A recombination hotspot leads to sequence variability within a novel gene (AK005651) and contributes to type 1 diabetes susceptibility.
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.
St. Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia.
Iris K L
IK
Tan
Leanne
L
Mackin
Nancy
N
Wang
Anthony T
AT
Papenfuss
Colleen M
CM
Elso
Michelle P
MP
Ashton
Fiona
F
Quirk
Belinda
B
Phipson
Melanie
M
Bahlo
Terence P
TP
Speed
Gordon K
GK
Smyth
Grant
G
Morahan
Thomas C
TC
Brodnicki
D000818:Animals; D001483:Base Sequence; D002874:Chromosome Mapping; D019295:Computational Biology; D003434:Crossing Over, Genetic / Q000235:genetics*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation; D006239:Haplotypes / Q000235:genetics; D051379:Mice; D016688:Mice, Inbred NOD; D008969:Molecular Sequence Data; D017422:Sequence Analysis, DNA