Linkage disequilibrium mapping of a type 1 diabetes susceptibility gene (IDDM7) to chromosome 2q31-q33.

The role of human chromosome 2 in type 1 diabetes was evaluated by analysing linkage and linkage disequilibrium at 21 microsatellite marker loci, using 348 affected sibpair families and 107 simplex families. The microsatellite D2S152 was linked to, and associated with, disease in families from three different populations. Our evidence localizes a new diabetes susceptibility gene, IDDM7, to within two centiMorgans of D2S152. This places it in a region of chromosome 2q that shows conserved synteny with the region of mouse chromosome 1 containing the murine type 1 diabetes gene, Idd5. These results demonstrate the utility of polymorphic microsatellites for linkage disequilibrium mapping of genes for complex diseases

Chromosome-specific microsatellite sets for fluorescence-based, semi-automated genome mapping.

To facilitate large-scale genetic mapping of the human genome, we have developed chromosome-specific sets of microsatellite marker loci suitable for use with a fluorescence-based automated DNA fragment analyser. We present 254 dinucleotide repeat marker loci (80% from the Généthon genetic linkage map) arranged into 39 sets, covering all 22 autosomes and the X chromosome. The average distance between adjacent markers is 13 centiMorgans, and less than 4% of the genome lies more than 20 cM from the nearest marker. Each set of microsatellites consists of up to nine marker loci, with allele size ranges that do not overlap. We selected marker loci on the basis of their reliability in the polymerase chain reaction, polymorphism content, map position and the accuracy with which alleles can be scored automatically by the Genotyper program

A genome-wide search for human type 1 diabetes susceptibility genes.

We have searched the human genome for genes that predispose to type 1 (insulin-dependent) diabetes mellitus using semi-automated fluorescence-based technology and linkage analysis. In addition to IDDM1 (in the major histocompatibility complex on chromosome 6p21) and IDDM2 (in the insulin gene region on chromosome 11p15), eighteen different chromosome regions showed some positive evidence of linkage to disease. Linkages to chromosomes 11q (IDDM4) and 6q (IDDM5) were confirmed by replication, and chromosome 18 may encode a fifth disease locus. There are probably no genes with large effects aside from IDDM1. Therefore polygenic inheritance is indicated, with a major locus at the major histocompatibility complex

Crosses of Nod Mice with the Related Non Strain - a Polygenic Model for Iddm

Chromosome locations of non-major histocompatibility complex (MHC) genes contributing to insulin-dependent diabetes mellitus (IDDM) in mice have been determined by outcrossing NOD mice to other inbred strains congenic for the NOD MHC haplotype (H2(g7)). At least nine non-MHC IDDM susceptibility genes (Idd) were previously identified at first backcross (BC1) after outcross of NOD to C57BL/10.H2(g7) congenic mice (B10.H2(g7)). We investigated whether the same set of Idd loci segregated with IDDM susceptibility after outcross of NOD to NON.H2(g7) congenic mice, Since the outcrosses to NON.H2(g7) and B10.H2(g7) were performed in the same vivarium, direct comparisons were made of the chromosomal locations and relative strengths of Idd alleles in diabetic progeny from the two different outcrosses, In comparison with the NOD x B10.H2(g7) outcross, the NOD x NON.H2(g7) outcross produced significantly higher IDDM: frequencies in Fl, F2, and BC1 generations, The high F2 diabetes frequency allowed evaluation of the effects of homozygous expression of both the susceptibility and the resistance allele at Idd loci, This analysis demonstrated that no single non-MHC Idd locus was essential for the onset of diabetes in this cross, After outcross to NON.H2(g7), Idd4 (chromosome [Chr] 11), Idd5 (Chr 1), and Idd8 (Chr 14) did not segregate with IDDM in either the BC1 or the F2 generation, Diabetogenic NOD-derived alleles at Idd2 (Chr 9), Idd3 (Chr 3), and Idd10 (Chr 3) were segregating in the BC1, An NON-derived allele contributing to susceptibility on Chr 7 (Idd7) was also detected, Dominant traits, detectable only in the F2 cross, were encoded by Chr 4 (Idd9) and two newly mapped loci on Chr 13 (Idd14) and 5 (Idd15). A third dominant trait was encoded by Chr 6 (possibly Idd6), but here, in contrast to Idd9, Idd14, and Idd15, the NON allele was diabetogenic, Stepwise logistic regression analysis of the BC1 and F2 data confirmed that the ability to identify certainty of the non-MHC Idd loci was contingent on the extent of homozygosity for NOD background genes, This study shows that the diabetogenic phenotype can be achieved through the actions of variable combinations of MHC-unlinked genes and a diabetogenic MHC haplotype

Chromosome-Specific Microsatellite Sets for Fluorescence-Based, Semiautomated Genome Mapping

To facilitate large-scale genetic mapping of the human genome, we have developed chromosome-specific sets of microsatellite marker loci suitable for use with a fluorescence-based automated DNA fragment analyser. We present 254 dinucleotide repeat marker loci (80% from the Genethon genetic linkage map) arranged into 39 sets, covering all 22 autosomes and the X chromosome. The average distance between adjacent markers is 13 centiMorgans, and less than 4% of the genome lies more than 20 cM from the nearest marker. Each set of microsatellites consists of up to nine marker loci, with allele size ranges that do not overlap. We selected marker loci on the basis of their reliability in the polymerase chain reaction, polymorphism content, map position and the accuracy with which alleles can be scored automatically by the Genotyper(TM) program