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Review
. 2018 Oct;34(10):777-789.
doi: 10.1016/j.tig.2018.07.005. Epub 2018 Aug 18.

Giving the Genes a Shuffle: Using Natural Variation to Understand Host Genetic Contributions to Viral Infections

Sarah R Leist  1 , Ralph S Baric  2
Affiliations
Review

Giving the Genes a Shuffle: Using Natural Variation to Understand Host Genetic Contributions to Viral Infections

Sarah R Leist et al. Trends Genet. 2018 Oct.

Abstract

The laboratory mouse has proved an invaluable model to identify host factors that regulate the progression and outcome of virus-induced disease. The paradigm is to use single-gene knockouts in inbred mouse strains or genetic mapping studies using biparental mouse populations. However, genetic variation among these mouse strains is limited compared with the diversity seen in human populations. To address this disconnect, a multiparental mouse population has been developed to specifically dissect the multigenetic regulation of complex disease traits. The Collaborative Cross (CC) population of recombinant inbred mouse strains is a well-suited systems-genetics tool to identify susceptibility alleles that control viral and microbial infection outcomes and immune responses and to test the promise of personalized medicine.

Keywords: Collaborative Cross; genetic mapping; host factors; immune response; systems genetics.

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Figures

Figure 1
Figure 1
Various Genetic Mouse Model Approaches to Narrow Quantitative Trait Locus (QTL) Regions. (A) Congenic mouse strains are produced by transferring a genomic region from an inbred donor strain to an inbred recipient strain through repeated backcrossing. (B) Consomic mouse strains contain an entire chromosome from a donor strain and are generated via backcrossing to the recipient strain. (C) In conplastic mouse strains, the entire mitochondrial DNA is derived from a donor strain and is generated through backcrossing of females from the donor strain to males from the recipient strain. (D) Recombinant inbred mouse strains are generated by crossing two inbred strains to obtain an F1 generation. These F1 mice are crossed to create an F2 generation, which is brother–sister mated for at least 20 generations to achieve mice with a fixed genetic background and equal contributions of the two parental strains. (E) Recombinant congenic strains are produced by crossing two inbred mouse strains. The resulting F1 generation is backcrossed twice (BC1 and BC2) before they are brother–sister mated for an additional 14 generations. The genome composition of the final strains is skewed towards one parental strain in a 7:8 ratio.
Figure 2
Figure 2
Generation of the Collaborative Cross Resource. (A) The Collaborative Cross panel of recombinant inbred mouse strains is a multiparental population that is derived from eight founder strains. Among these founder strains are classical laboratory mouse strains (A/J, C57BL/B6, 129S1/SvImJ), mouse models for human diseases (NOD/ShiLtJ – type 1 diabetes, NZO/HlLtJ – obesity), and wild-derived mouse strains (CAST/EiJ, PWK/PhJ, WSB/EiJ). Every mouse strain was assigned a letter (A–H) and a particular color that are used by the entire research community. (B) Breeding-funnel design of the Collaborative Cross that guarantees equal distribution of founder alleles to the resulting CC strain. Depicted is the specific breeding funnel for chromosome 19 of the CC strain CC001. (C) Genome architecture of CC001 with founder contributions displayed in their respective colors. Photograph: Klaus Schughart.
Figure 3
Figure 3
Schematic of Experimental Approach for Complex Genetic Studies of Viral Infections. eQTL, expression QTL; QTL, quantitative trait loci.
See this image and copyright information in PMC

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