The Genetics and Evolution of Extreme Body Size in Mice from Gough Island

描述（由申请人提供）： 具有极端表型的种群为进化机制提供了独特的见解。岛屿脊椎动物通常比它们的大陆亲戚大或小。这种模式在不同物种中的重复提出了一种令人兴奋的可能性，即共同的进化和遗传机制是负责的。尽管关于这种“岛屿规则”的进化原因已经争论了几十年，但关于其遗传基础的信息却很少。世界上最大的野生家鼠居住在戈夫岛;它们在短短数百代内进化出了极端的体型。Gough Island小鼠与广泛用于生物医学研究的实验室小鼠属于同一亚种，为体型进化的遗传解剖提供了强有力的平台。使用这个独特的系统，我们将整合遗传图谱，比较形态测量学和人口基因组学，提供第一个详细的遗传画像的快速身体大小进化的岛屿哺乳动物。具体来说，我们将（1）确定数量性状基因座（QTL），负责极端的身体大小和形状在戈夫岛小鼠的进化，（2）发现与快速适应岛屿栖息地使用新的基因组序列从这个群体的基因组区域。这项研究将揭示快速进化的遗传结构的关键特征，包括基因座的数量及其表型效应。通过进行一系列的杂交，我们将同时剖析岛屿与大陆的差异和岛屿内的变异的遗传。最近的选择性扫描戈夫岛人口将确定使用全基因组变异模式的分析，考虑到非平衡人口的历史的影响。我们 结合表型驱动和DNA驱动的研究将解决自然选择对岛屿规则的贡献，并有可能快速定位导致极端体型进化的突变。 几种常见的人类疾病，包括癌症、肥胖、糖尿病和心脏病，都与体型直接相关。我们在戈夫岛小鼠的大小变异的遗传画像将提供一个比较的背景下，在人类的大小相关疾病的全基因组关联研究。此外，我们的研究结果将有助于在自然性状变异的更大背景下研究用作疾病模型的实验室小鼠品系之间的表型差异。 公共卫生相关性： 体型与一系列常见的人类疾病有关，包括癌症、肥胖、糖尿病和心脏病。家鼠是阐明这些疾病遗传原因的首要模式生物。我们对自然界中极端体型进化的遗传表征将为实验室小鼠中与体型相关的疾病的研究提供信息，这些小鼠是野生小鼠的后代。此外，我们的研究结果将解决相同的基因组区域是否有助于人类和小鼠的自然大小变化的问题，为解释人类大小相关疾病的全基因组关联研究提供背景。

DESCRIPTION (provided by applicant): Populations with extreme phenotypes provide unique insights into the mechanisms of evolution. Island vertebrates are often unusually large or small compared to their mainland relatives. The repetition of this pattern across a diverse array of species raises the exciting possibility that common evolutionary and genetic mechanisms are responsible. Despite decades of debate about the evolutionary causes of this "island rule," little information exists about its genetic basis. The largest wild house mice in the world reside on Gough Island; they have evolved extreme body size in just hundreds of generations. Gough Island mice belong to the same subspecies as the laboratory mice widely used in biomedical research, providing a powerful platform for the genetic dissection of body size evolution. Using this unique system, we will integrate genetic mapping, comparative morphometrics, and population genomics to provide the first detailed genetic portrait of rapid body size evolution in an island mammal. Specifically, we will (1) identify quantitative trait loci (QTL) responsible for the evolution of extreme body size and shape in Gough Island mice, and (2) find genomic regions associated with rapid adaptation to the island habitat using new genome sequences from this population. This research will reveal key characteristics of the genetic architecture of rapid evolution, including the number of loci and their phenotypic effects. By performing a series of intercrosses, we will simultaneously dissect the genetics of island-mainland differences and within-island variation. Recent selective sweeps in the Gough Island population will be identified using analyses of genome-wide patterns of variation that take into account the effects of non-equilibrium population history. Our combination of phenotype-driven and DNA-driven studies will address the contribution of natural selection to the island rule and has the potential to rapidly localize mutations responsible for th evolution of extreme body size. Several common human diseases, including cancer, obesity, diabetes, and heart problems, are directly connected to body size. Our genetic portrait of size variation in Gough Island mice will provide a comparative context for genome-wide association studies of size-related disease in humans. In addition, our results will help situate phenotypic differences among laboratory mouse strains used as models for disease within the larger context of natural trait variation. PUBLIC HEALTH RELEVANCE: Body size is connected to a suite of common human diseases, including cancer, obesity, diabetes, and heart problems. The house mouse is the premier model organism for elucidating the genetic causes of these diseases. Our genetic characterization of extreme body size evolution in nature will inform studies of size- related disorders in laboratory mice, which descend from wild mice. Furthermore, our results will address the question of whether the same genomic regions contribute to natural size variation in humans and mice, providing context for interpreting genome-wide association studies of size-related diseases in humans.