Discovery and Characterization of Quantitative Trait Nucleotides

数量性状核苷酸的发现和表征

基本信息

批准号：
7937997
负责人：
Matthew Rockman
金额：
$ 30.36万
依托单位：
NEW YORK UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7937997
关键词：
Affect Agriculture Alleles Anecdotes Architecture Behavioral Biology C. elegans genome Caenorhabditis elegans Cataloging Catalogs Collection Complex Complex Genetic Trait Complex Mixtures Data Development Disease Dissection Environment Frequencies Gene Frequency Genes Genetic Genetic Epistasis Genetic Polymorphism Genetic Recombination Genetic Variation Genome Genomics Genotype Goals Health Heritability Human Individual Knowledge Learning Left Maps Measures Methods Modeling Molecular Mutation Nematoda Nucleotide Mapping Nucleotides Organism Phenotype Physiology Population Population Distributions Population Genetics Predisposition Quantitative Trait Loci Reading Recombinants Reporter Research Resolution Resources Shapes Sorting - Cell Movement Specificity Staging Tissues Transcript Transgenic Organisms Variant X Chromosome base design disorder risk genetic variant genome wide association study genome-wide human disease pleiotropism public health relevance success therapy development tool trait

项目摘要

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.

描述（由申请人提供）：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是未知的。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、效应较小的常见等位基因以及其影响取决于其他基因座的等位基因状态的所有频率等位基因的复杂混合物形成的。这种复杂性对于稳定选择下的数量性状（例如人类生理学）来说是预料之中的，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对于改善或预测疾病风险以及开发治疗方法至关重要。线虫秀丽隐杆线虫的转录丰度性状是稳定选择下复杂性状变异的有前途的模型。这些性状可以使用一组近等基因的自交系进行全面的遗传解剖，这些自交系在 X 染色体的一个小区间内变化，涉及数百个转录本丰度性状的遗传变异。这种永久绘图资源的创建和研究将允许在单个序列变体的分辨率下识别转录物丰度变化的因果变体，从而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类型、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，以及它们在组织、发育阶段和环境中的影响分布。从未收集过任何多细胞生物体映射到单变体分辨率的数量性状核苷酸，它们的特征将为发现人类复杂疾病性状的遗传基础的努力提供信息。公共卫生相关性：遗传变异可以解释人类疾病的大部分变异，但影响性状的实际遗传变异却异常难以确定。我们将确定影响模型物种性状的实际遗传变异，目的是了解哪些变异影响疾病性状及其原因。