High-Diversity Mouse Populations for Complex Traits

Abstract

Contemporary mouse genetic reference populations are a powerful platform to discover complex disease mechanisms. Advanced high-diversity mouse populations include the Collaborative Cross (CC) strains, Diversity Outbred (DO) stock, and their isogenic founder strains. When used in systems genetics and integrative genomics analyses, these populations efficiently harnesses known genetic variation for precise and contextualized identification of complex disease mechanisms. Extensive genetic, genomic, and phenotypic data are already available for these high-diversity mouse populations and a growing suite of data analysis tools have been developed to support research on diverse mice. This integrated resource can be used to discover and evaluate disease mechanisms relevant across species. The Challenge of Complex Disease Complex diseases present compelling biomedical challenges that can be studied using human and nonhuman animal genetics. Although advances in human genetics have identified loci for many heritable complex diseases [1-8], there are several well-known limitations of genomewide association studies (GWASs). (i) For many human disease loci, the biological mechanism of action is unknown. (ii) When little is known about a locus, the path from genetic association to clinically actionable targets is unclear. (iii) Disease process or developmental trajectory is not always obvious from a causal genetic variant. (iv) GWAS results may not generalize across human subpopulations. (v) Medical records and participant phenotyping is often incomplete, imprecise, and retrospective, whereas model organism phenotyping can include in-depth, prospective, and standardized measures. (vi) Sample size requirements are formidable in human GWASs. (vii) Power is insufficient to study interacting genetic loci. (viii) Studies of genetic interaction with development, environment, and sex are largely intractable. Further, heterogeneous diseases like psychiatric disorders manifest with overlapping symptoms, intertwined disease trajectories [9], and complex genetic regulation [9,10]. In summary, the SNP-to-disease association model underlying GWASs cannot readily capture complex disease biology without further biological context. These challenges are often tractable with discovery genetics in model organisms.

Genetic diversity of Collaborative Cross mice controls viral replication, clinical severity and brain pathology induced by Zika virus infection, independently of Oas1b

“…Investigating the genetic diversity of a large number of CC strains has significantly extended the range of phenotypes induced by ZIKV infection in mice and better model the heterogeneity of the human population. It has allowed testing important factors such as mouse gender and the method of viral load measurement across multiple host genetic background, providing robust conclusions (37). Importantly, we found no differences between male and female mice in their susceptibility to ZIKV disease, nor in the peak viral load (FIG 2E).…”

“…Likewise, we found that clinical severity did not correlate with the intensity of brain histological lesions and neuroinflammation, as summarized in Table 1. These dissociations between phenotypes provide evidence for partly distinct mechanisms and genetic control (37) and result in distinct mouse models.…”

“…A recent study has reported strain-specific differences in the susceptibility to neonatal ZIKV infection across four mouse laboratory strains, affecting neuropathology and behavior in adulthood (36). More extensive studies investigating the role of genome-wide genetic variations on the susceptibility to ZIKV infection are needed, using mouse models that accurately reflect the phenotypic and genetic diversity of the human population (37).…”

A comprehensive and comparative phenotypic analysis of the collaborative founder strains identifies new and known phenotypes

“…The mouse is the most extensively used mammalian model for biomedical research. Mouse genetic reference populations (GRPs) have become an important experimental system to model the heterogeneity in the human population (Saul et al 2019). Recently a new GRP, the Collaborative Cross (CC) was established (The Collaborative Cross Consortium 2012).…”

Gene-by-environmental modulation of longevity and weight gain in the murine BXD family

“…The mouse is an excellent mammalian model for research at the interface of metabolism and aging, sharing most protein-coding genes with humans (Pennacchio and Rubin, 2003), but with a much shorter life cycle that enables longevity studies in controlled environments and under various experimental and dietary conditions (Miller et al, 2007), (Yuan et al, 2011), (Strong et al, 2013). However, most rodent studies do not yet incorporate the level of genetic complexity such as is typical of human populations (Saul et al, 2019;Williams, 2006;Williams and Williams, 2017). Effects of DNA variants and dietary, drug, or environmental perturbations are almost inevitably studied on a single genome-often C57BL/6.…”