The researchers at the University of Pennsylvania have discovered that the mutations in the human TEX11 gene may be a genetic cause of infertility in men.
According to Jeremy Wang, assistant professor in the Department of Animal Biology at the University of Pennsylvania's School of Veterinary Medicine and colleagues, their study of the genetic causes of infertility is the first of its kind to link a particular sex chromosome meiosis-specific gene to sterility.
The TEX11 gene, just like mice, is also located on the human X chromosome. As the disruption of TEX11 causes azoospermia, or non-measurable sperm levels in mice, mutations in the human TEX11 gene may be a genetic cause of infertility in men.
As we know that men have only one X chromosome inherited from their mother, i.e. only one copy of the TEX11 gene, this would mean that any mutation might cause sterility. Thus, just like other X-linked disorders such as colour blindness and muscular dystrophy, genetic mutation causing a son's infertility could be passed from his mother.
The researchers hypothesize that a screening of the TEX11 gene may provide a pre-birth diagnosis for infertility in men. The study also reports the first meiosis-specific factor ever found on the X chromosome.
Meiosis is a cell division process that produces gametes in both sexes. During meiosis, homologous chromosomes undergo pairing, synapsis, recombination and faithful segregation. Meiosis leads to the exchange of genetic material between paternal and maternal genomes to produce genetically diverse gametes (sperm or eggs). Thus, any defects in meiosis are a leading cause of both infertility and birth defects.
An estimated 15 percent of couples are affected by infertility worldwide, yet the genetic causes of male infertility remain largely unknown. For decades, conventional wisdom stated that the X chromosome had little to do with meiosis or infertility because the X chromosome is silenced during male meiosis. This thinking led to fertility studies that focused on the Y chromosome and autosomes.
In an earlier study on mice male germ cells, it was found that almost one third of the identified germ cell-specific genes are located on the X-chromosome.
However, in the current study it was found that sex chromosomes do have a role to play in meiosis. Even though, these X-linked, germ cell-specific genes get inactivated during later stages of male meiosis, they play a role in the early stages.
The researchers found that TEX11 forms distinct foci on meiotic chromosomes and seems to be a novel constituent of the meiotic recombination machinery. Thus the researchers genetically engineered male mice that lacked TEX11 function and discovered that this led to chromosomal asynapsis during the process of gamete formation.
In other words, homologous chromosomes could not pair together during meiosis and chromosomes formed fewer crossovers, i.e. sites where they recombine, during the initial stages of meiosis. Subsequently, these failures led to elimination of spermatocytes at later stages in the genetic recombination process and, ultimately, male infertility.
The researchers believe that as TEX11 interacts with SYCP2, an integral component of the protein complex that mediates synapsis during meiosis, TEX11 promotes both synapsis and genetic recombination and may provide a physical link between these two meiotic processes.
The study is published in the latest issue of Genes & Development.