The genomic basis of environmental adaptation in house mice

项目总结 我们对适应的遗传基础的大部分理解来自于对简单性状的研究，在这些研究中， 很大一部分表型变异是由一个或几个主效基因控制的。然而，很多 进化涉及由许多基因控制的复杂特征的变化，这些基因的影响从小到中等不等。 复杂的特征也是人类之间大多数表型差异的基础，包括与人类相关的那些 健康。这项拟议的研究将研究家鼠环境适应的遗传基础。 肌肉，人类最好的哺乳动物模型。家居老鼠最近从美国扩展到美洲 它们的原产地在西欧。通过将遗传和表型变异研究结合在一起， 在人群和实验室中，这个项目将在几个基因和表型之间明确联系 复杂的特征。这项工作将利用最近对28个家鼠种群收集的大规模调查 横跨美洲，从S纬度55°到北纬54°。来自不同环境的小鼠新近交系 形成拟议工作的关键资源。来自较冷环境的老鼠进化成更大的老鼠 (伯格曼法则)和更短的四肢(艾伦法则)，符合两个记录最好的生态环境 哺乳动物的地理模式。此外，来自不同环境的小鼠在许多代谢特征上也有所不同， 包括活动水平、体重指数和血液化学方面。我们有两个主要目标 接下来的五年。首先，我们将确定复杂适应性的遗传结构和特定的基因座 利用(1)来自不同环境的野生小鼠近交系进行QTL定位，(2)表达 研究，包括识别cis-eQTL，以在广泛的QTL区间内识别特定基因，(3) 染色质可及性研究，以确定潜在的调控变化，(4)性状的关联研究 来自自然种群的大样本小鼠，以及(5)不同实验室饲养的近交系的研究 测量环境扰动对基因表达和生物的影响的环境- 水平特征。其次，我们将扩展我们以前的工作，通过以下方式研究野生鼠的SNP变异模式 使用来自自然种群的小鼠的长读PacBio测序和长读PacBio的组合 野生近交系基因组测序和Hi-C支架研究结构变异 跨基因组，包括(1)有助于环境适应的拷贝数变化，(2) 在适应性差异基础上的转座元件插入多态，以及(3)更大的结构 变异，如倒位多态。结构变化对基因表达的影响将是 使用来自相同动物的RNAseq进行评估。这种方法组合在一起将提供一个 无与伦比的小鼠多基因适应的基因组细节图，并将确定 可能与理解人与人之间差异相关的特征的基础。

PROJECT SUMMARY Much of our understanding of the genetic basis of adaptation derives from studies of simple traits in which a large proportion of the phenotypic variation is controlled by one or a few genes of major effect. However, much of evolution involves changes in complex traits that are controlled by many genes of small to modest effect. Complex traits also underlie most phenotypic differences among humans, including those related to human health. The proposed research will study the genetic basis of environmental adaptation in house mice, Mus musculus, the best mammalian model for humans. House mice have recently expanded into the Americas from their native range in Western Europe. By combining studies of genetic and phenotypic variation in natural populations and in the lab, this project will make explicit links between genotype and phenotype for several complex traits. This work will utilize recent large-scale surveys of 28 populations of house mice collected across the Americas from 55° S latitude to 54° N latitude. New inbred lines of mice from different environments form a critical resource for the proposed work. Mice from colder environments have evolved to become larger (Bergmann’s rule) and have shorter extremities (Allen’s rule), conforming to two of the best-documented eco- geographic patterns in mammals. In addition, mice from different environments differ in many metabolic traits, including activity levels, body mass index, and aspects of blood chemistry. We have two major goals for the next five years. First, we will identify the genetic architecture and specific loci underlying complex adaptive traits using (1) QTL mapping with wild-derived inbred lines of mice from different environments, (2) expression studies, including the identification of cis-eQTL, to identify specific genes within broad QTL intervals, (3) studies of chromatin accessibility to identify potential regulatory changes, (4) association studies of traits in large samples of mice from natural populations, and (5) studies of inbred lines reared in different laboratory environments to measure the effects of environmental perturbations on both gene expression and organismal- level traits. Second, we will expand on our previous work studying patterns of SNP variation of wild mice by using a combination of long-read PacBio sequencing of mice from natural populations and long-read PacBio sequencing and Hi-C scaffolding of genomes from wild-derived inbred strains to study structural variation across the genome, including (1) copy-number variation contributing to environmental adaptation, (2) transposable element insertion polymorphisms underlying adaptive differences, and (3) larger structural variants such as inversion polymorphisms. The impact of structural variation on gene expression will be assessed using RNAseq from the same animals. Together this combination of approaches will provide an unparalleled picture of the genomic details underlying polygenic adaptation in mice and will identify the genetic basis of traits likely to be relevant for understanding differences among humans.