Mapping recombination hotspots in human phosphoglucomutase (PGM1)

Human phosphoglucomutase (PGM1) is a highly polymorphic protein. Three mutations and four intragenic recombination events between the three mutation sites generate eight protein variants including the four universally common alleles, 1+, 1-, 2+ and 2-, and four others that are polymorphic in some Oriental populations, 3+, 3-, 7+ and 7-. The mutations 3/7, 2/1 and +/- are in exons 1A, 4 and 8, and are 40 and 18 kb apart, respectively. Using 12 polymorphic markers, including 2/1 and +/-, we have now obtained direct evidence for a high rate of intragenic recombination across this 58 kb region. From segregation analysis of PGM1 haplotypes in CEPH families, the recombination frequency was estimated to be 1.7%. We have also used a population genetics approach to map the patterns of linkage disequilibrium across the PGM1 gene in three diverse population samples (Caucasian, Chinese and Vietnamese). This has allowed us to compare indirect estimates of intragenic recombination with the meiotic data from family studies. Comprehensive pairwise allelic association analysis of the markers indicated the presence of two recombination 'hotspots': one between exons 1A and 4 and the other in the region of exon 7. These locations are in keeping with the meiotic data and with the original hypothesis of intragenic recombination based on PGM1 isozyme analysis.