The Jackson Laboratory, 600 Main Street, Bar Harbor, Maine, 04609, USA.
Tufts University, Graduate School of Biomedical Sciences, 136 Harrison Ave, Boston, MA, 02111, USA.
BMC Biol. 2021 Nov 19;19(1):239. doi: 10.1186/s12915-021-01165-3.
Through human-aided dispersal over the last ~ 10,000 years, house mice (Mus musculus) have recently colonized diverse habitats across the globe, promoting the emergence of new traits that confer adaptive advantages in distinct environments. Despite their status as the premier mammalian model system, the impact of this demographic and selective history on the global patterning of disease-relevant trait variation in wild mouse populations is poorly understood.
Here, we leveraged 154 whole-genome sequences from diverse wild house mouse populations to survey the geographic organization of functional variation and systematically identify signals of positive selection. We show that a significant proportion of wild mouse variation is private to single populations, including numerous predicted functional alleles. In addition, we report strong signals of positive selection at many genes associated with both complex and Mendelian diseases in humans. Notably, we detect a significant excess of selection signals at disease-associated genes relative to null expectations, pointing to the important role of adaptation in shaping the landscape of functional variation in wild mouse populations. We also uncover strong signals of selection at multiple genes involved in starch digestion, including Mgam and Amy1. We speculate that the successful emergence of the human-mouse commensalism may have been facilitated, in part, by dietary adaptations at these loci. Finally, our work uncovers multiple cryptic structural variants that manifest as putative signals of positive selection, highlighting an important and under-appreciated source of false-positive signals in genome-wide selection scans.
Overall, our findings highlight the role of adaptation in shaping wild mouse genetic variation at human disease-associated genes. Our work also highlights the biomedical relevance of wild mouse genetic diversity and underscores the potential for targeted sampling of mice from specific populations as a strategy for developing effective new mouse models of both rare and common human diseases.
在过去的约 10000 年里，通过人类辅助扩散，家鼠（Mus musculus）最近已经在全球范围内广泛分布于各种不同的栖息地，这促进了新特征的出现，使其在不同环境中具有适应性优势。尽管家鼠作为主要的哺乳动物模式生物系统，但这种人口统计学和选择性历史对野生鼠种群中与疾病相关的特征变异的全球模式的影响还知之甚少。
在这里，我们利用了来自不同野生家鼠种群的 154 个全基因组序列，调查了功能变异的地理组织，并系统地识别了正选择的信号。我们表明，野生鼠的大量变异是单个种群所特有的，包括许多预测的功能等位基因。此外，我们报告了许多与人类复杂和孟德尔疾病相关的基因中强烈的正选择信号。值得注意的是，与零假设相比，我们在与疾病相关的基因中检测到了显著的正选择信号过剩，这表明适应在塑造野生鼠种群功能变异景观方面发挥了重要作用。我们还在多个涉及淀粉消化的基因中发现了强烈的选择信号，包括 Mgam 和 Amy1。我们推测，人类-鼠共生关系的成功出现可能部分是由于这些基因座的饮食适应。最后，我们的工作揭示了多个隐性结构变异，这些变异表现为正选择的潜在信号，这突显了全基因组选择扫描中假阳性信号的一个重要且未被充分认识的来源。
总的来说，我们的研究结果强调了适应在塑造与人类疾病相关的野生鼠遗传变异方面的作用。我们的工作还突出了野生鼠遗传多样性的医学相关性，并强调了从特定种群有针对性地采样老鼠作为开发罕见和常见人类疾病新的有效小鼠模型的策略的潜力。
