Discovery and Characterization of Quantitative Trait Nucleotides

（4.4.6）项目概要/摘要 遗传变异是人类健康变异的基础，这种变异的分子基础是 基本上没有特征。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、影响小的常见等位基因和所有等位基因的复杂混合物形成。 其影响取决于其他基因座的等位基因状态的频率。预计这种复杂性将在 稳定选择下的数量性状，如人体生理学和复杂的结构， 这是对它们进行基因解剖的主要障碍。基因变异的知识 潜在的复杂性状是改善或预测疾病风险以及 开发治疗方法。线虫C.优雅是一种 稳定选择条件下复杂性状变异的理想模型。这些特征是可以接受的 使用一组近等基因近交系进行全面的遗传解剖， X染色体与数百种转录本丰度性状的遗传变异有关。 建立和研究这种永久性的绘图资源将有助于确定 在单个序列分辨率下转录本丰度变异的基础变异 变异，生成数量性状核苷酸的目录。这样的目录将揭示 导致复杂性状变异的突变，它们的作用方式，它们的加性和 交互效应大小，它们在自然群体中的频率，以及它们的效应分布 跨越组织、发育阶段和环境。数量性状核苷酸映射到 单变量分辨率从来没有收集到任何多细胞生物，其特征 将有助于发现人类复杂疾病特征的遗传基础。

(4.4.6) PROJECT SUMMARY/ABSTRACT 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.