Chapter 9 - Collaborative Cross as the Next-Generation Mouse Genetic Reference Population Designed for Dissecting Complex Traits

Abstract

Complex traits identified as multifactorial traits are controlled by interactions between polygenic inherited factors and environmental factors. The phenotypic characteristics and performance of complex traits are described well at baseline environmental conditions, starting from body weight, blood chemistry, and immune cell profiles, through phenotypic variations in host susceptibility to infectious and chronic diseases, to be considered complex diseases with complex etiologies. Furthermore, phenotypic variations are observed in the host response to common therapeutic agents, requiring a pharmacogenetics study aimed at the development of personalized therapies. The completion of the mapping of the human and mouse genomes brought about the realization of the genome-wide complexity in regard to multifactorial traits that involve multiple genes from multiple gene networks and their gene–gene and gene–environment interactions that generate certain phenotypic variations between different genetic backgrounds within common environmental conditions. Accordingly, immense efforts were made to map the host genetic factors contributing to these complex traits and subsequently clone the genes located within these loci. In parallel with human studies, various mouse models from different approaches were developed for the purpose of enhancing the mapping process and gene cloning efficacy. Among these mouse models are the F2 backcross, advanced intercross lines, outbred populations, and consomic, congenic, and recombinant inbred lines (RILs). Along with the favorable outcomes of the mentioned mouse models, the major constraints of these approaches were the limited resolution of the genomic mapping of quantitative trait loci (QTLs) associated with the complex traits of interest and the limited genetic diversity observed in the parental founders. To overcome these constraints, new, genetically highly diverse, RILs of a mouse population were established, namely the Collaborative Cross (CC) mouse model, created from full reciprocal matings of eight divergent founder strains of mice: A/J, C57BL/6J, 129S1/SvImJ, NOD/LtJ, NZO/HiLtJ, CAST/Ei, PWK/PhJ, and WSB/EiJ. Intercrosses between the eight founder strains succeeded in generating the newly developed CC lines (strains) resource, presenting a completely different genetic makeup compared to the eight parental strains, with heterosis introduced into the line, and subsequently exhibiting different responses compared with their primary founders. Moreover, defining the phenotypic responses of the eight parental founders is not essential prior to assessing the CC lines, in view of the belief that the genetic interactions of the genetic makeup of the new CC lines will reveal new phenotypic responses, completely different from those of the parental founders. Herein, we evince the power of the CC mouse model for genomic mapping of a variety of complex traits, including baseline body features and host susceptibility to infectious and chronic diseases as well as pharmacogenetic traits. Based on our various studies, the recommended strategy for the scientific community for using the CC population is to phenotype 50 or more CC lines for the trait of interest, with a limited number of biological replicates (three or four mice per line). Subsequently, obtain QTL mapping of the phenotypic complex trait to unprecedented precision (<1Mb), using the publicly available CC lines genotypic database and the sequence databases of the eight founders, leading to identification of strong potential candidate genes. These remarkable achievements are unique for the CC mouse model, presenting distinctive features that differ from any other currently available mouse resource populations.