Congenic mapping of the insulin-dependent diabetes (Idd) gene, Idd10, localizes two genes mediating the Idd10 effect and eliminates the candidate Fcgr1.
The development of autoimmune diabetes in the nonobese diabetic (NOD) mouse is under the control of multiple insulin-dependent diabetes (Idd) genes. The Idd3 gene, originally defined as a broad peak of linkage on mouse chromosome 3, was subsequently identified as two genes, Idd3 and Idd10, separated by at least 20 cM. The resistance alleles of Idd3 and Idd10 individually confer only partial protection from diabetes but, in combination, result in profound resistance to disease due to an epistatic genetic interaction. In this study, we used newly developed congenic strains to further localize Idd10. Surprisingly, we found that Idd10 itself comprises at least two linked loci: Idd10 and the newly designated Idd17. Idd17 was localized to a 1.1-cM region between D3Mit26 and D3Mit40, proximal to Fcgr1, a candidate gene encoding the high affinity Fc receptor for IgG. Idd10 was localized to a 10-cM region between D3Mit213 and D3Mit106, distal to Fcgr1. Thus, Fcgr1 was excluded as a candidate for either Idd10 or Idd17, despite the fact that the NOD strain expresses a mutant form of the receptor. Interestingly, although Idd10 and Idd17 participate in a genetic interaction with each other, Idd10 but not Idd17 participates in the genetic interaction with Idd3. Our study on chromosome 3 begins to reveal the extent of the polygenic nature of autoimmune diabetes, and demonstrates that the use of congenic strains is an effective mapping strategy, even in the dissection of multiple, linked genes with subtle effects.
Podolin
P L
PL
Department of Autoimmune Diseases Research, Merck Research Laboratories, Rahway, NJ 07065, USA.
Denny
P
P
Lord
C J
CJ
Hill
N J
NJ
Todd
J A
JA
Peterson
L B
LB
Wicker
L S
LS
Lyons
P A
PA
D000483:Alleles; D000818:Animals; D002874:Chromosome Mapping; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D017452:Receptors, IgG / Q000235:genetics*
D017452:Receptors, IgG