Inbred strains of laboratory mice have made significant contributions to biomedical research. However, for complex traits and diseases, deeper insight can be gained by working with genetically diverse mouse populations. The addition of genetic diversity to mouse-based studies improves the range and scope of their validity. Moreover, diverse mouse populations offer genetic and phenotypic variation that better recapitulates the human population, while providing added power for genetic mapping, as well as extensive tools and methodologies for experimental manipulation and validation.
Recombinant inbred (RI) and outbred populations of laboratory mice have been developed as research tools for complex trait and disease research. To create a panel of RI lines, two inbred strains are typically crossed to create F2’s, and F2’s are subsequently inbred through sibling intercrosses. The BXD recombinant inbred lines are a widely utilized panel that captures the allelic diversity resident in the two parental inbred strains, C57BL/6J and DBA/2J. To obtain greater allelic diversity, additional parental inbred strains can be added to these crosses. For example, the multi-parent Collaborative Cross (CC) RI lines were created through intercrossing and subsequent inbreeding of eight parental inbred strains. The CC lines increase mapping power, but like other RI panels retain the advantages of inbred mouse strains, including reproducible genomes. Derivatives of RI strains can be created through randomly intercrossing between RI lines. The Diversity Outbred (DO) mice were created from incipient CC RI lines. The DO population is genetically heterogeneous and therefore more closely matches the genetic structure of human populations. This diversity is particularly useful for measuring dose response across a population, high-resolution mapping of genes and quantitative trail loci (QTLs), and investigating genetic and environmental interactions that contribute to complex disease susceptibility, onset and progression, as well as behavioral phenotypes and drug response.
The BXD recombinant inbred (RI) lines were originally made for mapping highly penetrant Mendelian traits (Bailey et al., 1971, Taylor et al., 1973), but they were eventually adopted for the analysis of complex traits (Gora-Maslak et al. 1991). As a panel, these lines capture the allelic diversity resident in the two parental inbred strains, C57BL/6J and DBA/2J. Their main advantage relative to F2 crosses and heterogenous stocks is that each unique genotype (genetic individual) is represented by a stable inbred strain that can be replicated in large numbers — essentially a sexually reproducing clone. RIs are therefore an excellent resource for studies that benefit from replication across individuals (e.g. dosing and toxicity studies of genotypes) or across environments (i.e. studies on G×E), and for the gradual assembly of deep phenome data that can be used in G2P ((what is this?)) analysis. In mice, there are now sufficient numbers of RI strains to allow for comparatively precise and well-powered QTL mapping.
A number of RI panels are available from The Jackson Laboratory (https://www.jax.org/mouse-search/?stockType=Recombinant%20Inbred%20(RI)), including the BXD RI set (https://www.jax.org/mouse-search/?straingroup=BXD%20Strains)
The Collaborative Cross (CC) is a large, multiparental, recombinant inbred (RI) strain panel that was created through rapid and random mixing of the genomes of eight founder strains to create independent breeding lines (Churchill et al. 2004). Five classical inbred strains (A/J, C57BL/6 J, 129S1/SvImJ, NOD/LtJ, NZO/H1LtJ) and three wild-derived strains (CAST/EiJ, PWK/PhJ, and WSB/EiJ) were selected as the eight parental (founder) strains of this cross. Analysis of the allelic variation in mouse inbred strains demonstrates that the eight CC founder strains capture on average 90% of the known allelic diversity across all 1-Mb intervals spanning the entire house mouse genome (Roberts et al. 2007), including the three major Mus subspecies, domesticus, musculus, and castaneous.
The founder inbred strains of the Collaborative Cross are available through The Jackson Laboratory, A/J (000646), C57BL/6J (000664), 129S1/SvImJ (002448) NOD/ShiLtJ (001976) NZO/HiLtJ (002105), CAST/EiJ (000928), PWK/PhJ (003715), and WSB/EiJ (001145).
The Collaborative Cross lines are available from The University of North Carolina and The Jackson Laboratory (hyperlink: https://www.jax.org/mouse-search/?straingroup=Collaborative%20Cross)
The Diversity Outbred (DO) (Svenson et al., 2012) population is a heterogeneous stock derived from 160 incipient Collaborative Cross lines (Collaborative Cross Consortium, 2012). Each DO mouse is a unique individual with a high level of allelic heterozygosity, and the DO population provides an effectively unlimited source of novel allelic combinations. The current generation, G32, harbors sufficient recombination events to provide sub-Mb mapping resolution across most regions of the genome. Mapping resolution will continue to improve with each successive generation.
DO mice are available from The Jackson Laboratory (hyperlink: https://www.jax.org/strain/009376)
Collaborative Cross mice
Diversity Outbred mice