Twenty-first century mouse genetics is again at an inflection point.

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.