The Y chromosome that determines the male gender in newborns is slowly degrading and its loss endangers the health of elderly men, new studies confirm.
Males have an X and a Y chromosome (XY) while females have two Xs (XX). The human X and Y chromosomes evolved from a pair of autosomes approximately 180 million years ago.
Despite their shared evolutionary origin, extensive genetic decay has resulted in the human Y chromosome losing 97 percent of its ancestral genes while gene content and order remain highly conserved on the X chromosome.
Men’s sex chromosomes were originally a pair of typical XY chromosomes, a trait still observed in birds, reptiles, and monotreme mammals (platypuses and echidnas).
Within the last 166 million years, the human Y chromosome has lost most of its 1,600 genes at a rate of nearly 10 per million years. According to scientists, it is normal for sex chromosomes to break down over time.
The human male chromosome has lost its ability to recombine with its once homologous partner, the X chromosome. As a result, the majority of the Y chromosome’s gene content is being inherited as a unit, known as the human MSY, the male-specific region of the Y chromosome.
Based on the rate of the Y chromosome depletion, the male chromosome is estimated to disappear completely in a few million years, more specifically in about 4.5 million.
Loss of Y chromosome dangerous to old men’s hearts
Other than the evolutionary slow decrease of the male chromosome, many men over 70 lose the male chromosome, which may lead to serious health problems, even death.
The loss of the Y chromosome for many aging men can cause the heart muscle to scar and can lead to deadly heart failure, new research from the University of Virginia School of Medicine shows.
This finding may help explain why on average men die several years younger than women. According to UVA researcher Kenneth Walsh, PhD, the new discovery suggests that an estimated 40 percent of 70-year-old men who suffer Y chromosome loss may particularly benefit from an existing drug that targets dangerous tissue scarring.
Walsh suspects that the drug may help counteract the harmful effects of the chromosome loss, not only in the heart but in other parts of the body as well.
Many men begin to lose the chromosome in a fraction of their cells as they age. This appears to be especially true for smokers. The loss occurs predominantly in blood cells. Previous research has indicated that men who suffer Y chromosome loss are more likely to die at a younger age and suffer age-associated maladies such as Alzheimer’s disease.
Walsh’s new research, however, is believed to be the first hard evidence that the Y chromosome loss directly causes harmful effects on men’s health.
Walsh of UVA’s Division of Cardiovascular Medicine and Robert M. Berne Cardiovascular Research Center, and his team used cutting-edge CRISPR gene-editing technology to develop a special mouse model to better understand the effects of Y chromosome loss in the blood. They found that the loss accelerated age-related diseases, made the mice more prone to heart scarring and led to earlier death.
The researchers found that the mice suffered a complex series of responses in the immune system, leading to a process called fibrosis throughout the body. The researchers believe that fibrosis may accelerate disease development.
The scientists also looked at the effects of Y chromosome loss in men. They conducted three analyses of data compiled from the UK Biobank, a massive biomedical database, and found that Y chromosome loss was associated with cardiovascular disease and heart failure. They found that the increase in chromosome loss also increased the risk of death.
Male chromosome loss brings risk of cancer
The Y chromosome loss in aging men hampers the body’s ability to fight cancer as it helps cancer cells evade the body’s immune system, new research from Cedars-Sinai Cancer shows.
Based on their research, investigators are developing a test for loss of the male chromosome in tumors with the goal of helping clinicians tailor immune checkpoint inhibitor treatment for male patients with bladder cancer.
Dan Theodorescu, MD, PhD, director of Cedars-Sinai Cancer, Chair and corresponding author of the publication, who initiated the research said that, “the loss of the Y chromosome allows bladder cancer cells to elude the immune system and grow very aggressively.”
In men, loss of their gender chromosome has been observed in several cancer types, including 10-40 percent of bladder cancers. Loss of the Y chromosome also has been associated with heart disease and Alzheimer’s disease, as other studies show.
The Y chromosome contains the blueprints for certain genes. Based on the way these genes are expressed in normal cells in the bladder lining, researchers developed a scoring system to measure loss of the Y chromosome in cancers.
Then they reviewed data on two groups of men. One group had muscle invasive bladder cancer and had their bladders removed, but were not treated with an immune checkpoint inhibitor. The other group participated in a clinical trial and were treated with an immune checkpoint inhibitor. The results showed that patients with loss of the Y chromosome had poorer prognosis in the first group and much better overall survival rates in the latter.
The researchers then compared growth rates of bladder cancer cells from laboratory mice. They grew cancer cells in a dish where the cells were not exposed to immune cells. The researchers also grew the diseased cells in mice that were missing a type of immune cell called T-cells. In both cases, tumors with and without the Y chromosome grew at the same rate.
In mice with intact immune systems, tumors lacking the chromosome grew at a much faster rate than did tumors with the intact Y chromosome.
According to Dr, Theodorescu, when cells lose the Y chromosome, they exhaust T-cells. And without T-cells to fight the cancer, the tumor grows aggressively.
