Investigating the landscape and genetic architecture of germline mutagenesis

研究种系突变的景观和遗传结构

基本信息

批准号：
10672948
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
项目类别：
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

项目摘要

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.

项目摘要 DNA突变最终确定有多少人出生的速率有严重的遗传疾病放松一个人在患癌症之前可能寿命的时间。了解如何突变会产生遗传变异，以便从基因组数据中准确推断进化史。尽管对于人类健康和疾病的这种基本重要性，我们对突变率各种方式了解一无所知从人到人，哪些遗传因素可能导致突变率有所不同。我以前的研究有表明，来自不同人群的突变会偏向于不同的序列上下文。例如，与非洲人或东亚人相比，欧洲人在图案“ TCC”中包含更多的突变。这意味着每个人口受序列偏置突变过程的独特组合的影响。除非这些差异原因都是由环境变异引起的，其中一些必须是“突变等位基因”的签名微妙影响DNA损伤或DNA修复效率的遗传变异。这个建议描述了一种多管齐的策略，用于询问DNA复制变化的原因和后果实现。第一个步骤将是超越简短的三个字母的主题，以识别较长的DNA序列人群之间的可变性。为了实现这一目标，我们将调整最近使用的统计技术确定在免疫细胞中驱动超名的基序。一旦我们确定了这样的主题，我们将扫描它们与已知可以调节蛋白质结合和基因表达的富图库的一致性。为了第一次，我们提议将古代DNA纳入我们的人类突变频谱变化的分析中，旨在提高我们对突变率演变速度的理解，并审问全球Mi-i-I的作用传播突变器等位基因中的栅格事件。为了完成有关人类的这项工作，我们还将研究突变北极熊和棕熊的序列上下文变化，这些变化已经杂交了数千年北极熊移民进入棕熊种群，但从未有过反向，以单向方式。经过分析北极熊和棕熊在一系列等位基因的突变序列上下文的协方差年龄，我们将推断突变等位基因从一个物种越过另一种物种的频率。在自然种群中很难绘制突变剂等位基因的基因组位置，因为预计它们会迅速重组从它们创造的突变中；为了克服这一困难，我们正在与合作者合作研究诱变在模型生物中，可以使用近交的生物迫使突变与遗传背景保持联系它们出现的。我们将开发在两个不同的近交模型系统中绘制突变器等位基因的方法： BXD重组近交小鼠菌株和果蝇基因组参考面板，寻找区域特定遗传变异与特定序列上下文中的可突变性相关的基因组。一起，这些研究线将产生更全面的诱变图，作为定量性状，在人口和演变随着时间的流逝。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Evolution of the Mutation Spectrum Across a Mammalian Phylogeny.

DOI：
10.1093/molbev/msad213
发表时间：
2023-10-04
期刊：
MOLECULAR BIOLOGY AND EVOLUTION
影响因子：
10.7
作者：
Beichman, Annabel C.;Robinson, Jacqueline;Lin, Meixi;Moreno-Estrada, Andres;Nigenda-Morales, Sergio;Harris, Kelley
通讯作者：
Harris, Kelley

The randomness that shapes our DNA.

塑造我们 DNA 的随机性。