Advances in mouse genetics for the study of human disease

Abstract

The mouse is the pre-eminent model organism for studies of mammalian gene function and has provided an extraordinarily rich range of insights into basic genetic mechanisms and biological systems. Over several decades, the characterization of mouse mutants has illuminated the relationship between gene and phenotype, providing transformational insights into the genetic bases of disease. However, if we are to deliver the promise of genomic and precision medicine, we must develop a comprehensive catalogue of mammalian gene function that uncovers the dark genome and elucidates pleiotropy. Advances in large-scale mouse mutagenesis programmes allied to high-throughput mouse phenomics are now addressing this challenge and systematically revealing novel gene function and multi-morbidities. Alongside the development of these pan-genomic mutational resources, mouse genetics is employing a range of diversity resources to delineate gene-gene and gene-environment interactions and to explore genetic context. Critically, mouse genetics is a powerful tool for assessing the functional impact of human genetic variation and determining the causal relationship between variant and disease. Together these approaches provide unique opportunities to dissect in vivo mechanisms and systems to understand pathophysiology and disease. Moreover, the provision and utility of mouse models of disease has flourished and engages cumulatively at numerous points across the translational spectrum from basic mechanistic studies to pre-clinical studies, target discovery and therapeutic development.

Figure 1

Charting the key routes by which mouse genetics and genomics approaches (outer circle) contribute to the landscape of mechanistic, systems, pathobiology, disease genetics, pre-clinical and therapeutic studies (inner circle) that will be critical to address the challenges of genomic and precision medicine.

Figure 2

Integration of mouse mutant and mouse diversity resources will illuminate the complexities of disease genetic networks. In this example, pan-genomic null mutant resources, such as IMPC [G1, G2…] (40) are crossed to a set of BXD inbred lines (a BXD/G cross) to identify a number of modifier loci (annotated within the circles). The identified modifier loci become targets for further rounds of BXD/G crosses where the null mutant of a modifier locus is crossed to the BXD set. Common modifier loci identified in more than one BXD/G cross would be priorities for further BDX/G analysis, as exemplified by the modifier loci 914 and 1004 highlighted in the figure. In parallel, the large-scale generation and phenotyping of F1 diallel crosses (DAX) from BXD lines enables a powerful analysis of epistasis and dominance providing the basis for complex genetic models of the genetic pathways uncovered (62).