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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.

项目总结尽管生殖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，特别是关于个人比率如何以及为什么不同的问题。我们还缺乏一个解释发现的比较语境，因为，除了一个黑猩猩家庭，没有非人类灵长类动物生殖系突变率的直接估计。我们在认识上的这些差距对进化生物学也有重要的影响，特别是导致相当大的灵长类动物“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、黑猩猩和三个东半球的生殖系突变率猴子(OWM)物种。在目标1中，我们将阐明人类突变率的变异年龄、性别和跨家庭，分别针对不同的突变类型。我们将生成和分析八个哈特人核心家族(86个个体)的高质量基因组序列属于单一的，13代人的谱系。他们相对较高的血缘关系使我们能够估计父母传给孩子和纯合子片段的突变率都下降了来自一个更年长的共同祖先。依靠三代家庭，每个家庭有3到6个孩子，代替标准的三联设计，我们可以将突变分配给雄性或雌性生殖系，验证假定突变的传播，并估计生殖系嵌合体的比率。为此，我们将还对深度覆盖的突变子集进行了重新测序。在目标2中，我们将获得第一个直接估计OWM物种的突变率。具体地说，我们将生成和分析高- 七个三代轮尾猴家族的高质量基因组序列(43只，用于已知的年代)。这些个体属于11代谱系中2000多人的群体，因此，这些数据在结构上与哈特人的非常相似，并将由相同的方法，提供了与人类相匹配的比较。在目标3中，我们将研究类人猿和OWM的突变率的进化。我们将产生高质量的基因组西部黑猩猩5科54个重叠核心家族的序列猕猴(22只)和两个橄榄狒狒家族(13只)，它们的父母年龄是已知的。基因组数据将使用统一的方法生成，假定的突变子集将被重新排序以估计错误率。这一分析将产生第一次直接观察一组密切相关物种的突变率的进化，并使我们能够重新审视灵长类进化的年表和更可靠的分子时钟。因此，这项研究将阐明人类内部和密切相关物种之间突变过程的变异。作为副产品，这些数据将使灵长类进化基因组学和灵长类模式生物的图谱工作成为可能。