Improving the diagnostics of infertility in men

There is nothing better than the knowledge that what we do helps to improve the world, whether it’s healthcare, agriculture, nature etc. In case you were wondering about all the possibilities that Solis BioDyne products are offering, here is a little glimpse into the world of scientific discoveries. 

Around 10% of men globally struggle to conceive a child because of low sperm counts. Researchers from the University of Tartu (Estonia) and the Wellcome Sanger Institute (UK) lead by geneticist Pille Hallast carried out the biggest genetic study to date looking at Y-chromosome-linked infertility in men. “Human genome contains many complex genomic regions which are difficult to study but might be hiding previously unknown associations to medical conditions,” says Pille Hallast, the main author of the study. “With a careful approach it is possible to dig into these regions and to identify novel and even common risk factors. I believe our study is one such example.”

Pille Hallast
What they found was a specific region of the Y chromosome, which is prone to microdeletions that substantially increase the risk of severe spermatogenic impairment. “In European populations where this Y chromosome type is common, men could be screened for it and offered an option to store their sperm at a young age, ” explains Hallast.

One of the most widely considered genetic factors to cause infertility are karyotype abnormalities and recurrent de novo microdeletions of the Y-chromosomal Azoospermia Factor (AZF) a, b and c, the most prevalent deletion type being AZFc (~80%). The AZFc complete deletions remove a set of multicopy genes that are expressed in a testis-enriched manner and considered important in spermatogenesis (sperm production process). Therefore, testing for these deletions has been strongly recommended to infertility patients for years.

In the study 1190 Estonian patients with male factor infertility were analysed in comparison to 1134 reference men from the same population, including 2000 subjects with sperm parameter data available. The main goal was to investigate AZFc partial deletions in men, which has never been done on such a large scale before. The study also aimed to determine the role and contribution of gr/gr and b2/b3 deletion subtypes in spermatogenic impairment and to explore their potential in the clinical perspective.

Pille Hallast_Laura Kibena_Solis BioDyne
Pille Hallast and Laura Kibena at
the Wellcome Sanger Institute
The researchers discovered that complex AZFc rearrangements within a specific Y haplogroup,
R1a1-M458 and its sub-lineages, cause severe spermatogenic failure in the majority of carriers. This haplogroup carries a fixed r2/r3 inversion that destabilizes the AZFc region, predisposing to large recurrent microdeletions. Aforementioned inverted Y chromosome variant is relatively common among several European populations, but it is not found as widely in other continents. While the inversion itself has no direct effect on fertility, the risk of spermatogenic failure in these men with inversion and subsequent deletion is almost nine times higher compared to the rest of the men. Therefore, it can be passed down in families and remain unnoticed until an offspring has infertility issues. 

The scientist behind the study agreed that the survival of such a high-risk lineage in the population seems surprising, but may be explained by its possible age-specific effects on spermatogenesis. Study results suggest that these genetic changes may not harm fertility until later in life. Therefore, these genetic differences may have been less harmful when it was more common for men to have children earlier in life. So, the consequences of this risk could potentially be alleviated by early identification of the variant carriers and giving them an opportunity to store their sperm, but more studies are needed to confirm this finding. 

The amount of PCR runs
The researchers also got comparable results with previous studies, where the gr/gr deletion (under which AZFc partial losses belong) has been found to be a risk factor for spermatogenic impairment in European populations. Among Estonian men it creates more than a 2-fold increased susceptibility to infertility. Unexpectedly, one in four Estonian gr/gr deletion carriers belonged to the Y-chromosomal haplogroup R1a1-M458 (and its sub-lineages).

In conclusion the results of this study have a great potential to improve clinical and molecular diagnostics. Also help a significant fraction of men originating from Northern and Central European populations with impaired spermatogenesis and identify those at a higher risk of infertility in their early adulthood, giving them a chance to make decisions about future family planning early on.

Solis BioDyne product used:
® DNA polymerase

“Solis BioDyne has a nice range of products which have been used in our research over the years. The orders were delivered fast, prices reasonable and I have never had any issues with the products,” commented Pille Hallast.

Hallast P., Kibena L., Punab M., Arciero E., Rootsi S., Grigorova M., Flores R., Jobling M. A., Poolamets O., Pomm K., Korrovits P., Rull K., Xue Y., Tyler-Smith C., Laan M. (2021). A common 1.6 mb Y-chromosomal inversion predisposes to subsequent deletions and severe spermatogenic failure in humans. Elife; 10:e65420. doi: 10.7554/eLife.65420.