© BSIP/UNIVERSAL IMAGES GROUP VIA GETTY IMAGESA set of human chromosomes, with a pair of XY and XX chromosomes in the bottom right.
Now a new study — the largest yet of this phenomenon — estimates that 20 percent of 205,011 men in a large genetic database called the UK Biobank have lost Y chromosomes from some detectable proportion of their blood. By age 70, 43.6 percent of men had the same issue. It's unclear exactly why, but the authors think these losses might be the most glaring sign of something else going wrong inside the bodies of these men: They are allowing mutations of all kinds to accumulate, and these other mutations could be the underlying links to cancer and heart disease.
Mutations are, after all, spontaneously popping up in the human body all the time. Every cell division produces errors as small as miscopying one letter or as large as losing an entire chromosome. So over a lifetime, this can lead to what scientists call "clonal mosaicism" — in which a person's body is a mosaic of distinct populations of cells, each with their accumulated mutations. This is true of everyone to some extent, but it becomes more relevant as you get older. "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, loss of the Y chromosome in some cells is the most commonly observed mosaicism, but there are countless other examples. In women, some blood cells lose one X chromosome. Other subsets of blood cells might gain a mutation in just one gene, lose only a small bit of a chromosome, or even gain an entire chromosome. (Red blood cells don't carry DNA at all, so this applies only to white blood cells.)
Perry and his colleagues also wanted to understand why the Y chromosome disappears in some men but not others. They looked into whether certain genetic variants on other chromosomes predisposed men one way or another, and they ended up finding 156 variants linked to Y-chromosome loss. Many are also near cancer-susceptibility genes, and having these same variants was correlated with higher risk of prostate and testicular cancer in men — as well as glioma, kidney, and other cancers in both men and women.
"That was, I think, the really interesting part," says Siddhartha Jaiswal, a pathologist at Stanford who studies blood. It suggests that losing a Y chromosome is probably not the ultimate cause of bad health outcomes correlated with it, because the women never had a Y chromosome to lose. Rather, the same genetic variants that predispose someone to Y-chromosome loss might be also putting that person at risk for cancer. The two outcomes could have a common cause, because both are rooted in errors in DNA. Cancer is the result of many accumulated mutations that allow a cell to replicate out of control. Y-chromosome loss is one big glaring mutation. Perry suggests both could be the result of some hitch in the normal process of responding to and repairing DNA damage."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.
But why is the Y chromosome lost more frequently than others? It is the smallest chromosome and possibly the most dispensable. "Probably because it carries relatively few genes, its loss is tolerated better than others," says David Steensma, an oncologist at Dana-Farber Cancer Institute. But the fact that Y-chromosome loss is so common, he says, also suggests it might confer some small advantage to the cells that have lost it. Researchers have found men who are missing the Y chromosome in as many as 87 percent of cells in their blood.
Perry says that advantage might be a lower energetic cost of dividing with one fewer chromosome, or it could be nixing a growth-suppressing gene on the Y. In any case, this matters because the blood cells in your body are all in a vast competition with one another for resources. A mutation that confers a small advantage will allow cells with it to win out. In fact, Perry says, the formation of human blood cells is "a perfect example of evolution on a microscale."
In recent years, researchers have started gaining a much more detailed understanding of the different subsets of blood cells all living inside one person. "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. Fifty years ago, doctors painstakingly counting chromosomes in individual blood cells noticed the loss of Y chromosomes. Today, scientists are able to analyze all of the genes in blood from thousands of people — and see that blood cells are far from identical inside a single person.
I, instead, as 'Y"?
R.C.
Being silly.
RC