Combined congenic mapping and nuclease-based gene targeting for studying allele-specific effects of Tnfrsf9 within the Idd9.3 autoimmune diabetes locus

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Abstract Rodent complex trait genetic studies involving a cross between two inbred strains are usually followed by congenic mapping to refine the loci responsible for the phenotype. However, progressing from a chromosomal region to the actual causal gene remains challenging because multiple polymorphic genes are often closely linked. The goal of this study was to develop a strategy that allows candidate gene testing by allele-specific expression without prior knowledge of the credible causal variant.Tnfrsf9(encoding CD137) is a candidate gene for theIdd9.3type 1 diabetes (T1D) susceptibility locus in the nonobese diabetic (NOD) mouse model. A C57BL/10Sn (B10)-derived diabetes resistanceIdd9.3congenic region has been shown to enhance accumulation of CD137+regulatory T cells and serum soluble CD137 in NOD mice. By combining the power of congenic mapping and nuclease-based gene targeting, we established a system where a pair of F1 hybrids expressed either the B10 or NODTnfrsf9allele mimicking coisogenic strains. Using this approach, we demonstrated that the allelic difference in B10 and NODTnfrsf9alone was sufficient to cause differential accumulation of CD137+regulatory T cells and serum soluble CD137 levels. This strategy can be broadly applied to other rodent genetic mapping studies.

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