To produce a 25 cM base genetic map in Pima Indians, we have genotyped over 150 highly heterozygous short tandem repeat polymorphisms, STRPs, scattered across the genome in a data set of 1000 individuals comprising 250 nuclear families. The average heterozygosity in Pima Indians is approximately 11% lower than the reported in Caucasians for these STRPs. Linkage analysis using these STRP markers revealed several chromosomal regions that show linkage to various aspects of carbohydrate or fat metabolism or show linkage to diabetes. Based on linkage analysis in Pima Indians, we have located a genetic element at 1p31 that is estimated to account for 80% of the genetic variance in the first phase of insulin secretion in response to an intravenous glucose infusion. We have genotyped additional markers in the regions of linkage on chromosome 1, and have completed a YAC contig and physical map this region covering approximately 9 cM to further refine and localize this genetic element that influences this aspect of insulin secretion. This map is based on 34 overlapping yeast artificial chromosomes (YACs), and radiation hybrid mapping. The map spans approximately 9 megabases of DNA and includes loci encoding phosphoglucomutase 1 (PGM1), Janus Kinase 1 (JAK1), Phosphodiesterase 4B (PDE4B), c-JUN (JUN), GADD45 (GADD45) which encodes a DNA repair protein and the Leptin receptor (LEPR). Additional sequence tagged sites (STSs) were mapped including WI-9515, WI-6550, WI-6555, and NIB514 all representing brain c-DNAs, and WI-8883, WI-8883 both c-DNAs derived from spleen. Genotyping of additional polymorphic markers, including GATA P18625, D1S1603, and D1S2886 has narrowed the region at 1p31 which contains the locus influencing the acute insulin response. The structure of the leptin receptor, a candidate gene, was deduced and all 20 exons sequenced in 20 individuals. Squence analysis uncovered several nucleotide substitutions that result in amino acid substitutions. One of these is associated with increased obesity in the sample of 20 individuals sequenced.
