Embryos are gonadally identical, regardless of genetic sex, until a certain point in development when the testis-determining factor causes male sex organs to develop. A typical male
karyotype is XY, whereas a female's is XX. There are exceptions, however, in which SRY plays a major role. Individuals with
Klinefelter syndrome inherit a normal Y chromosome and multiple X chromosomes, giving them a karyotype of XXY. Atypical
genetic recombination during
crossover, when a sperm cell is developing, can result in karyotypes that are not typical for their phenotypic expression. Most of the time, when a developing sperm cell undergoes crossover during meiosis, the SRY gene stays on the Y chromosome. If the SRY gene is transferred to the X chromosome instead of staying on the Y chromosome, testis development will no longer occur. This is known as
Swyer syndrome, characterized by an XY karyotype and a female phenotype. Individuals who have this syndrome have normally formed uteri and fallopian tubes, but the gonads are not functional. Swyer syndrome individuals are usually considered as females. On the other spectrum,
XX male syndrome, also known as
de la Chapelle syndrome, occurs when a body has 46:XX Karyotype and SRY attaches to one of them through translocation. People with XX male syndrome have a XX Karyotype but are male. Individuals with either of these syndromes can experience delayed puberty, infertility, and growth features of the opposite sex they identify with. XX male syndrome expressers may develop breasts, and those with Swyer syndrome may have facial hair. While the presence or absence of SRY has generally determined whether or not testis development occurs, it has been suggested that there are other factors that affect the functionality of SRY. Therefore, there are individuals who have the SRY gene, but still develop as females, either because the gene itself is defective or mutated, or because one of the contributing factors is defective. This can happen in individuals exhibiting a XY, XXY, or XX SRY-positive karyotype Additionally, other sex determining systems that rely on SRY beyond XY are the processes that come after SRY is present or absent in the development of an embryo. In a normal system, if SRY is present for XY, SRY will activate the medulla to develop gonads into testes. Testosterone will then be produced and initiate the development of other male sexual characteristics. Comparably, if SRY is not present for XX, there will be a lack of the SRY based on no Y chromosome. The lack of SRY will allow the cortex of embryonic gonads to develop into ovaries, which will then produce estrogen, and lead to the development of other female sexual characteristics.
Role in other diseases SRY has been shown to
interact with the
androgen receptor and individuals with XY karyotype and a functional SRY gene can have an outwardly female phenotype due to an underlying
androgen insensitivity syndrome (AIS). Individuals with AIS are unable to respond to androgens properly due to a defect in their androgen receptor gene, and affected individuals can have complete or partial AIS. SRY has also been linked to the fact that males are more likely than females to develop
dopamine-related diseases such as
schizophrenia and
Parkinson's disease. SRY encodes a protein that controls the concentration of dopamine, the neurotransmitter that carries signals from the brain that control movement and coordination. Research in mice has shown that a mutation in SOX10, an SRY encoded transcription factor, is linked to the condition of Dominant
megacolon in mice. This mouse model is being used to investigate the link between SRY and
Hirschsprung disease, or congenital megacolon in humans. This missense mutation causes defective
chondrogenesis, or the process of cartilage formation, and manifests as skeletal CD. Two thirds of 46,XY individuals diagnosed with CD have fluctuating amounts of male-to-female sex reversal. 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. but this was later followed by other forms of testing based on hormone levels. In March 2025
World Athletics announced it will do
cheek swabbing tests for gender eligibility, specifically looking for the SRY gene, but that this would only be a first screen in determining eligibility, so that individuals with
CAIS or
Swyer's syndrome would not automatically be excluded from female competition.
Ongoing research Despite the progress made during the past several decades in the study of sex determination, the SRY gene, and its protein, work is still being conducted to further understanding in these areas. There remain factors that need to be identified in the sex-determining molecular network, and the chromosomal changes involved in many other human sex-reversal cases are still unknown. Scientists continue to search for additional sex-determining genes, using techniques such as
microarray screening of the genital ridge genes at varying developmental stages, mutagenesis screens in mice for sex-reversal phenotypes, and identifying the genes that transcription factors act on using
chromatin immunoprecipitation. Another study done on mice used TALEN technology to produce an SRY knockout model. These mice expressed external and internal genitalia as well as a normal female level of circulating testosterone. These mice, despite having XY chromosomes, expressed a normal estrus cycle albeit with reduced fertility. Both of these studies highlighted the role that SRY plays in the development of the testes and other male reproductive organs.
SRY knock-in CRISPR-Cas9 technology has been used to insert the SRY gene into XX individuals, thus creating a genetically female organism that is phenotypically male. Only a fragment of 14-kilobases of genomic DNA is necessary for the induction of testis. This alteration in addition to gene drives would allow for the induction of sterility to aid in population control of either unfavorable or invasive species. However, to utilize this knock-in, the relocation of the SRY gene onto the 17th chromosome (autosome) would be most efficient. These transgenic species would then be released into the wild to mate with the natural population, resulting in the creation of predominantly male offspring, thus decreasing reproductive rates. An autosomal SRY knock-in would result in a 75% SRY inheritance rate, whereas a 90% inheritance can be achieved when inserted into the t-complex on the 17th chromosome. Although, previously unsuccessful in mammals, more recent research has found that although thought to only contain single exon for the last 30 years, a second SRY exon has been located named SRY-T . == See also ==