Sleeping Beauty Transposon Mutagenesis as a Tool for Gene Discovery in the NOD Mouse Model of Type 1 Diabetes

Abstract A number of different strategies have been used to identify genes for which genetic variation contributes to type 1 diabetes (T1D) pathogenesis. Genetic studies in humans have identified >40 loci that affect the risk for developing T1D, but the underlying causative alleles are often diff...

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Bibliographic Details
Published in:G3 : genes - genomes - genetics 2015-12, Vol.5 (12), p.2903-2911
Main Authors: Elso, Colleen M, Chu, Edward P F, Alsayb, May A, Mackin, Leanne, Ivory, Sean T, Ashton, Michelle P, Bröer, Stefan, Silveira, Pablo A, Brodnicki, Thomas C
Format: Article
Language:English
Subjects:
Animals
Chromosome Breakpoints
Diabetes Mellitus, Type 1 - genetics
Disease Models, Animal
DNA Transposable Elements
Female
Gene Dosage
Gene Expression
Genes, Reporter
Genetic Association Studies
Genetic Vectors - genetics
Male
Mice
Mice, Inbred NOD
Mice, Transgenic
Mutagenesis, Insertional
Mutant Screen Report
Mutation
Quantitative Trait Loci
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Summary:Abstract A number of different strategies have been used to identify genes for which genetic variation contributes to type 1 diabetes (T1D) pathogenesis. Genetic studies in humans have identified >40 loci that affect the risk for developing T1D, but the underlying causative alleles are often difficult to pinpoint or have subtle biological effects. A complementary strategy to identifying “natural” alleles in the human population is to engineer “artificial” alleles within inbred mouse strains and determine their effect on T1D incidence. We describe the use of the Sleeping Beauty (SB) transposon mutagenesis system in the nonobese diabetic (NOD) mouse strain, which harbors a genetic background predisposed to developing T1D. Mutagenesis in this system is random, but a green fluorescent protein (GFP)-polyA gene trap within the SB transposon enables early detection of mice harboring transposon-disrupted genes. The SB transposon also acts as a molecular tag to, without additional breeding, efficiently identify mutated genes and prioritize mutant mice for further characterization. We show here that the SB transposon is functional in NOD mice and can produce a null allele in a novel candidate gene that increases diabetes incidence. We propose that SB transposon mutagenesis could be used as a complementary strategy to traditional methods to help identify genes that, when disrupted, affect T1D pathogenesis.
ISSN:2160-1836
2160-1836
DOI:10.1534/g3.115.021709