A Novel Wild-derived Diversity Mouse Population for Precision Mapping and Systems Genetics - PROJECT SUMMARY Inbred mouse strains are integral tools for both preclinical and basic research. While the absence of genetic diversity is a widely perceived strength of inbred strains, it is also a critical limitation, as a single inbred genetic background cannot capture the full spectrum of phenotypic responses observed in genetically diverse human populations. This limits the translation success from inbred mouse models to human clinical outcomes and underscores the need for mouse platforms that more accurately model human genetic variation. The Diversity Outbred (DO) mouse population was founded in 2012 to meet these crucial research needs. The DO was initiated from eight genetically diverse inbred mouse strains, including wild-derived representatives from each of three cardinal house mouse subspecies, and has been maintained by pseudo-random mating for over 50 generations. However, the inclusion of founder strains derived from reproductively isolated subspecies has, over time, exposed genetic incompatibilities and unchecked selfish elements, resulting in allele frequency distortions that have compromised the genetic integrity of the DO. Here, we propose to generate a new, high diversity outbred mouse population, the Wild Mouse Diversity Panel (WMDP), founded from novel wild-derived inbred strains of single subspecies origin (Mus musculus domesticus). Our recent work has shown that a large proportion of variants in the genomes of these newly developed M. m. domesticus strains are absent from existing inbred mouse strains, and that these strains capture novel neurobehavioral, metabolic, physiological, and biochemical phenotypes not observed in common laboratory mouse models. Thus, the WMDP stands to minimize potential haplotype distortion due to genetic incompatibilities between subspecies, allow functional assessment of millions of variants that have never been tested in the laboratory, and empower investigations of natural genome complexity. In Aim 1, we will initiate an outbred population from four phenotypically and genetically diverse wild- derived M. m. domesticus inbred strains, implementing routine genomic monitoring of allele frequencies to ensure the genetic integrity and longevity of the WMDP resource. To aid discovery efforts in this new population, we will generate key genomic resources for the founder strains in Aim 2, including high quality de novo genome assemblies, comprehensive variant call sets, and a gene expression atlas of several tissues. In Aim 3, we will provide a proof-of-principle study to underscore the power and utility of the WMDP. We will profile phenotypic diversity for several morphological, metabolic, behavioral, and clinical traits in early outbreeding generations of the WMDP, map causal loci, and integrate our findings with human data to identify human-mouse translational parallels at the levels of both genes and gene networks. This project will yield a new outbred mouse population poised for near limitless discovery in all areas of basic and preclinical research. This resource will become part of the Special Mouse Strain Resource at The Jackson Laboratory, which will provide the framework and setting for its long-term maintenance and distribution to the global research community.
