Characterizing and Mapping Deleterious Mutations in Humans

项目总结 人类遗传学的一个基本目标是识别和表征有害的突变 疾病。有害的疾病等位基因是通过突变引入的，然后通过 遗传漂移和自然选择的影响。他们的最终命运取决于他们对健康的影响 在杂合子和纯合子中。尽管有明确的证据表明人类背负着有害的负担 突变、此类突变的总数及其典型的适合性后果尚不清楚。 此外，尚不清楚纯合子突变是否也具有微妙的适合性。 杂合子时的影响。然而，杂合子的轻微健身影响可能不会出现临床症状。 会极大地影响这些等位基因在进化时间尺度上的频率。最后，研究人员发现 传统上仅限于研究在出生后表现出有害影响的突变，因此 胚胎致死等位基因在很大程度上仍未确定。相当大比例的人类基因似乎 受到很强的选择性限制，但没有已知的功能，大概是因为它们是必需的 对于正常的胚胎发育来说。拟议研究的目标是解决这些悬而未决的问题 描述和绘制人类有害突变的问题。具体地说，拟议的工作 结合生物信息学、人口遗传学和人类基因组学来估计 有害的隐性等位基因，决定了被归类为隐性突变的适合性和显性效应， 并鉴定显性和隐性胚胎致死突变。第一个目标是利用同源合子 在创始人群体中的区域，哈特利特人，以估计强有害基因的缺乏和 将结果与一群谱系结构相似的马尾猴进行比较，以了解差异 在种群和物种之间。第二个目标是开发一个可能性框架，并使用现实 模拟人类人口学历史以检验有害等位基因在基因中的频率分布 被注释为完全隐性的基因与杂合子中没有任何适合度效应是一致的。这个 第三个目标是对流产样本进行排序，并开发一条生物信息学管道来确定候选 突变是胚胎致死的基础。在这里，生物信息学管道将公开提供给 由对了解导致自发突变感兴趣的临床研究团体使用 流产。总而言之，这项拟议的研究将解决关于老年人群体遗传学的核心问题 有害的等位基因，并为影响人类遗传持久性的力量提供了新的见解 疾病。 好了！

PROJECT SUMMARY A fundamental goal of human genetics is to identify and characterize deleterious mutations responsible for disease. Deleterious disease alleles are introduced by mutation, then increase or decrease in frequency through the effects of genetic drift and natural selection. Their ultimate fate depends critically on their effects on fitness in heterozygotes and homozygotes. Although there is clear evidence that humans carry a burden of deleterious mutations, the total number of such mutations and their typical fitness consequences remain unclear. Furthermore, it is unknown if mutations responsible for disease when homozygous also have subtle fitness effects when heterozygous. Minor fitness effects in heterozygotes may not present clinical symptoms, however can dramatically impact the frequencies of such alleles over evolutionary timescales. Finally, researchers have traditionally been limited to studying mutations that manifest their deleterious effects after birth and thus embryonic lethal alleles have remained largely unidentified. A substantial proportion of human genes appear to be under strong selective constraint, however have no known function, presumably because they are required for normal embryonic development. The goal of the proposed research is to address these unanswered questions in characterizing and mapping deleterious mutations in humans. Specifically, the proposed work combines bioinformatics, population genetics, and human genomics to estimate the burden of strongly deleterious recessive alleles, determine the fitness and dominance effects of mutations classified as recessive, and identify dominant and recessive embryonic lethal mutations. The first aim is to take advantage of autozygous regions in a founder population, the Hutterites, to estimate the deficiency of strongly deleterious genotypes and compare the result to a colony of vervet monkeys with a similar pedigree structure to understand differences among populations and species. The second aim is to develop a likelihood framework and use realistic simulations of human demographic history to test if the frequency distribution of deleterious alleles in genes annotated as completely recessive is consistent with the absence of any fitness effects in heterozygotes. The third aim is to sequence miscarriage samples and develop a bioinformatics pipeline to identify candidate mutations underlying embryonic lethality. Here, the bioinformatics pipeline will be made publically available for use by the clinical research community interested in understanding mutations responsible for spontaneous miscarriage. Together, the proposed research will address central questions about the population genetics of deleterious alleles and provide new insight into the forces that influence the persistence of human genetic disease. !