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 characterisation 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.

Vestibular Deficits in Deafness: Clinical Presentation, Animal Modeling, and Treatment Solutions

“…Naturally arising mutations in more than 340 genes have been reported to cause inner ear malformation or dysfunction in mice [Table S2 in ( 96 )], but these genes only partially overlap with the more than 200 genes identified in humans. Ongoing programs, such as the International Mouse Phenotyping Consortium (IMPC), aiming to produce null alleles by deleting an early critical exon in each mouse gene ( 214 , 215 ), will significantly increase the number of mutant mice with hearing and balance/vestibular deficits available ( 216 – 218 ). By early 2021, 9,719 knockout mice had been generated, 7,455 of which had been phenotyped through the IMPC comprehensive phenotyping pipeline including inner ear measurements ( 214 ), These mice are available to investigators worldwide ( http://www.mousephenotype.org/ ) ( 215 ).…”

“…Ongoing programs, such as the International Mouse Phenotyping Consortium (IMPC), aiming to produce null alleles by deleting an early critical exon in each mouse gene ( 214 , 215 ), will significantly increase the number of mutant mice with hearing and balance/vestibular deficits available ( 216 – 218 ). By early 2021, 9,719 knockout mice had been generated, 7,455 of which had been phenotyped through the IMPC comprehensive phenotyping pipeline including inner ear measurements ( 214 ), These mice are available to investigators worldwide ( http://www.mousephenotype.org/ ) ( 215 ). More thorough studies of these models, with dedicated experimental tools for vestibular evaluations, should improve our understanding of the properties and singularities of vestibular organs.…”

Contribution of model organism phenotypes to the computational identification of human disease genes

“…The discovery and building of models of human phenotypes in non-human animals has, over the past half-century, proven to be of substantial importance in improving our understanding of human disease and its underlying biology ( Aitman et al, 2011 ; Wangler et al, 2017 ; Brown, 2021 ; Baldridge et al, 2021 ), and is providing insights that may be used to develop new therapeutic and diagnostic capabilities. The amount of data available that relate genetics, in particular genetic variation, to phenotypes associated with disease, is increasing rapidly.…”

Knockout mouse models as a resource for rare diseases studies

“…In this context, (Seaby et al 2021) highlight the contribution of mouse models in connecting target genes to large genomic datasets as part of a "gene-to-patient" approach. The establishment of such synergetic efforts with clinician and patient groups, improves the characterization of monogenic RD with the potential to accelerate novel areas for therapeutic exploitation (Brown 2021).…”