Skip to main content
SpringerLink
Log in

The molecular genetics of human sex determination

  • Review
  • Published:
Journal of Molecular Medicine Aims and scope Submit manuscript

Abstract

The classical conception of the chromosomal mechanism of sex determination presumes a chromosome unique for and determining the heterogametic sex. On the basis of recent evidence, however, this picture is becoming increasingly complex, with a multitude of genes appearing to interact simultaneously or successively to bring about the gonadal phenotype. The genes identified so far that are thought to be involved in the process of human sex determination are distributed on various chromosomes, but the consecution of their function remains to be elucidated. To the Y chromosome only a relative role can be ascribed, and it has not yet been established which gene is on top of the cascade. All of the genes under discussion are involved in transcriptional control, and at least the majority of them appear to exert pleiotropic effects. The regulation of their expression must still be defined, and it will be a long way before a link to gonadal morphogenesis is ultimately found.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

MIS :

Müllerian inhibiting substance

WAGR :

Wilm's tumor, aniridia, genitourinary malformations, mental retardation

DDS :

Denys Drash syndrome

SF-1 :

Steroidogenic factor 1

AHC :

Adrenal hypoplasia congenita

HHG :

Hypogonadotropic hypogonadism

References

  1. Jost A (1947) Recherches sur la différenciation sexuelle de l'embryon de lapin. III. Rôle des gonades foetales dans la différenciation sexuelle somatique. Archs Anat Microsc Morphol Exp 36:271–315

    Google Scholar 

  2. Burgoyne PS (1988) Role of mammalian Y chromosome in sex determination. Phil Trans R Soc Lond B 322:63–72

    Google Scholar 

  3. Parkhurst SM, Meneely PM (1994) Sex determination and dosage compensation: lessons from flies and worms. Science 264:924–932

    Google Scholar 

  4. Wolf U, Schempp W, Scherer G (1992) Molecular biology of the human Y chromosome. Rev Physiol Biochem Pharmacol 121:147–213

    Google Scholar 

  5. Goodfellow PN, Lovell-Badge R (1993) SRY and sex determination in mammals. Annu Rev Genet 27:71–92

    Google Scholar 

  6. Hawkins JR (1994) Sex determination. Hum Mol Genet 3:1463–1467

    Google Scholar 

  7. Behlke MA, Bogan JS, Beer-Romero P, Page DC (1993) Evidence that the SRY protein is encoded by a single exon on the human Y chromosome. Genomics 17:736–739

    Google Scholar 

  8. Jantzen H-M, Admon A, Bell SP, Tjian R (1990) Nuclear transcription factor hUBF contains a DNA-binding motif with homology to HMG proteins. Nature 344:830–836

    Google Scholar 

  9. Gubbay J, Collignon J, Koopman P, Capel B, Economou A, Münsterberg A, Vivian N, Goodfellow P, Lovell-Badge R (1990) A gene mapping to the sex-determining region of the mouse Y chromosome is a member of a novel family of embryonically expressed genes. Nature 346:245–250

    Google Scholar 

  10. Koopman P, Münsterberg A, Capel B, Vivian N, Lovell-Badge R (1990) Expression of a candidate sex-determining gene during mouse testis differentiation. Nature 348:450–452

    Google Scholar 

  11. Magre S, Jost A (1980) The initial phases of testicular organogenesis in the rat. An electron microscope study. Arch Anat Microsc Morph Exp 69:297–318

    Google Scholar 

  12. Burgoyne PS, Buehr M, Koopman P, Rossant J, McLaren A (1988) Cell-autonomous action of the testis-determinig gene: Sertoli cells are exclusively XY in XX ↔ XY chimaeric mouse testes. Development 102:443–450

    Google Scholar 

  13. Koopman P, Gubbay J, Vivian N, Goodfellow P, Lovell-Badge R (1991) Male development of chromosomally female mice transgenic for Sry. Nature 351:117–121

    Google Scholar 

  14. McElreavy K, Vilain E, Abbas N, Costa J-M, Souleyreau N, Kucheria K, Boucekkine C, Thibaud E, Brauner R, Flamant F, Fellous M (1992) XY sex reversal associated with a deletion 5' to the SRY “HMG box” in the testis-determining region. Proc Natl Acad Sci USA 89:11016–11020

    Google Scholar 

  15. Tajima T, Nakae J, Shinohara N, Fujieda K (1994) A novel mutation localized in the 3' non-HMG box region of the SRY gene in 46,XY gonadal dysgenesis. Hum Mol Genet 3:1187–1189

    Google Scholar 

  16. Whitfield LS, Lovell-Badge R, Goodfellow PN (1993) Rapid sequence evolution of the mammalian sex-determining gene SRY. Nature 364:713–715

    Google Scholar 

  17. Ferrari S, Harley VR, Pontiggia A, Goodfellow PN, Lovell-Badge R, Bianchi ME (1992) SRY, like HMG1, recognizes sharp angles in DNA. EMBO J 11:4497–4506

    Google Scholar 

  18. Pontiggia A, Rimini R, Harley VR, Goodfellow PN, Lovell-Badge R, Bianchi ME (1994) Sex-reversing mutations affect the architecture of SRY-DNA complexes. EMBO J 13:6115–6124

    Google Scholar 

  19. Call KM, Glaser T, Ito CY, Buckler AJ, Pelletier J, Haber DA, Rose EA, Kral A, Yeger H, Lewis WH, Jones C, Housman DE (1990) Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus. Cell 60:509–520

    Article  CAS  PubMed  Google Scholar 

  20. Gessler M, Poustka A, Cavenee W, Neve RL, Orkin SH, Bruns GAP (1990) Homozygous deletion in Wilms tumours of a zinc-finger gene identified by chromosome jumping. Nature 343:774–778

    Google Scholar 

  21. Pelletier J, Bruening W, Kashtan CE, Mauer SM, Manivel JC, Striegel JE, Houghton DC, Junien C, Habib R, Fouser L, Fine RN, Silverman BL, Haber DA, Housman D (1991) Germline mutations in the Wilms' tumor suppressor gene are associated with abnormal urogenital development in Denys-Drash syndrome. Cell 67:437–447

    Google Scholar 

  22. Pritchard-Jones K, Fleming S, Davidson D, Bickmore W, Porteous D, Gosden C, Bard J, Buckler A, Pelletier J, Housman D, Heyningen V van, Hastie N (1990) The candidate Wilms' tumour gene is involved in genitourinary development. Nature 346:194–197

    Article  CAS  PubMed  Google Scholar 

  23. Pelletier J, Schalling M, Buckler AJ, Rogers A, Haber DA, Housman D (1991) Expression of the Wilms' tumor gene WT1 in the murine urogenital system. Genes Dev 5:1345–1356

    Google Scholar 

  24. Kreidberg JA, Sariola H, Loring JM, Maeda M, Pelletier J, Housman D, Jaenisch R (1993) WT-1 is required for early kidney development. Cell 74:679–691

    Article  CAS  PubMed  Google Scholar 

  25. Lala DS, Rice DA, Parker KL (1992) Steroidogenic factor 1, a key regulator of Steroidogenic enzyme expression, is the mouse homolog of fushi tarazu factor 1. Mol Endocrinol 6:1249–1258

    Google Scholar 

  26. Taketo M, Parker KL, Howard TA, Tsukiyama T, Wong M, Niwa O, Morton CC, Miron PM, Seidin MF (1995) Homologs of Drosophila fushi-tarazu factor 1 map to mouse chromosome 2 and human chromosome 9q33. Genomics 25:565–567

    Google Scholar 

  27. Ikeda Y, Shen W-H, Ingraham HA, Parker KL (1994) Developmental expression of mouse steroidogenic factor 1, an essential regulator of the steroid hydroxylases. Mol Endocrinol 8:654–662

    Google Scholar 

  28. Shen W-H, Moore CCD, Ikeda Y, Parker KL, Ingraham HA (1994) Nuclear receptor steroidogenic factor 1 regulates the Müllerian inhibiting substance gene: a link to the sex determination cascade. Cell 77:651–661

    Google Scholar 

  29. Luo X, Ikeda Y, Parker KL (1994) A cell-specific nuclear receptor is essential for adrenal and gonadal development and sexual differentiation. Cell 77:481–490

    Google Scholar 

  30. Cohen-Haguenauer O, Picard JY, Mattel M-G, Serero S, Van Cong N, Tand M-F de, Guerrier D, Hors-Cayla M-C, Josso N, Frézal J (1987) Mapping of the gene for anti-Müllerian hormone to the short arm of human chromosome 19. Cytogenet Cell Genet 44:2–6

    Google Scholar 

  31. Cate RL, Mattaliano RJ, Hession C, Tizard R, Farber NM, Cheung A, Ninfa EG, Frey AZ, Gash DJ, Chow EP, Fisher RA, Bertonis JM, Torres G, Wallner BP, Ramachandran KL, Ragin RC, Manganaro TF, MacLaughlin DT, Donahoe PK (1986) Isolation of the bovine and human genes for Müllerian inhibiting substance and expression of the human gene in animal cells. Cell 45:685–698

    Google Scholar 

  32. Picard J-Y, Benarous R, Guerrier D, Josso N, Kahn A (1986) Cloning and expression of cDNA for anti-Müllerian hormone. Proc Natl Acad Sci USA 83:5464–5468

    Google Scholar 

  33. Knebelmann B, Boussin L, Guerrier D, Legai L, Kahn A, Josso N, Picard J-Y (1991) Anti-Müllerian hormone Bruxelles: a nonsense mutation associated with the persistent Müllerian duct syndrome. Proc Natl Acad Sci USA 88:3767–3771

    Google Scholar 

  34. Vigier B, Watrin F, Magre S, Tran D, Josso N (1987) Purified bovine AMH induces a characteristic freemartin effect in fetal rat prospective ovaries exposed to it in vitro. Development 100:43–55

    Google Scholar 

  35. Vigier B, Forest MG, Eychenne B, Bézard J, Garrigou O, Robel P, Josso N (1989) Anti-Müllerian hormone produces endocrine sex reversal of fetal ovaries. Proc Natl Acad Sci USA 86:3684–3688

    Google Scholar 

  36. Behringer RR, Cate RL, Froelick GJ, Palmiter RD, Brinster RL (1990) Abnormal sexual development in transgenic mice chronically expressing Müllerian inhibiting substance. Nature 345:167–170

    Google Scholar 

  37. Haqq CM, King C-Y, Ukiyama E, Falsafi S, Haqq TN, Donahoe PK, Weiss MA (1994) Molecular basis of mammalian sexual determination: Activation of Müllerian inhibiting substance gene expression by SRY. Science 266:1494–1500

    Google Scholar 

  38. Münsterberg A, Lovell-Badge R (1991) Expression of the mouse anti-Müllerian hormone gene suggests a role in both male and female sexual differentiation. Development 113:613–624

    Google Scholar 

  39. Wright EM, Snopek B, Koopman P (1993) Seven new members of the Sox gene family expressed during mouse development. Nucl Acids Res 21:744

    Google Scholar 

  40. Tommerup N, Schempp W, Meinecke P, Pedersen S, Bolund L, Brandt C, Goodpasture C, Guldberg P, Held KR, Reinwein H, Saugstad OD, Scherer G, Skjeldal O, Toder R, Westvik J, Hagen CB van der, Wolf U (1993) Assignment of an autosomal sex reversal locus (SRA1) and campomelic dysplasia (CMPD1) to17q24.3-q25.1. Nature Genet 4:170–174

    Google Scholar 

  41. Foster JW, Dominguez-Steglich MA, Guioli S, Kwok C, Weller PA, Stevanovic M, Weissenbach J, Mansour S, Young ID, Goodfellow PN, Brook JD, Schafer AJ (1994) Campomelic dysplasia and autosomal sex reversal caused by mutations in an SRY-related gene. Nature 372:525–530

    Google Scholar 

  42. Wagner T, Wirth J, Meyer J, Zabel B, Held M, Zimmer J, Pasantes J, Dagna Bricarelli F, Keutel J, Hustert E, Wolf U, Tommerup N, Schempp W, Scherer G (1994) Autosomal sex reversal and campomelic dysplasia are caused by mutations in and around the SRY-related gene SOX9. Cell 79:1111–1120

    Google Scholar 

  43. Houston CS, Opitz JM, Spranger JW, Macpherson RI, Reed MH, Gilbert EF, Herrmann J, Schinzel A (1983) The campomelic syndrome: review, report of 17 cases, and follow-up on the currently 17-year old boy first reported by Maroteaux et al. in 1971. Am J Med Genet 15:3–28

    Google Scholar 

  44. Bridge J, Sanger W, Mosher G, Buehler B, Nelson R, Welsh M, Newland J, Kafka M (1985) Partial deletion of distal 17q. Am J Med Genet 21:225–229

    Google Scholar 

  45. Wright E, Hargrave MR, Christiansen J, Cooper L, Kun J, Evans T, Gangadharan U, Greenfield A, Koopman P (1995) The SRY-related gene Sox9 is expressed during chondrogenesis in mouse embryos. Nature Genet 9:15–20

    Google Scholar 

  46. Bernstein R, Jenkins T, Dawson B, Wagner J, Dewald G, Koo GC, Wachtel SS (1980) Female phenotype and multiple abnormalities in sibs with a Y chromosome and partial X chromosome duplication: H-Y antigen and Xg blood group findings. J Med Genet 17:291–300

    Google Scholar 

  47. Scherer G, Schempp W, Baccichetti C, Lenzini E, Dagna Bricarelli F, Doria Lamba Carbone L, Wolf U (1989) Duplication of an Xp segment that includes the ZFX locus causes sex inversion in man. Hum Genet 81:291–294

    Google Scholar 

  48. Bardoni B, Zanaria E, Guioli S, Floridia G, Worley K, Tonini G, Ferrante E, Chiumello G, McCabe ERB, Fraccaro M, Zuffardi O, Camerino G (1994) A dosage sensitive locus at chromosome Xp21 is involved in male to female sex reversal. Nature Genet 7:497–501

    Google Scholar 

  49. Zanaria E, Muscatelli F, Bardoni B, Strom TM, Guioli S, Guo W, Lalli E, Moser C, Walker AP, McCabe ERB, Meitinger R, Monaco AP, Sassone-Corsi P, Camerino G (1994) An unusual member of the nuclear hormone receptor superfamily responsible for X-linked adrenal hypoplasia congenita. Nature 372:635–641

    Google Scholar 

  50. Muscatelli F, Strom TM, Walker AP, Zanaria E, Récan D, Meindl A, Bardoni B, Guioli S, Zehetner G, Rabl W, Schwarz HP, Kaplan J-C, Camerino G, Meitinger T, Monaco AP (1994) Mutations in the DAX-1 gene give rise to both X-linked adrenal hypoplasia congenita and hypogonadotropic hypogonadism. Nature 372:672–676

    Google Scholar 

  51. Bennett CP, Doherty Z, Robb SA, Ramani P, Hawkins JR, Grant D (1993) Deletion 9p and sex reversal. J Med Genet 30:518–520

    Google Scholar 

  52. Wilkie AOM, Campbell FM, Daubeney P, Grant DB, Daniels RJ, Mullarkey M, Affara NA, Fitchett M, Huson SM (1993) Complete and partial XY sex reversal associated with terminal deletion of 10q: report of 2 cases and literature review. Am J Med Genet 46:597–600

    Google Scholar 

  53. McElreavey K, Vilain E, Abbas N, Herskowitz I, Fellous M (1993) A regulatory cascade hypothesis for mammalian sex determination: SRY represses a negative regulator of male development. Proc Natl Acad Sci USA 90:3368–3372

    Google Scholar 

  54. Bogan JS, Page DC (1994) Ovary? Testis? — a mammalian dilemma. Cell 76:603–607

    Google Scholar 

  55. Smith MJ (1994) Turning on sex. Current Biology 4:1003–1005

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institut für Humangenetik und Anthropologie, Universität Freiburg, Breisacher Strasse 33, D-79106, Freiburg, Germany

    U. Wolf

Authors
  1. U. Wolf
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wolf, U. The molecular genetics of human sex determination. J Mol Med 73, 325–331 (1995). https://doi.org/10.1007/BF00192884

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00192884

Key words

Search

Navigation