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Heterozygote excess is repeatedly observed in females at the BRCA2 locus N372H
  1. M D Teare1,
  2. A Cox1,
  3. J Shorto1,
  4. C Anderson2,
  5. D T Bishop3,
  6. C Cannings1
  1. 1Division of Genomic Medicine, University of Sheffield, Sheffield, UK
  2. 2Institute of Cell, Animal and Population Biology, Ashworth Laboratories, West Mains Road, University of Edinburgh, Edinburgh, Scotland, EH9 3JT, UK
  3. 3Genetic Epidemiology Division, Cancer Research UK Clinical Centre, St James’s University Hospital, Leeds, UK
  1. Correspondence to:
 M D Teare, PhD
 Mathematical Modelling and Genetic Epidemiology, Division of Genomic Medicine, University of Sheffield, Royal Hallamshire Hospital, Glossop Road, Sheffield, S10 2JF, UK;

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Evidence of genotype specific selection at the BRCA2 polymorphism N372H was originally reported by Healey et al.1 These workers found significant evidence of a heterozygous excess in women control samples when studying the polymorphism for breast cancer association. They then genotyped a large series of newborn boys and girls to examine if this effect was also seen at birth. The newborn girls were consistent with the women but the newborn boys were significantly different. The genotypes in the boys appeared to demonstrate a significant deficit of heterozygotes. Healey et al suggested that sex differential viabilities resulted in a stable allele frequency, but this was not formally investigated. We wanted to explore further this apparent sex specific selection in two ways; to refine the estimates of fitness, and we examined the mathematical properties of the sex specific selection model to determine if the data were consistent with a stable equilibrium.


Three control populations were available for additional genotyping. These were blood donors, colon cancer controls, and mammography screening control women. Anonymous blood donors were recruited from the Sheffield Blood Transfusion Service in 1996, and their ages and sexes were recorded. Blood DNA samples were obtained for the mammography screening series of controls from white women attending for routine mammography screening at the Sheffield Breast Screening Service between September 2000 and August 2002. Women’s DNA samples were included in the study if the mammogram showed no evidence of a breast lesion. All women resident in Sheffield and on the Community Health Index, who are between the ages of 50 and 65, are invited to attend for screening every three years, and the uptake in Sheffield is 81.2%. Ethical approval for this study was obtained from the South Sheffield Research Ethics Committee and informed written consent was obtained from all subjects. Colon …

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  • This research has been supported by Yorkshire Cancer Research, The Breast Cancer Campaign and the Food Standards Agency. JS is funded by a White Rose Studentship.

  • Conflicts of interest: none declared.