Discovery and Characterization of Quantitative Trait Nucleotides

(4.4.6)项目摘要/摘要 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是 在很大程度上没有特征。最近的研究结果表明，人类疾病风险的可遗传变异可能是 由稀有等位基因、小影响的常见等位基因和所有等位基因的复杂混合体塑造 其影响取决于其他基因座上的等位基因状态的频率。这样的复杂性是意料之中的 稳定选择下的数量性状，如人类生理和复杂结构 这些特征的缺失是他们基因解剖的主要障碍。关于遗传变异的知识 潜在的复杂性状是改善或预测疾病风险和 开发治疗方法。线虫的转录丰度特征是一种 稳定选择条件下复杂性状变异的有效模型。这些特点是可以接受的。 使用一组在很小的间隔内变化的近等基因自交系来进行完全的遗传解剖 X染色体与数百个转录本丰度性状的可遗传变异有关。 创建和研究这样的永久地图资源将允许确定原因 在单个序列分辨率下转录本丰度变化的潜在变体 变种，生成数量性状核苷酸目录。这样的目录将揭示出 导致复杂性状变异的突变，它们的作用模式，它们的相加性和 交互效应的大小、它们在自然种群中的频率以及它们的效应的分布 跨越组织、发育阶段和环境。数量性状核苷酸被定位到 从未收集过任何多细胞生物体的单变型分辨率及其特征 将为发现人类复杂疾病特征的遗传基础的努力提供信息。

(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.