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.

Keywords: complex genetics; complex traits; genetic diversity; mouse; systems genetics.

Figure 1

Summary of the genome structures of the primary advanced mouse strains. The common origin of the genomic variation contained within these mice allows for their use as an integrated set of tools to investigate the genetic basis of complex traits. A) Founder strains include five common laboratory inbred strains and three wild-derived inbred strains. Together, these strains recapitulate about 90% of the genetic variation observed in Mus musculus and represent genotypic variation comparable to human populations. B) Collaborative Cross strains are a panel of eight-way recombinant inbred strains derived from the founders. Approximately 50 Collaborative Cross strains are presently under distribution. C) Diversity Outbred mice were derived from sustained outbreeding of the founder genotypes, resulting in continuous variation in genome structure and high heterozygosity while retaining variants useful for mapping.

Figure 2, Key Figure

Typical pipelines for discovery using diversity mice from biological question to results. Diversity mice can contribute through multiple integrated applications to research on complex traits. The selection of the ideal mouse population is dependent upon the research question being asked. Complex traits can be established as heritable, then dissected into multiple phenotypic and genotypic outputs. Furthermore, extreme and multivariate outlier strains allow for establishment of research models that can correlate and dissociate important aspects of biology.

Figure 3

Multiple diversity mouse resources can be used in separate experiments to dissect a single biological question at multiple levels. In this case, multiple published experiments deposited in the Mouse Phenome Database include information about body weight as a complex trait. A) Strain surveys on the founder strains demonstrate heritable variation of, e.g., body weight (MPD: Morgan1). B) Trait correlation in the Collaborative Cross strains demonstrate a biologically significant link between traits (MPD: McMullan1). In this example, there is a high correlation between body weight and percentage body fat. This method identifies extreme strains (blue) and a multivariate outlier strain (red) that may be models for future study (gray: 95% prediction interval). C) QTL mapping in the Diversity Outbred population (MPD: Recla1). For body weight, significant QTL were identified on chromosomes 2 and 10. Combined with expression data, significant findings can be further resolved to the gene level and contextualized as elements of gene coexpression networks.