GENOMIC MISMATCH SCANNING IDENTIFIES HUMAN GENOMIC DNA SHARED IDENTICAL BY DESCENT

Genomic mismatch scanning (GMS) is a high-throughput, high-resolution identity by descent mapping technique that enriches for genomic DNA fr agments that are shared between related individuals. In GMS, DNA heter oduplexes are formed from restriction-digested genomic DNA fragments f rom two relatives. Mismatch-free DNA heteroduplexes, likely representi ng DNA shared identical by descent between the two individuals, are re latively purified by depleting the mismatch-containing heteroduplexes using the Escherichia coli mismatch repair proteins and exonuclease, H ere, we demonstrate using quantitative microsatellite genotyping that, despite the complexity of the human genome, GMS can enrich the majori ty of restriction fragments that are identical by descent between two related humans, As the entire genome is selected in GMS, an extraordin arily dense set of markers (up to 200,000 markers) may be screened in parallel. The demonstration of the molecular enrichment of identical D NA fragments in the context of the whole human genome establishes cond itions for the application of GMS to human genetics, This forms a fram ework for the further development of GMS as a hybridization-based mapp ing technique that utilizes DNA microarray technology to map the selec ted identical by descent DNA fragments. (C) 1998 Academic Press.