Genetic analysis of segregating recessive variation

项目总结/摘要 大多数种群都含有大量的低频隐性等位基因， 暴露为纯合子，为理解 他们的影响。这个问题需要一个实验上易于处理的分离模型 隐性变异该模型应包括罕见的等位基因转移到更容易处理 频率，完全测序的基因组和高度可复制的二倍体基因型 它们的位置和纯合性程度不同。这一建议回答了 通过解剖样本中有害隐性变异的遗传基础， 从专性小杆线虫29的自然种群中提取的基因组， 与雌雄同体实验室模式C. 优雅这些线虫与C.优雅的遗传研究的特殊美德， 包括紧凑的基因组、短的世代时间、高繁殖力和能力， 冷冻保存与C.这个物种拥有大量的 分离隐性变异。这项建议的目的是建立一个 永久资源映射有害的隐性等位基因，表型 在一系列纯合性的生殖适应性，和预测的建设， 将纯合性的表型效应与特定分子 分离等位基因的特征。 低频隐性等位基因的更精确的分子表征将是 在从序列定义的变异推断遗传风险方面具有重要价值。将 在个体表型预测中特别有价值，这是遗传学的一个关键目标。 药

Project Summary/Abstract Most populations harbor enormous numbers of low-frequency recessive alleles, rarely exposed as homozygotes, creating great statistical challenges for efforts to understand their effects. The problem calls for an experimentally tractable model of segregating recessive variation. The model should include rare alleles shifted to more tractable frequencies, completely sequenced genomes, and highly replicable diploid genotypes that vary in the location and extent of their homozygosity. This proposal answers that call by dissecting the genetic basis of deleterious recessive variation in a sample of genomes extracted from a natural population of Caenorhabditis sp. 29, obligate outcrossing nematodes closely related to the hermaphroditic laboratory model C. elegans. These nematodes share with C. elegans exceptional virtues for genetic study, including a compact genome, a short generation time, high fecundity, and the capacity for cryopreservation. Unlike C. elegans, this species harbors a substantial load of segregating recessive variation. The aims of this proposal involve the creation of a permanent resource for mapping the deleterious recessive alleles, the phenotyping of reproductive fitness across a range of homozygosities, and the construction of predictive models that connect the phenotypic effects of homozygosity to specific molecular features of the segregating alleles. A more precise molecular characterization of low-frequency recessive alleles will be of great value in inferring genetic risk from sequence-defined variants. It will be particularly valuable in individual phenotypic prediction, a key goal for genetic medicine.