Investigating the landscape and genetic architecture of germline mutagenesis

研究种系突变的景观和遗传结构

• 批准号: 10218214
• 负责人: Kelley Harris
• 金额: $ 36.83万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-07 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10218214
• 关键词: Affect; African; Age; Alleles; Animal Model; Asians; Binding Proteins; Biological Models; Cells; Complement; DNA; DNA Damage; DNA Repair; DNA Sequence; DNA Sequence Alteration; DNA biosynthesis; Disease; Drosophila genome; European; Event; Evolution; Gene Expression; Genetic; Genetic Diseases; Genetic Variation; Genome; Genomics; Health; Human; Hybrids; Immune; Inbred Strains Mice; Inbreeding; Individual; Letters; Libraries; Link; Location; Malignant Neoplasms; Maps; Methods; Migrant; Mutagenesis; Mutate; Mutation; Persons; Play; Polar Bear; Population; Process; Recombinants; Recording of previous events; Research; Role; Scanning; Techniques; Time; Ursidae Family; Variant; Work; environmental mutagens; genetic architecture; genetic variant; genomic data; improved; innovation; offspring; reference genome; trait

PROJECT SUMMARY The rate at which DNA mutates ultimately determines how many people are born with serious genetic dis- eases, as well as how long a person is likely to live before getting cancer. It is also crucial to understand how mutations generate genetic variation in order to accurately infer evolutionary history from genomic data. Despite this fundamental importance for human health and disease, we know little about how the mutation rate varies from person to person and what genetic factors might cause the mutation rate to vary. My previous research has shown that mutations from different populations are biased to occur in different sequence contexts; for example, Europeans contain more mutations in the motif “TCC” than Africans or East Asians do. This implies that each population is affected by a distinctive combination of sequence-biased mutational processes. Unless these dif- ferences are all induced by environmental mutagens, some of them must be the signatures of “mutator alleles,” genetic variants that subtly affect the likelihood of DNA damage or the efficacy of DNA repair. This proposal describes a multi-pronged strategy for interrogating the causes and consequences of variation in DNA replication fidelity. The first step will be to look beyond short, three-letter motifs to identify longer DNA sequences that differ in mutability between populations. To achieve this, we will adapt statistical techniques that have recently been used to identify the motifs that drive hypermutation in immune cells. Once we identify such motifs, we will scan them for concordance with the rich libraries of motifs that are known to regulate protein binding and gene expression. For the first time, we propose to incorporate ancient DNA into our analyses of human mutation spectrum variation, aiming to improve our understanding of the pace of mutation rate evolution and interrogate the role of global mi- gration events in spreading mutator alleles. As a complement to this work on humans, we will also study mutation sequence context variation in polar bears and brown bears, which have been hybridizing for thousands of years in a unidirectional way with polar bear migrants entering the brown bear population but never the reverse. By analyzing the covariance of mutational sequence context in polar bears and brown bears across a range of allele ages, we will infer how often mutator alleles have crossed from one species to another. In natural populations, is difficult to map the genomic locations of mutator alleles because they are predicted to quickly recombine away from mutations they create; to overcome this difficulty, we are working with collaborators to study mutagenesis in model organisms, where inbreeding can be used to force mutations to stay linked to the genetic backgrounds on which they arise. We will develop methods to map mutator alleles in two different inbred model systems: the BXD recombinant inbred mouse strains and the Drosophila Genome Reference Panel, looking for regions of the genome where specific genetic variants are associated with mutability in specific sequence contexts. Together, these lines of research will generate a fuller picture of mutagenesis as a quantitative trait that varies between populations and evolves over time.

项目概要 DNA 突变的速度最终决定了有多少人出生时就患有严重的遗传疾病。 缓解，以及一个人在患癌症之前可能活多久。了解如何 突变会产生遗传变异，以便从基因组数据准确推断进化历史。尽管 这种对人类健康和疾病的根本重要性，我们对突变率如何变化知之甚少 因人而异，以及哪些遗传因素可能导致突变率有所不同。我之前的研究有 表明来自不同群体的突变倾向于发生在不同的序列环境中；例如， 欧洲人比非洲人和东亚人含有更多的“TCC”基序突变。这意味着每个 群体受到序列偏向突变过程的独特组合的影响。除非这些不同 所有的推断都是由环境诱变剂诱发的，其中一些肯定是“突变等位基因”的特征， 微妙地影响 DNA 损伤可能性或 DNA 修复效率的遗传变异。这个提议 描述了一种多管齐下的策略来探究 DNA 复制变异的原因和后果 保真度。第一步是超越短的三字母基序来识别更长的 DNA 序列，这些序列在 群体之间的可变性。为了实现这一目标，我们将采用最近使用的统计技术 识别驱动免疫细胞超突变的基序。一旦我们识别出这些图案，我们就会扫描它们 与已知调节蛋白质结合和基因表达的丰富基序库一致。为了 第一次，我们建议将古代 DNA 纳入我们对人类突变谱变异的分析中， 旨在提高我们对突变率进化速度的理解并质疑全球突变率的作用 传播突变等位基因的摩擦事件。作为对人类这项工作的补充，我们还将研究突变 北极熊和棕熊的序列背景变异，它们已经杂交了数千年 北极熊迁徙者以单向方式进入棕熊种群，但绝不会相反。经过 分析北极熊和棕熊一系列等位基因突变序列背景的协方差 年龄，我们将推断突变等位基因从一个物种杂交到另一个物种的频率。在自然种群中， 很难绘制突变等位基因的基因组位置图，因为预计它们会快速重组 来自他们创造的突变；为了克服这个困难，我们正在与合作者合作研究诱变 在模型生物中，近亲繁殖可用于迫使突变与遗传背景保持联系 它们由此产生。我们将开发在两个不同的近交模型系统中映射突变等位基因的方法： BXD 重组近交小鼠品系和果蝇基因组参考面板，寻找 基因组，其中特定的遗传变异与特定序列环境中的可变性相关。一起， 这些研究方向将更全面地了解诱变作为一种数量性状，其变化范围如下： 人口并随着时间的推移而演变。