A Resource for the Genetic Dissection of Complex Traits

项目总结 一大套不同的常见人类疾病，以及大多数与生物医学相关的特征 生物生物学家经常瞄准的目标是复杂和多基因的。这些性状的群体变异有一个 相当大的遗传成分，剖析这种变异可以带来更好的诊断和治疗方法，以及 能够详细描述疾病和性状变异背后的分子和细胞过程。 全基因组关联研究在很大程度上促进了分析的显著进展。 近些年来，人类的复杂特征。GWA已经将许多基因与人类健康的变异联系在一起，并且 这意味着很大一部分性状变异是由数以千计的微效应控制的，主要是调控位点 沿着基因组传播。尽管有这种批判性的洞察力，但我们对 致因位置的性质。GWAS方法的一个值得注意的警告是其固有的对中间体的偏见- 频率等位基因；GWAS不适合发现稀有的大效应等位基因和含有几个的基因 个别罕见的突变，突变-选择平衡模型预测的事件会导致性状变异。 对模型生物中复杂特征的剖析提供了极大的实验灵活性，而 有机会部署与占主导地位的GWAS范例协同的方法，从而产生更完整的 性状变异的遗传基础图解。考虑到这一点，我们建立了DSPR(果蝇合成 种群资源)作为苍蝇复杂特性分析的共享工具包。1600株DSPR菌株 来自15个高度特征化的方正基因，代表了最广泛的多亲本 动物可用的种群(MPP)。DSPR被许多研究小组使用，使 鉴定了数千个QTL，并发现了与性状变异相关的稀有等位基因。DSPR是对 Gwas方法揭示了导致复杂性状的等位基因变异的全部频谱。 在目标1中，我们将验证和提炼所有DSPR菌株的基因类型，加强生命资源 我们将继续与果蝇社区分享，并通过以下方式提高收藏的可用性 将分析程序集成到功能强大的R/qtl2软件平台中。在目标2中，我们将延长DSPR，并 启用极端QTL(或X-QTL)定位。对于许多特征，一种高效和用户友好的策略来识别 QTL是比较表型极端重组群体和对照群体的等位基因频率 一群人。我们将派生出这样的混合DSPR种群，通过实验改进我们的方法，并分发 人口和软件，以促进新的、调查者驱动的研究。在目标3中，我们将扩大 探讨DSPR基因表达调控的本质。使用宿主-病原体模型，我们将利用 在免疫反应过程中发生的快速调节变化，以开发动态eQTL作图方法， 找到导致调控反应轨迹变化的基因座。这些一般资源将 允许使用任何MPP的研究人员超越群体中基因表达的静态图像。

PROJECT SUMMARY A large, diverse set of common human diseases, and most of the biomedically-relevant traits that model organism biologists routinely target, are complex and polygenic. Population variation in these traits has a sizeable genetic component, and dissecting this variation can yield improved diagnostics and therapeutics, and enable detailed descriptions of the molecular and cellular processes underlying disease and trait variation. Genomewide association studies (GWAS) are largely responsible for dramatic progress in the analysis of human complex traits in recent years. GWAS have linked many genes to variation in human health, and imply a significant fraction of trait variation is controlled by thousands of tiny-effect, primarily regulatory sites spread along the genome. Despite this critical insight, there remain many gaps in our understanding of the nature of causative loci. One notable caveat of the GWAS approach is its inherent bias towards intermediate- frequency alleles; GWAS are ill-suited to uncovering rare alleles of large effect and genes harboring several individually-rare mutations, events that mutation-selection balance models predict contribute to trait variation. The dissection of complex traits in model organisms offers great experimental flexibility, and the opportunity to deploy methods synergistic with the dominant GWAS paradigm, yielding a more complete picture of the genetic basis of trait variation. With this in mind we established the DSPR (Drosophila Synthetic Population Resource) as a shareable toolkit for complex trait analysis in flies. The set of 1600 DSPR strains were derived from 15 highly-characterized founder genotypes, and represent the most extensive multiparental population (MPP) available in animals. The DSPR is used by many research groups, has enabled the identification of thousands of QTL, and has associated rare alleles with trait variation. The DSPR complements GWAS approaches for uncovering the full spectrum of allelic variation contributing to complex traits. In Aim 1 we will validate and refine the genotypes of all DSPR strains, strengthening the living resource we will continue to share with the Drosophila community, and enhance the usability of the collection by integrating analytical routines into the powerful R/qtl2 software platform. In Aim 2 we will extend the DSPR, and enable extreme QTL (or X-QTL) mapping. For many traits, an efficient and user-friendly strategy to identify QTL is to compare allele frequencies in phenotypically-extreme recombinant populations to those in control cohorts. We will derive such mixed DSPR populations, experimentally refine our approach, and distribute populations and software to facilitate novel, investigator-driven research. In Aim 3 we will broaden the utility of the DSPR to explore the nature of expression regulation. Using a host-pathogen model, we will exploit the rapid regulatory change that occurs during the immune response to develop dynamic eQTL mapping methods, finding loci that contribute to variation in the trajectory of the regulatory reaction. These general resources will allow researchers employing any MPP to move beyond static pictures of gene expression in populations.