Tracing the evolution of the human mutation rate

追踪人类突变率的演变

• 批准号: 9117987
• 负责人: Kelley Harris
• 金额: $ 5.61万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 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/9117987
• 关键词: Acceleration; Affect; Africa; African; African American; Alleles; American; Americas; Architecture; Asians; Autistic Disorder; Base Pairing; Bayesian Analysis; Cancer Biology; Child; Chromosome Mapping; 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; Health; Hereditary Disease; Human; Individual; Latino; Left; Machine Learning; Malignant Neoplasms; Maps; Mutation; Mutation Spectra; 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; rare variant; rate of change; success; trait; transition mutation

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（由适用提供）：所有遗传变异均由突变，由于DNA损伤而产生的变化或在DNA复制过程中复制错误。突变通常足够多，平均而言，一个孩子的30亿基对基因组包含74种新的遗传变异，这两个父母的基因组中都不存在。这种新突变会比较旧的突变更高的疾病风险，因为它们尚未通过几代父母和后代生存的考验。我们的目标是指出人类离开非洲并适应了全球潜水员的新环境时，人类突变率如何发展。一个具体的目标将跟进我的初步研究，该研究表明，欧洲人在与非洲人和亚洲人分歧后经历了变化率。这一变化的主要证据是，欧洲基因组的燃烧比突变型TCC→TTC的非洲或亚洲基因组高，其中三核苷酸“ TCC”在其中心位置经历了从“ C”到“ T”的突变。我们希望通过查看混合祖先拉丁裔和非裔美国人个体中的稀有变体来改变这种突变率的遗传基础。特别是，我们将隔离在过去10-15代中可能通过突变而产生的年轻遗传变异，此后，从欧洲到美洲的吉恩·奥（Gene Ow）已经开始。我们将推断出每个新突变都会出现并寻找欧洲群体与TCC→TCC→TTC突变密切相关的基因组区域的遗传背景（欧洲，非洲或美洲原住民）。这些将是最有可能带有因果等位基因的地区，这改变了欧洲人突变积累的过程。这项工作有可能对黑色素瘤产生宝贵的见解，黑色素瘤主要影响欧洲血统的个体，其体细胞突变信号由TCC→TTC主导。第二个具体目的是寻找其他在人类物种中或更广泛的大猿中发生的突变率变化的特征。我们将使用称为潜在Dirichlet分配（LDA）的自然语言处理技术来识别其速率似乎在常见遗传控制下的突变类型的集合。除了TCC→TTC以外，一些突变类型显示了人群之间速率差异的信号较弱，我们将尝试推断出有多少单独的突变率变化事件来解释这些信号。从特定目的I中的混合映射技术也可以适应近期可能发生的其他突变率变化的遗传基础。这些努力应提高我们对人类突变率的遗传结构的理解以及人群之间的突变率如何不同。