1. Evolutionary Biology
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Structural genetic change may increase risk of male fertility

A flipped section of the Y chromosome may put men at risk of infertility, especially as they age – a finding that may help at-risk individuals take steps to preserve their fertility.
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Men who carry a Y chromosome where a section has flipped may be at risk of genetic mutations that lead to infertility, shows a study published today in eLife.

The findings suggest that identifying men at risk of infertility because of this genetic alteration early in life may allow them to take steps to prevent this condition.

Around 10% of men globally experience difficulty conceiving a child because of low sperm counts. A few genetic causes of male infertility have been identified, but many cases remain unexplained which can make treating the condition more difficult.

“Our study aimed to determine the role of certain genetic deletions on the Y chromosome in reducing sperm counts, and see whether this information could be used to develop new male infertility management strategies,” says first author Pille Hallast, Senior Staff Scientist at the Institute of Biomedicine and Translational Medicine, University of Tartu, Estonia, and the Wellcome Sanger Institute, Hinxton, UK.

Hallast and colleagues investigated a region of the Y chromosome that has previously been linked to sperm production in 1,190 Estonian men with unexplained low sperm counts causing infertility and 1,134 Estonian men, the majority of whom had normal sperm counts. They found that the men with infertility were more likely to have deletions in a particular stretch of the Y chromosome. These genetic alterations likely caused low sperm counts because they affected genes that are important to sperm production.

The team also found that these deletions were more common in men who carry a specific Y-chromosome subtype with a flipped (or inverted) genomic section. More than 20% of men in several European populations carry a Y chromosome with this inversion. While the inversion itself has no direct effect on fertility, the study suggests the risk of low sperm counts in these men with inversion and subsequent deletion is almost nine times higher than those with a normal Y chromosome. “This inversion disrupts the structural integrity of the Y chromosome, which may make it more susceptible to recurrent deletions that severely impair sperm production,” Hallast explains.

Chris Tyler-Smith, co-senior author and Former Senior Group Leader at the Wellcome Sanger Institute, adds: “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 toxic combination of genetics and environment?”

Why this inversion remains common in European men despite its potentially harmful effects on fertility is an important question. But a surprising finding in the study may suggest an explanation. One 18-year-old participant who had normal sperm production had both the inversion and a harmful deletion, which may suggest that these genetic changes may not harm fertility until later in life. As a result, these genetic differences may have been less harmful when it was more common for men to have children earlier in life.

“More studies are needed to confirm our finding, but if this is true, it may suggest a new approach to preserving fertility for men with these potentially harmful genetic changes,” says co-senior author Maris Laan, Professor of Human Genetics at the Institute of Biomedicine and Translational Medicine, University of Tartu. “Identifying those who have this Y chromosome inversion and deletion early in life would allow them to store sperm to ensure a better chance of having children later on.”

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