MNM的真实比率导致了对错误选择推断的强烈和系统的偏向。这种偏差在经验推导的条件下足以产生假阳性推断，就像分支现场测试从经验数据中推断出阳性选择一样频繁。尽管一些BST阳性的基因可能是适应性进化的，但该测试不能区分真正的阳性选择产生的序列模式和中性固定的MNM引起的序列模式。因此，许多已发表的使用该技术的适应性进化推断可能是由未结合的中性突变过程引起的模型破坏的人工制品。我们介绍了一个结合了MNMS的模型，并可能有助于改善这种偏见。
Phylogenetic tests of adaptive evolution, such as the widely used branch-site test, assume that nucleotide substitutions occur singly and independently. But recent research has shown that errors at adjacent sites often occur during DNA replication, and the resulting multinucleotide mutations (MNMs) are overwhelmingly likely to be nonsynonymous. We evaluated whether the branch-site test (BST) might misinterpret sequence patterns produced by MNMs as false support for positive selection. We analyzed two genome-scale datasets– one from mammals and one from flies – and found that codons with multiple differences account for virtually all the support for lineage-specific positive selection in the BST. Simulations under conditions derived from these alignments but without positive selection show that realistic rates of MNMs cause a strong and systematic bias towards false inferences of selection. This bias is sufficient under empirically derived conditions to produce false positive inferences as often as the branch-site test infers positive selection from the empirical data. Although some genes with BST-positive results may have evolved adaptively, the test cannot distinguish sequence patterns produced by authentic positive selection from those caused by neutral fixation of MNMs. Many published inferences of adaptive evolution using this technique may therefore be artifacts of model violation caused by unincorporated neutral mutational processes. We introduce a model that incorporates MNMs and may help to ameliorate this bias.
登录
查看更多内容
影响因子：
64.8
作者：
Clark, Andrew G.;Eisen, Michael B.;MacCallum, Iain
通讯作者：
MacCallum, Iain
影响因子：
10.7
作者：
Kosiol, Carolin;Holmes, Ian;Goldman, Nick
通讯作者：
Goldman, Nick
影响因子：
10.7
作者：
Bloom, Jesse D.
通讯作者：
Bloom, Jesse D.
影响因子：
10.7
作者：
Anisimova, Maria;Yang, Ziheng
通讯作者：
Yang, Ziheng
影响因子：
14.9
作者：
Arana, Mercedes E.;Seki, Mineaki;Wood, Richard D.;Rogozin, Igor B.;Kunkel, Thomas A.
通讯作者：
Kunkel, Thomas A.