Large study identified new genetic link to male infertility

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Newswise – The results published in eLife show that men with this unstable Y chromosome subtype have a significantly increased risk of genomic rearrangements. These rearrangements affect the process of sperm production (spermatogenesis), and as a result, these men can be up to nine times more likely to have fertility problems. Molecular diagnostics of this genetic variant could help identify those most at risk in early adulthood, giving them the opportunity to make decisions about future family planning early on. Currently, the exact cause of infertility remains unknown in more than half of men with spermatogenic deficiency.

In the large-scale study led by geneticist Pille Hallast and conducted in cooperation between the Human Genetics Research Group of the Institute of Biomedicine and Translational Medicine at the University of Tartu, the Andrology Center of the Tartu University Hospital and the Wellcome Sanger Institute, the Y chromosomes of more than 2,300 Estonian men were analyzed. The men were involved in the study at the Andrology Center of Tartu University Hospital by Professor Margus Punab’s team.

The region of the Y chromosome studied in this article has been previously associated with male infertility, but this is the first time that genetic variation in such a large clinical sample has been investigated. According to Hallast, this is the most sophisticated in-depth analysis of the genetic variation of the Y chromosome in patients with spermatogenic deficiency.

One of the study’s lead co-authors, University of Tartu human genetics professor Maris Laan, said the previously undescribed Y chromosome subtype, discovered in cooperation with UK colleagues, results in a high risk of severe spermatogenic deficiency. “At some point in evolution, the ancestor of these Y chromosomes underwent the inversion of a long segment of DNA, causing instability of this Y chromosome and predisposing to the deletion of surrounding DNA segments”, Laan explained.

This variant of the inverted Y chromosome is relatively common and does not always lead to partial DNA removal or fertility problems. Therefore, it can be passed on in families and remain unnoticed until an offspring has problems with infertility. It is estimated that in this Y line deletion of genetic material that interferes with spermatogenesis occurs in about one in ten men, if not less often. This subtype is carried by a significant number of men of European descent, but it is not found as widely in other continents. In Estonia, it is found in 5-6% of men, but in Poland and the Czech Republic the figure reaches almost 20%.

The world’s leading population geneticist, Dr Chris Tyler-Smith, a collaborator at the Wellcome Sanger Institute, stressed the need for more synergistic research between population genetics and reproduction teams to map unfavorable variants of the Y chromosome linked to altered spermatogenesis and understand how they evolved and survived demographically.

Prof. Maris Laan underlined the potential practical value of molecular diagnostics from this research, as early identification of the genetic reason for male spermatogenic deficiency could allow more targeted clinical management of infertile couples. “While deletions in the region of the Y chromosome studied were previously known to interfere with sperm production, we now know that deletion of DNA sequences results in a genetic predisposition to infertility depending on the Y chromosome lineage.” , she added.

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