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: 10213629
• 负责人: Joshua Michael Akey
• 金额: $ 56.89万
• 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 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10213629
• 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：家犬衰老和长寿相关性状的遗传学 摘要 本杰明·富兰克林有一句名言：“在这个世界上，没有什么可以说是确定的，除了死亡， 几十年的研究已经导致了对遗传和 长寿的环境决定因素。尽管如此，在如何和 为什么个体在衰老和长寿相关的表型上存在差异，主要是由于以下因素的复杂相互作用： 影响生活数量和质量的变量。驯化的狗是理想的模式生物， 研究衰老和长寿相关表型的遗传结构， 背景和与人类共享的环境暴露。该项目的目标是利用 最先进的基因组学、统计学和计算工具，以系统地探测衰老的遗传结构 和长寿相关的特征。具体而言，在目标1中，我们将开发强大的基因组学资源 通过对35只精心挑选的狗进行全基因组测序，并使用这个和现有的基因组， 规模数据，以补充现有的高密度SNP基因分型芯片。我们将对所有10，000只狗进行基因分型， 大约235，000个单核苷酸多态性。这些数据将促进所有下游 本项目的分析，以及作为U19一部分的其他项目的分析。在目标2中，我们将 全面调查长寿和疾病相关性状分离的遗传结构， 10,000只狗特别是，我们将进行全基因组关联研究（GWAS）的共同 疾病、细胞和免疫相关性状，以及项目1中开发的脆弱性测量。重要的是，我们将 利用环境部收集的独特而强大的环境协变量集合 核心D将提高遗传作图的能力，并能够检测基因x环境的相互作用。 最后，在目标3中，我们将研究百岁狗的遗传结构（定义为 前1%的品种特定年龄分布）。为此，我们将使用常见的变体执行GWAS， 对500个与衰老相关的基因进行靶向重测序，以检验以下假设： 这些基因影响着非凡的寿命。总的来说，这些数据将深刻地增加我们对 关于衰老和长寿相关性状的遗传决定因素以及这些因素如何与 环境此外，我们的数据将是科学界的一个相当大的资源，我们将使 所有项目数据都很容易获取。