AN APPROACH FOR IDENTIFYING SIMPLE SEQUENCE REPEAT DNA POLYMORPHISMS NEAR CLONED CDNAS AND GENES - LINKAGE STUDIES OF THE ISLET AMYLOID POLYPEPTIDE AMYLIN AND LIVER-GLYCOGEN SYNTHASE GENES AND NIDDM

Genetic factors contribute to the development of NIDDM, and genes invo lved in regulating pancreatic beta-cell function and insulin's effects on glucose metabolism are good candidates for being NIDDM susceptibil ity loci. However, testing candidate genes for Linkage with NIDDM depe nds on the identification of highly informative DNA polymorphisms in o r near the candidate locus. Here we describe an approach for identifyi ng highly polymorphic markers near candidate genes that utilizes the e merging physical map of the human genome. A sequence-tagged site from the candidate gene is used to screen the Centre d'Etude du Polymorphis me Humain megabase-insert yeast artificial chromosome library, which c ontains information on the physical localization of >3,000 genetically mapped simple sequence repeat DNA polymorphisms. Thus, identification of a yeast artificial chromosome containing the candidate locus will in many instances also identify a physically linked simple sequence re peat DNA polymorphism that can be used as a marker for the candidate g ene in linkage studies. We have used this approach to identify a marke r for the islet amyloid polypeptide gene on chromosome 12. The physica l mapping of this gene to a yeast artificial chromosome showed that it was in the same yeast artificial chromosome as the gene encoding live r glycogen synthase, another possible NIDDM susceptibility gene. Affec ted sib pair studies using a simple sequence repeat DNA polymorphism p hysically linked to the islet amyloid polypeptide and liver glycogen s ynthase genes showed no evidence for linkage with NIDDM, indicating th at they are not major genes contributing to NIDDM susceptibility.