Discovery and Characterization of Quantitative Trait Nucleotides

描述（由申请人提供）：遗传变异是人类健康变异的基础，该变异的分子基础在很大程度上尚未表征。最近的研究结果表明，人类疾病风险的遗传变异可能是由罕见的等位基因，常见的等位基因的影响小，和所有频率的等位基因，其影响取决于在其他基因座的等位基因状态的复杂混合物。这种复杂性是预期的数量性状下稳定的选择，如人类生理学，和复杂的结构，这些性状是一个主要的障碍，他们的遗传解剖。了解复杂性状的遗传变异是改善或预测疾病风险和开发治疗方法的核心。线虫C.在稳定选择下，线虫是一个很有前途的复杂性状变异模型。这些性状适合于使用近等基因近交系的小组进行完全遗传解剖，所述近等基因近交系在涉及数百个转录本丰度性状的可遗传变异的X染色体的小间隔内变化。创建和研究这样一个永久的映射资源将允许识别的因果变异的基础上的变化，在个别序列变异的分辨率转录本丰度，产生一个目录的数量性状核苷酸。这样的目录将揭示导致复杂性状变异的突变类型、它们的作用模式、它们的加性和交互作用大小、它们在自然群体中的频率，以及它们在组织、发育阶段和环境中的作用分布。映射到单变异分辨率的定量性状核苷酸从未被任何多细胞生物收集过，它们的特征将为发现人类复杂疾病性状的遗传基础提供信息。 公共卫生相关性：遗传变异解释了人类疾病的大部分变异，但影响性状的实际遗传变异非常难以确定。我们将识别影响模型物种特征的实际遗传变异，目的是学习关于什么样的变异影响疾病特征以及为什么影响疾病特征的规则。

DESCRIPTION (provided by applicant): Heritable variation underlies variation in human health, and the molecular basis for that variation is largely uncharacterized. Recent results suggest that heritable variation in human disease risk may be shaped by a complex mixture of rare alleles, common alleles of small effect, and alleles of all frequencies whose effects depend on allelic states at other loci. Such complexity is expected for quantitative traits under stabilizing selection, such as human physiology, and the complex architecture of such traits is a major obstacle to their genetic dissection. Knowledge of the genetic variants underlying complex traits is central to methods for ameliorating or predicting disease risk and for developing therapies for treatment. Transcript abundance traits in the nematode C. elegans are a promising model for variation in complex traits under stabilizing selection. These traits are amenable to full genetic dissection using panel of near-isogenic inbred lines of that vary within a small interval of the X chromosome implicated in heritable variation in hundreds of transcript abundance traits. Creation and study of such a permanent mapping resource will permit identification of the causal variants underlying variation in transcript abundances at the resolution of individual sequence variants, generating a catalog of quantitative trait nucleotides. Such a catalog will reveal the types of mutations that contribute to variation in complex traits, their modes of action, their additive and interactive effect sizes, their frequencies in natural populations, and the distribution of their effects across tissues and developmental stages and environments. Quantitative trait nucleotides mapped to single-variant resolution have never been collected for any multicellular organism, and their features will inform efforts to discover the genetic basis of complex disease traits in humans. PUBLIC HEALTH RELEVANCE: Genetic variation explains much of the variation in human disease, but the actual genetic variants that affect traits are exceptionally hard to pinpoint. We will identify the actual genetic variants that affect traits in a model species with the goal of learning rules about what kind of variants influence disease traits and why.