Summary
Mutation rates for X-linked recessive diseases have so far been estimated indirectly by postulating an equilibrium between the loss of defective genes caused by the low reproductive fitness of affected males and the gain resulting from new mutations. Here, for the first time, we directly estimate both the overall and sex-specific mutation rates for haemophilia B by detecting the gene defect of the families registered at the Malmö Haemophilia Centre. These represent a complete sample of the Swedish haemophilia B population (45 out of 77 pedigrees) and contain 23 families with a single affected male. Fifteen of these males had mothers available for study, and of these mothers, 13 had parents available for study. We show that 3 of the above patients and 10 of their mothers carry new mutations, and by extrapolation calculate that 8 males and 98 females should carry new haemophilia B mutations in the Swedish population (8.52 × 106 individuals). This leads to the following estimate of the mutation rates: overall μ = 4.1 × 10-6; male specific v = 2.1 × 10-5; and female specific u = 1.9 × 10-6. The ratio of such male to female specific mutation rates is thus v/u = 11.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Ananthakrishnan R, D'Souza S (1979) Some aspects of the occurrence of new mutations in haemophilia. Hum Hered 29:90–94
Barrai I, Cann HM, Cavalli-Sforza LL, Barbujani G, De Nicola P (1985) Segregation analysis of haemophilia A and B. Hum Genet 37:680–699
Bernardi F, Marchetti G, Bertagnolo V, Faggioli L, Volinia S, Patracchini P, Bartolai S, Vannini F, Felloni L, Rossi L, Panicucci F, Conconi F (1987) RFLP analysis in families with sporadic hemophilia A: estimate of the mutation ratio in male and female gametes. Hum Genet 76:253–256
Biggs R, Rizza CR (1976) The sporadic case of haemophilia A. Lancet II:431–433
Cotton RGH, Rodriguez NR, Campbell RD (1988) Reactivity of cytosine and thymine in single-base-pair mismatches with hydroxylamine and osmium tetroxide and its application to the study of mutations. Proc Natl Acad Sci USA 85:4397–4401
Ferrari N, Rizza CA (1986) Estimation of genetic risks of carriership for possible carriers of Christmas disease (haemophilia B). Braz J Genet 9:87–99
Green PM, Bentley DR, Mibashan RS, Nilsson IM, Giannelli F (1989) Molecular pathology of haemophilia B. EMBO J 8:1067–1072
Green PM, Montandon AJ, Ljung R, Bentley DR, Nilsson IM, Kling S, Giannelli F (1991) Haemophilia B mutations in a complete Swedish population sample. A test of a new strategy for the genetic counselling of diseases with high mutational heterogeneity. Br J Haematol 78:390–397
Haldane JBS (1935) The rate of spontaneous mutation of a human gene. J Genet 31:317–326
Haldane JBS (1947) The mutation rate of the gene for haemophilia and its segregation ratios in males and females. Ann Eugenet (Lond) 13:262–271
Kling S, Coffey AJ, Ljung R, Sjorin E, Nilsson IM, Hoemberg L, Giannelli F (1991) Moderate haemophilia B in a female carrier caused by preferential inactivation of the paternal X chromosome. Eur J Haematol 47:257–261
Kling S, Ljung R, Sjorin E, Montandon AJ, Green PM, Giannelli F, Nilsson IM (1992) Origin of mutation in sporadic cases of haemophilia B. Eur J Haematol (in press)
Kosower N, Christiansen R, Morton NE (1962) Sporadic cases of haemophilia and the question of a possible sex difference in mutation rates. Am J Hum Genet 14:159–171
Montandon AJ, Green PM, Giannelli F, Bentley DR (1989) Direct detection of point mutations by mismatch analysis: application to haemophilia B. Nucleic Acids Res 17:3347–3358
Nilsson IM (1974) Haemorrhagic and thrombotic disease. Wiley, London, pp 220–223
Rosendaal FR, Brocker-Vriends AHJT, Houwelingen JC van, Smit C, Varekamp I, Dijck H van, Suurmeijer TPBM, Vandenbroucke JP, Briet E (1990) Sex ratio of the mutation frequencies in haemophilia A: estimation and meta-analysis. Hum Genet 86:139–146
Vogel F (1977) A probable sex difference in some mutation rates. Am J Hum Genet 29:312–319
Wallmark A, Ljung R, Nilsson IM, Hoemberg L, Hedner U, Lindvall K, Sjogren H-O (1985) Polymorphism of normal factor IX detected by mouse monoclonal antibodies. Proc Natl Acad Sci USA 82:3839–3843
Winter RM, Tuddenham EGD, Goldman E, Matthews KB (1983) A maximum likelihood estimate of the sex ratio of mutation rates in haemophilia A. Hum Genet 64:156–159
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Montandon, A.J., Green, P.M., Bentley, D.R. et al. Direct estimate of the haemophilia B (factor IX deficiency) mutation rate and of the ratio of the sex-specific mutation rates in Sweden. Hum Genet 89, 319–322 (1992). https://doi.org/10.1007/BF00220550
Received:
Issue Date:
DOI: https://doi.org/10.1007/BF00220550