LINKAGE-DISEQUILIBRIUM MAPPING WITHOUT GENOTYPING

Genomic mismatch scanning (GMS) is a technique that enriches for regio ns of identity by descent (IBD) between two individuals without the ne ed for genotyping or sequencing. Regions of IBD selected by GMS are ma pped by hybridization to a microarray containing ordered clones of gen omic DNA from chromosomes of interest. Here we demonstrate the feasibi lity and efficacy of this form of linkage-mapping, using congenital hy perinsulinism (HI), an autosomal recessive disease, whose relatively h igh frequency in Ashkenazi Jews suggests a founder effect. The gene re sponsible (SUR1) encodes the sulfonylurea receptor, which maps to chro mosome 11p15.1. We show that the combination of CMS and hybridization of IBD products to a chromosome-11 microarray correctly maps the HI ge ne to a 2-Mb region, thereby demonstrating linkage-disequilibrium mapp ing without genotyping.