Estimating the Genome-wide Mutation Rate with Three-Way Identity by Descent
Estimating the Genome-wide Mutation Rate with Three-Way Identity by Descent
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DOI：
10.1016/j.ajhg.2019.09.012
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发表时间：
2019-11-07
影响因子：
9.8
通讯作者：
Browning, Sharon R.
中科院分区：
文献类型：
--
作者：
Tian, Xiaowen;Browning, Brian L.;Browning, Sharon R.
估计全基因组突变率的两种主要方法是计算亲代-后代三人组中的从头突变和比较密切相关物种之间的序列数据。对于亲子三元组分析，很难控制基因型误差，并且分辨率有限，因为每个三元组仅提供来自两个减数分裂的信息。由于分离物种的减数分裂数目的不确定性，物种间比较很难校准，而且它可能因选择和随时间变化的突变率而产生偏差。避免这些限制的另一类估计突变率的方法是基于过去几千年内共同祖先产生的按血统身份(IBD)片段。现有的基于IBD的方法仅限于高度近亲繁殖的样本，或者对基因错误和估计人口历史中的错误缺乏稳健性。我们提出了一种基于IBD的方法，该方法使用IBD片段在三组个体之间的共享来估计突变率。我们的方法适用于精确的阶段性基因数据，例如使用孟德尔遗传规则进行阶段性的亲子三元组数据。与标准的亲子分析不同，我们的方法利用了远亲关系，并且对基因错误具有很强的稳健性。我们将我们的方法应用于NHLBI TOPMed项目排序的弗雷明翰心脏研究中1,307名欧洲血统个人的数据。我们获得了每个减数分裂每个碱基对1.29×10(-8)个突变的估计，95%的可信区间为[1.02×10(-8)，1.56×10(-8)]。
The two primary methods for estimating the genome-wide mutation rate have been counting de novo mutations in parent-offspring trios and comparing sequence data between closely related species. With parent-offspring trio analysis it is difficult to control for genotype error, and resolution is limited because each trio provides information from only two meioses. Inter-species comparison is difficult to calibrate due to uncertainty in the number of meioses separating species, and it can be biased by selection and by changing mutation rates over time. An alternative class of approaches for estimating mutation rates that avoids these limitations is based on identity by descent (IBD) segments that arise from common ancestry within the past few thousand years. Existing IBD-based methods are limited to highly inbred samples, or lack robustness to genotype error and error in the estimated demographic history. We present an IBD-based method that uses sharing of IBD segments among sets of three individuals to estimate the mutation rate. Our method is applicable to accurately phased genotype data, such as parent-offspring trio data phased using Mendelian rules of inheritance. Unlike standard parent-offspring analysis, our method utilizes distant relationships and is robust to genotype error. We apply our method to data from 1,307 European-ancestry individuals in the Framingham Heart Study sequenced by the NHLBI TOPMed project. We obtain an estimate of 1.29 x 10(-8) mutations per base pair per meiosis with a 95% confidence interval of [1.02 x 10(-8),1.56 x 10(-8)].