Fine mapping NIDDM QTL 1 using heterogeneous stock rats

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DESCRIPTION (provided by applicant): Non-insulin dependent diabetes mellitus (NIDDM) is a growing health problem with over 360 million people worldwide projected to be affected by 2030. While genetic background along with the environment play a role in the development and progression of NIDDM, little is known about the role of the genome in this disease. While a large number of quantitative trait loci (QTL) have been identified in animal models for diabetes, identification of causative genes has remained elusive due to lack of sufficient recombination and allelic representation. The high degree of recombination and increased allele representation in heterogeneous stock (HS) rats allow for fine-mapping of QTL in a relatively short time-period (less than two years). Rat NIDDM QTL 1 (NIDDM1) is a 36 centiMorgan region on rat chromosome one identified in multiple F2 intercrosses for glucose intolerance. To date, no causative genes have been identified in this region. We propose to use heterogeneous stock (HS) rats to fine-map rat NIDDM1 in an effort to identify a causative variant(s) or gene(s) in this region. Specifically, we plan to phenotype 500 HS animals using a glucose tolerance test. We will genotype these animals using microsatellite and SNP markers spaced every 250 to 500 Kilobases within the NIDDM1 region. The data will be analyzed using a software program, HAPPY, that constructs probabalistic ancestral haplotypes prior to QTL analysis. We expect that more than one locus will be identified within this region and that each locus will encompass a one to two Megabase region. We will sequence the strongest QTL in the eight founding inbred strains of the HS and identify causative variants based on phenotype and genotype comparisons in the founder strains. By working with my mentor and co-mentors I will gain knowledge and skills in the genetics of diabetes and statistical analysis of complext traits. Training will be accomplished via personalized mentoring, specified short courses and conference participation. This training will be an important step toward becoming an independent researcher in the field of the molecular genetics of diabetes. With the increasing rate of diabetes today, it is pertinent to increase our understanding of the mechanisms underlying this disorder. Identifying susceptibility genes for NIDDM will not only provide a better understanding of the mechanisms that play a role in this disorder but will also lead to better diagnosis and treatment.