Project 2: Genetics of aging and longevity related traits in the domesticated dog

项目2：家养狗衰老和长寿相关性状的遗传学

• 批准号: 10440339
• 负责人: Joshua Michael Akey
• 金额: $ 41.08万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10440339
• 关键词: Age Distribution; Aging; Animal Model; Canis familiaris; Centenarian; Cessation of life; Chromosome Mapping; Collection; Communities; Companions; Complex; Custom; Data; Detection; Disease; Environment; Environmental Exposure; Environmental Risk Factor; Etiology; Genes; Genetic; Genetic Determinism; Genetic study; Genomics; Genotype; Goals; Heritability; Human; Immune; Individual; Knowledge; Linkage Disequilibrium; Longevity; Maps; Measures; Molecular; Pattern; Phenotype; Quality of life; Research; Resolution; Resources; SNP genotyping; Sampling; Targeted Resequencing; Taxes; Testing; Variant; Work; cohort; comorbidity; computerized tools; density; disease phenotype; dog genome; frailty; gene environment interaction; genetic architecture; genetic association; genome sequencing; genome wide association study; genome-wide; genomic variation; healthy aging; high dimensionality; improved; insight; interdisciplinary approach; molecular phenotype; novel; rare variant; tool; trait; whole genome

Project 2: Genetics of aging and longevity related traits in the domesticated dog Abstract Benjamin Franklin famously remarked, “In this world nothing can be said to be certain, except death and taxes”, and decades of research have led to remarkable progress in understanding the genetic and environmental determinants of longevity. Nonetheless, considerable gaps in knowledge remain about how and why individuals differ in aging and longevity related phenotypes, largely due to the complex interaction of variables that influence the quantity and quality of life. The domesticated dog is an ideal model organism to investigate the genetic architecture of aging and longevity related phenotypes given its simplified genetic background and shared environmental exposures with humans. The goal of this project is to leverage state of the art genomics, statistical, and computational tools to systematically probe the genetic architecture of aging and longevity related traits in 10,000 dogs. Specifically, in Aim 1 we will develop powerful genomics resources by performing whole-genome sequencing on 35 carefully selected dogs, and use this and existing genome- scale data, to supplement existing high-density SNP genotyping chips. We will genotype all 10,000 dogs for approximately 235,000 SNPs throughout the canine genome. These data will facilitate all downstream analyses in this project, as well as analyses in other projects as part of the U19. In Aim 2, we will comprehensively investigate the genetic architecture of longevity and disease related traits segregating in the panel of 10,000 dogs. In particular, we will perform genome-wide association studies (GWAS) of common diseases, cellular and immune related traits, and measures of frailty developed in Project 1. Importantly, we will take advantage of the unique and powerful collection of environmental covariates collected by the Environment Core D that will improve power for genetic mapping and enable detection of gene x environment interactions. Finally, in Aim 3 we will investigate the genetic architecture of centenarian dogs (defined as individuals in the top 1% of breed specific age distributions). To this end, we will perform GWAS with common variants and targeted resequencing of 500 aging-related genes to test the hypothesis that rare and common variants in these genes influence exceptional lifespan. Collectively, these data will profoundly increase our understanding on the genetic determinants of aging and longevity related traits and how these factors interact with the environment. Moreover, our data will be a considerable resource to the scientific community, and we will make all project data easily accessible.

项目2：驯化狗的衰老和寿命相关特征的遗传学 抽象的 本杰明·富兰克林（Benjamin Franklin）著名地说：“在这个世界上，除了死亡和 税收”，数十年的研究在理解遗传和 寿命的环境决定者。尽管如此，知识的差距仍然存在有关方法和 为什么个体在衰老和寿命相关的表型方面有所不同，这主要是由于复杂的相互作用 影响生活数量和质量的变量。驯养的狗是理想的模型生物 鉴于其简化的遗传 背景和共享的环境暴露与人类。该项目的目的是利用 ART基因组学，统计和计算工具系统地探测衰老的遗传结构 和10,000只狗的寿命相关特征。具体而言，在AIM 1中，我们将开发强大的基因组学资源 通过对35只精心选择的狗进行全基因组测序，并使用此和现有的基因组 - 比例数据，以补充现有的高密度SNP基因分型芯片。我们将基因类型所有10,000只狗 整个犬类基因组中约有235,000个SNP。这些数据将有助于下游 在U19的一部分中，该项目的分析以及其他项目的分析。在AIM 2中，我们将 全面研究寿命和疾病与疾病相关特征的遗传结构。 10,000只狗的面板。特别是，我们将进行全基因组关联研究（GWAS） 疾病，细胞和免疫性特征以及项目1中发展的脆弱性措施。重要的是，我们将 利用环境收集的独特而强大的环境协变量集合 核心D将提高基因映射并实现基因X环境相互作用的能力。 最后，在AIM 3中，我们将研究一百岁狗的遗传结构（定义为个人 特定年龄分布的最高1％）。为此，我们将使用常见变体执行GWAS，并且 针对500个与老化相关的基因的针对性重新定价，以检验以下假设。 这些基因会影响特殊的寿命。总的来说，这些数据将深刻提高我们的理解 关于衰老和寿命相关特征的遗传决定者，以及这些因素如何与 环境。此外，我们的数据将是科学界的考虑资源，我们将使 所有项目数据易于访问。