The laboratory mouse has been the premier model organism for biomedical research owing to the availability of multiple well-characterized inbred strains, its mammalian physiology and its homozygous genome, and because experiments can be performed under conditions that control environmental variables. Moreover, its genome can be genetically modified to assess the impact of allelic variation on phenotype. Mouse models have been used to discover or test many therapies that are commonly used today. Mouse genetic discoveries are often made using genome-wide association study methods that compare allelic differences in panels of inbred mouse strains with their phenotypic responses. Here we examine changes in the methods used to analyze mouse genetic models of biomedical traits during the twenty-first century. To do this, we first examine where mouse genetics was before the first inflection point, which was just before the revolution in genome sequencing that occurred 20 years ago, and then describe the factors that have accelerated the pace of mouse genetic discovery. We focus on mouse genetic studies that have generated findings that either were translated to humans or could impact clinical medicine or drug development. We next explore how advances in computational capabilities and in DNA sequencing methodology during the past 20 years could enhance the ability of mouse genetics to produce solutions for twenty-first century public-health problems.

由于有多种特征明确的近交系、哺乳动物生理学和纯合子基因组的可用性，并且因为实验可以在控制环境变量的条件下进行，因此实验室小鼠一直是生物医学研究的主要模式生物。此外，其基因组可以进行基因改造以评估等位基因变异对表型的影响。小鼠模型已被用于发现或测试当今常用的许多疗法。小鼠遗传发现通常是使用全基因组关联研究方法进行的，该方法将近交小鼠品系组中的等位基因差异与其表型反应进行比较。在这里，我们研究了 21 世纪用于分析生物医学特征小鼠遗传模型的方法的变化。为此，我们首先研究小鼠遗传学在第一个拐点之前的位置，就在 20 年前发生的基因组测序革命之前，然后描述加快小鼠遗传发现步伐的因素。我们专注于小鼠遗传学研究，这些研究结果要么被转化为人类，要么可能影响临床医学或药物开发。接下来，我们探讨了过去 20 年计算能力和 DNA 测序方法的进步如何增强小鼠遗传学为 21 世纪公共卫生问题提供解决方案的能力。