Discovery and Characterization of Quantitative Trait Nucleotides

描述(申请人提供)：可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还没有确定。最近的结果表明，人类疾病风险的可遗传变异可能是由稀有等位基因、常见的小效应等位基因和所有频率的等位基因的复杂混合物形成的，这些等位基因的影响取决于其他基因座的等位基因状态。在稳定选择的情况下，数量性状的复杂性是可以预料的，例如人类生理学，而这些性状的复杂结构是其遗传解剖的主要障碍。了解复杂性状背后的遗传变异是改善或预测疾病风险以及开发治疗方法的核心。线虫的转录本丰度性状是稳定选择下复杂性状变异的一种很有前途的模式。这些性状可以用一组近等基因的自交系进行完全的遗传解剖，这些自交系在X染色体的一小段时间内变化，涉及数百个转录本丰度性状的可遗传变异。建立和研究这样一个永久性的图谱资源将能够在单个序列变异的分辨率下识别转录丰度变化的原因变异，从而产生一个数量性状核苷酸目录。这样的目录将揭示导致复杂特征变异的突变类型、它们的作用模式、它们的相加和相互作用的大小、它们在自然种群中的频率，以及它们的影响在组织、发育阶段和环境中的分布。映射到单变量分辨率的数量性状核苷酸从未在任何多细胞生物体中收集到，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。 与公共卫生相关：基因变异解释了人类疾病中的大部分变异，但影响特征的实际遗传变异特别难确定。我们将识别影响模式物种特征的实际遗传变异，目的是学习关于哪种变异影响疾病特征及其原因的规则。

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.