Loss of Y Chromosome A Cause of Earlier Death in Men?
A new study published in Science outlines how a loss of the Y chromosome as men age could have harmful effects on health and reduce lifespan. The research, led by scientists at the University of Virginia (UVA) School of Medicine, may also provide an explanation for why women typically live longer than men.
The X and Y chromosomes
In our body, the enormous amount of DNA material that encodes our entire genome is neatly packaged into microscopic chromosomes. We inherit these chromosomes from our parents, with our mothers and fathers contributing 23 chromosomes each. All individuals assigned male at birth possess an X and a Y chromosome, whereas individuals assigned female at birth possess two X chromosomes.
Over 50% of the Y chromosome comprises DNA repeats, which – historically – presented challenges for scientists wanting to study its physiological role. As a result, for many years the Y chromosome was considered a “genetic wasteland”. Now, advanced technologies in genomics are starting to unravel its complexity, revealing findings that could have implications for men’s health.
Loss of chromosome Y (or LOY) is a type of mosaic aneuploidy, a phenomenon where cells possess an abnormal number of chromosomes, that was first identified several decades ago. “It was observed in 1963, by crude karyotype analyses, that men lose their Y chromosome as they aged,” says Dr. Kenneth Walsh, a researcher in the Internal Medicine Department at UVA.
What is a karyotype analysis?
A karyotype refers to an individual’s complete set of chromosomes. Karyotype analysis, sometimes referred to as a cytogenetic test, involves looking closely at the chromosomes of an individual to identify whether there are any abnormalities.
Creating an experimental model of LOY
Initially LOY was recognized as a “neutral” karyotype – one that doesn’t have a particularly harmful effect – that occurred in some men as they aged. However, since its initial discovery, our understanding of LOY has become increasingly refined.
Genetic studies identified it as one of the most commonly occurring mutations in a male’s genome, and association studies have linked the presence of LOY with several age-related diseases, such as Alzheimer’s and cardiovascular disease (CVD). In 2014, Professor Lars Forsberg of Uppsala University discovered an association between LOY and reduced lifespan.
“However, these associations do not provide evidence for a causality (i.e., whether Y chromosome loss has a direct effect on the pathological processes). For example, loss of the Y chromosome could be a marker of aging, like grey hair or wrinkles in skin, that does not directly contribute to the aging process or age-dependent diseases. This is a major limitation of epidemiological studies,” explains Walsh.
Historically, the repeated DNA sequences of the Y chromosome has made its study somewhat difficult. “In effect, one gets ‘lost’ as they try to decipher the nucleotide sequence,” Walsh describes. In the new study published in Science, Walsh and colleagues utilized CRISPR-Cas/9 genome editing technology to target the repeat DNA sequences and create an experimental mouse model of LOY. Generating a model of LOY allows for scientists to study the exact biological mechanisms that may underpin its association with diseases and shorter lifespan in males.
“The CRISPR editing tool, delivered with a modified virus, introduced breaks in the DNA strand of the Y chromosome at these repeat sequences and the Y chromosome is destroyed and effectively eliminated from the cell,” Walsh explains. LOY is prevalent in the white blood cells of men, and so the research team conducted their genome editing in the hematopoietic (blood) system. “The approach was surprisingly effective and relatively easy,” Walsh reflects.
Loss of chromosome Y associated with age-related diseases in mice
The researchers evaluated the phenotypic consequences of LOY in their mouse model. Mice with LOY had shorter-life spans than control mice, and older mice with LOY experienced short-term working memory deficits when subject to cognitive tests, including the Y-maze and novel object recognition tests. Such deficits were not observed in younger LOY mice.
As LOY is associated with CVD in male humans, the researchers also focused on the cardiovascular system of the mouse model. Echocardiographs showed that LOY mice experienced accelerated age-associated cardiomyopathy, a general weakening of the heart muscle whereby the chambers can become stretched, stiff or thickened, and scarring of the heart (fibrosis).
Digging deeper into the immune response – which is known to be involved in age-related diseases – the research team made a surprising discovery in the LOY mouse.
“While we typically associate pathological changes in the immune system with pro-inflammatory actions, loss of the Y chromosome had the opposite effect – it had an anti-inflammatory and pro-fibrotic effect on the immune cells. This was what led to the excessive deposition of connective tissue (fibrosis) in the mouse organs,” Walsh says. “We could measure this by looking at the genes that were being turned on and off in the immune cells (specifically the macrophages) and we were able to perform autopsy analyses on the mice to inspect the accumulation of fibrosis in their organs.”
In addition to their mouse in vivo studies, the research team turned to the UK Biobank, a large-scale biomedical database to collect human data. In a prospective analysis, they explored whether the presence of LOY was associated with CVD and increased mortality. “The percentage of blood cells lacking chromosome Y in each male participant at baseline was estimated using intensity data from single nucleotide polymorphism experiments,” the research team describe in the publication. Using a range of statistical analysis approaches, they identified that LOY – detected in the participants’ leukocytes – was associated with death from CVD in men.
A potential drug candidate?
Taking their work one step further, Walsh and colleagues considered whether there could be a pharmacological approach for mitigating the effects of LOY, putting forth an already US Food and Drug Administration (FDA)-approved drug as an initial suggestion. “It is just speculation at this point,” Walsh says. “However, we were able to show that we could inhibit the pathological effects of loss of the Y chromosome on the heart in mice by blocking TGF-b, a key molecule involved [in] the fibrosis.”
“Thus, we speculate that pirfenidone, an FDA-approved drug, and other anti-fibrotic drugs that are currently under development at pharmaceutical firms, could be particularly effective in men who have appreciable loss of their Y chromosome,” he adds.
First “hard evidence” on the physiological effect of LOY
The novel experimental model provides the first “hard evidence” on the physiological effects of LOY and why it might be associated with specific age-related diseases and reduced lifespan. To further advance their work, the scientists are assessing the specific genes on the Y chromosome that are lost in LOY and thus contribute to this disease process. “Better defining the Y chromosome genes that confer the effect of the entire Y chromosome loss will permit deeper understanding of mechanism. This will provide a better understanding of the age-associated diseases that are promoted by Y chromosome loss and could lead to new avenues of therapy,” Walsh says.
In the study, the research team adopted a bioinformatic analysis known as an “SNP array” to detect LOY. However, in the clinical space, LOY can be a challenging diagnosis for physicians to make, requiring a genetic test of the blood to confirm its presence.
Forsberg – who collaborated on the study with Walsh – has developed a “simple, inexpensive PCR-based assay”, not too dissimilar from the PCR tests used to diagnose COVID-19, to detect LOY. Its use is limited to research purposes right now – but this could change. “If future research documents the clinical utility for assessing loss of the Y chromosome in men (i.e., to determine whether men should be further assessed for fibrotic diseases or whether they should be prophylactically placed on an anti-fibrotic medication), then it would be relatively simple to develop a widely available assay for this condition,” Walsh explains.
Determining its clinical utility requires further study of human patients. “Clinically, we need to perform surveys of Y chromosome loss on patient cohorts that are better defined (i.e., better phenotyped) in terms of their disease characteristics than exist in the large databanks such as the UK Biobank,” Walsh concludes.
Dr. Kenneth Walsh was speaking to Molly Campbell, Senior Science Writer for Technology Networks.
Reference: Sano S, Horitani K, Ogawa H, et al. Hematopoietic loss of Y chromosome leads to cardiac fibrosis and heart failure mortality. Sci Adv. 2022. doi: 10.1126/science.abn3100.