The genomic basis of environmental adaptation in house mice

家鼠环境适应的基因组基础

• 批准号: 10623622
• 负责人: MICHAEL W. NACHMAN
• 金额: $ 39.1万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10623622
• 关键词: Americas; Animals; Biology; Blood Chemical Analysis; Body mass index; Chromatin; Climate; Complex; Copy Number Polymorphism; DNA Insertion Elements; DNA Transposable Elements; Disease; Environment; Evolution; Gene Expression; Genes; Genetic; Genetic Polymorphism; Genetic study; Genome; Genomics; Genotype; Geography; Goals; Health; Hi-C; House mice; Human; Inbred Strain; Inbreeding; Laboratories; Limb structure; Link; Mammals; Maps; Measures; Metabolic; Metabolic Diseases; Modeling; Mus; Pattern; Phenotype; Population; Quantitative Trait Loci; Research; Resources; Sampling; Surveys; Variant; Western Europe; Work; environmental adaptation; genetic architecture; scaffold; trait; transcriptome sequencing

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.

项目摘要 我们对适应的遗传基础的理解大多来自于对简单性状的研究， 大部分的表型变异是由一个或几个主效基因控制的。然而，许多 进化的过程涉及到复杂性状的变化，这些性状由许多影响小到中等的基因控制。 复杂的性状也是人类之间大多数表型差异的基础，包括与人类遗传相关的那些。 健康这项拟议中的研究将研究家鼠环境适应的遗传基础， musculus，最好的哺乳动物模型为人类。家鼠最近已经扩展到美洲， 它们的原产地在西欧。通过结合自然界中遗传和表型变异的研究， 群体和实验室中，该项目将使基因型和表型之间的明确联系，为几个 复杂的特征这项工作将利用最近收集的28个家鼠种群的大规模调查 从南纬55度到北纬54度横跨美洲。来自不同环境的小鼠新近交系 为拟议的工作提供关键资源。来自寒冷环境的老鼠进化得更大 （伯格曼规则）和四肢较短（艾伦规则），符合两个最好的记录生态- 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存在差异， 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， 未来五年首先，我们将确定复杂适应性的遗传结构和特定位点 使用（1）来自不同环境的野生小鼠近交系的QTL作图，（2）表达 研究，包括cis-eQTL的鉴定，以鉴定宽QTL区间内的特定基因，（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， 从自然种群中采集大样本，（5）对不同实验室饲养的近交系进行研究 环境来测量环境扰动对基因表达和生物体的影响， 水平特征。其次，我们将通过以下方式扩展我们先前研究野生小鼠SNP变异模式的工作： 使用来自自然种群的小鼠的长读PacBio测序和长读PacBio测序的组合， 对来自野生来源的近交系的基因组进行测序和Hi-C支架，以研究结构变异 在整个基因组中，包括（1）有助于环境适应的拷贝数变异，（2） 转座因子插入多态性潜在的适应性差异，和（3）较大的结构 变体如倒位多态性。结构变异对基因表达的影响将是 使用来自相同动物的RNAseq评估。这些方法的结合将提供一个 无与伦比的基因组细节的图片背后的多基因适应小鼠，并将确定遗传 可能与理解人类差异相关的特征基础。