SRY gene
The SRY gene, located on the Y chromosome, is a critical factor in male sex determination in mammals. It encodes a transcription factor that initiates the development of male characteristics during embryonic development. In the absence of the SRY protein, individuals develop female phenotypes. Mutations in the SRY gene, particularly those affecting its DNA-binding domain, can lead to XX individuals displaying male characteristics or XY individuals with female phenotypes, a condition known as sex reversal.
Understanding sex determination mechanisms has evolved significantly, with research indicating that the presence of the Y chromosome is essential for male phenotype development, while other genes on different chromosomes also play important roles. The SRY gene is relatively small but highly conserved among therian mammals, reflecting its fundamental role in sex differentiation. In contrast, other species, such as the platypus, exhibit distinct sex-determination systems. The study of SRY and its mutations provides valuable insights into the complexities of sex development and fertility in humans and other mammals.
SRY gene
SIGNIFICANCE: The SRY gene is on the Y chromosome and encodes a transcription factor that triggers development of the male phenotype. The absence of this protein results in development of the female phenotype. Most mutations in SRY that disable the protein’s DNA-binding domain result in XY females.
SRY and Sex Determination
The biological mechanisms of sex determination vary widely throughout the animal and plant kingdoms, ranging from purely nongenetic to fully genetic mechanisms. The XX-XY genetic system, in which females have a pair of homomorphic X chromosomes and males a pair of heteromorphic X and Y chromosomes, was investigated most extensively in Drosophila melanogaster in the early part of the twentieth century. In 1925, Calvin Bridges published abundant evidence that the ratio of X chromosomes to autosomes determines sex in Drosophila. Of particular note was the observation that XXY flies are fertile females, and XO flies are infertile males. The Drosophila Y chromosome plays no role in sex determination although it is essential for male fertility.
In 1921, Theophilus Painter identified the Y chromosome in human and opossum males, and demonstrated that it pairs with and segregates from the X chromosome during meiosis. These discoveries suggested an evolutionarily ancestral XX-XY system for both eutherian (placental) and metatherian (marsupial) mammals, which has since been confirmed.
The observation that both Drosophila and humans have XX-XY systems of sex determination led most geneticists to assume that the mechanism of sex determination in humans was the same as in Drosophila. This assumption persisted until 1959, when C. E. Ford and K. W. Jones found that a woman with Turner syndrome had an XO chromosome constitution, while P. A. Jacobs and J. A. Strong showed that a man with Klinefelter syndrome had an XXY chromosome constitution. That same year, W. J. Welshons and L. B. Russell demonstrated that XO mice are female. The evidence from these and subsequent studies pointed to the presence or absence of the Y chromosome as the principal sex-determining factor in mammals.
People with sex-reversal phenotypes (XY females and XX males) offered clues regarding the molecular mechanism of sex determination in humans. Most XX males had a portion of the Y chromosome translocated onto one of their X chromosomes. The translocated region of the Y chromosome apparently triggered development of the male phenotype and was named the testis determining factor, or TDF.
Analysis by Peter Goodfellow and coworkers of these Y-derived translocated sequences in XX males narrowed the region on the Y chromosome containing TDF to a 35-kilobase (kb) segment. Within this segment is an open-reading frame, which they named SRY, for sex-determining region Y. Evidence that SRY is TDF in humans accumulated as numerous XY females were found to have mutations in the region of SRY encoding the DNA-binding domain. Moreover, Goodfellow and coworkers provided powerful evidence that SRY is the testis determining factor when they recovered a phenotypically male XX mouse that was transgenic for the region containing the mouse orthologue Sry. The accumulated evidence points to SRY as the initial trigger that determines male phenotypic development, although other genes on the Y chromosome, the X chromosome, and autosomes are essential for development of male and female phenotypes and for fertility.
Molecular Genetics and Evolution
SRY is a relatively small (3.8-kb) intronless gene that encodes a transcription factor with an HMG (high mobility group) DNA-binding domain. This region encoding this domain is highly conserved in all therian mammals. The sequences within the gene on either side of this conserved region, however, are highly variable among species, indicative of very rapid evolution. The platypus, by contrast, has a different sex-determination mechanism, governed by five X chromosomes and five Y chromosomes. These chromosomes are most closely related to the bird Z chromosome. The therian X and Y chromosomes probably evolved from an ancient autosomal pair of chromosomes ancestral to platypus chromosome 6 after the divergence of therian mammals and monotremes, approximately 166 million years ago.
Impact
The most significant clinical effect of mutations in SRY is sex reversal. Nearly all nonsynonymous mutations within the region that encodes the HMG domain result in complete sex reversal, observed as an XY individual with an unambiguous female phenotype.
Key terms
- sex determinationthe biological mechanism that determines the sex of an individual
- sex reversalan XY female or XX male
- XO chromosome constitutionan individual with one X chromosome and no corresponding X or Y chromosome
- XXY chromosome constitutionan individual with two X chromosomes and one Y chromosome
Bibliography
Carlson, Elof Axel. The 7 Sexes: Biology of Sex Determination. Indiana UP, 2013.
Coward, Kevin, and Dagan Wells. Textbook of Clinical Embryology. Cambridge UP, 2013.
Goodfellow, Peter N., and Robin Lovell-Badge. “SRY and Sex Determination in Mammals.” Annual Review of Genetics, vol. 27, 1993, pp. 71–92.
Richardson, Sarah S. Sex Itself: The Search for Male and Female in the Human Genome. U of Chicago P, 2013.
Sinclair, A. H., et al. “A Gene from the Human Sex-Determining Region Encodes a Protein with Homology to a Conserved DNA-Binding Motif.” Nature, 1990, pp. 240–45.
"SRY Gene." Medline Plus, National Library of Medicine, 28 Sept. 2022, medlineplus.gov/genetics/gene/sry/. Accessed 6 Sept. 2024.
Veyrunes, F., et al. “Bird-Like Sex Chromosomes of Platypus Imply Recent Origin of Mammal Sex Chromosomes.” Genome Research, vol. 18, 2008, pp. 965–73.