People normally have one pair of sex chromosomes in each cell, females have two X chromosomes while men have one X and one Y chromosome. The Y chromosome spans over 59 million building blocks of DNA and represents almost 2% of the total DNA in cells. Many genes are unique to the Y chromosome which likely contains 70 to 200 genes that provide instruction for making proteins.
Throughout their lifespan men progressively lose the Y chromosomes, and this loss can be detected in 40% of 70-year-old men. In 2022, Kenneth Walsh, Ph.D., discovered that this loss can contribute to heart muscle scarring and lead to deadly heart failure, and the loss is increasingly thought to play a role in diseases ranging from cancer to Alzheimer’s disease.
More recently in follow up research he and his team at UVA discover how Y chromosome loss triggers changes in heart immune cells that make cells more likely to cause scarring and heart failure. According to the team they also found that they could reverse the harmful changes by giving mice a drug that targets the fibrosis process that leads to heart scarring which could lead to a treatment for humans.
“Our previous work identified that it was loss of the entire Y chromosome that contributed to heart disease in men,” said Walsh, the director of UVA’s Hematovascular Biology Center. “This new work identified a single gene on the Y chromosome that can account for the disease-promoting effects of Y chromosome loss.”
This groundbreaking research suggests an explanation for why heart failure is more common in men than women. Y chromosome loss only occurs in a small percentage of men’s cells, resulting in what is called “mosaicism”, which is where genetically different cells occur within one individual. While it isn’t entirely clear why this loss occurs, it predominantly affects elderly men and men who smoke compared to those who don’t smoke.
Genes found on the Y chromosome were examined to determine which may be more important to heart scarring, and they identified a gene called Uty which helps to control operating instructions for macrophages and monocytes immune cells. According to the team, when Uty was disrupted, it triggered changes in the immune cells such as the macrophages becoming much more pro-fibrotic or prone to scarring which also accelerated heart failure.
Giving the mice a specially designed monoclonal antibody was found to protect the macrophages from the harmful changes and suggests an approach to treat and/or avoid heart failure and other fibrotic disease in men with Y chromosome loss. The team believe that a small group of genes found on the Y chromosome may have effects on a wide range of diseases, and this new work identifies mechanisms that may lead to this, making them hopeful that future research will provide better understanding for unknown causes of sickness and death among men.
“The identification of a single gene on the Y chromosome provides information about a new druggable target to treat fibrotic diseases,” said Walsh, of UVA’s Division of Cardiovascular Medicine and Robert M. Berne Cardiovascular Research Center.
“Currently, we are working with our clinician colleagues in the Division of Cardiovascular Medicine at UVA to assess whether loss of the Y chromosome in men is associated with greater scarring in the heart,” Walsh said. “This research will provide new avenues for understanding the causes of heart disease.”
“This research further documents the utility of studying the genetics of mutations that are acquired after conception and accumulate throughout life,” Walsh said. “These mutations appear to be as important to health and lifespan as the mutations that are inherited from one’s parents. The study of these age-acquired mutations represents a new field of human genetics.”
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