SRY
Encyclopedia
SRY is a sex
-determining gene
on the Y chromosome
in the theria
ns (placental mammals and marsupials).
This intron
less 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 theria
n 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
.
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.
, 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 positive
s 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
.
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.
of the X chromosome bound gene SOX3
, a member of the Sox family. This duplication occurred after the split between monotreme
s and theria
ns. Monotremes lack SRY and have a ZW
-like sex determination system, likely involving DMRT1
, whereas therians (marsupial
s 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.
with the androgen receptor
.
Sex
In biology, sex is a process of combining and mixing genetic traits, often resulting in the specialization of organisms into a male or female variety . Sexual reproduction involves combining specialized cells to form offspring that inherit traits from both parents...
-determining gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
on the Y chromosome
Y chromosome
The Y chromosome is one of the two sex-determining chromosomes in most mammals, including humans. In mammals, it contains the gene SRY, which triggers testis development if present. The human Y chromosome is composed of about 60 million base pairs...
in the theria
Theria
Theria is a subclass of mammals that give birth to live young without using a shelled egg, including both eutherians and metatherians . The only omitted extant mammal group is the egg-laying monotremes....
ns (placental mammals and marsupials).
This intron
Intron
An intron is any nucleotide sequence within a gene that is removed by RNA splicing to generate the final mature RNA product of a gene. The term intron refers to both the DNA sequence within a gene, and the corresponding sequence in RNA transcripts. Sequences that are joined together in the final...
less gene encodes a transcription factor
Transcription factor
In molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...
that is a member of the SOX (SRY-like box) gene
SOX genes
SOX genes encode a family of transcription factors that bind to the minor groove in DNA, and belong to a super-family of genes characterized by a homologous sequence called the HMG box. This HMG box is a DNA binding domain that is highly conserved throughout eukaryotic species...
family of DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
-binding proteins. This protein is the theria
Theria
Theria is a subclass of mammals that give birth to live young without using a shelled egg, including both eutherians and metatherians . The only omitted extant mammal group is the egg-laying monotremes....
n testis determining factor
Testis determining factor
Testis-determining factor is a general term for the gene that results in maleness in humans and some other species.Certain genes cause chemical reactions that result in the development of testes...
(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
Swyer syndrome
Swyer syndrome, or XY gonadal dysgenesis, is a type of hypogonadism in a person whose karyotype is 46,XY. The person is externally female with streak gonads, and left untreated, will not experience puberty...
); translocation of part of the Y chromosome containing this gene to the X chromosome causes XX male syndrome
XX male syndrome
XX male syndrome is a rare sex chromosomal disorder. Usually it is caused by unequal crossing over between X and Y chromosomes during meiosis in the father, which results in the X chromosome containing the normally-male SRY gene...
.
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 (SertoliSertoli cell
A Sertoli cell is a 'nurse' cell of the testes that is part of a seminiferous tubule.It is activated by follicle-stimulating hormone and has FSH-receptor on its membranes.-Functions:...
and Leydig
Leydig cell
Leydig cells, also known as interstitial cells of Leydig, are found adjacent to the seminiferous tubules in the testicle. They produce testosterone in the presence of luteinizing hormone...
cells) or female cells (follicle
Ovarian follicle
Ovarian follicles are the basic units of female reproductive biology, each of which is composed of roughly spherical aggregations of cells found in the ovary. They contain a single oocyte . These structures are periodically initiated to grow and develop, culminating in ovulation of usually a single...
cells and Theca
Theca of follicle
The theca folliculi comprise a layer of the ovarian follicles. They appear as the follicles become tertiary follicles.The theca are divided into two layers, the theca interna and the theca externa....
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
SOX9
Transcription factor SOX-9 is a protein that in humans is encoded by the SOX9 gene.- Function :SOX-9 recognizes the sequence CCTTGAG along with other members of the HMG-box class DNA-binding proteins...
, a transcription factor with a DNA-binding site very similar to SRY's. SOX9 in turn upregulates fibroblast growth factor 9 (Fgf9
FGF9
Glia-activating factor is a protein that in humans is encoded by the FGF9 gene.-Interactions:FGF9 has been shown to interact with Fibroblast growth factor receptor 3.-Further reading:...
), 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
Positive feedback
Positive feedback is a process in which the effects of a small disturbance on a system include an increase in the magnitude of the perturbation. That is, A produces more of B which in turn produces more of A. In contrast, a system that responds to a perturbation in a way that reduces its effect is...
). 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 chromosomeX chromosomeThe X chromosome is one of the two sex-determining chromosomes in many animal species, including mammals and is common in both males and females. It is a part of the XY sex-determination system and X0 sex-determination system...
s (XXYKlinefelter's syndromeKlinefelter syndrome, 46/47, XXY, or XXY syndrome is a condition in which human males have an extra X chromosome. While females have an XX chromosomal makeup, and males an XY, affected individuals have at least two X chromosomes and at least one Y chromosome...
, XXXY etc.) are usually males. - Individuals with a male phenotypePhenotypeA phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
and an XX (female) karyotypeKaryotypeA karyotype is the number and appearance of chromosomes in the nucleus of an eukaryotic cell. The term is also used for the complete set of chromosomes in a species, or an individual organism.p28...
—XX male syndromeXX male syndromeXX male syndrome is a rare sex chromosomal disorder. Usually it is caused by unequal crossing over between X and Y chromosomes during meiosis in the father, which results in the X chromosome containing the normally-male SRY gene...
—have been observed; these males have the SRY gene in one or both X chromosomes, moved there by chromosomal translocationChromosomal translocationIn genetics, a chromosome translocation is a chromosome abnormality caused by rearrangement of parts between nonhomologous chromosomes. A gene fusion may be created when the translocation joins two otherwise separated genes, the occurrence of which is common in cancer. It is detected on...
. (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 GamesOlympic Games
The Olympic Games is a major international event featuring summer and winter sports, in which thousands of athletes participate in a variety of competitions. The Olympic Games have come to be regarded as the world’s foremost sports competition where more than 200 nations participate...
, under a system implemented by the International Olympic Committee
International Olympic Committee
The International Olympic Committee is an international corporation based in Lausanne, Switzerland, created by Pierre de Coubertin on 23 June 1894 with Demetrios Vikelas as its first president...
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
1996 Summer Olympics
The 1996 Summer Olympics of Atlanta, officially known as the Games of the XXVI Olympiad and unofficially known as the Centennial Olympics, was an international multi-sport event which was celebrated in 1996 in Atlanta, Georgia, United States....
were ruled false positive
Type I and type II errors
In statistical test theory the notion of statistical error is an integral part of hypothesis testing. The test requires an unambiguous statement of a null hypothesis, which usually corresponds to a default "state of nature", for example "this person is healthy", "this accused is not guilty" or...
s 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
American Medical Association
The American Medical Association , founded in 1847 and incorporated in 1897, is the largest association of medical doctors and medical students in the United States.-Scope and operations:...
, stating that the method used was uncertain and ineffective. The screening was eliminated as of the 2000 Summer Olympics
2000 Summer Olympics
The Sydney 2000 Summer Olympic Games or the Millennium Games/Games of the New Millennium, officially known as the Games of the XXVII Olympiad, were an international multi-sport event which was celebrated between 15 September and 1 October 2000 in Sydney, New South Wales, Australia...
.
SRY-related diseases and defects
Individuals with XY genotype and functional SRY gene can have an outwardly female phenotypePhenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
due to an underlying androgen insensitivity syndrome
Androgen insensitivity syndrome
Androgen insensitivity syndrome is a condition that results in the partial or complete inability of the cell to respond to androgens. The unresponsiveness of the cell to the presence of androgenic hormones can impair or prevent the masculinization of male genitalia in the developing fetus, as...
(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
Swyer syndrome
Swyer syndrome, or XY gonadal dysgenesis, is a type of hypogonadism in a person whose karyotype is 46,XY. The person is externally female with streak gonads, and left untreated, will not experience puberty...
).
SRY has been linked to the fact that men are more likely than women to develop dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
-related diseases such as schizophrenia
Schizophrenia
Schizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...
and Parkinson's disease
Parkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...
. 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 duplicationGene duplication
Gene duplication is any duplication of a region of DNA that contains a gene; it may occur as an error in homologous recombination, a retrotransposition event, or duplication of an entire chromosome.The second copy of the gene is often free from selective pressure — that is, mutations of it have no...
of the X chromosome bound gene SOX3
SOX3
Transcription factor SOX-3 is a protein that in humans is encoded by the SOX3 gene.This gene encodes a member of the SOX family of transcription factors involved in the regulation of embryonic brain development and in determination of cell fate. The encoded protein acts as a transcriptional...
, a member of the Sox family. This duplication occurred after the split between monotreme
Monotreme
Monotremes are mammals that lay eggs instead of giving birth to live young like marsupials and placental mammals...
s and theria
Theria
Theria is a subclass of mammals that give birth to live young without using a shelled egg, including both eutherians and metatherians . The only omitted extant mammal group is the egg-laying monotremes....
ns. Monotremes lack SRY and have a ZW
ZW sex-determination system
The ZW sex-determination system is a system that determines the sex of offspring in birds, some fish and crustaceans such as the giant river prawn, some insects , and some reptiles, including Komodo dragons...
-like sex determination system, likely involving DMRT1
DMRT1
Doublesex and mab-3 related transcription factor 1, also known as DMRT1, is a protein which in humans is encoded by the DMRT1 gene.- Function :...
, whereas therians (marsupial
Marsupial
Marsupials are an infraclass of mammals, characterized by giving birth to relatively undeveloped young. Close to 70% of the 334 extant species occur in Australia, New Guinea, and nearby islands, with the remaining 100 found in the Americas, primarily in South America, but with thirteen in Central...
s 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 interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with the androgen receptor
Androgen receptor
The androgen receptor , also known as NR3C4 , is a type of nuclear receptor that is activated by binding of either of the androgenic hormones testosterone or dihydrotestosterone in the cytoplasm and then translocating into the nucleus...
.