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，而这种变异的分子基础在很大程度上是未表征的。最近的结果表明，人类疾病风险的遗传变异可能是由罕见等位基因、影响较小的常见等位基因和所有频率的等位基因（其影响取决于其他位点的等位基因状态）的复杂混合物形成的。这种复杂性是在稳定选择下的数量性状（如人类生理）所期望的，而这类性状的复杂结构是其遗传解剖的主要障碍。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。在稳定选择下，秀丽隐杆线虫的转录物丰度性状是复杂性状变异的一个有希望的模型。这些性状可以用一组近等基因自交系进行完全的遗传解剖，这些自交系在X染色体的一个小间隔内变化，涉及数百个转录丰度性状的遗传变异。创建和研究这样一个永久性的图谱资源将允许在单个序列变异的分辨率下识别转录本丰度变化的因果变异，生成数量性状核苷酸目录。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，它们的加性和相互作用效应大小，它们在自然种群中的频率，以及它们在组织、发育阶段和环境中的影响分布。单变异分辨率的数量性状核苷酸从未在任何多细胞生物中收集过，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。

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.