Nucleic Acids Research, 1990, Vol. 18, No. 11 3227-3231
© 1990
MOLECULAR BIOLOGY |
The incidence and distribution of CpG
Tpg transitions in the coagulation factor IX gene. A fresh look at CPG mutitional hospots
Paediatric research unit, Division of Medical and Molecular Genetics 7th Floor Guy's Hospital Tower, London Bridge, London SE1 9RT, UK
1Department of Coagulation Disorders, University of Lund, General Hospital S-214 01 Malm
, Swrdon
Received March 3, 1990. Accepted May 14, 1990.
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 x107 substitutions per 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 Xlinked genes particularly susceptible to selective forces that tend to fix CpG sites arising at critical positions.
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