A study carried out by Estonian and U.K. researchers has discovered a structural variant in the Y-chromosome that predisposes men who carry it to be infertile.

The research team, co-led by Maris Laan, Ph.D., a professor of human genetics at the University of Tartu in Estonia and Chris Tyler-Smith, Ph.D., former senior group leader at the Wellcome Sanger Institute, found that men carrying the previously undiscovered inversion mutation were almost 9-times more likely to have a very low sperm production than non-carriers.

“Being able to identify the genetic reason for these men having impaired sperm production will help give them a diagnosis and access to the support that this brings,” says Laan.

“While some deletions on the Y chromosome were previously known to interfere with sperm production, understanding at this level of detail is important for the management of male fertility issues, and in this case the options of having children early in life or preserving sperm for later use could be discussed.”

Around 5% to 10% of all men are infertile, but surprisingly little is known about genetic factors that can contribute to poor or absent sperm production. The cause of the infertility of around 60% of these men remains unknown.

To investigate the genetics of this common problem further, the researchers carried out an in-depth examination of the Y chromosomes of 2,324 Estonian men. Of these, 1,190 had some level of sperm production failure ranging from mild to severe. The remaining 1,134 men in the group served as fertile controls.

In previous studies, it has been established that men with deletions in the AZFa, AZFb and AZFc regions of the Y chromosome are more likely to have sperm failure than men who do not. Around 80% of these deletions fall in the AZFc region.

Different Y chromosomes have different lineages depending on where the male ancestors of the man in question originate from. A specific Y lineage, R1a1-M458, is Slavic in origin and present in more than 20% of European men.

The results of this study, which are published in the journal eLife, show that a previously undiscovered genetic inversion (r2/r3) of approximately 1.6Mb in the R1a1-M458 Y lineage strongly destabilizes the AZFc region and makes it much more vulnerable to deletions that can impact fertility.

Overall, 13 men in the entire group had the r2/r3 inversion plus deletions in the AZFc section of their Y chromosomes. Notably, although this inversion increased the risk for sperm failure 8.6-fold, three of the 13 men had relatively normal sperm levels and were in the reference group. They were all young, aged 18-23 years, which might possibly be significant, but the numbers are too small to be sure.

“The biggest surprise is that a Y chromosome subtype with such a deleterious effect on fertility is present in the population at all. Why hasn’t it disappeared if it is so harmful? Has it perhaps only started to have this effect on fertility recently, as sperm counts have declined for environmental reasons in the last few decades and resulted in a detrimental combination of genetics and environment?” says Tyler-Smith.