Rapid Evolution of Genomic Architecture and Multi-omics Traits

摘要 表型性状的进化对于我们理解进化理论， 遗传流行病学和统计遗传学。通过这个建议，我将使用大规模测序， 多组学分析来测试性状进化的速度。为了验证这一假设，我将提出我们的 了解罕见的变异和突变，精细规模的人口结构，和多组学特征， 疾病 目前的项目 1)美洲原住民的进化与健康在一次合作中，我开始与秘鲁国家研究所， 最近，我们对来自秘鲁的150个主要是美洲原住民血统的个体进行了测序， 现在正在评估脂肪酸去饱和酶的全球进化动力学， （FADS）基因簇，这是多不饱和脂肪酸调控的关键。 2)TOPMed中的罕见变体。在Trans-Omics for Precision Medicine（TOPMed）项目中， 开发了一种新的方法来评估不同的注释类别之间的罕见变化密切相关 同伙我发现功能变异（例如无义）也更容易受到种群结构的影响。 3)祖先的变异。在两个项目中，我测试了不同祖先的突变模式的差异。在 首先，我证明了癌细胞系在体细胞突变率上因祖先而异。在第二种情况下， 我发现，阿米什人平均比非创始人欧洲人少3个从头突变。 未来项目 1)罕见变异和研究设计。从我们在当前项目3中的分析扩展， 不是通过类别而是通过计算机模拟预测因子的一些连续值比较变异的方法 以及更广泛的方法。 2)罕见变异IBD。我们将开发一种新的方法来识别相同的小片段， 通过利用罕见的变异来降低IBD。这将是我们如何建立基因组关系矩阵模型的关键 关联模型。 3)不同祖先的突变率差异。从目前的项目3的建设，我们将使用从头突变 我们在TOPMed中识别的三个计数作为全基因组关联分析的表型结果。 初步的研究结果显示了一些有希望的结果，我们将在酵母中使用分子检测进行跟踪。 4)快速变化特征的进化系统生物学。使用此程序，我们将开发一个 近似贝叶斯计算（ABC）框架，用于识别疾病的复杂系统生物学模型 由分子表型介导的性状。

Abstract The evolution of phenotypic traits is important both for our understanding of evolutionary theory, but also for genetic epidemiology and statistical genetics. Through this proposal, I will use large scale sequencing and multi-omics profiling to test the rapidness of trait evolution. To test this hypothesis, I will advance our understanding of rare variation and mutation, fine-scale population structure, and multi-omics traits and disease. Current Projects 1) Native American evolution and health. In a collaboration I started with the Peruvian National Institute of Health, we have sequence 150 predominantly Native American ancestry individuals from Peru, recently published in PNAS and now are evaluating the global evolutionary dynamics of the Fatty Acid Desaturase (FADS) gene cluster, which is critical to poly-unsaturated fatty acid regulation. 2) Rare variants in TOPMed. Within the Trans-Omics for Precision Medicine (TOPMed) project, I developed a new means of evaluating different annotation categories of rare variation between closely related cohorts. I find that functional variation (e.g. non-sense) are also more susceptible to population structure. 3) Mutation by ancestry. In two projects, I test for differences in mutational patterns by ancestry. In the first, I demonstrate that cancer cell lines have differences in somatic mutation rates by ancestry. In the second, I show that Amish individuals have on average 3 less de novo mutations than non-Founder Europeans. Future Projects 1) Rare variants and study design. Expanding from our analysis in current project 3, we will extend this methodology to compare variation not by categories, but for some continuous values for in silico predictors of deleteriousness and for a wider range of methodologies. 2) Rare variant IBD. We will develop a new method to identify small segments that are identical-by- descent (IBD) by leveraging rare variation. This will be critical in how we model the genomic relationship matrix for association models. 3) Mutation rate variation by ancestry. Building from current project 3, we will use the de novo mutation counts we identify in trios across TOPMed as a phenotypic outcome for a genome-wide association analysis. Preliminary findings show some promising results that we will follow-up using molecular assays in yeast. 4) Evolutionary systems biology of rapidly changing traits. Using this program, we will develop an Approximate Bayesian Computation (ABC) framework to identify complex systems biology models of disease traits mediated by molecular phenotypes.