Mapping by Genetic Interaction
High-Resolution Congenic Mapping of the Type 1 Diabetes Loci Idd10 and Idd18 in the NOD Mouse
- Paul A. Lyons1,
- Nicola Armitage1,
- C.J. Lord15,
- Michael S. Phillips2,
- John A. Todd1,
- Laurence B. Peterson3 and
- Linda S. Wicker14
- 1Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Cambridge University, Cambridge, U.K.
- 2Department of Human Genetics, Merck Research Laboratories, West Point, Pennsylvania
- 3Department of Pharmacology, Merck Research Laboratories, Rahway, New Jersey
- 4Departments of Immunology and Rheumatology, Merck Research Laboratories, Rahway, New Jersey
- 5Institute of Cancer Research, Chester Beatty Laboratories, London, U.K.
Abstract
As many of the linked chromosome regions that predispose to type 1 diabetes in the NOD mouse have been dissected, it has become apparent that the initially observed effect is in fact attributable to several loci. One such cluster of loci on distal chromosome 3, originally described as Idd10, is now known to comprise three separate loci, Idd10, Idd17, and Idd18. Although these loci have a significant combined effect on diabetes development, their individual effects are barely detectable when diabetes is used as a read-out, which makes fine-mapping them by use of a conventional congenic approach impractical. In this study, we demonstrate that it is possible to map loci, with modest effects, to regions small enough for systematic gene identification by capitalizing on the fact that the combined loci provide more profound, measurable protection. We have mapped the Idd10 and Idd18 loci to 1.3- and 2.0-cM intervals, respectively, by holding the Idd3 allele constant. In addition, we have excluded Csf1 and Nras as candidates for both loci.
Footnotes
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Address correspondence and reprint requests to Dr. Paul Lyons, JDRF/WT Diabetes and Inflammation Laboratory, Cambridge University, Wellcome Trust/MRC Building, Addenbrooke’s Hospital, Hills Rd., Cambridge CB2 2XY, U.K. E-mail: paul.lyons{at}cimr.cam.ac.uk.
Received for publication 9 May 2001 and accepted in revised form 13 August 2001.
L.B.P is employed by and holds stock in Merck.
NOD.Idd3/10/18, NOD.B6 Idd3 Idd10 Idd18; PCR, polymerase chain reaction; R1, NOD.B6 Idd3 Idd10R1; R47, NOD.B6 Idd3 Idd10R47; R53, NOD.B6 Idd3 Idd10 Idd18R53; R93, NOD.B6 Idd3 Idd18R93; R135, NOD.B6 Idd3 Idd10 Idd18R135; R323, NOD.B6 Idd3 Idd10 Idd18R323; R450, NOD.B6 Idd3R450.
