Jenny Graves, Distinguished Professor of Genetics and Vice Chancellor's Fellow, La Trobe University
Men tend to lose the Y chromosome from their cells as they age. But because the Y bears few genes other than for male determination, it was thought this loss would not affect health.
But evidence has mounted over the past few years that when people who have a Y chromosome lose it, the loss is associated with serious diseases throughout the body, contributing to a shorter lifespan.
Loss of the Y in older men
New techniques to detect Y chromosome genes show frequent loss of the Y in tissues of older men. The increase with age is clear: 40% of 60-year-old men show loss of Y, but 57% of 90-year-olds. Environmental factors such as smoking and exposure to carcinogens also play a role.
Loss of Y occurs only in some cells, and their descendants never get it back. This creates a mosaic of cells with and without a Y in the body. Y-less cells grow faster than normal cells in culture, suggesting they may have an advantage in the body – and in tumours.
The Y chromosome is particularly prone to mistakes during cell division – it can be left behind in a little bag of membrane that gets lost. So we would expect that tissues with rapidly dividing cells would suffer more from loss of Y.
Why should loss of the gene-poor Y matter?
The human Y is an odd little chromosome, bearing only 51 protein-coding genes (not counting multiple copies), compared with the thousands on other chromosomes. It plays crucial roles in sex determination and sperm function, but was not thought to do much else.
The Y chromosome is frequently lost when cells are cultured in the lab. It is the only chromosome that can be lost without killing the cell. This suggests no specific functions encoded by Y genes are necessary for cellular growth and function.
Indeed, males of some marsupial species jettison the Y chromosome early in their development, and evolution seems to be rapidly dispensing with it. In mammals, the Y has been degrading for 150 million years and has already been lost and replaced in some rodents.
So the loss of Y in body tissue late in life should surely not be a drama.
Association of loss of Y with health problems
Despite its apparent uselessness to most cells in the body, evidence is accumulating that loss of Y is associated with severe health conditions, including cardiovascular and neurodegenerative diseases and cancer.
Loss of Y frequency in kidney cells is associated with kidney disease.
Several studies now show a relationship between loss of Y and cardiac disease. For instance, a very large German study found men over 60 with high frequencies of loss of Y had an increased risk of heart attacks.
Loss of Y has also been linked to death from COVID, which might explain the sex difference in mortality. A tenfold higher frequency of loss of Y has been found in Alzheimer’s disease patients.
Several studies have documented associations of loss of Y with various cancers in men. It is also associated with a poorer outcome for those who do have cancer. Loss of Y is common in cancer cells themselves, among other chromosome anomalies.
Does loss of Y cause disease and mortality in older men?
Figuring out what causes the links between loss of Y and health problems is difficult. They might occur because health problems cause loss of Y, or perhaps a third factor might cause both.
Even strong associations can’t prove causation. The association with kidney or heart disease could result from rapid cell division during organ repair, for instance.
Cancer associations might reflect a genetic predisposition for genome instability. Indeed, whole genome association studies show loss of Y frequency is about one-third genetic, involving 150 identified genes largely involved in cell cycle regulation and cancer susceptibility.
However, one mouse study points to a direct effect. Researchers transplanted Y-deficient blood cells into irradiated mice, which then displayed increased frequencies of age-related pathologies including poorer cardiac function and subsequent heart failure.
Similarly, loss of Y from cancer cells seems to affect cell growth and malignancy directly, possibly driving eye melanoma, which is more frequent in men.
Role of the Y in body cells
The clinical effects of loss of Y suggest the Y chromosome has important functions in body cells. But given how few genes it hosts, how?
The male-determining SRY gene found on the Y is expressed widely in the body. But the only effect ascribed to its activity in the brain is complicity in causing Parkinson’s disease. And four genes essential for making sperm are active only in the testis.
But among the other 46 genes on the Y, several are widely expressed and have essential functions in gene activity and regulation. Several are known cancer suppressors.
These genes all have copies on the X chromosome, so both males and females have two copies. It may be that the absence of a second copy in Y-less cells causes some kind of dysregulation.
As well as these protein-coding genes, the Y contains many non-coding genes. These are transcribed into RNA molecules, but never translated into proteins. At least some of these non-coding genes seem to control the function of other genes.
This might explain why the Y chromosome can affect the activity of genes on many other chromosomes. Loss of Y affects expression of some genes in the cells that make blood cells, as well as others that regulate immune function. It may also indirectly affect differentiation of blood cell types and heart function.
The DNA of the human Y was only fully sequenced a couple of years ago – so in time we may track down how particular genes cause these negative health effects.
Jenny Graves receives funding from The Australian Research Council.
