An international collaboration with The University of Queensland has found a hidden DNA fragment that is critical for male sex determination.
Male sex determination
The mammalian sex-determining region Y (Sry) is a gene located on the Y chromosome that induces male development. For several decades, researchers have believed that Sry contains a single exon. In a study, published in Science, researchers have identified a cryptic second exon of mouse Sry and a corresponding two-exon type Sry transcript (Sry-T).
Performing a series of loss- and gain-of-function analyses using CRISPR technology, the team revealed that XY mice lacking Sry-T were sex-reverse. In addition, ectopic expression of Sry-T in XX mice induced male development.
They found that Sry-T messenger RNA is expressed similarly to that of canonical single-exon type Sry (Sry-S). However, SRY-T protein is expressed predominantly because of the absence of a degron in the C terminus of SRY-S. The team believe that Sry exon 2 evolved recently in mice. They suggest this occurred through the acquisition of a retrotransposon-derived coding sequence to replace the degron.
UQ’s Institute of Molecular Biosciences Emeritus Professor Peter Koopman, stated:
“For the last 30 years, we’ve been trying to figure out how this works.
Sry is a master switch gene because it flicks the switch for male development, it gets the ball rolling for a whole series of genetic events that result in a baby being born as a male instead of female.
This new piece of the gene is absolutely essential for its function; without that piece, the gene simply doesn’t work.
We’ve discovered something massively important in biology here, because without Sry there can be no sexual reproduction and hence no propagation and survival of mammalian species.”
Implications
Their findings suggest that in nature, SRY-T is in fact the bona fide testis-determining factor. As a result, this discovery may have implications for manipulating sex ratios in agriculture or for biological pest management. Most importantly, this development raises ethical questions regarding the utilisation within human embryos.
Although human Sry does not have this added exon, this discovery may reveal new functions that might be shared between mouse and human Sry. For example, it may provide insight into genes and protein that interact with Sry. Importantly, studying how Sry interacts could help explain some cases of intersex development, a poorly understood group of conditions.
Image credit: By Leonid Yastremskiy – canva.com
