THE INCIDENCE AND DISTRIBUTION OF CPG-]TPG TRANSITIONS IN THE COAGULATION FACTOR-IX GENE - A FRESH LOOK AT CPG MUTATIONAL HOTSPOTS

The mutations of 76 haemophilia B patient srepresenting the whole population registered with the Malmd haemophilia centre (42) and referrals from the UK, were characterised. RFLP haplotype analysis of the defective genes indicated that 51 single base pair substitutions were definitely of Independent origin and 27 of these were CpG - TpG or CpA transitions. This represents a 38-fold excess over other single-base changes. Most of such transitions (82%) occur at 9 CpG sites occupying critical positions (transitions at 3 sites substitute essential arginines, while at 6 sites transition to TpG creates stop codons). Sixteen of the 18 possible transitions at these 9 sites cause clear haemophilia B and should be fully ascertained in our haemophilia B population. This allowed the direct estimate of the rate of CpG transitions. This Is 1.05 ×107 substitutionsper base per gamete per generation. The marked excess of CpG ransitions in haemophilia B appears partly due to the high proportion of CpG sites at critical positions (at least 9 out of 20). We propose that this follows from the fact that male hemizygosity makes Xlinkedgenes particularly susceptible to selective forces that tend to fix CpG sites arising at critical positions. © 1990 Oxford University Press.