Men Lose Y Chromosomes With Age

Mutations spontaneously appear in humans all the time; each cell division produces errors as small as a miscopy of one letter or as large as gaining/losing an entire chromosome. Over a lifetime this can lead to clonal mosaicism in which the body is a mosaic of distinct populations of cells each with their accumulated mutations; this is true to some extent for everyone, but it becomes more relevant with age. 

“The more you age, the more errors have taken place in cell division,” says John R. B. Perry, a biologist at the University of Cambridge who led the recent study.

In blood the loss of the Y chromosome in some cells is called mosaicism, another example is in women when some blood cells lose one X chromosome. Other blood cells might gain a mutation on just one gene or gain an entire chromosome. 

To better understand why the Y chromosome disappears in some men but not others the research team investigated whether certain genetic variants on other chromosomes predisposed men in one way or another; many are near cancer susceptibility genes and having the same variants was correlated with an increased risk of prostate and testicular cancer in men, as well as kidney, glioma, and other cancers in both genders. 

Findings suggest that losing a Y chromosome is not the main cause of bad health outcomes correlated with the loss as women never had a Y chromosome, rather the same genetic variants that predispose a person to Y chromosome loss may be also what is putting that person at risk for cancer. Both outcomes may have a common cause as both are rooted in DNA errors, and cancer is the result of many accumulated mutations that allow a cell to replicate out of control. Y chromosome loss is just one mutation, both could be the result of a glitch in the normal process of responding to and repairing DNA damage. 

“That was, I think, the really interesting part,” says Siddhartha Jaiswal, a pathologist at Stanford who studies blood. “Y-chromosome loss is a manifestation of broader genome instability,” he says. In other words, the disappearing Y chromosome is a sign the body is allowing DNA errors to accumulate.

The Y chromosome loss may be more frequent because it is one of the smallest and possibly most dispensable, and most likely because it carries relatively few genes, meaning that it’s loss would be more tolerated than others, according to David Steensma, an oncologist at Dana-Farber Cancer Institute, who also suggests that the fact it is so common may confer some small advantage to the cells that have lost it. 

Research indicates that men are missing the Y chromosome in as may as 87% of their blood cells; possible advantage may be the lower energetic cost of dividing one fewer chromosome or it may be halting a growth suppressing gene on the Y. Whatever the case may be the loss matters because blood cells are all in competition with each other for resources, a small mutation such as this confers a small advantage that will allow cells with it to win out. According to Perry the formation of human blood cells is “a perfect example of evolution on a microscale.”

Researchers have begun to gain more detailed understandings of different sublets of blood cells with the human body. “What changed the story was the technological capacity to look at the whole genome,” says Lambert Busque, a blood cancer biologist at Hôpital Maisonneuve-Rosemont. When doctors began counting chromosomes decades ago in individual blood cells they discovered the loss of Y chromosomes, today scientists can analyze all of the genes in blood from thousands of patients and see that blood cells are far from being identical inside a single individual.