As men grow older, they often experience a gradual loss of the Y chromosome from some of their cells. Although the Y chromosome has few genes, its loss has been increasingly linked to serious diseases and shorter lifespan.
New methods for detecting Y chromosome genes have revealed that Y loss is common in the tissues of older men and becomes more frequent with age. Studies indicate that about 40% of men at age 60 show some Y chromosome loss, rising to around 57% among those aged 90. Factors such as smoking and exposure to cancer-causing substances may further increase the risk.
Y chromosome loss occurs in only a portion of cells, and once lost, it is not restored in their descendants. This results in a mosaic of cells, some carrying the Y chromosome and others lacking it. Laboratory studies suggest that Y-deficient cells may grow faster than normal cells, potentially giving them an advantage in tissues and tumors.
Why the Y Chromosome Is Prone to Loss During Cell Division
The Y chromosome is also especially vulnerable to errors during cell division. It can sometimes be left behind in a small membrane-bound structure that is eventually discarded. As a result, tissues containing rapidly dividing cells may be more likely to experience Y chromosome loss.
The human Y chromosome contains just 51 protein-coding genes and, while crucial for sex determination and sperm production, was once thought to have few other functions.
The Y chromosome is also commonly lost when cells are grown in laboratory conditions. Remarkably, it is the only chromosome that cells can lose without necessarily dying. This has suggested that the genes carried on the Y chromosome may not be essential for basic cell growth and survival.
Some marsupials lose the Y chromosome early, and it has been declining for 150 million years, disappearing in some rodents where other sex-determining mechanisms evolved.
Therefore, the loss of the Y chromosome from some body cells later in life might seem unlikely to cause serious problems.
Y-Chromosome Loss Linked to Kidney and Heart Disease
A higher frequency of Y-chromosome loss in kidney cells has been associated with kidney disease. Research has also increasingly linked the loss of the Y chromosome to cardiovascular problems. For example, a large German study found that men over 60 who had high levels of Y-chromosome loss faced a greater risk of heart attacks.
Y-chromosome loss has also been associated with a higher risk of death from COVID-19, potentially contributing to differences in mortality between men and women. Studies have further reported that this chromosomal loss occurs at much higher rates in people with Alzheimer’s disease.
In addition, several studies have connected Y-chromosome loss with different types of cancer in men. Among men who develop cancer, the loss of the Y chromosome has also been associated with poorer disease outcomes. This alteration is relatively common in cancer cells, alongside other abnormalities involving chromosomes.
Determining why Y-chromosome loss is associated with various health problems is challenging. These conditions could contribute to the loss of the Y chromosome, rather than being caused by it, or another underlying factor could be responsible for both.
Y-Chromosome Loss May Reflect Genetic and Cellular Factors
Even strong statistical associations do not necessarily demonstrate cause and effect. For example, Y-chromosome loss may be linked to increased cell division during organ repair. Likewise, its association with cancer may reflect an underlying genetic tendency toward genome instability. About one-third of Y-chromosome loss is influenced by genetics, involving roughly 150 genes linked to cell-cycle regulation and cancer risk.
However, research in mice provides evidence that Y-chromosome loss may have direct effects on health. In one study, scientists transplanted Y-deficient blood cells into irradiated mice. The animals subsequently developed more age-related health problems, including impaired heart function and, eventually, heart failure.
Similarly, the loss of the Y chromosome in cancer cells appears to directly influence their growth and aggressiveness. This effect may contribute to the development of eye melanoma, a cancer that occurs more frequently in men.
The health effects associated with Y-chromosome loss suggest that the chromosome has important roles in cells throughout the body. But considering that it contains relatively few genes, the question remains: how does it exert such broad effects?
The Diverse Roles of Y-Chromosome Genes in the Body
The SRY gene, which determines male sex development, is active in many tissues throughout the body. However, its activity in the brain has so far mainly been linked to Parkinson’s disease. In contrast, four Y-chromosome genes involved in sperm production are active exclusively in the testes.
Of the remaining Y-chromosome genes, several are expressed throughout the body and perform important functions in gene regulation and cellular activity. Some of these genes also act as tumor suppressors. They have counterparts on the X chromosome, meaning that males and females normally carry two copies of these genes. When cells lose the Y chromosome, the missing second copy could potentially disrupt normal gene regulation.
The Y chromosome also contains numerous non-coding genes. These genes produce RNA molecules rather than proteins, and at least some appear to influence the activity of other genes.
This could help explain why the Y chromosome can affect genes located on other chromosomes. Studies have found that Y-chromosome loss can alter the expression of genes in blood-forming cells and affect genes involved in immune responses. It may also indirectly influence how blood cells develop and how the heart functions.
The complete DNA sequence of the human Y chromosome was only determined relatively recently. As research advances, scientists may be able to identify exactly how specific Y-chromosome genes contribute to these health effects.
Read the original article on: livescience
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