Evolution of Phenotypic Extremes and Mechanisms Governing Inheritance

项目总结 我们提出了一个进化遗传学和基因组学的研究计划，强调两个不同的主题。 第一个主题集中在岛屿规则上--人口进化异体的普遍现象 殖民岛屿后的大小。我们实验室的进展已经建立了来自高夫岛的最大的小鼠 世界上最大的野生家鼠，作为理解遗传机制的一个易处理的系统 极端体型的进化。通过对新的同源基因菌株的全面鉴定，我们将 确定岛国规则的这一实例中涉及的基因和突变。阐明原因和 巨人症的后果，我们将扩展这一独特的系统，从基因上剖析另一个相关的特征 岛屿上的进化：探索性行为。这一研究方向将揭示复合体的发生规律。 在新环境中的特征进化。 第二个主题是重组，这是一个使后代基因组多样化并确保适当的 许多物种减数分裂过程中的染色体分离。使用单细胞方法，使我们能够量化 在个体重组中，我们发现家鼠在基因组上进化出了很大的差异 在短时间尺度上的交叉数量，雌性和雄性表现出不协调的轨迹。动机是 这一进展，我们将重建重组景观在家鼠身上的进化动力学 跨越基因组尺度(从热点到整个基因组)和时间尺度(从数千到数百万 年)。为了确定参与重组进化的细胞过程，我们将整合高度的 与关键减数分裂表型的细胞图谱杂交的分辨率、特定性别的定位。这 研究方向将揭示驱动遗传变异的主要决定因素进化的机制。 这些不同的研究主题展示了一个利用遗传学和基因组学的力量的项目 家鼠以广度和深度解决基本的进化问题。超越它们的进化 重要的是，感兴趣的特征与常见的人类疾病有关。重组中的缺陷是 出生缺陷的主要遗传原因，身体大小与代谢综合征有关，以及探索活动 与神经系统疾病有关。我们的研究提供了通过以下方式阐明这些条件的可能性 破译人类疾病的首屈一指的遗传模式生物的自然变异。

PROJECT SUMMARY We propose a research program in evolutionary genetics and genomics that emphasizes two distinct themes. The first theme focuses on the island rule – the widespread phenomenon of populations evolving unusual body sizes after colonizing islands. Advances in our laboratory have established mice from Gough Island, the largest wild house mice in the world, as a tractable system for understanding genetic mechanisms responsible for the evolution of extreme body size. Through comprehensive characterization of novel congenic strains, we will identify genes and mutations involved in this instance of the island rule. To elucidate causes and consequences of gigantism, we will extend this unique system to genetically dissect another trait associated with evolution on islands: exploratory behavior. This research direction will reveal genetic principles of complex trait evolution in novel environments. The second theme centers on recombination, a process that diversifies offspring genomes and ensures proper chromosomal segregation during meiosis in many species. Using single-cell methods that enable us to quantify recombination in individuals, we have discovered that house mice evolved substantial differences in genomic crossover number over short timescales, with females and males showing discordant trajectories. Motivated by this advance, we will reconstruct the evolutionary dynamics of the recombination landscape in house mice across genomic scales (from hotspots to whole genomes) and temporal scales (from thousands to millions of years). To identify cellular processes involved in the evolution of recombination, we will integrate high- resolution, sex-specific positioning of crossovers with cellular profiling of key meiotic phenotypes. This research direction will unveil mechanisms that drive the evolution of a primary determinant of genetic variation. These distinct themes of research showcase a program that exploits the power of genetics and genomics in house mice to address fundamental evolutionary questions with breadth and depth. Beyond their evolutionary significance, the traits of interest are connected to common human diseases. Defects in recombination are the leading genetic cause of birth defects, body size is related to the metabolic syndrome, and exploratory activity is associated with neurological disorders. Our research offers potential to illuminate these conditions by deciphering natural variation in the premier genetic model organism for human disease.