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Mosaic loss of Y chromosome leads to increased mortality in aging men

New research using CRISPR-Cas9 has shed light on the condition of mosaic loss of Y chromosome, a previously unexplained risk factor for age-related cardiovascular disease in men.

A study, published in Science, determined how mosaic loss of Y chromosome triggered tissue damage that led to heart failure in mice and could be linked to cardiovascular dysfunction and associated mortality.

Researchers from the University of Virginia School of Medicine mimicked the human condition in mice and utilised data from the UK Biobank to capture genetic and health information. They also identified a neutralizing antibody could reverse some cardiac impacts caused by the condition.

Mosaic loss of Y chromosome

Although the Y chromosome is the smallest and contains few genes, its functions are not fully understood. The authors commented that the Y chromosome has previously been considered a “genetic wasteland.”

Mosaic loss of Y chromosome (mLOY) is a condition that frequently arises in ageing men, occurring in roughly 40 percent of men aged over 70. In the condition, an increasing number of hematopoietic cells display a loss of the Y chromosome and mLOY is associated with increased risk of mortality and age-related diseases. In human somatic cells, mLOY is the most commonly acquired mutation in the male’s genome. When mutations occur in somatic stem cells, the mutation “spreads” in a mosaic manner, appearing in the progeny of mutated stem cells but not in cells from non-mutated stem cells. 

“mLOY is a major risk factor for heart failure and cardiac fibrosis in men growing older,” the authors reported. “However, a relationship between mLOY and pathogenesis has not yet been established.”

Mouse model confirms mLOY increases mortality

Using CRISPR-Cas9, the team developed a mouse model of hematopoietic mLOY by reconstituting their bone marrow with cells lacking the Y chromosome. They then discovered that these mice displayed increased mortality and were more prone to age-related cardiac fibrosis and decreased cardiac function.

According to the findings, bone marrow-derived mLOY macrophages that infiltrated the heart triggered high transforming growth factor β1 (TGF-β1) activity. This then led to fibroblast proliferation and accelerated cardiac tissue fibrosis.

The study also revealed that a TGF-β1 neutralizing antibody could reverse some cardiac impacts caused by mLOY.

Prospective human study

The team also used prospective data from the UK Biobank. An analysis of human patients showed that those with mLOY in their blood were also at a greater risk for cardiovascular dysfunction and associated mortality. This suggests the mouse study findings have clinical relevance.

“Indeed, several unexpected links between the Y chromosome, immune system, and complex polygenic traits have been discovered, suggesting an influence of the Y chromosome on immune and inflammatory responses in men,” wrote Andreas Zeiher and Thomas Braun in a related Perspective.

The research uncovered functionality of the Y chromosome in maintaining a healthy innate immune system, but further research is required to clarify the mechanisms.

While a potential therapy to counteract losing the Y chromosome in blood cells may not be imminent, men with mLOY could be a patient group that responds particularly well to such treatment.

Written by Poppy Jayne Morgan, Front Line Genomics

Image Credit: Canva