Pedigree-based and phylogenetic methods support surprising patterns of mutation rate and spectrum in the gray mouse lemur
Pedigree-based and phylogenetic methods support surprising patterns of mutation rate and spectrum in the gray mouse lemur
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DOI：
10.1038/s41437-021-00446-5
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发表时间：
2021-07-16
期刊：
影响因子：
3.8
通讯作者：
Yoder, Anne D.
中科院分区：
文献类型：
--
作者：
Campbell, C. Ryan;Tiley, George P.;Yoder, Anne D.
突变是进化作用的原材料，了解它们的频率和基因组分布对于理解进化如何在长时间和短时间尺度上运作至关重要。目前，从头突变的速率和谱已在相对较少的谱系中被直接表征。我们的研究提供了第一个直接的突变率估计的链球菌（即，狐猴和懒猴），这包括近一半的灵长类分支。使用高覆盖率的连接阅读测序灰鼠狐猴（Microcebus murinus）的焦点四重奏，我们估计突变率是哺乳动物中计算出的最高突变率之一，为1.52 x 10（-8）（95%可信区间：1.28 x 10（-8）-1.78 x 10（-8））突变/位点/代。此外，我们发现了一个意想不到的低计数的父亲突变，只有一个温和的过度代表性的突变在CpG位点。尽管这些结果的令人惊讶的性质，我们发现的速率和频谱是强大的操作范围广泛的计算过滤标准。我们还对技术重复进行测序，以估计我们数据的假阴性和假阳性率，并表明从头突变率的任何点估计都应该考虑很大程度的不确定性。为了验证，我们对灰鼠狐猴和另外五种灵长类动物进行了独立的上下文相关替代类型分析，其中还估计了从头突变率。这些比较揭示了一般的一致性的突变谱之间的系谱为基础的分析和替代率为所有物种进行比较。
Mutations are the raw material on which evolution acts, and knowledge of their frequency and genomic distribution is crucial for understanding how evolution operates at both long and short timescales. At present, the rate and spectrum of de novo mutations have been directly characterized in relatively few lineages. Our study provides the first direct mutation-rate estimate for a strepsirrhine (i.e., the lemurs and lorises), which comprises nearly half of the primate clade. Using high-coverage linked-read sequencing for a focal quartet of gray mouse lemurs (Microcebus murinus), we estimated the mutation rate to be among the highest calculated for a mammal at 1.52 x 10(-8) (95% credible interval: 1.28 x 10(-8)-1.78 x 10(-8)) mutations/site/generation. Further, we found an unexpectedly low count of paternal mutations, and only a modest overrepresentation of mutations at CpG sites. Despite the surprising nature of these results, we found both the rate and spectrum to be robust to the manipulation of a wide range of computational filtering criteria. We also sequenced a technical replicate to estimate a false-negative and false-positive rate for our data and show that any point estimate of a de novo mutation rate should be considered with a large degree of uncertainty. For validation, we conducted an independent analysis of context-dependent substitution types for gray mouse lemur and five additional primate species for which de novo mutation rates have also been estimated. These comparisons revealed general consistency of the mutation spectrum between the pedigree-based and the substitution-rate analyses for all species compared.