SRY

This article is about the SRY gene. For other uses, see SRY (disambiguation).

Sex determining region Y
PDB rendering based on 1hry.
Available structures PDB 1HRY, 1HRZ, 1J46, 1J47, 2GZK
Identifiers
Symbols	SRY; TDF; TDY
External IDs	OMIM: 480000 MGI: 98660 HomoloGene: 48168 GeneCards: SRY Gene
Gene Ontology Molecular function • DNA binding • sequence-specific DNA binding transcription factor activity • protein binding Cellular component • nucleus • cytoplasm • nuclear speck • intracellular membrane-bounded organelle Biological process • sex differentiation • cell differentiation • male sex determination • positive regulation of transcription, DNA-dependent Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	6736	21674
Ensembl	ENSG00000184895	ENSMUSG00000069036
UniProt	Q05066	Q2T9H0
RefSeq (mRNA)	NM_003140.1	NM_011564
RefSeq (protein)	NP_003131.1	NP_035694
Location (UCSC)	Chr Y: 2.65 – 2.66 Mb	Chr Y: 1.95 – 1.95 Mb
PubMed search	[1]	[2]

SRY (Sex-determining region Y) is a sex-determining gene on the Y chromosome in the therians (placental mammals and marsupials).

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, moved there by chromosomal translocation. (However, these males are infertile.)
• 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 a 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.

SRY-related diseases and defects

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 SRY gene from Y chromosome means XY individuals that are normally male will have 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.

Evolution

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.

Interactions

SRY has been shown to interact with the androgen receptor.

See also

• Y chromosome
• Sex-determination system
• Testis-determining factor

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 9780470868737. 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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1682856. 
• 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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=557025. 
• 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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1682588. 
• 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. (1991). "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. 

External Links

• GeneReviews/NCBI/NIH/UW entry on 46,XX Testicular Disorder of Sex Development
• OMIM entries on 46,XX Testicular Disorder of Sex Development
• MeSH Genes,+sry
• MeSH Sex-Determining+Region+Y+Protein