Genetic analysis of segregating recessive variation

分离隐性变异的遗传分析

• 批准号: 9218968
• 负责人: Matthew Rockman
• 金额: $ 30.67万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-17 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9218968
• 关键词: Address; Alleles; Animal Model; Architecture; Biological; Biological Assay; Biometry; Caenorhabditis; Caenorhabditis elegans; Catalogs; Characteristics; Cryopreservation; Data; Diploidy; Evolution; Experimental Designs; Experimental Models; Extinction (Psychology); Fertility; Frequencies; Generations; Genetic; Genetic Load; Genetic Medicine; Genetic Risk; Genetic Transcription; Genetic study; Genome; Genomics; Genotype; Goals; Health; Homozygote; Human; Inbreeding; Individual; Laboratories; Location; Masks; Measures; Mental Depression; Methods; Modeling; Molecular; Mutation; Nematoda; Phenotype; Population; Population Control; Population Dynamics; Population Sizes; Process; Quantitative Genetics; Recombinants; Resources; Sampling; Source; System; Techniques; Testing; Time; Transcript; Variant; Work; comparative genomics; design; design and construction; experimental study; fitness; functional genomics; genetic analysis; genomic data; novel strategies; predictive modeling; rare variant; reproductive fitness; sex; whole genome

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.

项目摘要/摘要 大多数人群都有大量的低频隐性等位基因，很少 作为纯合子暴露，为了解的努力带来了巨大的统计挑战 他们的影响。该问题要求建立一个可隔离模型的实验模型 隐性变化。该模型应包括稀有等位基因，转移到更易于处理的 频率，完全测序的基因组和高度可复制的二倍体基因型 这在其纯合性的位置和程度上有所不同。该建议回答 通过在样本中解剖有害隐性变异的遗传基础来调用 从天然群体中提取的基因组。 29，义务 与雌雄同体实验室模型密切相关的线虫杂交线虫。 秀丽隐杆线。这些线虫与秀丽隐杆线虫共享遗传研究的特殊美德， 包括紧凑的基因组，短生成时间，高繁殖力和能力 用于冷冻保存。与秀丽隐杆线虫不同，该物种具有重大负载 隔离隐性变化。该提案的目的涉及创建 映射有害隐性等位基因的永久资源，表型 一系列纯合子的生殖健康和预测的构建 将纯合性与特定分子的表型效应联系起来的模型 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为 从序列定义的变体中推断遗传风险的巨大价值。这将是 在单个表型预测中特别有价值，这是遗传的关键目标 药品。