A recombination hotspot leads to sequence variability within a novel gene (AK005651) and contributes to type 1 diabetes susceptibility
- Iris K.L. Tan1,2,6,
- Leanne Mackin1,6,
- Nancy Wang1,2,
- Anthony T. Papenfuss3,
- Colleen M. Elso1,
- Michelle P. Ashton1,2,
- Fiona Quirk3,
- Belinda Phipson3,4,
- Melanie Bahlo3,
- Terence P. Speed3,
- Gordon K. Smyth3,
- Grant Morahan5 and
- Thomas C. Brodnicki1,7
- 1 St. Vincent's Institute of Medical Research, Fitzroy, Victoria 3065, Australia;
- 2 Department of Medicine, The University of Melbourne, Parkville, Victoria 3010, Australia;
- 3 The Walter & Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia;
- 4 Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia;
- 5 The Western Australian Institute of Medical Research, Perth, Western Australia 6000, Australia
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↵6 These authors contributed equally to this work.
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 complex conversion tract. The Idd11 haplotype and recombination hotspot are located within a predicted gene of unknown function, which exhibits decreased expression in relevant tissues of NOD mice. Notably, it was the recombination hotspot that aided our mapping of Idd11 and confirms that recombination hotspots can create genetic variation affecting a common polygenic disease. This finding has implications for human genetic association studies, which may be affected by the approximately 33,000 estimated hotspots in the genome.
Footnotes
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↵7 Corresponding author.
E-mail tbrodnicki{at}svi.edu.au; fax 613-9416-2676.
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[Supplemental material is available online at http://www.genome.org. The sequence data from this study have been submitted to dbSNP (http://www.ncbi.nlm.nih.gov/projects/SNP/) under accession nos. ss262803370, ss262803372, ss262803374, ss262803376, ss262803379, ss262803382, ss262803385, ss262803388, ss262803390, ss262803391, ss262803392, ss262803394, ss262803397, ss262803400, ss262803402, ss262803403, ss262803404, and ss262803405, and to the NCBI Probe Database (http://www.ncbi.nlm.nih.gov/sites/entrez?db=probe) under accession nos. 10544425–10544446.]
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Article published online before print. Article and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.101881.109.
- Received October 15, 2009.
- Accepted August 24, 2010.
- Copyright © 2010 by Cold Spring Harbor Laboratory Press