Effect of the assignment of ancestral CpG state on the estimation of nucleotide substitution rates in mammals.
Effect of the assignment of ancestral CpG state on the estimation of nucleotide substitution rates in mammals.
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DOI：
10.1186/1471-2148-8-265
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发表时间：
2008-09-30
影响因子：
3.4
通讯作者：
Keightley PD
中科院分区：
文献类型：
--
作者：
Gaffney DJ;Keightley PD
哺乳动物的分子进化研究通常分别估计CpG二核苷酸内部和外部的核苷酸取代率。通常，在两个序列的比对中，将位点划分为CpG和非CpG类别仅仅基于任一序列中CpG二核苷酸的存在或不存在，我们将该程序称为CpG/非CpG分配。虽然这一程序可能存在偏倚，但一般认为，如果物种非常接近，则偏倚可忽略不计。使用模拟的DNA序列进化，我们表明，分配的祖先CpG状态的基础上简单的存在/不存在的CpG二核苷酸可以严重偏差估计的取代率，因为许多真正的非CpG的变化被误分配为CpG。巧合的是，这种偏差在密切相关的物种之间最为严重，因为在两个分支树中，将真正的祖先CpG位点错配为非CpG需要最少两个取代，而将真正的祖先非CpG位点错配为CpG仅需要单个取代。我们还表明，CpG错误分配的偏见差异影响四倍退化和非编码位点，由于碱基组成的差异，使四倍退化位点可以出现比非编码位点更慢的发展。我们表明，我们的模拟预测的影响发生在一个真实的进化环境中，通过比较替代率估计从人类黑猩猩编码和内含子序列使用CpG/非CpG分配与估计来自一种方法，在很大程度上是免费的偏见。我们的研究表明，一种常见的方法分配到CpG和非CpG类的成对比对的网站是严重偏见，并建议反对通过特设的祖先状态分配的方法。
Molecular evolutionary studies in mammals often estimate nucleotide substitution rates within and outside CpG dinucleotides separately. Frequently, in alignments of two sequences, the division of sites into CpG and non-CpG classes is based simply on the presence or absence of a CpG dinucleotide in either sequence, a procedure that we refer to as CpG/non-CpG assignment. Although it likely that this procedure is biased, it is generally assumed that the bias is negligible if species are very closely related. Using simulations of DNA sequence evolution we show that assignment of the ancestral CpG state based on the simple presence/absence of the CpG dinucleotide can seriously bias estimates of the substitution rate, because many true non-CpG changes are misassigned as CpG. Paradoxically, this bias is most severe between closely related species, because a minimum of two substitutions are required to misassign a true ancestral CpG site as non-CpG whereas only a single substitution is required to misassign a true ancestral non-CpG site as CpG in a two branch tree. We also show that CpG misassignment bias differentially affects fourfold degenerate and noncoding sites due to differences in base composition such that fourfold degenerate sites can appear to be evolving more slowly than noncoding sites. We demonstrate that the effects predicted by our simulations occur in a real evolutionary setting by comparing substitution rates estimated from human-chimp coding and intronic sequence using CpG/non-CpG assignment with estimates derived from a method that is largely free from bias. Our study demonstrates that a common method of assigning sites into CpG and non CpG classes in pairwise alignments is seriously biased and recommends against the adoption of ad hoc methods of ancestral state assignment.
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