This type of Y chromosome loss is called mLOY (mosaic Loss Of Y). Mosaic refers to a mix of chromosomally different cells, with some being 46,XY and others being 45,X,-Y.
Chromosomally normal males have 46 chromosomes, with two of them being sex chromosomes, an X and a Y (46, XY), and as men age, they can lose some of those chromosomes. A new study published in Science found that the loss of Y chromosomes in white blood cells is associated with an increased risk of dying from heart disease.
This type of Y chromosome loss is called mLOY (mosaic Loss Of Y). Mosaic refers to a mix of chromosomally different cells, with some being 46, XY and others being 45, X,-Y.
The Y chromosome is the smallest of the chromosomes and contains very few genes. However, as the authors note, “its functions are not fully understood. It has been observed, however, that mosaic loss of the Y chromosome in blood cells frequently occurs with age, and this alteration is associated with various medical conditions.”
In studies in mice, cells that lacked the Y chromosome are more likely to develop fibrosis (scarring) and decreased cardiac function. However, they benefited from treatment with a transforming growth factor beta 1-neutralizing antibody. In this study, working with male mice who were reconstituted with bone marrow cells lacking the Y chromosome, they found they had increased mortality and age-related profibrotic symptoms, including decreased cardiac function.
Cardiac macrophages, a type of immune cell, that did not have Y chromosomes, tended toward more fibrosis. But treatment with a transforming growth factor beta 1-neutralizing antibody improved cardiac function in mLOY mice.
They don’t know if the mLOY in the white blood cells has a direct effect on disease progression in other organs.
“The DNA of all our cells inevitably accumulate mutations as we age,” Kenneth Walsh, Ph.D., co-author of the study, said. Walsh is a researcher at the University of Virginia. The study was conducted with researchers from Uppsala University in Sweden. “This includes the loss of the entire Y chromosome within a subset of cells within men. Understanding that the body is a mosaic of acquired mutations provides clues about age-related diseases and the aging process itself.”
The researcher leveraged CRISPR-Cas9 gene editing to create mouse models with mLOY in their white blood cells. The mLOY directly damaged the mice’s internal organs. Mice with mLOY did not survive as long as those without mLOY.
Lars Forsberg, Ph.D., co-author of the study at Uppsala, stated, “In the mouse models used in the study, the mouse Y chromosome was eliminated to mimic the human mLOY condition and we analysed the direct consequences that this had. Examination of mice with mLOY showed an increased scarring of the heart, known as fibrosis. We see that mLOY causes the fibrosis which leads to a decline in heart function.”
The study analyzed data from the U.K. Biobank of 500,000 normally aging people between 40 and 70 years of age at the beginning of the study. Men with mLOY in their blood at the beginning of the study had a 30% increased risk of dying from heart failure and other types of cardiovascular disease during 11 years of follow-up.
Forsberg said, “We also see that men with a higher proportion of white blood cells with mLOY in the blood have a greater risk of dying from cardiovascular disease. This observation is in line with the results from the mouse model and suggests that mLOY has a direct physiological effect also in humans.”
He went on to note, “The link between mLOY and fibrosis is very interesting, especially given the new treatment strategies for heart failure, pulmonary fibrosis and certain cancers that aim to counteract the onset of fibrosis. Men with mLOY could be a patient group that responds particularly well to such treatment.”
