Key Y Chromosome Genes Linked To Male Fertility Identified

Researchers at the Francis Crick Institute have identified key genes on the Y chromosome that control sperm development and affect male fertility in mice. The findings could improve understanding of why some men produce too few sperm and are infertile.

In most cases, males have one X and one Y chromosome, while females have two X chromosomes. Scientists have long known that the Y chromosome is vital for male fertility. However, they haven’t been sure which specific genes matter most or how they function.

In a study published in Science, the Crick team created 13 different strains of male mice. Each strain had different Y chromosome genes removed. The researchers then studied the fertility of these mice by looking at how many offspring they had, how much sperm they produced, and how the sperm looked and moved.

They discovered that certain Y-linked genes are essential for reproduction. When these genes were missing, the mice could not father offspring. This was due to a lack or low number of sperm, absence of sperm stem cells, or sperm that had abnormal shape or poor movement.

Some genes, when deleted on their own, had no clear effect. But when removed together, they caused defects in sperm. This was especially true for three genes that match a region of the human Y chromosome known as AZFa. Deletions in this area are a common cause of severe male infertility, but it has been unclear which specific genes were to blame.

The study suggests that multiple Y genes contribute to fertility. Often, these genes can back each other up if one is missing. But when several are lost at the same time, infertility can occur.

The researchers also found that some Y-linked genes are active in other parts of the body, such as the brain and heart. In aging men, Y chromosome loss in blood cells is linked to conditions like Alzheimer’s disease and cancer. The team now plans to study how Y gene deletions affect these other organs in mice.

James Turner, senior author and head of the Sex Chromosome Biology Lab at the Crick, said, “Infertility is a major issue, affecting 1 in 6 couples. Many cases are due to genetic causes, often involving the Y chromosome. But it’s been difficult to study, partly because the Y chromosome is technically challenging to sequence.”

He added, “Now that we better understand the role of Y genes, the next step is to sequence the Y chromosome in more people. This could help explain some cases of unexplained infertility. In the future, it might even be possible to replace missing genes in sperm-producing cells to help couples conceive using IVF.”