Researchers at the Crick have uncovered which genes on the Y chromosome regulate the development of sperm and impact fertility in male mice. This research could help us understand why some men don't produce enough sperm and are infertile.
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.
In research published today in Science , a research team at the Crick resolved this question by generating thirteen different mouse models, each with different Y genes removed, and investigated their fertility.
The researchers studied the ability of these adult mice to reproduce, including looking at the number of offspring, number of sperm produced and the appearance and motility of the sperm.
They found that several Y genes were critical for reproduction. If these genes were removed, the mice couldn't produce young, due to 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 a group of three genes which model a region of the chromosome called AZFa in humans. AZFa deletions are a common cause of the most severe cases of male infertility, but it has been hard to tell which genes in the region are responsible.
The 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.
As well as regulating sperm generation, some Y genes are also active in other organs, like the heart and the brain, where they may be very important. Also, as they age, some men can 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.
Jeremie Subrini, Postdoctoral Research Assistant in the Sex Chromosome Biology Laboratory at the Crick, and first author, 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. Historically, the Y chromosome has been misunderstood. For a long time, it wasn't thought to be essential in adults, and some even hypothesised that it was going to disappear altogether. We now know that this is clearly not the case!"
James Turner, Principal Group Leader of the Sex Chromosome Biology Laboratory at the Crick, and senior author, said: "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.
"Now that we've 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."
Peer reviewed
Experimental study
Animals
