Y Chromosome Genes That Impact Sperm Development and Fertility Uncovered in Mice

Researchers at the Francis Crick Institute studying male mice engineered with different Y chromosome deletions have uncovered which genes on the mouse Y chromosome regulate the development of sperm and impact fertility. Their results could help scientists better understand why some men don’t produce enough sperm and are infertile.

Jeremie Subrini, PhD, a postdoctoral research assistant in the Sex Chromosome Biology Laboratory at the Crick, said, “Our research has shown that more Y genes are required for mouse fertility than first thought. We saw that some genes are crucial, but others have a cumulative effect.”

Some Y genes are also active in other organs, and the team suggested that their study may provide a resource for further investigating Y gene function in other tissues. Subrini added, “Historically, the Y chromosome has been misunderstood. For a long time, it wasn’t thought to be essential in adults, and some even hypothesized that it was going to disappear altogether. We now know that this is clearly not the case!”

Subrini is first author of the team’s published paper in Science, titled “Systematic identification of Y-chromosome gene functions in mouse spermatogenesis,” in which the investigators commented, “We demonstrated that more Y genes are required for normal murine spermatogenesis than previously known, and they function in more spermatogenic processes than previously thought.”

Males typically have one copy of the Y chromosome and one copy of the X chromosome, whereas females typically have two X chromosomes. Scientists know that the Y chromosome is essential for male fertility, but which genes are the most important and how they work is less clear. “… our understanding of the specific Y genes necessary for spermatogenesis and their precise roles remains incomplete,” the authors noted. “The functions of only a few genes have been identified.”

For their newly reported research the Crick team aimed to resolve this question by generating thirteen different knockout (KO) mouse models, each with different Y genes removed, some as single gene deletions, and others with multiple genes deleted. “The multigene KOs also allowed us to interrogate combinatorial effects of Y-gene loss on spermatogenesis,” they wrote. The scientists then investigated the engineered animals’ fertility, studying the ability of the adult knockout mice to reproduce when mated with normal females. They considered multiple factors, not just whether the males with particular Y gene deletions could produce offspring.

“Ability to reproduce does not necessarily mean that spermatogenesis is normal,” the scientists pointed out. “We therefore developed a phenotyping pipeline to exhaustively characterize the reproductive fitness of individual Y deletants. We assayed litter sizes, offspring sex ratios, testis weights and histology, sperm counts, sperm head morphology, sperm motility, and in vitro fertilization (IVF) success rates.”

Their results indicated that several Y genes were critical for reproduction. If these genes were removed, the mice couldn’t produce young, due to the absence or reduced number of sperm, failure to produce a reservoir of sperm stem cells, or abnormal sperm shape or movement.

Interestingly, some other genes had no impact when removed individually, but did lead to the production of abnormal sperm when removed together. This was the case for the mouse model of the azoospermia factor a (AZFa) deletion, which encompasses three genes. In men AZFa deletion is a cause of the most severe cases of infertility, characterized by a complete absence of germ cells, but it has been hard to tell which genes in the region are responsible. “We used this model to understand the etiology of AZFa-related infertility and to examine functional divergence of the Y chromosome in mice and men,” the authors stated.

The collective study results suggest that many Y genes play a role in fertility and can compensate for each other if one gene is lost. This also means that some cases of infertility likely result from multiple genes being deleted at the same time.

Senior author James Turner, PhD, principal group leader of the Sex Chromosome Biology Laboratory at the Crick, commented, “Infertility is a big problem, with 1 in 6 couples struggling to conceive. In a significant proportion of cases, genetic factors, particularly those involving the Y chromosome, are the cause. However, the details have been difficult to pinpoint, partly because sequencing and studying the Y chromosome has been technically challenging.” Turner further commented that having now shed light on the Y genes, it will be important to start sequencing the Y chromosome in more individuals, to potentially uncover unexplained causes of male infertility. “With more research, we may be able to one day replace missing genes in the cells that make sperm to help couples have children through IVF.”

As well as regulating sperm production, some Y genes are active in organs such as the heart and the brain, where they may be very important. Also, some men can, as they age, lose their Y chromosomes in blood due to errors in cell division. This loss is associated with conditions like Alzheimer’s disease or cancer, so the lab is now aiming to understand what happens in other organs in the mice with Y gene deletions.

“Some Y genes are also expressed outside of the testis, and potential roles in nonreproductive organs may contribute to their evolutionary survival,” the researchers stated. “A rapidly increasing volume of research supports this notion, linking Y chromosome loss to aging and a wide range of conditions including cancer and heart disease. Our Y-deletant mouse models present a valuable resource with which to unravel these phenotypes at the single-gene level.”