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The incidence and distribution of CpG----TpG transitions in the coagulation factor IX gene. A fresh look at CpG mutational hotspots

Green, P M; Montandon, A J; Bentley, D R; Ljung, R LU ; Nilsson, Inga Marie and Giannelli, F (1990) In Nucleic Acids Research 18(11). p.31-3227
Abstract

The mutations of 76 haemophilia B patients representing the whole population registered with the Malmö 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... (More)

The mutations of 76 haemophilia B patients representing the whole population registered with the Malmö 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 x 10(-7) substitutions per base per gamete per generation. The marked excess of CpG transitions 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 X-linked genes particularly susceptible to selective forces that tend to fix CpG sites arising at critical positions.

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Contribution to journal
publication status
published
subject
keywords
Amino Acids, Dinucleoside Phosphates, Exons, Factor IX, Genes, Haplotypes, Hemophilia A, Humans, Mutation, Polymorphism, Restriction Fragment Length, Journal Article, Research Support, Non-U.S. Gov't
in
Nucleic Acids Research
volume
18
issue
11
pages
31 - 3227
publisher
Oxford University Press
external identifiers
  • Scopus:0025337460
ISSN
0305-1048
DOI
10.1093/nar/18.11.3227
language
English
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yes
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1e1b5441-b50a-481a-aea5-ea2e5df3c610
date added to LUP
2016-11-08 14:58:32
date last changed
2016-11-21 09:26:23
@misc{1e1b5441-b50a-481a-aea5-ea2e5df3c610,
  abstract     = {<p>The mutations of 76 haemophilia B patients representing the whole population registered with the Malmö 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 x 10(-7) substitutions per base per gamete per generation. The marked excess of CpG transitions 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 X-linked genes particularly susceptible to selective forces that tend to fix CpG sites arising at critical positions.</p>},
  author       = {Green, P M and Montandon, A J and Bentley, D R and Ljung, R and Nilsson, Inga Marie and Giannelli, F},
  issn         = {0305-1048},
  keyword      = {Amino Acids,Dinucleoside Phosphates,Exons,Factor IX,Genes,Haplotypes,Hemophilia A,Humans,Mutation,Polymorphism, Restriction Fragment Length,Journal Article,Research Support, Non-U.S. Gov't},
  language     = {eng},
  month        = {06},
  number       = {11},
  pages        = {31--3227},
  publisher    = {ARRAY(0xa38e5a8)},
  series       = {Nucleic Acids Research},
  title        = {The incidence and distribution of CpG----TpG transitions in the coagulation factor IX gene. A fresh look at CpG mutational hotspots},
  url          = {http://dx.doi.org/10.1093/nar/18.11.3227},
  volume       = {18},
  year         = {1990},
}