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Combined congenic mapping and nuclease-based gene targeting for studying allele-specific effects of Tnfrsf9 within the Idd9.3 autoimmune diabetes locus. Sci Rep 2019 03 13;9(1):4316

Date

03/15/2019

Pubmed ID

30867509

Pubmed Central ID

PMC6416332

DOI

10.1038/s41598-019-40898-8

Scopus ID

2-s2.0-85062884116   4 Citations

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 the Idd9.3 type 1 diabetes (T1D) susceptibility locus in the nonobese diabetic (NOD) mouse model. A C57BL/10Sn (B10)-derived diabetes resistance Idd9.3 congenic 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 NOD Tnfrsf9 allele mimicking coisogenic strains. Using this approach, we demonstrated that the allelic difference in B10 and NOD Tnfrsf9 alone 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.

Author List

Forsberg MH, Foda B, Serreze DV, Chen YG

Author

Yi-Guang Chen PhD Professor in the Pediatrics department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Alleles
Animals
Animals, Congenic
Chromosome Mapping
Deoxyribonucleases
Diabetes Mellitus, Type 1
Gene Targeting
Genetic Loci
Genetic Predisposition to Disease
Mice
Mice, Inbred C57BL
Mice, Inbred NOD
T-Lymphocytes, Regulatory
Tumor Necrosis Factor Receptor Superfamily, Member 9