The Y chromosome is emerging as a major player in male health, far beyond its reproductive role. Could the Y hold the key to ageing, disease and even longevity?
Two researchers in the Sex Chromosome lab at the Crick. Credit: Dave Guttridge.
For Crick geneticist James Turner, when it comes to the Y chromosome, sex is only the beginning of the story.
Both sex chromosomes – the Y chromosome and its partner X – originally evolved from a pair of autosomes – the name for the other 22 pairs of chromosomes. Then, over the course of evolution, the Y lost almost all of its genes, meaning it carries just 2% of DNA in a male cell.
Given that the gene for testis development sits on the Y chromosome, research has mainly focused on its coordination of sex determination.
However, much less is known about the roles of other genes on the Y chromosome. “Given the Y has shrunk over the course of human evolution, one explanation for why these genes survived is that maybe they’re doing something important elsewhere in the body,” says James.
To better understand the Y chromosome, James, along with then-PhD student Jeremie Subrini, initially focused on fertility, investigating the role each gene on the Y chromosome plays in male mice. They used genetic editing to essentially ‘knock out’ the Y chromosome’s genes one at a time, creating several genetically different groups of mice.
The researchers then looked at how the mice’s ability to reproduce was affected when a given Y gene was knocked out, including effects on testes such as reduced sperm count, sperm appearance and function, and number of pups produced.
Their findings showed that some of these genes were indeed critical for reproduction, including aspects like testes function and sperm production, as knocking them out caused infertility or reduced fertility.
But many of these genes simply had no impact on mice’s ability to reproduce. “We could finally demonstrate that if you knock out some genes on the Y, testes aren’t affected,” says James.
Every cell in the body, from the heart to the brain to the lungs, contains sex chromosomes too. And as men age, researchers have spotted an unexpected phenomenon: these cells can start to lose their Y chromosomes.
“We’ve known about this for a while – during blood collections, we can see some men’s blood cells are missing the Y chromosome – but we didn’t really think it mattered. After all, it’s needed for male reproduction; why would the Y be important for blood cells?” muses James. “But over the last five years or so, a flurry of research has linked Y-loss with dementia, cancer and heart disease. Sadly, it looks like men losing their Ys are more likely to die younger.”
It’s both a problem and an opportunity. If scientists can work out what the Y genes are doing in other cells in the body, can they see a pattern? Could these lost genes ever be replaced by genetic editing or could the consequences of losing a Y gene be targeted?
That’s the idea for James. “The ultimate goal would be to identify a gene which, if lost, increases the risk of dementia, for example,” he says. “Then we can work out why and how the loss of this gene causes dementia. And then give someone a drug which could stop that happening.”
He’s now kick-started the process by re-investigating the same genetically engineered strains of mice. This time, instead of looking at reproduction, the team are giving the mice a full-body MOT, investigating what happens in their heart, lungs, immune system, brain, and so on, when each Y gene is knocked out.
And what about the X chromosome? “The Y genes have ‘partner’ genes on the X chromosome,” says James. “So, loss of a second X likely poses similar risks to women as loss of a Y poses to men.
“But there’s so much to investigate. A recent study by scientists in the US showed that some genes on the second X can be switched on rather than deactivated with age, and that this could protect brain health.”
James’s journey is a classic example of scientific serendipity. James and his team were investigating the Y’s role in fertility long before research groups looking at cancer and other diseases became interested in the punch this tiny chromosome packs.
“We’ve successfully outlined the role of genes on the Y in mouse fertility, and this is critical information, given one in six couples struggle to conceive,” says James. “But it has also sparked interest in a new horizon of sex chromosome research: the role these genes play throughout the body and their impact on our health.”
Science from inside the Crick.
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