The genomic basis of environmental adaptation in mice

小鼠环境适应的基因组基础

• 批准号: 9789339
• 负责人: MICHAEL W. NACHMAN
• 金额: $ 33.55万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-21 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9789339
• 关键词: Age; Alberta province; Alleles; Americas; Arizona; Biology; Blood Chemical Analysis; Body Size; Body mass index; Brazil; Candidate Disease Gene; Chromosome Mapping; Climate; Complex; Disease; Ear; Environment; Evolution; Exhibits; Florida; Foundations; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Generations; Genes; Genetic; Genetic Variation; Genetic study; Genome Scan; Genomic Segment; Genomics; Genotype; Geography; Goals; Health; House mice; Human; Inbreeding; Individual; Laboratories; Limb structure; Link; Linkage Disequilibrium Mapping; Liver; Mammals; Maps; Measures; Metabolic; Metabolic Diseases; Metabolism; Modeling; Morphology; Mus; New York; North America; Pattern; Phenotype; Physiology; Population; Population Genetics; Quantitative Genetics; Quantitative Trait Loci; RNA Sequences; Research; Resolution; Role; Sampling; South America; Structure; Study models; Surveys; System; Tail; Testing; Tissues; Variant; Western Europe; Work; environmental adaptation; exome; experimental study; genetic approach; genomic data; human model; insight; novel; trait; whole genome

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 with crosses 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 20 populations of house mice collected across the Americas from 55° S latitude to 54° N latitude. New inbred lines of mice from different environments will be used to measure phenotypes in a common laboratory environment and to perform controlled crosses. Mice from colder environments in the Americas 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. Here, we build on a recent genome-scan for selection among 50 mice in Eastern North America in four ways. (1) Exomes will be sequenced at moderate coverage and whole genomes will be sequenced at low coverage in an additional 150 mice from two transects, one in Western North America and one in South America, to identify loci underlying environmental adaptation using models that account for population structure. Replicated patterns in separate transects will provide additional evidence of selection. (2) Patterns of gene expression will be studied in both wild-caught mice and in laboratory crosses. Identification of cis-acting expression quantitative trait loci (cis- eQTL) will help pinpoint genes underlying adaptation. (3) Loci underlying phenotypic differences will be mapped using laboratory crosses of progeny derived from mice from different environments. (4) Finally, association studies will be conducted in two populations to more precisely map specific genes underlying phenotypic traits. Associations will also be used in combination with estimates of allele age to test polygenic modes of adaptation for several traits. Together, laboratory crosses and association studies will provide links between genotype and phenotype with resolution at the level of individual genes. The combination of quantitative-genetic and population-genetic approaches in this study will identify loci underlying polygenic adaptation in mice and will identify the genetic basis of traits likely to be relevant for understanding metabolic differences among humans.

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。家居老鼠最近已经扩展到美洲 从它们在西欧的原生范围。通过将遗传和表型变异研究结合在一起， 在实验室中有杂交的群体，这个项目将在基因型和表型之间建立明确的联系 几个复杂的特征。这项工作将利用最近对20个家鼠种群的大规模调查 从S纬度55°到北纬54°的整个美洲采集。不同来源小鼠的新近交系 环境将被用来在公共实验室环境中测量表型并执行 受控十字架。来自美洲较冷环境的老鼠已经进化成更大的老鼠 (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。在这里，我们基于最近的一项 基因组扫描在北美东部的50只小鼠中以四种方式进行选择。(1)外显体将被 中等覆盖率的测序和低覆盖率的全基因组测序将在另外150个基因组中进行 来自两个横断面的老鼠，一个在北美西部，一个在南美，以识别潜在的基因座 使用考虑人口结构的模型进行环境适应。在单独的环境中复制模式 横断面图将提供选择的额外证据。(2)将研究两者的基因表达模式。 野捕的老鼠和实验室的十字架。顺式作用表达数量性状基因座(cis-1)的鉴定 EQTL)将有助于精确定位潜在的适应基因。(3)潜在表型差异的基因座 使用来自不同环境的小鼠的后代的实验室杂交进行作图。(4)最后， 将在两个种群中进行关联研究，以更准确地定位潜在的特定基因 表型性状。关联性也将与等位基因年龄的估计结合使用来测试多基因 几个特征的适应模式。实验室交叉试验和关联性研究将一起提供联系 基因和表型之间的差异与个体基因水平上的分辨率。这两种技术的结合 这项研究中的数量遗传学和群体遗传学方法将确定多基因的潜在基因座 并将确定可能与了解代谢相关的性状的遗传基础 人类之间的差异。