Tracing the evolution of the human mutation rate

追踪人类突变率的演变

基本信息

批准号：
9397848
负责人：
Kelley Harris
金额：
$ 0.05万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-06-15 至 2018-06-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9397848
关键词：
Acceleration Affect Africa African African American Alleles American Americas Architecture Asians Autistic Disorder Base Pairing Bayesian Analysis Cancer Biology Child Collection DNA Damage DNA biosynthesis Disease Doctor of Philosophy Employee Strikes Environment Europe European Event Evolution Exhibits Generations Genes Genetic Genetic Variation Genome Genomic Segment Germ-Line Mutation Hereditary Disease Human Individual Latino Left Machine Learning Malignant Neoplasms Maps Mutation Native Americans Natural Language Processing Parents Pongidae Population Process Recording of previous events Research Risk Risk Factors Schizophrenia Signal Transduction Site Somatic Mutation Techniques Testing Time Variant Work admixture mapping base design developmental disease disorder risk experience follow-up genetic risk factor genetic variant improved insight learning strategy melanoma offspring public health relevance rare variant rate of change success trait transition mutation

项目摘要

DESCRIPTION (provided by applicant): All genetic variation is created by mutations, changes that arise due to DNA damage or copying mistakes during DNA replication. Mutations are frequent enough that, on average, a child's 3-billion base pair genome contains 74 new genetic variants that are not present in the genome of either parent. Such new mutations confer a higher disease risk than older mutations because they have not passed the test of surviving through several generations of parents and offspring. We aim to pinpoint how the human mutation rate has evolved as humans left Africa and adapted to diverse new environments across the globe. One specific aim will follow up on my preliminary research which showed that Europeans experienced a mutation rate change after diverging from Africans and Asians. The primary evidence for this change is that European genomes have a higher burden than African or Asian genomes of the mutation type TCC→TTC, where the trinucleotide "TCC" has experienced a mutation from "C" to "T" at its central site. We wish to and the genetic basis of this mutation rate change by looking at rare variants in mixed- ancestry Latino and African-American individuals. Specially, we will isolate young genetic variants that probably arose via mutation within the past 10-15 generations, after gene ow from Europe into the Americas had already begun. We will infer the genetic background (European, African, or Native American) upon which each new mutation arose and look for genomic regions where European ances- try correlates strongly with an excess of TCC→TTC mutations. These will be the regions most likely to harbor a causal allele that changed the process of mutation accumulation in Europeans. This work has the potential to yield valuable insights into melanoma, a cancer that predominantly affects individuals of European ancestry and whose somatic mutational signature is dominated by TCC→TTC. A second specific aim is to look for other signatures of mutation rate change that have occurred within the human species or, more broadly, within the great apes. We will use a natural language processing technique called Latent Dirichlet Allocation (LDA) to identify collections of mutation types whose rates appear to be under common genetic control. A few mutation types besides TCC→TTC show weak signals of rate differentiation between populations, and we will attempt to infer how many separate mutation rate change events are necessary to explain these signals. The admixture mapping technique from Specific Aim I can also be adapted to interrogate the genetic basis of other mutation rate changes that might have occurred in the recent past. These efforts should improve our understanding of the human mutation rate's genetic architecture and how mutation rates differ between populations.

描述（由申请人提供）：所有遗传变异都是由突变造成的，这些变化是由于 DNA 损伤或 DNA 复制过程中的复制错误而产生的。突变非常频繁，平均而言，一个孩子的 30 亿碱基对基因组包含 74 个新的碱基对。此类新突变比旧突变具有更高的疾病风险，因为它们尚未通过后代和后代父母的几代生存测试。率有随着人类离开非洲并适应全球不同的新环境，我的初步研究表明欧洲人在从非洲人和亚洲人那里潜水后经历了突变率的变化，这一变化的主要证据是欧洲人。基因组比 TCC→TTC 突变类型的非洲或亚洲基因组具有更高的负担，其中三核苷酸“TCC”在其中心位点经历了从“C”到“T”的突变，我们希望了解这一点的遗传基础。通过观察稀有突变率的变化特别是，在基因从欧洲流入美洲之后，我们将分离出可能在过去 10-15 代内通过突变产生的年轻遗传变异。每个新突变产生的背景（欧洲、非洲或美洲原住民），并寻找欧洲血统与过量 TCC→TTC 突变密切相关的基因组区域，这些区域最有可能存在因果关系。这项工作有可能对黑色素瘤产生有价值的见解，黑色素瘤是一种主要影响欧洲血统的癌症，其体细胞突变特征以 TCC→TTC 为主。寻找人类物种或更广泛的类人猿中发生的突变率变化的其他特征我们将使用一种称为潜在狄利克雷分配（LDA）的自然语言处理技术来识别出现率的突变类型集合。除了TCC→TTC之外，一些突变类型在群体之间表现出微弱的速率差异信号，我们将尝试推断需要多少单独的突变率变化事件来解释这些信号。目标 I 还可以用于询问最近可能发生的其他突变率变化的遗传基础，这些努力应该可以提高我们对人类突变率遗传结构以及人群之间突变率差异的理解。