Characterizing and Mapping Deleterious Mutations in Humans

项目摘要 人类遗传学的一个基本目标是识别和表征导致人类遗传学异常的有害突变。 疾病有害的疾病等位基因是通过突变引入的，然后通过突变增加或减少频率。 遗传漂变和自然选择的影响。它们的最终命运主要取决于它们对健康的影响 在杂合子和纯合子中。尽管有明确的证据表明人类携带着有害的 然而，这些突变的总数及其典型的适应性后果仍然不清楚。 此外，尚不清楚纯合子引起疾病的突变是否也具有微妙的适应性 杂合子的影响。然而，杂合子中的轻微适应性效应可能不会出现临床症状， 在进化的时间尺度上会极大地影响这些等位基因的频率。最后，研究人员 传统上仅限于研究出生后表现出有害影响的突变， 胚胎致死等位基因在很大程度上仍未被确定。很大一部分人类基因似乎 在强烈的选择性约束下，然而没有已知的功能，大概是因为它们是必需的 正常的胚胎发育。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。具体而言，拟议的工作 结合了生物信息学、群体遗传学和人类基因组学， 有害的隐性等位基因，决定被归类为隐性的突变的适合性和显性效应， 并识别显性和隐性胚胎致死突变。第一个目的是利用自体受精的优势， 在一个创始人人口，哈特派，估计缺乏强烈有害基因型， 将结果与具有相似谱系结构的黑长尾猴群体进行比较，以了解差异 在种群和物种之间。第二个目标是制定一个可能性框架，并使用现实的 模拟人类人口统计学历史，以测试基因中有害等位基因的频率分布 注释为完全隐性与杂合子中不存在任何适合度效应一致。的 第三个目标是对流产样本进行测序，并开发生物信息学管道来识别候选人。 导致胚胎致死的突变。在这里，生物信息学管道将可用于 用于有兴趣了解自发性突变的临床研究社区 流产总之，拟议中的研究将解决有关人口遗传学的核心问题， 有害的等位基因，并提供新的洞察力的力量，影响人类遗传的持久性 疾病 !

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. !