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|Sex determining region Y|
PDB rendering based on 1hry.
|RNA expression pattern|
This intronless gene encodes a transcription factor that is a member of the SOX (SRY-like box) gene family of DNA-binding proteins. This protein is the therian testis determining factor (TDF), referred to as the sex-determining region Y protein or SRY protein which initiates male sex determination. Mutations in this gene give rise to XY females with gonadal dysgenesis (Swyer syndrome); translocation of part of the Y chromosome containing this gene to the X chromosome causes XX male syndrome.
Molecular biology of testis determination 
During gestation, the cells of the primordial gonad that lie along the urogenital ridge are in a bipotential state, meaning they possess the ability to become either male cells (Sertoli and Leydig cells) or female cells (follicle cells and Theca cells). SRY initiates testis differentiation by activating male-specific transcription factors that allow these bipotential cells to differentiate and proliferate. SRY accomplishes this by upregulating SOX9, a transcription factor with a DNA-binding site very similar to SRY's. SOX9 in turn upregulates fibroblast growth factor 9 (Fgf9), which is necessary for proper Sertoli cell differentiation. Fgf9 then feeds back and upregulates SOX9. SOX9 can also upregulate itself by binding to its own enhancer region (positive feedback loop). Once proper SOX9 levels are reached, the bipotential cells of the gonad begin to differentiate into Sertoli cells. Additionally, cells expressing SRY will continue to proliferate to form the primordial testis. While this constitutes the basic series of events, this brief review should be taken with caution since there are many more factors that influence sex differentiation.
Effect upon anatomical sex 
Since its discovery, the importance of the SRY gene in sex determination has been extensively documented:
- Humans with one Y chromosome and multiple X chromosomes (XXY, XXXY etc.) are usually males.
- Individuals with a male phenotype and an XX (female) karyotype—XX male syndrome—have been observed; these males have the SRY gene in one or both X chromosomes (or possibly on an autosome), moved there by chromosomal translocation. (However, these males are infertile.) Translocation of the SRY to the X chromosome, followed by activation of the SRY in only some cells, can cause both testicular and ovarian tissues to form in the same individual. Thus, chromosomal translocation is a main cause of hermaphroditism.
- Similarly, there are females with an XXY or XY karyotype. These females have no SRY gene in their Y chromosome, or the SRY gene exists but is defective (mutated).
SRY and the Olympics 
One of the most controversial uses of this discovery was as a means for gender verification at the Olympic Games, under a system implemented by the International Olympic Committee in 1992. Athletes with an SRY gene were not permitted to participate as females, although all athletes in whom this was "detected" at the 1996 Summer Olympics were ruled false positives and were not disqualified. In the late 1990s, a number of relevant professional societies in United States called for elimination of gender verification, including the American Medical Association, stating that the method used was uncertain and ineffective. The screening was eliminated as of the 2000 Summer Olympics.
Individuals with XY genotype and functional SRY gene can have an outwardly female phenotype due to an underlying androgen insensitivity syndrome (AIS). SRY is essential for maleness. Loss of the SRY gene from the Y chromosome result in XY individuals, normally male, having female characteristics (Swyer syndrome).
SRY has been linked to the fact that men are more likely than women to develop dopamine-related diseases such as schizophrenia and Parkinson's disease. SRY makes a protein that controls concentrations of dopamine, the neurotransmitter that carries signals from the brain that control movement and coordination.
SRY may have arisen from a gene duplication of the X chromosome bound gene SOX3, a member of the Sox family. This duplication occurred after the split between monotremes and therians. Monotremes lack SRY and have a ZW-like sex determination system, likely involving DMRT1, whereas therians (marsupials and placental mammals) use the XY sex determination system. SRY is a rapidly evolving gene. A small number of mammals lack this gene entirely and use an alternative form of sex determination.
See also 
- Wallis MC, Waters PD, Graves JA (June 2008). "Sex determination in mammals - Before and after the evolution of SRY". Cell. Mol. Life Sci. 65 (20): 3182–95. doi:10.1007/s00018-008-8109-z. PMID 18581056.
- "Entrez Gene: SRY sex determining region Y".
- Margarit, E.; Coll, M. D.; Oliva, R.; g�Mez, D.; Soler, A.; Ballesta, F. (2000). "SRY gene transferred to the long arm of the X chromosome in a Y-positive XX true hermaphrodite". American Journal of Medical Genetics 90 (1): 25–28. doi:10.1002/(SICI)1096-8628(20000103)90:1<25::AID-AJMG5>3.0.CO;2-5. PMID 10602113.
- Biason-Lauber A, Konrad D, Meyer M, DeBeaufort C, Schoenle EJ (May 2009). "Ovaries and Female Phenotype in a Girl with 46,XY Karyotype and Mutations in the CBX2 Gene". Am. J. Hum. Genet. 84 (5): 658–63. doi:10.1016/j.ajhg.2009.03.016. PMC 2680992. PMID 19361780. Lay summary – New Scientist.
- Facius GM (2004-08-01). "The Major Medical Blunder of the 20th Century". Gender Testing. facius-homepage.dk. Retrieved 2011-06-12.
- Elsas LJ, Ljungqvist A, Ferguson-Smith MA, Simpson JL, Genel M, Carlson AS, Ferris E, de la Chapelle A, Ehrhardt AA (2000). "Gender verification of female athletes". Genet. Med. 2 (4): 249–54. doi:10.1097/00125817-200007000-00008. PMID 11252710.
- Dickinson BD, Genel M, Robinowitz CB, Turner PL, Woods GL (October 2002). "Gender verification of female Olympic athletes". Med Sci Sports Exerc 34 (10): 1539–42; discussion 1543. doi:10.1097/00005768-200210000-00001. PMID 12370551.
- Dewing, P; Chiang CW, Sinchak K, Sim H, Fernagut PO, Kelly S, Chesselet MF, Micevych PE, Albrecht KH, Harley VR, Vilain E (Feb 21 2006). "Direct regulation of adult brain function by the male-specific factor SRY". Current Biology 16 (4): 415–20. doi:10.1016/j.cub.2006.01.017. PMID 16488877.
- Katoh K, Miyata T (1999). "A heuristic approach of maximum likelihood method for inferring phylogenetic tree and an application to the mammalian SOX-3 origin of the testis-determining gene SRY". FEBS Lett 463 (1–2): 129–32. doi:10.1016/S0014-5793(99)01621-X. PMID 10601652.
- Veyrunes F, Waters PD, Miethke P et al. (2008). "Bird-like sex chromosomes of platypus imply recent origin of mammal sex chromosomes". Genome Res 18 (6): 965–73. doi:10.1101/gr.7101908. PMC 2413164. PMID 18463302.
- Bowles J, Schepers G, Koopman P (2000). "Phylogeny of the SOX family of developmental transcription factors based on sequence and structural indicators". Dev Biol 227 (2): 239–55. doi:10.1006/dbio.2000.9883. PMID 11071752.
- Kuroiwa A, Handa S, Nishiyama C, Chiba E, Yamada F, Abe S, Matsuda Y (June 2011). "Additional copies of CBX2 in the genomes of males of mammals lacking SRY, the Amami spiny rat (Tokudaia osimensis) and the Tokunoshima spiny rat (Tokudaia tokunoshimensis)". Chromosome Res 19 (5): 635–44. doi:10.1007/s10577-011-9223-6. PMID 21656076.
- Yuan X, Lu ML, Li T, Balk SP (December 2001). "SRY interacts with and negatively regulates androgen receptor transcriptional activity". J. Biol. Chem. 276 (49): 46647–54. doi:10.1074/jbc.M108404200. PMID 11585838.
Further reading 
- Haqq CM, King CY, Ukiyama E et al. (1995). "Molecular basis of mammalian sexual determination: activation of Müllerian inhibiting substance gene expression by SRY". Science 266 (5190): 1494–500. doi:10.1126/science.7985018. PMID 7985018.
- Goodfellow PN, Lovell-Badge R (1994). "SRY and sex determination in mammals". Annu. Rev. Genet. 27: 71–92. doi:10.1146/annurev.ge.27.120193.000443. PMID 8122913.
- Hawkins JR (1994). "Mutational analysis of SRY in XY females". Hum. Mutat. 2 (5): 347–50. doi:10.1002/humu.1380020504. PMID 8257986.
- Harley VR (2002). "The molecular action of testis-determining factors SRY and SOX9". Novartis Found. Symp. Novartis Foundation Symposia 244: 57–66; discussion 66–7, 79–85, 253–7. doi:10.1002/0470868732.ch6. ISBN 978-0-470-86873-7. PMID 11990798.
- Jordan BK, Vilain E (2003). "Sry and the genetics of sex determination". Adv. Exp. Med. Biol. 511: 1–13; discussion 13–4. PMID 12575752.
- Oh HJ, Lau YF (2006). "KRAB: a partner for SRY action on chromatin". Mol. Cell. Endocrinol. 247 (1–2): 47–52. doi:10.1016/j.mce.2005.12.011. PMID 16414182.
- Polanco JC, Koopman P (2007). "Sry and the hesitant beginnings of male development". Dev. Biol. 302 (1): 13–24. doi:10.1016/j.ydbio.2006.08.049. PMID 16996051.
- Hawkins JR, Taylor A, Berta P et al. (1992). "Mutational analysis of SRY: nonsense and missense mutations in XY sex reversal". Hum. Genet. 88 (4): 471–4. doi:10.1007/BF00215684. PMID 1339396.
- Hawkins JR, Taylor A, Goodfellow PN et al. (1992). "Evidence for increased prevalence of SRY mutations in XY females with complete rather than partial gonadal dysgenesis". Am. J. Hum. Genet. 51 (5): 979–84. PMC 1682856. PMID 1415266.
- Ferrari S, Harley VR, Pontiggia A et al. (1992). "SRY, like HMG1, recognizes sharp angles in DNA". EMBO J. 11 (12): 4497–506. PMC 557025. PMID 1425584.
- Jäger RJ, Harley VR, Pfeiffer RA et al. (1993). "A familial mutation in the testis-determining gene SRY shared by both sexes". Hum. Genet. 90 (4): 350–5. PMID 1483689.
- Vilain E, McElreavey K, Jaubert F et al. (1992). "Familial case with sequence variant in the testis-determining region associated with two sex phenotypes". Am. J. Hum. Genet. 50 (5): 1008–11. PMC 1682588. PMID 1570829.
- Müller J, Schwartz M, Skakkebaek NE (1992). "Analysis of the sex-determining region of the Y chromosome (SRY) in sex reversed patients: point-mutation in SRY causing sex-reversion in a 46,XY female". J. Clin. Endocrinol. Metab. 75 (1): 331–3. doi:10.1210/jc.75.1.331. PMID 1619028.
- McElreavey KD, Vilain E, Boucekkine C et al. (1992). "XY sex reversal associated with a nonsense mutation in SRY". Genomics 13 (3): 838–40. doi:10.1016/0888-7543(92)90164-N. PMID 1639410.
- Sinclair AH, Berta P, Palmer MS et al. (1990). "A gene from the human sex-determining region encodes a protein with homology to a conserved DNA-binding motif". Nature 346 (6281): 240–4. doi:10.1038/346240a0. PMID 1695712.
- Berkovitz GD, Fechner PY, Zacur HW et al. (1991). "Clinical and pathologic spectrum of 46,XY gonadal dysgenesis: its relevance to the understanding of sex differentiation". Medicine (Baltimore) 70 (6): 375–83. PMID 1956279.
- Berta P, Hawkins JR, Sinclair AH et al. (1990). "Genetic evidence equating SRY and the testis-determining factor". Nature 348 (6300): 448–50. doi:10.1038/348448A0. PMID 2247149.
- Jäger RJ, Anvret M, Hall K, Scherer G (1991). "A human XY female with a frame shift mutation in the candidate testis-determining gene SRY". Nature 348 (6300): 452–4. doi:10.1038/348452a0. PMID 2247151.
- Ellis NA, Goodfellow PJ, Pym B et al. (1989). "The pseudoautosomal boundary in man is defined by an Alu repeat sequence inserted on the Y chromosome". Nature 337 (6202): 81–4. doi:10.1038/337081a0. PMID 2909893.
- Whitfield LS, Hawkins TL, Goodfellow PN, Sulston J (1995). "41 kilobases of analyzed sequence from the pseudoautosomal and sex-determining regions of the short arm of the human Y chromosome". Genomics 27 (2): 306–11. doi:10.1006/geno.1995.1047. PMID 7557997.
- GeneReviews/NCBI/NIH/UW entry on 46,XX Testicular Disorder of Sex Development
- OMIM entries on 46,XX Testicular Disorder of Sex Development
- Genes, sry at the US National Library of Medicine Medical Subject Headings (MeSH)
- Sex-Determining Region Y Protein at the US National Library of Medicine Medical Subject Headings (MeSH)