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：
10542240
负责人：
Kelley Harris
金额：
$ 3.23万
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：
2019-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10542240
关键词：
Affect African Age Aging Alleles Animal Model Binding Proteins Biological Models Cells Child DNA DNA Damage DNA Repair DNA Sequence DNA Sequence Alteration DNA biosynthesis Disease Drosophila genome East Asian European Event Evolution Fathers Gene Expression Genetic Genetic Diseases Genetic Variation Genome Genomics Health Human Immune Inbred Strains Mice Inbreeding Individual Killifishes Letters Libraries Link Location Malignant Neoplasms Maps Methods Modeling Mothers Mutagenesis Mutate Mutation Parental Ages Parents Persons Play Population Process Recombinants Recording of previous events Research Role Scanning Techniques Time Variant age effect environmental mutagens genetic architecture genetic variant genomic data improved innovation migration non-genetic offspring reference genome trait

Affect African Age Aging Alleles Animal Model Binding Proteins Biological Models Cells Child DNA DNA Damage DNA Repair DNA Sequence DNA Sequence Alteration DNA biosynthesis Disease Drosophila genome East Asian European Event Evolution Fathers Gene Expression Genetic Genetic Diseases Genetic Variation Genome Genomics Health Human Immune Inbred Strains Mice Inbreeding Individual Killifishes Letters Libraries Link Location Malignant Neoplasms Maps Methods Modeling Mothers Mutagenesis Mutate Mutation Parental Ages Parents Persons Play Population Process Recombinants Recording of previous events Research Role Scanning Techniques Time Variant age effect environmental mutagens genetic architecture genetic variant genomic data improved innovation migration non-genetic offspring reference genome trait

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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. We aim to improve our understanding of the pace of mutation rate evolution, interrogating the role of global migration events in spreading mutator alleles, as well as the contribution of non-genetic factors such as the parental age effect. In humans, it is known that the ages of mothers and fathers at the time children are conceived impacts both the rate and spectrum of mutagenesis, and we propose to investigate this effect in greater generality by sequenc- ing young and old parents together with their offspring in a several species of killiﬁsh, a model vertebrate that is famous for maturing and aging extremely rapidly. We plan to exploit the utility of model organisms in another way as well: 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, but in lab-reared populations, 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。我们旨在提高我们对突变率演变速度的理解，询问全球移民的作用扩散突变器等位基因的事件以及非遗传因素（例如父母年龄）的贡献影响。在人类中，众所周知，当时孩子们的母亲和父亲的年龄都受到构想的影响诱变的速率和频谱，我们建议通过序列较大的一般性研究这种影响与年轻的父母以及他们的后代在几种杀虫剂中，这是一种模型脊椎动物以非常迅速的成熟和衰老而闻名。我们计划利用另一个模型生物的效用方式也是如此：在自然种群中，很难映射突变器等位基因的基因组位置预计会迅速将其从其创建的突变中重新组合，但是在实验室的种群中，繁殖可以是用于迫使突变与产生的遗传背景有关。我们将开发方法在两个不同的近交模型系统中绘制突变器等位基因：BXD重组近交小鼠菌株和果蝇基因组参考面板，寻找特定遗传变异的基因组区域与特定序列上下文中的可突变性有关。这些研究路线将产生更富裕的随着时间的流逝，诱变作为一种定量性状的图像在人群和人群之间变化。