Human Genetics

, Volume 86, Issue 1, pp 25–32 | Cite as

Selective advantage of fra (X) heterozygotes

  • F. Vogel
  • W. E. Crusio
  • C. Kovac
  • J. P. Fryns
  • M. Freund
Original Investigations


The high incidence of the fra (X) syndrome (about 1∶2000 male newborns) requires an explanation in view of the low fitness of mentally retarded hemizygous males and heterozygous females. In the past, it has been proposed that the mutation rate may be unusually high, and that mutations occur exclusively in male germ cells. According to an alternative hypothesis, a moderately high mutation rate might combine with a selective advantage of clinically unaffected heterozygotes. In earlier studies, such a combined hypothesis was shown to lead to plausible implications regarding mutation rate and fitness. Moreover, a mutation rate in male germ cells of the magnitude required by the exclusive mutation hypothesis was excluded by studies on comprehensive pedigree data. In this third study in the series, an increased fitness of heterozygous females is demonstrated directly by a comparison of the reproductive performance of heterozygotes with that of adequate controls (mothers and grandparents of Down's syndrome patients). Since average numbers of children have decreased during recent decades in populations of industrialized countries, heterozygotes (mothers of affected probands and their female relatives in their own generation) were subdivided into those born before and after 1940. Moreover, sibship sizes of probands' mothers and fathers were analyzed separately for family branches in which the fra (X) trait segregated (mostly the maternal branch), or did not segregate (in most instances the paternal branch). In all four categories reproductive performance in heterozygotes was found to be higher than in the controls. This difference was significant statistically for two of the four groups: it was small and nonsignificant only for the parental family branch in which the fra (X) mutant did not segregate and for mothers born after 1940. Fitness estimates ranged between 1.11 and 1.36. A higher incidence of dizygotic twinning suggests a biological component for this increased fertility. On the other hand, fra (X) families have a significantly lower social status than the controls. This suggests a socio-psychological component of their higher fertility. Apparently, both components contribute to their fertility: at present, their relative importance cannot be assessed.


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  1. Fryns JP (1986) The female and the fragile X. A study of 144 obligate female carriers. Am J Med Genet 23:157–169Google Scholar
  2. Haldane JBS (1935) The rate of spontaneous mutation of a human gene. J Genet 31:317–326Google Scholar
  3. Herbst DS, Miller JR (1980) Nonspecific X-linked mental retardation 11: the frequency in British Columbia. Am J Med Genet 7:461–469Google Scholar
  4. Krüger J, Propping P (1976) Rückgang der Zwillingsgeburten in Deutschland. Dtsch Med Wochenschr 101:475–480Google Scholar
  5. Laird CD (1987) Proposed mechanism of inheritance and expression of the human fragile X-syndrome of mental retardation. Genetics 117:587–599Google Scholar
  6. Laird CD, Jaffe E, Karpen G, Lamb M, Nelson R (1987) Fragile sites in human chromosomes as regions of late-replicating DNA. Trends Genet 3:274–281Google Scholar
  7. Müller KV (1956) Empirische Beiträge zur Frage der differentiellen Fruchtbarkeit im Nachkriegsdeutschland. Homo 7:87–110Google Scholar
  8. Paul J, Froster-Iskenius U, Moje W, Schwinger E (1984) Heterozygous female carriers of the marker-X-chromosome: I. Q. testimation and replication status of fra (X)q. Hum Genet 66:344–346Google Scholar
  9. Pembrey ME, Winter RM, Davies KE (1985) A premutation that generates a defect at crossing over explains the inheritance of fragile (X) mental retardation. Am J Med Genet 21:709–717Google Scholar
  10. Penrose LS (1963) Outline of human genetics, 2nd edn. Heine-Mann, LondonGoogle Scholar
  11. Propping P, Krüger J (1976) Über die Häufigkeit von Zwillingsgeburten. Dtsch Med Wochenschr 101:506–512Google Scholar
  12. Reiss AL, Freund L, Vinogradov S, Hagerman R, Cronister A (1989) Parental inheritance and psychological disability in fragile X females. Am J Hum Genet 45:697–705Google Scholar
  13. Seemanova E, Kovarik J, Subrt I, Steinbicker V, Goetz P, Houstek J, Nosek M, Chyleova L, Lippert P, Schmidt A, Jungmannova C (1987) Ultraschalluntersuchung der Ovarien bei Carriern für fra (X) und bei geistig behinderten Mädchen nach der Menarche (abstract), 20. Tagung der Gesellschaft für Anthropologie und Humangenetik, Giessen 1987. p 113Google Scholar
  14. Seemanova E, Steinbicker V, Huistek J (1989) tSyndrom des fra (X): Ergebnisse einer Phänotypenanalyse bei obligaten und möglichen Carriern (in press)Google Scholar
  15. Seemanova E, Steinbicker V, Kovarik J (1990) (in Czech). Cesk Pediatr (in press)Google Scholar
  16. Sherman SL, Morton NE, Jacobs PA, Turner G (1984) The marker (X) syndrome: a cytogenetic and genetic analysis. Ann Hum Genet 48:21–37Google Scholar
  17. Sherman SL, Jacobs PA, Morton NE, Froster-Iskenius U, Howard-Peebles PN, Nielsen KB, Partington MW, Sutherland GR, Turner G, Watson M (1985) Further segregation analysis of the fragile (X) syndrome with special reference to transmitting males. Hum Genet 69:289–299Google Scholar
  18. Siegel S (1956) Nonparametric statistics for the behavioral sciences. McGraw-Hill, New YorkGoogle Scholar
  19. Steinbach P (1986) Mental impairment in Martin-Bell syndrome is probably determined by interaction of several genes: simple explanation of phenotypic differences between unaffected and affected males with the same X chromosome. Hum Genet 72:248–252MathSciNetMATHGoogle Scholar
  20. Sutherland GR (1982) Heritable fragile sites of human chromoSomes, VIII. Preliminary population cytogenetic data on the folic-acid-sensitive sites. Am J Hum Genet 34:452–458Google Scholar
  21. Sutherland GR (1985) Heritable fragile sites on human chromosomes, XII. Population cytosenetics. Ann Hum Genet 49:153–161Google Scholar
  22. Turner G, Jacobs P (1983) Marker (X)-linked mental retardation. Adv Hum Genet 13:83–112Google Scholar
  23. Vogel F (1977) A probable sex difference in some mutation rates. Am J Hum Genet 29:312–319Google Scholar
  24. Vogel F (1984) Mutation and selection in the marker (X) syndrome. Ann Hum Genet 48:327–332Google Scholar
  25. Vogel F, Motulsky AG (1986) Human genetics — problems and Approaches, 2nd edn, Springer, Berlin Heidelberg New YorkGoogle Scholar
  26. Vogel F, Rathenberg R (1975) Spontaneous mutation in man. Adv Hum Genet 5:223–318Google Scholar
  27. Vogel F, Krüger J, Brondum Nielsen K, Fryns JP, Schindler D, Schinzel A, Schmidt A, Schwinger E (1985) Recurrent mutation pressure does not explain the prevalence of the marker (X) syndrome. Hum Genet 71:1–6Google Scholar
  28. Webb T (1989) The epidemiology of the fragile (X) syndrome. In: Davies KE (ed) The fragile (X) syndrome. Oxford University Press. Oxford New York Tokyo, pp 40–55Google Scholar
  29. Weinberg W (1902) Beiträge zur Physiologie und Pathologie der Mehrlingsgeburten beim Menschen und Probleme der Mehrlingsgeburtenstatistik. Z Geburtshilfe Gynäkol 47:12Google Scholar
  30. Weinberg W (1909) Der Einfluß von Alter und Geburtenzahl der Mutter auf die Häufigkeit der einund zweieiigen Zwillingsgeburten. Z Geburtshilfe Gynäkol 65:318–324Google Scholar

Copyright information

© Springer-Verlag 1990

Authors and Affiliations

  • F. Vogel
    • 1
  • W. E. Crusio
    • 1
  • C. Kovac
    • 1
  • J. P. Fryns
    • 2
  • M. Freund
    • 3
  1. 1.Institut für Humangenetik und Anthropologie der UniversitätHeidelbergGermany
  2. 2.Division of Human GeneticsUniversity HospitalGasthuisbergBelgium
  3. 3.Centre de Génétique MédicaleUniversité Catholique de LouvainBrusselsBelgium

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