Identification of a new susceptibility locus for insulin-dependent diabetes mellitus by ancestral haplotype congenic mapping.
The number and exact locations of the major histocompatibility complex (MHC)-linked diabetogenic genes (Idd-1) are unknown because of strong linkage disequilibrium within the MHC. By using a congenic NOD mouse strain that possesses a recombinant MHC from a diabetes-resistant sister strain, we have now shown that Idd-1 consists of at least two components, one in and one outside the class II A and E regions. A new susceptibility gene (Idd-16) was mapped to the < 11-centiMorgan segment of chromosome 17 adjacent to, but distinct from, previously known Idd-1 candidates, class II A, E, and Tap genes. The coding sequences and splicing donor and acceptor sequences of the Tnfa gene, a candidate gene for Idd-16, were identical in the NOD, CTS, and BALB/c alleles, ruling out amino acid changes in the TNF molecule as a determinant of insulin-dependent diabetes mellitus susceptibility. Our results not only map a new MHC-linked diabetogenic gene(s) but also suggest a new way to fine map disease susceptibility genes within a region where strong linkage disequilibrium exists.
Ikegami
H
H
Department of Geriatric Medicine, Osaka University Medical School, Japan.
Makino
S
S
Yamato
E
E
Kawaguchi
Y
Y
Ueda
H
H
Sakamoto
T
T
Takekawa
K
K
Ogihara
T
T
D000818:Animals; D001483:Base Sequence; D002874:Chromosome Mapping; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D006239:Haplotypes; D015810:Linkage Disequilibrium; D008285:Major Histocompatibility Complex; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008969:Molecular Sequence Data