The Deep Genome Project

Abstract

Genetically modified mice enable statistically powered, randomized, and blinded experiments using sex-balanced and age-matched cohorts of mutant mice alongside appropriate genetic controls with sufficient sensitivity and specificity to reliably assess gene function and dysfunction in relation to specific traits, development, genetic context, and/or other physical and environmental conditions. [...]the scale and breadth of mouse genetics research is increasingly driving the use of mouse mutants and phenotyping data to inform human genomic diagnostic projects, including the US NIH Centers for Mendelian Genomics (www.mendelian.org), the Undiagnosed Diseases Network (https://undiagnosed.hms.harvard.edu/), Canada’s Care4Rare (http://care4rare.ca), The Gabriella Miller Kids First Pediatric Research Program (https://kidsfirstdrc.org/), the Genomics England Project (https://www.genomicsengland.co.uk/), and the “Fondation Maladies Rares” (https://fondation-maladiesrares.org/eng/). [...]much of the human genome remains unexplored and considered “dark” [12]. Critically, for both human and model organisms, our knowledge of pleiotropy and multi-morbidities is often incomplete, undermining our understanding of gene function and disease mechanisms. [...]our knowledge of phenotypic heterogeneity and its potentially underlying genetic bases (e.g., locus and allelic heterogeneity, multi-locus variation, modifier loci), as well as our understanding of multiple disease phenotypes converging on a single gene locus, age-dependent penetrance, and variable expressivity, are all limited.