Will the baby be a girl or a boy? What decides the outcome? These might well be among the earliest questions asked by ourancestors. We can now offer a fairly comprehensive two-line answer. The SRY gene, located on the Y chromosome, triggers development along the male pathway. In its absence, development proceeds along the default female pathway.
Exceptional instances of femalespossessing the SRY gene have been reported three times in the medical literature. Two were in 2024 itself: one from researchers at the Renato Dulbecco University Hospital in Italy, in the journal Genes, and the other from researchers at the Cincinnati Children’s Hospital Medical Center, USA, in Molecular Genetics and Genomic Medicine.
These exceptions further strengthen the SRY gene’s claim to the primary role in male development.
The SRY gene
All eggs are alike but all sperm are not. All eggs contain one copy of each of our chromosomes (numbered 1-22) plus one copy of the sex chromosome (called X). Sperm cells also contain one copy each of chromosomes 1-22. But only half of them contain the X chromosome: the other half contain the other sex chromosome, Y.
The fusion of a sperm cell and an egg cell produces the zygote cell, from which the baby develops. Thus, the baby has two copies of chromosomes 1-22, plus either two Xs (XX) or an X and a Y (XY). Those with the Y chromosome develop into males. Those with two X chromosomes develop into females.
After a baby grows to become an adult, depending on their sex it will be their turn to make eggs/sperm. Only one chromosome of each of the 23 pairs is transmitted to the eggs and sperm. Again, the eggs and sperm contain one copy each of chromosomes 1-22. All eggs contain an X, while half of the sperm contain the X and the other half the Y.
The Y chromosome, which leads the development of maleness, contains the SRY gene. An XY embryo that receives an SRY gene rendered non-functional by a mutation develops ovaries, which produce the female hormone oestrogen and lead to the development of other female sexual characteristics.
SRY in an XX individual
Very rarely, a mutation can occur that transfers the SRY gene from the Y chromosome to the X. These mutations are called translocations. When a sperm bearing a translocation X chromosome fertilises an egg, an XX baby is born with the SRY gene.
In most cases, XX individuals with the SRY gene develop testes and become biological males. The testes produce the male hormone testosterone and initiate the development of other male sexual characteristics. However, they don’t produce mature sperm because other Y chromosomal genes required for sperm formation are absent. Since these males are sterile, the translocation is not transmitted to future generations.
Consider, however, the exceptional XX biological femalesfound to possess the SRY gene. The Italy group identified four healthy biological females in three generations of a family, all with the SRY gene. Their discovery has shown it’s possible for an SRY-bearing translocation X chromosome to be passed through generations via fertile females. The individuals bearing the translocation showed no evidence of any abnormalities.
The researchers from the Cincinnati hospital reported the discovery of a different SRY-bearing X translocation in an otherwise typical female foetus. The foetus went on to develop into a healthy female baby. But after the baby’s birth, the family didn’t accede to follow-up studies.
What is it about these two translocation chromosomes that led to the development of healthy females instead of infertile males?
The answer seemed to lie in a detail both groups spotted: both translocations occurred in parallel to the loss of a small portion of the X chromosome, which did away with one or more genes required for viability. The translocations that produced infertile males didn’t have these deletions.
Random v. biased inactivation
During female development in mammals, one of the two X chromosomes is inactivated in all the body’s cells. This makes the effective ‘dosage’ of X chromosome genes the same in XY males and XX females. The X chromosome’s inactivation also promotes female development by lowering the levels of maleness genes located on the X chromosome.
In some cells, the inactivated X chromosome is the one inherited from the father, and in other cells it is the one received from the mother. Thus, female mammals effectively have two types of cells: those that express the paternally- or the maternally-derived X.
In the exceptional SRY-positive females, however, the translocation X chromosome that had become inactivated. Had the inactivated chromosome been the non-translocation X, the cell wouldn’t have survived because essential genes missing from the translocation X wouldn’t be expressed. The ‘biased’ X inactivation resulted in silencing the SRY gene, allowing for typical female development.
That only a silenced SRY gene can persist in a biological female’s genome underscores its significance in triggering male development.
The Cincinnati researchers expressed their concern that low-level expression of the translocated SRY gene in later life could lead to disorders in sex development. Surveilling this possibility would require long-term follow-up through puberty. Unfortunately, the family wasn’t available for postnatal follow-up studies.
The two studies highlight the importance of examining translocation chromosomes for associated deletions that selectively inactivates the X chromosome. The genome sequences of thousands of biological females are now available. Knowing how many of them carry cryptic SRY-bearing translocations could in future help genetic counsellors make more informed personal and medical decisions.
D.P. Kasbekar is a retired scientist.
Published – February 10, 2025 03:03 am IST
