Journal article

A recombination hotspot leads to sequence variability within a novel gene (AK005651) and contributes to type 1 diabetes susceptibility

Iris KL Tan, Leanne Mackin, Nancy Wang, Anthony T Papenfuss, Colleen M Elso, Michelle P Ashton, Fiona Quirk, Belinda Phipson, Melanie Bahlo, Terence P Speed, Gordon K Smyth, Grant Morahan, Thomas C Brodnicki

GENOME RESEARCH | COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT | Published : 2010

Abstract

More than 25 loci have been linked to type 1 diabetes (T1D) in the nonobese diabetic (NOD) mouse, but identification of the underlying genes remains challenging. We describe here the positional cloning of a T1D susceptibility locus, Idd11, located on mouse chromosome 4. Sequence analysis of a series of congenic NOD mouse strains over a critical 6.9-kb interval in these mice and in 25 inbred strains identified several haplotypes, including a unique NOD haplotype, associated with varying levels of T1D susceptibility. Haplotype diversity within this interval between congenic NOD mouse strains was due to a recombination hotspot that generated four crossover breakpoints, including one with a comp..

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Grants

Awarded by Juvenile Diabetes Research Foundation


Awarded by Australian NHMRC


Awarded by NIH/NIDDK


Awarded by NHMRC


Awarded by NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES


Funding Acknowledgements

We thank S. Foote, J. Stankovich, Y. Hu, and S. Mannering for useful discussions; V. Marshall, M. Martyn, and G. Brammar for technical assistance; E.H. Leiter for providing genomic DNA for various inbred mouse strains; and the mouse care facility staff at the Walter & Eliza Hall Institute and Department of Medicine at The University of Melbourne. This work was supported by the Juvenile Diabetes Research Foundation (1-2005-925), the Cooperative Research Centre for Discovery of Genes for Common Human Diseases, the Australian NHMRC (575552), and the NIH/NIDDK (1R01 DK062882-01A1). I.K.L.T. is supported by a Melbourne International Research Scholarship. N.W. and M.P.A. are supported by Australian Postgraduate Awards. M.P.A. is also supported by a St. Vincent's Institute Foundation Scholarship. C.E. is supported by a Peter Doherty Fellowship. M.B. is supported by an NHMRC Career Development Award. G.S. is supported by a NHMRC Senior Research Fellowship. G.M. is supported by NHMRC Program Grant 516700 and by the Diabetes Research Foundation of Western Australia. T.S. is supported by an Australia Fellowship.