POSITIONAL CLONING OF A DIABETES GENE ON CHROMOSOME 11

我们以前已经确定了一个区域的联系，以身体质量指数（LOD=3.6），年龄调整的糖尿病（LOD=1.7）和糖尿病的联合表型（LOD=5.2）的染色体11 q23 -24。我们对另外3,000名根据BMI选择的个体进行了该区域内的10个标记物的基因分型，但这些个体不一定来自糖尿病的家族信息。在第二组Pimas中没有与BMI的联系，表明最初的联系取决于BMI和糖尿病之间的相互作用。通过对11 q22 -24区域内的所有已知候选基因（包括Apo CIII/AIV/A2基因簇、两个内向整流钾通道和多巴胺受体DRD 2）进行基因分型，分析每个基因中的几个单核苷酸多态性（SNP）。DRD 2中的几个SNP显示与BMI显著相关;因此，对该基因进行了完整测序，并在1300只Pimas中对两个SNP进行了基因分型。不幸的是，在DRD 2中检测到的SNP似乎不会导致在该区域观察到的与BMI的联系。我们还创建了一个物理地图，通过确定重叠的YAC克隆在整个区域的连锁chrom 11 q。我们目前正在构建这一区域的BAC重叠群。每个BAC上的SNPs都被鉴定出来，然后在200个信息丰富的同胞对的DNA上进行基因分型。- 定位克隆、单核苷酸多态性、遗传作图-人类受试者

We have previously identified a region of linkage to both body mass index (LOD=3.6), age-adjusted diabetes (LOD=1.7) and the combined phenotype of diabesity (LOD=5.2)on chrom 11q23-24. We genotyped 10 markers within this region on 3,000 additional individuals who were selected for BMI, but were not necessarily from families informative for diabetes. There was no linkage to BMI in this second set of Pimas, indicating that the initial linkage was dependent upon an interaction between BMI and diabetes. All known candidate genes in the region from 11q22-24, including the Apo CIII/AIV/A2 gene cluster, two inwardly rectifying potassium channels, and the dopamine receptor DRD2 were analyzed by genotyping several single nucleotide polymorphisms (SNPs)in each gene. Several SNPs in DRD2 showed a significant association with BMI; therefore, this gene was sequenced in its entirety and two SNPs were genotyped in 1300 Pimas. Unfortunately, SNPs detected in DRD2 do not appear to result in the linkage to BMI observed in this region. We have also created a physical map by identifying overlapping YAC clones across the region of linkage on chrom 11q. We are currently contructing a BAC contig across this region. SNPs are being identified on each of the BACs and are then being genotyped on DNAs from 200 informative sibpairs. - positional cloning, single nucleotide polymorphisms, genetic mapping - Human Subjects