Sex in mammals, including mouse and human, is determined genetically and depends on the paternal sex chromosome - X or Y - received at the time of fertilisation. If nothing goes wrong, an XX individual develops as a girl, whereas an XY individual develops as a boy.
But if something does go wrong, the individual may be born infertile or with ambiguous genitals. It happens more often than you might think, too - approximately 1 in 4,500 births - so how can we ensure everything runs smoothly during sex development?
In research published today in Science, I - along with colleagues from Australia and Japan - found that an enzyme called Jmjd1a controls expression of the key gene on the Y chromosome that is necessary and sufficient for male development, known as Sry.
Steering cell differentiation
Arguably, the most important process influenced by Sry is the differentiation of a bundle of cells in the embryo called the bipotential gonadal precursor into a testis, if Sry is present and functional, and into an ovary, if Sry is absent.
Ovaries and testes not only function as the incubators of egg and sperm, which carry genetic information from one generation to the next, but also produce hormones that drive the differentiation of most, if not all, secondary sexual characteristics, including external genitalia.
Hence, without proper development of these organs, reproduction of the individual and survival of the species are not possible.
The proper development of testes and ovaries is driven by a tightly regulated network of genes and regulatory factors. Misregulation of this network in humans results in atypical development of chromosomal, gonadal or anatomical sex, resulting in so-called disorders of sex development (DSDs).
The “umbrella” term DSD includes a variety of different disorders, from relatively mild, such as hypospadias (abnormally placed opening of the urethra) to complete sex reversal where, for instance, XY individuals develop as females.
Many DSDs are associated with ambiguous genitalia and infertility. In addition, they often are linked to secondary complications such as an increase in the susceptibility to develop testicular or ovarian cancer.
Optimal care of patients with DSD require a multidisciplinary team including geneticists, endocrinologists, neonatologists, gynaecologists, psychiatrists, surgeons and social workers, thereby representing a major health-care burden.
Although in recent years, progress has been made in identifying genes linked to these disorders, many are still unexplained at the molecular level, suggesting some key players remain to be identified.
Our current knowledge of mammalian sex determination is based on two lines of evidence:
- The characterisation of the biological events that determine the sexual development of the individual
- The study of genetic mutations in humans and mice that lead to abnormal sexual development.
In contrast, epigenetics, which in broad terms can be used to describe anything other than the DNA sequence to influence the development of an organism, had not been implicated in mammalian sex determination to date.
In this most recent study, led by Makoto Tachibana from Kyoto University, we analysed mice in which an enzyme called Jmjd1a, which is involved in epigenetic regulation, had been inactivated.
This epigenetic regulation involves packing and, in this case, unpacking of DNA. DNA is a long string that can be wrapped around special proteins, so-called histones, like on a spool.
Wrapping of the DNA around histones leaves these areas of the DNA inactive, whereas unpacking can activate it.
Surprisingly, loss of Jmjd1a resulted in a skewing of the sex ratio at birth towards females. Analysis showed that these mice displayed XY sex reversal, thus developing as females.
Further investigation revealed that normally Jmjd1a unwraps the DNA very specifically in the Sry region, allowing the production of Sry protein and therefore the differentiation of a testis and the male phenotype.
Loss of this enzyme leaves the Sry region tightly packed so no Sry protein is made and the gonadal precursor develops into an ovary, hence resulting in XY sex reversal.
While this mechanism has been only shown in mouse to date, it is highly likely that the same regulation for Sry is happening in humans.
Up to 80% of DSD patients are lacking an accurate diagnosis even after sequencing the known candidate genes, demonstrating that key genes or regulatory mechanisms are still unknown.
The identification and analysis of this new, epigenetic regulation of sex determination will help with accurate diagnosis of at least some of these patients, which will allow for improved clinical management of DSDs and its complications including risks of infertility and the occurrence of gonadal tumours.