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。与它们的大陆近亲相比，海岛脊椎动物往往是异常大或小。这种模式在一系列不同的物种中重复，增加了共同进化和遗传机制负责的令人兴奋的可能性。尽管几十年来关于这一“岛国规则”的进化原因一直争论不休，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；它们在短短数百代人的时间里进化出了极端的身体尺寸。戈夫岛小鼠与广泛应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大的平台。使用这一独特的系统，我们将整合基因图谱、比较形态计量学和种群基因组学，以提供第一个关于岛屿哺乳动物快速体型进化的详细基因画像。具体地说，我们将(1)识别导致高夫岛小鼠极端体型和体型进化的数量性状基因座(QTL)，以及(2)使用来自该种群的新基因组序列找到与快速适应岛屿栖息地相关的基因组区域。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-大陆差异和岛屿内变异的遗传学。考虑到非平衡种群历史的影响，将通过对全基因组变异模式的分析来确定戈夫岛种群最近的选择性扫荡。我们的 表型驱动和DNA驱动相结合的研究将解决自然选择对孤岛规则的贡献，并有可能迅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、肥胖症、糖尿病和心脏问题，都与体型直接相关。我们对高夫岛小鼠体型变异的基因描述将为人类体型相关疾病的全基因组关联研究提供一个比较背景。此外，我们的结果将有助于在自然性状变异的更大背景下，确定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、糖尿病和心脏问题。家鼠是阐明这些疾病的遗传原因的主要模式生物。我们对自然界极端体型进化的遗传特征将为研究实验室小鼠的大小相关疾病提供信息，这些疾病是从野生小鼠进化而来的。此外，我们的结果将解决这样一个问题，即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，为解释人类大小相关疾病的全基因组关联研究提供了背景。

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.