Rapid Evolution of Genomic Architecture and Multi-omics Traits

基因组结构和多组学特征的快速进化

• 批准号: 10439761
• 负责人: Timothy David O'Connor
• 金额: $ 46.31万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10439761
• 关键词: African ancestry; Amish; Architecture; Asthma; Bayesian Analysis; Biological Assay; Cancer cell line; Categories; Collaborations; Complex; Data; Development; Disease; Disease model; Distant; European; Evolution; Fatty Acid Desaturases; Future; Gene Cluster; Genetic; Genomics; Health; Human; Individual; Large-Scale Sequencing; Mediating; Methodology; Methods; Modeling; Molecular; Mutation; Native American Ancestry; Native Americans; Outcome; Pattern; Peru; Peruvian; Phenotype; Polyunsaturated Fatty Acids; Population; Publishing; Regulation; Research Design; Somatic Mutation; Structure; Systems Biology; Testing; Trans-Omics for Precision Medicine; United States National Institutes of Health; Variant; Yeasts; cohort; computer framework; de novo mutation; follow-up; genetic architecture; genetic epidemiology; genome wide association study; identity by descent; in silico; molecular phenotype; multiple omics; programs; rare variant; theories; trait

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.

抽象的 表型性状的进化不仅对于我们理解进化论很重要，而且对于 遗传流行病学和统计遗传学。通过这个提案，我将使用大规模测序和 多组学分析来测试性状进化的速度。为了检验这个假设，我将推进我们的 了解罕见变异和突变、精细群体结构和多组学特征 疾病。 当前项目 1）美洲原住民的进化和健康。在我与秘鲁国家研究所的合作中 最近，我们对来自秘鲁的 150 名主要是美洲原住民血统的个体进行了测序 发表在 PNAS 上，现在正在评估脂肪酸去饱和酶的全球进化动态 （FADS）基因簇，对多不饱和脂肪酸调节至关重要。 2) TOPMed 中的罕见变体。在精准医学跨组学 (TOPMed) 项目中，我 开发了一种新方法来评估密切相关之间罕见变异的不同注释类别 队列。我发现功能变异（例如无意义）也更容易受到群体结构的影响。 3）祖先突变。在两个项目中，我测试了祖先突变模式的差异。在 首先，我证明癌细胞系的体细胞突变率因祖先而异。在第二个中， 我发现阿米什人的新生突变平均比非创始人欧洲人少 3 个。 未来的项目 1) 罕见变异和研究设计。扩展当前项目 3 中的分析，我们将扩展此 方法不是按类别比较变化，而是按计算机预测变量的某些连续值进行比较 有害性和更广泛的方法。 2) 罕见变异IBD。我们将开发一种新方法来识别相同的小片段 利用罕见的变异来进行血统（IBD）。这对于我们如何建模基因组关系矩阵至关重要 对于关联模型。 3) 祖先的突变率变化。从当前项目 3 开始，我们将使用 de novo 突变 我们在 TOPMed 的三重奏中确定了计数，作为全基因组关联分析的表型结果。 初步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后续研究。 4）快速变化性状的进化系统生物学。使用这个程序，我们将开发一个 用于识别疾病的复杂系统生物学模型的近似贝叶斯计算 (ABC) 框架 由分子表型介导的性状。