Mutation rate variation in primates

灵长类动物的突变率变化

基本信息

批准号：
9903385
负责人：
MOLLY F PRZEWORSKI
金额：
$ 33.89万
依托单位：
COLUMBIA UNIV NEW YORK MORNINGSIDE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-05-15 至 2022-03-31
项目状态：
已结题

项目摘要

PROJECT SUMMARY Despite the critical importance of germline mutation in human genetics, we still lack the answer to basic questions, notably about how and why rates differ among individuals. We also lack a comparative context for interpreting findings, as, other than for one chimpanzee family, there are no direct estimates of germline mutation rates for non-human primates. These gaps in our understanding have important implications for evolutionary biology as well, leading in particular to considerable uncertainty about the steadiness of the “molecular clock” in primates. We therefore propose to obtain direct estimates of germline mutation rates within humans, in chimpanzees, and in three Old World monkey (OWM) species. In Aim 1, we will elucidate variation in human mutation rates with age, sex, and across families, separately for different mutation types. We will generate and analyze high-quality genome sequences for eight nuclear families of Hutterites (86 individuals) who belong to a single, 13-generation pedigree. Their relatively high consanguinity allows us to estimate mutation rates both in transmissions from parents to children and in autozygous segments descended from an older common ancestor. By relying on three-generation families with 3–6 children each, instead of the standard trio design, we can assign mutations to male or female germlines, verify transmission of putative mutations, and estimate rates of germline mosaicism. To these ends, we will also resequence a subset of mutations at deep coverage. In Aim 2, we will obtain the first direct estimate of mutation rates in an OWM species. Specifically, we will generate and analyze high- quality genome sequences for seven three-generation families of vervet monkeys (43 individuals, for which ages are known). These individuals belong to a colony of 2,000+ in an 11-generation pedigree, so the data are very similar in structure to that of the Hutterites, and will be analyzed by the same approaches, providing a well-matched comparison to humans. In Aim 3, we will examine the evolution of mutation rates across apes and OWMs. We will generate high-quality genome sequences for ten overlapping nuclear families of western chimpanzees (54 individuals), five families of rhesus macaques (22), and two families of olive baboons (13), for which parental ages are known. The genomic data will be generated using a uniform approach, and a subset of putative mutations will be resequenced to estimate error rates. This analysis will yield the first direct look at the evolution of mutation rates across a set of closely related species, and allow us to revisit the chronology of primate evolution with a more reliable molecular clock. Thus, this study will elucidate variation in the mutation process within human and among closely related species. As a byproduct, the data will enable primate evolutionary genomics and mapping efforts in primate model organisms.

项目摘要尽管种系突变在人类遗传学中至关重要，但我们仍然缺乏答案基本问题，尤其是关于个人如何以及为什么在个人之间有所不同的问题。我们也缺乏解释发现的比较背景，例如，除了一个黑猩猩家族以外，没有非人类隐私的种系突变率的直接估计。这些差距在我们的理解中对进化生物学也具有重要意义，尤其是考虑对主要的“分子钟”稳定性的不确定性。因此，我们建议获得直接估计人类，黑猩猩和三个旧世界内的种系突变率猴子（Owm）物种。在AIM 1中，我们将阐明人类突变率的变化年龄，性别和跨家庭，分别用于不同的突变类型。我们将生成并分析八个Hutter石（86个个体）的高质量基因组序列属于单一的13代血统。它们相对较高的血亲和力使我们能够估计突变率在从父母到子女的传播中以及自动基因段中的变异率下降来自一个年长的共同祖先。通过依靠有3-6个孩子的三代家庭，我们可以将突变分配给男性或女性种系，而不是标准的三人设计，而是验证推定突变的传播和种系镶嵌率的估计速率。到这些目的，我们将还要在深层覆盖范围内重新安置突变的子集。在AIM 2中，我们将获得第一个直接 OWM物种突变率的估计。具体而言，我们将生成和分析高七个三代猴子家族的质量基因组序列（43个个体，用于哪个年龄是已知的）。这些人属于11代血统中的2,000多个殖民地，因此，数据在结构上与Hutterites的结构非常相似，并且将通过相同的分析方法，提供与人类匹配的匹配。在AIM 3中，我们将检查猿类和owms之间突变率的演变。我们将产生高质量的基因组西方黑猩猩（54个人）的十个重叠核科的序列，五个家庭恒河猕猴（22）和两个橄榄狒狒家族（13），为父母的年龄。基因组数据将使用统一的方法生成，一部分推定突变将重新计算估计错误率。该分析将首次直接观察一组密切相关的物种的突变率的演变，使我们能够重新审视灵长类动物进化的年代学，具有更可靠的分子钟。那是这项研究将阐明人类和密切相关的物种中突变过程的变化。作为副产品，这些数据将使灵长类动物的进化基因组学和绘制私人模型生物的映射工作。