Skip to main content
PMC home page
American Journal of Human Genetics logoLink to American Journal of Human Genetics
. 1993 Jan;52(1):152–166.

Germ-line origins of mutation in families with hemophilia B: the sex ratio varies with the type of mutation.

R P Ketterling 1, E Vielhaber 1, C D Bottema 1, D J Schaid 1, M P Cohen 1, C L Sexauer 1, S S Sommer 1
PMCID: PMC1682121  PMID: 8434583

Abstract

Previous epidemiological and biochemical studies have generated conflicting estimates of the sex ratio of mutation. Direct genomic sequencing in combination with haplotype analysis extends previous analyses by allowing the precise mutation to be determined in a given family. From analysis of the factor IX gene of 260 consecutive families with hemophilia B, we report the germ-line origin of mutation in 25 families. When combined with 14 origins of mutation reported by others and with 4 origins previously reported by us, a total of 25 occur in the female germ line, and 18 occur in the male germ line. The excess of germ-line origins in females does not imply an overall excess mutation rate per base pair in the female germ line. Bayesian analysis of the data indicates that the sex ratio varies with the type of mutation. The aggregate of single-base substitutions shows a male predominance of germ-line mutations (P < .002). The maximum-likelihood estimate of the male predominance is 3.5-fold. Of the single-base substitutions, transitions at the dinucleotide CpG show the largest male predominance (11-fold). In contrast to single-base substitutions, deletions display a sex ratio of unity. Analysis of the parental age at transmission of a new mutation suggests that germ-line mutations are associated with a small increase in parental age in females but little, if any, increase in males. Although direct genomic sequencing offers a general method for defining the origin of mutation in specific families, accurate estimates of the sex ratios of different mutational classes require large sample sizes and careful correction for multiple biases of ascertainment. The biases in the present data result in an underestimate of the enhancement of mutation in males.

Full text

PDF
152

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Ames B. N., Gold L. S. Too many rodent carcinogens: mitogenesis increases mutagenesis. Science. 1990 Aug 31;249(4972):970–971. doi: 10.1126/science.2136249. [DOI] [PubMed] [Google Scholar]
  2. Bakker E., Veenema H., Den Dunnen J. T., van Broeckhoven C., Grootscholten P. M., Bonten E. J., van Ommen G. J., Pearson P. L. Germinal mosaicism increases the recurrence risk for 'new' Duchenne muscular dystrophy mutations. J Med Genet. 1989 Sep;26(9):553–559. doi: 10.1136/jmg.26.9.553. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bernardi F., Marchetti G., Bertagnolo V., Faggioli L., Volinia S., Patracchini P., Bartolai S., Vannini F., Felloni L., Rossi L. RFLP analysis in families with sporadic hemophilia A. Estimate of the mutation ratio in male and female gametes. Hum Genet. 1987 Jul;76(3):253–256. doi: 10.1007/BF00283618. [DOI] [PubMed] [Google Scholar]
  4. Bobrow M., Walker A., Walton J. The parental origin of mutations causing Duchenne muscular dystrophy. Arch Neurol. 1988 Jan;45(1):85–87. doi: 10.1001/archneur.1988.00520250091027. [DOI] [PubMed] [Google Scholar]
  5. Bottema C. D., Bottema M. J., Ketterling R. P., Yoon H. S., Janco R. L., Phillips J. A., 3rd, Sommer S. S. Why does the human factor IX gene have a G + C content of 40%? Am J Hum Genet. 1991 Oct;49(4):839–850. [PMC free article] [PubMed] [Google Scholar]
  6. Bottema C. D., Ketterling R. P., Yoon H. S., Sommer S. S. The pattern of factor IX germ-line mutation in Asians is similar to that of Caucasians. Am J Hum Genet. 1990 Nov;47(5):835–841. [PMC free article] [PubMed] [Google Scholar]
  7. Bottema C. D., Koeberl D. D., Sommer S. S. Direct carrier testing in 14 families with haemophilia B. Lancet. 1989 Sep 2;2(8662):526–529. doi: 10.1016/s0140-6736(89)90653-3. [DOI] [PubMed] [Google Scholar]
  8. Bröcker-Vriends A. H., Briët E., Dreesen J. C., Bakker B., Reitsma P., Pannekoek H., van de Kamp J. J., Pearson P. L. Somatic origin of inherited haemophilia A. Hum Genet. 1990 Aug;85(3):288–292. doi: 10.1007/BF00206748. [DOI] [PubMed] [Google Scholar]
  9. Casula L., Murru S., Pecorara M., Ristaldi M. S., Restagno G., Mancuso G., Morfini M., De Biasi R., Baudo F., Carbonara A. Recurrent mutations and three novel rearrangements in the factor VIII gene of hemophilia A patients of Italian descent. Blood. 1990 Feb 1;75(3):662–670. [PubMed] [Google Scholar]
  10. Coulondre C., Miller J. H., Farabaugh P. J., Gilbert W. Molecular basis of base substitution hotspots in Escherichia coli. Nature. 1978 Aug 24;274(5673):775–780. doi: 10.1038/274775a0. [DOI] [PubMed] [Google Scholar]
  11. Driscoll D. J., Migeon B. R. Sex difference in methylation of single-copy genes in human meiotic germ cells: implications for X chromosome inactivation, parental imprinting, and origin of CpG mutations. Somat Cell Mol Genet. 1990 May;16(3):267–282. doi: 10.1007/BF01233363. [DOI] [PubMed] [Google Scholar]
  12. Giannelli F., Green P. M., High K. A., Sommer S., Lillicrap D. P., Ludwig M., Olek K., Reitsma P. H., Goossens M., Yoshioka A. Haemophilia B: database of point mutations and short additions and deletions--third edition, 1992. Nucleic Acids Res. 1992 May 11;20 (Suppl):2027–2063. doi: 10.1093/nar/20.suppl.2027. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Gitschier J., Kogan S., Levinson B., Tuddenham E. G. Mutations of factor VIII cleavage sites in hemophilia A. Blood. 1988 Sep;72(3):1022–1028. [PubMed] [Google Scholar]
  14. Gitschier J. Maternal duplication associated with gene deletion in sporadic hemophilia. Am J Hum Genet. 1988 Sep;43(3):274–279. [PMC free article] [PubMed] [Google Scholar]
  15. Gitschier J., Wood W. I., Tuddenham E. G., Shuman M. A., Goralka T. M., Chen E. Y., Lawn R. M. Detection and sequence of mutations in the factor VIII gene of haemophiliacs. 1985 May 30-Jun 5Nature. 315(6018):427–430. doi: 10.1038/315427a0. [DOI] [PubMed] [Google Scholar]
  16. Grover H., Phillips M. A., Lillicrap D. P., Giles A. R., Garvey M. B., Teitel J., Rivard G., Blanchette V., White B. N., Holden J. J. Carrier detection of haemophilia A using DNA markers in families with an isolated affected male. Clin Genet. 1987 Jul;32(1):10–19. doi: 10.1111/j.1399-0004.1987.tb03316.x. [DOI] [PubMed] [Google Scholar]
  17. Gustafson S., Proper J. A., Bowie E. J., Sommer S. S. Parameters affecting the yield of DNA from human blood. Anal Biochem. 1987 Sep;165(2):294–299. doi: 10.1016/0003-2697(87)90272-7. [DOI] [PubMed] [Google Scholar]
  18. Henderson B. E., Ross R., Bernstein L. Estrogens as a cause of human cancer: the Richard and Hinda Rosenthal Foundation award lecture. Cancer Res. 1988 Jan 15;48(2):246–253. [PubMed] [Google Scholar]
  19. Higuchi M., Kazazian H. H., Jr, Kasch L., Warren T. C., McGinniss M. J., Phillips J. A., 3rd, Kasper C., Janco R., Antonarakis S. E. Molecular characterization of severe hemophilia A suggests that about half the mutations are not within the coding regions and splice junctions of the factor VIII gene. Proc Natl Acad Sci U S A. 1991 Aug 15;88(16):7405–7409. doi: 10.1073/pnas.88.16.7405. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Higuchi M., Kochhan L., Olek K. A somatic mosaic for haemophilia A detected at the DNA level. Mol Biol Med. 1988 Feb;5(1):23–27. [PubMed] [Google Scholar]
  21. Higuchi M., Kochhan L., Schwaab R., Egli H., Brackmann H. H., Horst J., Olek K. Molecular defects in hemophilia A: identification and characterization of mutations in the factor VIII gene and family analysis. Blood. 1989 Aug 15;74(3):1045–1051. [PubMed] [Google Scholar]
  22. Higuchi M., Wong C., Kochhan L., Olek K., Aronis S., Kasper C. K., Kazazian H. H., Jr, Antonarakis S. E. Characterization of mutations in the factor VIII gene by direct sequencing of amplified genomic DNA. Genomics. 1990 Jan;6(1):65–71. doi: 10.1016/0888-7543(90)90448-4. [DOI] [PubMed] [Google Scholar]
  23. Holloway S. M., Smith C. Equilibrium frequencies in X-linked recessive disease. Am J Hum Genet. 1973 Jul;25(4):388–396. [PMC free article] [PubMed] [Google Scholar]
  24. Kazazian H. H., Jr, Wong C., Youssoufian H., Scott A. F., Phillips D. G., Antonarakis S. E. Haemophilia A resulting from de novo insertion of L1 sequences represents a novel mechanism for mutation in man. Nature. 1988 Mar 10;332(6160):164–166. doi: 10.1038/332164a0. [DOI] [PubMed] [Google Scholar]
  25. Kling S., Ljung R., Sjörin E., Montandon J., Green P., Giannelli F., Nilsson I. M. Origin of mutation in sporadic cases of haemophilia-B. Eur J Haematol. 1992 Mar;48(3):142–145. doi: 10.1111/j.1600-0609.1992.tb00585.x. [DOI] [PubMed] [Google Scholar]
  26. Koeberl D. D., Bottema C. D., Ketterling R. P., Bridge P. J., Lillicrap D. P., Sommer S. S. Mutations causing hemophilia B: direct estimate of the underlying rates of spontaneous germ-line transitions, transversions, and deletions in a human gene. Am J Hum Genet. 1990 Aug;47(2):202–217. [PMC free article] [PubMed] [Google Scholar]
  27. Koeberl D. D., Bottema C. D., Sarkar G., Ketterling R. P., Chen S. H., Sommer S. S. Recurrent nonsense mutations at arginine residues cause severe hemophilia B in unrelated hemophiliacs. Hum Genet. 1990 Apr;84(5):387–390. doi: 10.1007/BF00195805. [DOI] [PubMed] [Google Scholar]
  28. Levinson B., Lehesjoki A. E., de la Chapelle A., Gitschier J. Molecular analysis of hemophilia A mutations in the Finnish population. Am J Hum Genet. 1990 Jan;46(1):53–62. [PMC free article] [PubMed] [Google Scholar]
  29. Loeb L. A. Endogenous carcinogenesis: molecular oncology into the twenty-first century--presidential address. Cancer Res. 1989 Oct 15;49(20):5489–5496. [PubMed] [Google Scholar]
  30. Ludwig M., Grimm T., Brackmann H. H., Olek K. Parental origin of factor IX gene mutations, and their distribution in the gene. Am J Hum Genet. 1992 Jan;50(1):164–173. [PMC free article] [PubMed] [Google Scholar]
  31. Millar D. S., Steinbrecher R. A., Wieland K., Grundy C. B., Martinowitz U., Krawczak M., Zoll B., Whitmore D., Stephenson J., Mibashan R. S. The molecular genetic analysis of haemophilia A; characterization of six partial deletions in the factor VIII gene. Hum Genet. 1990 Dec;86(2):219–227. doi: 10.1007/BF00197709. [DOI] [PubMed] [Google Scholar]
  32. Montandon A. J., Green P. M., Bentley D. R., Ljung R., Nilsson I. M., Giannelli F. Two factor IX mutations in the family of an isolated haemophilia B patient: direct carrier diagnosis by amplification mismatch detection (AMD). Hum Genet. 1990 Jul;85(2):200–204. doi: 10.1007/BF00193196. [DOI] [PubMed] [Google Scholar]
  33. Moser H. Duchenne muscular dystrophy: pathogenetic aspects and genetic prevention. Hum Genet. 1984;66(1):17–40. doi: 10.1007/BF00275183. [DOI] [PubMed] [Google Scholar]
  34. Paynton C., Sarkar G., Sommer S. S. Identification of mutations in two families with sporadic hemophilia A. Hum Genet. 1991 Aug;87(4):397–400. doi: 10.1007/BF00197155. [DOI] [PubMed] [Google Scholar]
  35. Risch N., Reich E. W., Wishnick M. M., McCarthy J. G. Spontaneous mutation and parental age in humans. Am J Hum Genet. 1987 Aug;41(2):218–248. [PMC free article] [PubMed] [Google Scholar]
  36. Rosendaal F. R., Bröcker-Vriends A. H., van Houwelingen J. C., Smit C., Varekamp I., van Dijck H., Suurmeijer T. P., Vandenbroucke J. P., Briët E. Sex ratio of the mutation frequencies in haemophilia A: estimation and meta-analysis. Hum Genet. 1990 Dec;86(2):139–146. doi: 10.1007/BF00197695. [DOI] [PubMed] [Google Scholar]
  37. Sarkar G., Paynton C., Sommer S. S. Segments containing alternating purine and pyrimidine dinucleotides: patterns of polymorphism in humans and prevalence throughout phylogeny. Nucleic Acids Res. 1991 Feb 11;19(3):631–636. doi: 10.1093/nar/19.3.631. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Schwaab R., Ludwig M., Oldenburg J., Brackmann H. H., Egli H., Kochhan L., Olek K. Identical point mutations in the factor VIII gene that have different clinical manifestations of hemophilia A. Am J Hum Genet. 1990 Oct;47(4):743–744. [PMC free article] [PubMed] [Google Scholar]
  39. Sommer S. S. Assessing the underlying pattern of human germline mutations: lessons from the factor IX gene. FASEB J. 1992 Jul;6(10):2767–2774. doi: 10.1096/fasebj.6.10.1634040. [DOI] [PubMed] [Google Scholar]
  40. Sommer S. S., Bowie E. J., Ketterling R. P., Bottema C. D. Missense mutations and the magnitude of functional deficit: the example of factor IX. Hum Genet. 1992 May;89(3):295–297. doi: 10.1007/BF00220543. [DOI] [PubMed] [Google Scholar]
  41. Stoflet E. S., Koeberl D. D., Sarkar G., Sommer S. S. Genomic amplification with transcript sequencing. Science. 1988 Jan 29;239(4839):491–494. doi: 10.1126/science.3340835. [DOI] [PubMed] [Google Scholar]
  42. Tanimoto M., Kojima T., Kamiya T., Takamatsu J., Ogata K., Obata Y., Inagaki M., Iizuka A., Nagao T., Kurachi K. DNA analysis of seven patients with hemophilia B who have anti-factor IX antibodies: relationship to clinical manifestations and evidence that the abnormal gene was inherited. J Lab Clin Med. 1988 Sep;112(3):307–313. [PubMed] [Google Scholar]
  43. Taylor S. A., Deugau K. V., Lillicrap D. P. Somatic mosaicism and female-to-female transmission in a kindred with hemophilia B (factor IX deficiency). Proc Natl Acad Sci U S A. 1991 Jan 1;88(1):39–42. doi: 10.1073/pnas.88.1.39. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Vidaud M., Chabret C., Gazengel C., Grunebaum L., Cazenave J. P., Goossens M. A de novo intragenic deletion of the potential EGF domain of the factor IX gene in a family with severe hemophilia B. Blood. 1986 Oct;68(4):961–963. [PubMed] [Google Scholar]
  45. Wang N. S., Zhang M., Thompson A. R., Chen S. H. Factor IX Chongqing: a new mutation in the calcium-binding domain of factor IX resulting in severe hemophilia B. Thromb Haemost. 1990 Feb 19;63(1):24–26. [PubMed] [Google Scholar]
  46. Wiebauer K., Jiricny J. Mismatch-specific thymine DNA glycosylase and DNA polymerase beta mediate the correction of G.T mispairs in nuclear extracts from human cells. Proc Natl Acad Sci U S A. 1990 Aug;87(15):5842–5845. doi: 10.1073/pnas.87.15.5842. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Winship P. R., Rees D. J., Alkan M. Detection of polymorphisms at cytosine phosphoguanadine dinucleotides and diagnosis of haemophilia B carriers. Lancet. 1989 Mar 25;1(8639):631–634. doi: 10.1016/s0140-6736(89)92141-7. [DOI] [PubMed] [Google Scholar]
  48. Winter R. M. Estimation of male to female ratio of mutation rates from carrier-detection tests in X-linked disorders. Am J Hum Genet. 1980 Jul;32(4):582–588. [PMC free article] [PubMed] [Google Scholar]
  49. Winter R. M., Tuddenham E. G., Goldman E., Matthews K. B. A maximum likelihood estimate of the sex ratio of mutation rates in haemophilia A. Hum Genet. 1983;64(2):156–159. doi: 10.1007/BF00327115. [DOI] [PubMed] [Google Scholar]
  50. Yoshitake S., Schach B. G., Foster D. C., Davie E. W., Kurachi K. Nucleotide sequence of the gene for human factor IX (antihemophilic factor B). Biochemistry. 1985 Jul 2;24(14):3736–3750. doi: 10.1021/bi00335a049. [DOI] [PubMed] [Google Scholar]
  51. Youssoufian H., Antonarakis S. E., Aronis S., Tsiftis G., Phillips D. G., Kazazian H. H., Jr Characterization of five partial deletions of the factor VIII gene. Proc Natl Acad Sci U S A. 1987 Jun;84(11):3772–3776. doi: 10.1073/pnas.84.11.3772. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Youssoufian H., Antonarakis S. E., Bell W., Griffin A. M., Kazazian H. H., Jr Nonsense and missense mutations in hemophilia A: estimate of the relative mutation rate at CG dinucleotides. Am J Hum Genet. 1988 May;42(5):718–725. [PMC free article] [PubMed] [Google Scholar]
  53. Youssoufian H., Kasper C. K., Phillips D. G., Kazazian H. H., Jr, Antonarakis S. E. Restriction endonuclease mapping of six novel deletions of the factor VIII gene in hemophilia A. Hum Genet. 1988 Oct;80(2):143–148. doi: 10.1007/BF00702857. [DOI] [PubMed] [Google Scholar]
  54. Youssoufian H., Kazazian H. H., Jr, Phillips D. G., Aronis S., Tsiftis G., Brown V. A., Antonarakis S. E. Recurrent mutations in haemophilia A give evidence for CpG mutation hotspots. 1986 Nov 27-Dec 3Nature. 324(6095):380–382. doi: 10.1038/324380a0. [DOI] [PubMed] [Google Scholar]
  55. Youssoufian H., Wong C., Aronis S., Platokoukis H., Kazazian H. H., Jr, Antonarakis S. E. Moderately severe hemophilia A resulting from Glu----Gly substitution in exon 7 of the factor VIII gene. Am J Hum Genet. 1988 Jun;42(6):867–871. [PMC free article] [PubMed] [Google Scholar]

Articles from American Journal of Human Genetics are provided here courtesy of American Society of Human Genetics

RESOURCES