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

项目2：家犬衰老和长寿相关性状的遗传学 摘要 本杰明·富兰克林曾说过一句名言：“在这个世界上，没有什么是确定的，除了死亡和 税收“，以及数十年的研究已经导致在理解遗传和 长寿的环境决定因素。尽管如此，关于如何以及如何实现这一目标的认识仍然存在相当大的差距 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 影响生活数量和质量的变量。家犬是一种理想的模式生物 研究衰老和长寿相关表型的遗传结构及其简化的遗传 背景和与人类共同的环境暴露。该项目的目标是利用 ART基因组学、统计学和计算工具，系统地探索衰老的遗传结构 以及10,000只狗与长寿相关的特征。具体地说，在目标1中，我们将开发强大的基因组资源 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 犬类基因组中大约有235,000个SNPs。这些数据将促进所有下游 本项目中的分析，以及作为U19一部分的其他项目中的分析。在目标2中，我们将 全面研究长寿和疾病相关性状分离的遗传结构 10,000只狗组成的小组。特别是，我们将进行共同的全基因组关联研究(GWAS)。 疾病、细胞和免疫相关特征，以及在项目1中开发的脆弱度量。重要的是，我们将 利用环境组织收集的独特而强大的环境协变量 核心D，这将提高遗传图谱的能力，并能够检测基因x环境相互作用。 最后，在目标3中，我们将研究百岁狗的遗传结构(在 前1%的品种特定年龄分布)。为此，我们将使用常见的变体和 对500个与衰老相关的基因进行有针对性的重新测序，以检验以下假设： 这些基因会影响超乎寻常的寿命。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，我们的数据将成为科学界的重要资源，我们将使 所有项目数据均可轻松访问。

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.