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（由申请人提供）：所有遗传变异都是由突变产生的，这些突变是由于DNA复制过程中的DNA损伤或复制错误而引起的。突变是非常频繁的，平均而言，一个孩子的30亿碱基对基因组包含74个新的遗传变异，这些变异在父母的基因组中都不存在。这种新的突变比旧的突变带来更高的疾病风险，因为它们没有通过几代父母和后代的生存测试。我们的目标是查明人类的突变率是如何随着人类离开非洲并适应地球仪的各种新环境而演变的。 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开后经历了突变率的变化。这种变化的主要证据是欧洲人基因组比非洲人或亚洲人基因组具有更高的突变类型TCC→TTC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。我们希望通过观察拉丁美洲和非洲裔美国人混血个体中的罕见变异来了解这种突变率变化的遗传基础。特别是，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，在基因从欧洲进入美洲已经开始之后。我们将推断每个新突变产生的遗传背景（欧洲人、非洲人或美洲原住民），并寻找欧洲人与TCC→TTC突变过量密切相关的基因组区域。这些区域最有可能拥有一个改变欧洲人突变积累过程的致病等位基因。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个体的癌症，其体细胞突变特征由TCC→TTC主导。 第二个具体目标是寻找人类物种或更广泛地说，在类人猿中发生的突变率变化的其他标志。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突变类型的集合，这些突变类型的发生率似乎受到共同的遗传控制。除了TCC→TTC之外，还有一些突变类型显示出种群间的速率分化信号，我们将尝试推断需要多少单独的突变速率变化事件来解释这些信号。来自特定目标I的混合物作图技术也可以适用于询问最近可能发生的其他突变率变化的遗传基础。这些努力应该会提高我们对人类突变率遗传结构的理解，以及突变率在人群之间的差异。