Researchers have identified inherited genetic variants that may predict the loss of one copy of a woman’s two X chromosomes as she ages, a phenomenon known as mosaic loss of chromosome X, or mLOX. These genetic variants may play a role in promoting abnormal blood cells (that have only a single copy of chromosome X) to multiply, which may lead to several health conditions, including cancer. The study, co-led by researchers at the National Cancer Institute, part of the National Institutes of Health, was published in Nature.
To better understand the causes and effects of mLOX, researchers analysed circulating white blood cells from nearly 900 000 women across eight biobanks, of whom 12% had the condition. The researchers identified 56 common genetic variants – located near genes associated with autoimmune diseases and cancer susceptibility – that influenced whether mLOX developed. In addition, rare variants in a gene known as FBXO10 were associated with a doubling in the risk of mLOX.
In women with mLOX, the investigators also identified a set of inherited genetic variants on the X chromosome that were more frequently observed on the retained X chromosome than on the one that was lost. These variants could one day be used to predict which copy of the X chromosome is retained when mLOX occurs. This is important because the copy of the X chromosome with these variants may have a growth advantage that could elevate the woman’s risk for blood cancer.
The researchers also looked for associations of mLOX with more than 1,200 diseases and confirmed previous findings of an association with increased risk of leukemia and susceptibility to infections that cause pneumonia.
The scientists suggest that future research should focus on how mLOX interacts with other types of genetic variation and age-related changes to potentially alter disease risk.
X-chromosome inactivation varies across different areas of brains. Here, fluorescent imaging data from a mouse reveal where the father’s X chromosome is most active (white) and least active (blue). Credit: Eric Szelenyi
A study using mice published in the journal Cell Reports suggests how chromosome inactivation may protect women from autism disorder inherited from their father’s X chromosome.
Because cells do not need two copies of the X chromosome, the cells inactivate one copy early in embryonic development, a well-studied process known as X chromosome inactivation. As a result of this inactivation, every female is made up of a mix of cells, some have an active X chromosome from her father and others from her mother, a phenomenon known as mosaicism.
For many years, it has been thought that this was random and would result, on average, in a roughly 50/50 mix of cells, with 50% having an active paternal X chromosome and 50% an active maternal X chromosome.
Now a new study finds that, in the mouse brain at least, this is not the case. Instead, there appears to be a bias in the process that results in the paternal X chromosome being inactivated in 60% of the cells rather than the expected 50%.
When the X-linked mutation that is the most common cause of autism spectrum disorder is inherited from the father, the pattern of X-chromosome inactivation in the brain circuitry of females can prevent the effects of that mutation, the study found.
“This bias may be a way to reduce the risk of harmful mutations, which occur more frequently in male chromosomes,” said corresponding author Eric Szelenyi, acting assistant professor of biological structure at the University of Washington School of Medicine in Seattle.
The X-chromosome is of particular interest because it carries more genes involved in brain development than any other chromosome. Mutations in the chromosome are linked to more than 130 neurodevelopmental disorders, including fragile X syndrome and autism.
In the study, the researchers first determined the ratio of X chromosome inactivation in healthy mice by analyzing roughly 40 million brain cells per mouse. The scientists did this by using high-throughput volumetric imaging and automated counting. This analysis revealed a systematic 60:40 ratio across all possible anatomical regions.
They then examined what would happen if they genetically added a mouse model for fragile X syndrome. This syndrome is the most common form of inherited intellectual and developmental disability in humans.
They first tested the mice for behaviors thought to be analogous to those impaired in people with fragile X syndrome. These tests evaluate such things as their sensorimotor function, spatial memory and tendencies towards anxiety and sociability.
They found that the mice who inherited the mutation on their mother’s X chromosome, which are less likely to be inactivated in the 60:40 ratio, were more likely to exhibit behaviour analogous to fragile X syndrome. They exhibited more signs of anxiety, less sociability, poor performance in spatial learning, and deficits in sensorimotor function.
But mice that inherited the mutation from one their father’s X chromosomes, which were more likely to be inactivated, did not appear impaired.
“What was most interesting is that using each animal’s behavioural performance was most accurately predicted by X chromosome inactivation in brain circuits, rather than just looking at the brain as a whole, or single brain regions,” said Szelenyi. “This suggests that having more mutant X-active cells due to maternal inheritance increases overall disease risk, but specific mosaic pattern within brain circuitry ultimately decides which behaviors are impacted the most.”
“This suggests that the 20% difference in mutant X-active cells created by the bias can be protective against X mutations from the father, which occur more commonly,” he said.
The findings may also explain why symptoms of X-linked syndromes, like X-linked autism spectrum disorder, vary more in females than males.
A woman with Systemic Lupus Erythematosus. Source: Wikimedia CC0
The autoimmune condition lupus occurs in women at a rate nine times higher than in men. Some of the factors that cause the disease’s high prevalence in women have eluded discovery, but in a new study published in the Journal of Clinical Investigation Insight, Johns Hopkins Medicine researcher investigated the immune system processes in lupus and the X chromosome, and uncovered answers about the disease’s frequency in females.
A number of dysregulated genetic and biological pathways contribute to the development of lupus and its varied symptoms of muscle and joint pain, skin rashes, kidney problems and other complications throughout the body. One such pathway involves a protein in the immune system called toll-like receptor 7 (TLR7), which, in lupus, reacts to the body’s own RNA, molecules that act as messengers of genetic information. TLR7’s reaction to RNA triggers an immune response that damages healthy tissue.
In the full article, researchers honed in on this TLR7 immune response in lupus, looking specifically at how a piece of genetic material only found in women, known as X-inactive specific transcript (XIST), could trigger TLR7’s immune system response. XIST is a type of RNA that plays a crucial role in inactivating one of the two X chromosomes found in female cells so that females do not have imbalanced gene expression.
“XIST has previously been implicated in autoimmunity, but more as something that could prevent autoimmune conditions like lupus, rather than drive the disease’s development,” says study author and lead researcher Erika Darrah, PhD. “Our findings show the opposite, that XIST actually plays a role in promoting autoimmunity – increasing the susceptibility to lupus and its severity in women.”
The research team first tested whether XIST could bind to TLR7 and initiate the receptor’s immune response using cellular experiments. They observed that XIST could strongly bind to TLR7 and trigger the production of molecules called interferons, an immune system protein seen at high levels in lupus that contributes to tissue damage in this disease. Rather than protect from TLR7 and interferon’s negative effects on the body, these tests illustrated that XIST drove the process of an overactive immune response and therefore contributed to lupus development.
“XIST has now taken on a different role, an alarm signal related to autoimmunity,” says study author Brendan Antiochos, MD. “The immune system activation through XIST and TLR7 is female-specific, helping explain the observation that lupus is so much more common in women compared to men.”
To further study XIST’s role in lupus, researchers also examined XIST levels in patients from two lupus cohorts. The team tested blood samples from patients at the Johns Hopkins Lupus Center for XIST levels, and also used publicly available data from another study that showed XIST and interferon levels in white blood cells taken from the kidneys of people with lupus. They assessed that not only did the levels of XIST in the kidney correlate with higher interferon levels, but also, those with more XIST in their blood cells experienced greater disease severity and worsened lupus symptoms.
Darrah and Antiochos say these findings may implicate XIST in other autoimmune conditions that are more often seen in women, and that more research should be conducted to investigate this female-specific process.
Researchers also say that understanding XIST’s role in lupus development may lead to creative therapies that target the XIST-TLR7 pathway, as well as offer an additional explanation for patients who may wonder about the origins of their disease.
As men age, some of their cells lose their Y chromosome and this loss hampers the body’s ability to fight cancer, according to new research from Cedars-Sinai Cancer. The study, published in Nature, found that loss of the Y chromosome helps cancer cells evade the immune system, resulting in aggressive bladder cancer. Somehow, this also renders the disease more responsive to immune checkpoint inhibitors.
Based on their research, investigators are developing a test for loss of the Y chromosome in tumours with the goal of helping clinicians tailor immune checkpoint inhibitor treatment for male patients with bladder cancer.
“This study for the first time makes a connection that has never been made before between loss of the Y chromosome and the immune system’s response to cancer,” said corresponding author Dan Theodorescu, MD, PhD, who initiated the research. “We discovered that loss of the Y chromosome allows bladder cancer cells to elude the immune system and grow very aggressively.”
Lead collaborators on the study also included Johanna Schafer, a postdoctoral fellow, and Zihai Li, MD, PhD, medical oncologist and immunologist, both at The Ohio State University Comprehensive Cancer Center-James Cancer Hospital and Solove Research Institute.
In men, loss of the Y chromosome has been observed in several cancer types, including 10%–40% of bladder cancers. Loss of the Y chromosome also has been associated with heart disease and Alzheimer’s disease.
The Y chromosome contains the blueprints for certain genes. Based on the way these genes are expressed in normal cells in the bladder lining, investigators developed a scoring system to measure loss of the Y chromosome in cancers.
The investigators then 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. They found that patients with loss of the Y chromosome had poorer prognosis in the first group and much better overall survival rates in the latter.
To determine why this happens, investigators next compared growth rates of bladder cancer cells from laboratory mice.
Cancer cells were grown in vitro and not exposed to immune cells. The researchers also grew the diseased cells in mice that were missing T-cells. In both cases, tumours with and without the Y chromosome grew at the same rate.
In mice with intact immune systems, tumours lacking the Y chromosome grew at a much faster rate than did tumours with the intact Y chromosome.
“The fact that we only see a difference in growth rate when the immune system is in play is the key to the ‘loss-of-Y’ effect in bladder cancer,” Theodorescu said. “These results imply that when cells lose the Y chromosome, they exhaust T-cells. And without T-cells to fight the cancer, the tumor grows aggressively.”
Based on their results derived from human patients and laboratory mice, Theodorescu and his team also concluded that tumours missing the Y chromosome, while more aggressive, were also more vulnerable and responsive to immune checkpoint inhibitors. This therapy, one of the two mainstay bladder cancer treatments available to patients today, reverses T-cell exhaustion and allows the body’s immune system to fight the cancer.
“Fortunately, this aggressive cancer has an Achilles’ heel, in that it is more sensitive than cancers with an intact Y chromosome to immune checkpoint inhibitors,” said co-first author Hany Abdel-Hafiz, PhD, associate professor at Cedars-Sinai Cancer.
Preliminary data not yet published shows that loss of the Y chromosome also renders prostate cancers more aggressive, Theodorescu said.
“Our investigators postulate that loss of the Y chromosome is an adaptive strategy that tumour cells have developed to evade the immune system and survive in multiple organs,” said Shlomo Melmed, MB, ChB, dean of the Medical Faculty at Cedars-Sinai. “This exciting advance adds to our basic understanding of cancer biology and could have far-reaching implications for cancer treatment going forward.”
Further work is needed to help investigators understand the genetic connection between loss of the Y chromosome and T-cell exhaustion.
“If we could understand those mechanics, we could prevent T-cell exhaustion,” Theodorescu said. “T-cell exhaustion can be partially reversed with checkpoint inhibitors, but if we could stop it from happening in the first place, there is much potential to improve outcomes for patients.”
While women do not have a Y chromosome, Theodorescu said these findings could have implications for them as well. The Y chromosome contains a set of related genes, called paralogue genes, on the X chromosome, and these might play a role in both women and in men. Additional research is needed to determine what that role might be.
“Awareness of the significance of Y chromosome loss will stimulate discussions about the importance of considering sex as a variable in all scientific research in human biology,” Theodorescu said. “The fundamental new knowledge we provide here may explain why certain cancers are worse in either men or women, and how best to treat them. It also illustrates that the Y chromosome does more than determine human biologic sex.”
Researchers report in Cell Systems that they have discovered another difference between cancer cells and normal cells besides mutations: the X chromosome, typically only inactivated in XX female cells, can also be inactivated across different male-derived cancers.
“To balance the expression of genes between the sexes, in normal development, one copy of the female X chromosome is inactivated at random across the human body. We wanted to know if this process that occurs in normal development goes awry in genetically unstable male or female cancer cells,” says senior author Srinivas Viswanathan, a cancer geneticist and medical oncologist at the Dana-Farber Cancer Institute.
By using publicly available datasets comprising of thousands of DNA samples from cancer patients around the world, the team of researchers stumbled upon the high expression of XIST – the gene responsible for shutting down gene expression on the X chromosome – in about 4% of the male cancer samples analysed.
While XIST may be expressed in very early development in all sexes, X inactivation is thought to be a female-specific process later in development. It was previously shown that some female cancer cells may lose the ability to turn off one of the X chromosomes, leading to increased X-linked gene expression, but this ability of X inactivation had still only been studied primarily in female cells.
Within the 4% of anomalous male cancer samples identified, 74% were from reproductive cancers already shown to inactivate the X chromosome, but that left 26% of samples from other cancer types. These included liver, brain, skin, heart, lung, and thyroid cancers.
“We were very surprised by this result since XIST is a transcript typically used to classify female cancers, and so we wanted to ensure that this was not merely a result of mis-annotation. Yet, we do in fact see that some male cancers of diverse subtypes activate XIST and display features of X inactivation,” says Viswanathan.
“We have to be aware of the caveats of working with these types of datasets. These samples have been in many people’s hands, and there is more room for human error,” said co-corresponding author Cheng-Zhong Zhang, cancer biologist at the Dana-Farber Cancer Institute. “This is the biggest source of uncertainty for us; we have to be creative in how we look at the data and find controls.”
One possible explanation for why this phenomenon is occurring is genetic instability. Cancers often have multiple copies of chromosomes, and if two X chromosomes happen to be in one cell, then it may be necessary to inactivate one of them by activating XIST, regardless of whether that cell is in a female or male individual.
“Another possibility is there are some important genes on the X chromosome that, when silenced, enable the cancer to grow. We will investigate this in future studies,” says Viswanathan.
“In some ways, sex is the ultimate biomarker in that it subdivides the human population, but we often don’t think about how genetic differences between the sexes may inform cancer prognosis or response to therapy,” says Viswanathan.
As many men age, they lose their Y chromosome, which causes heart muscle to scar and can lead to deadly heart failure, new research from the shows. The finding, which appears in Science, may help explain why men die, on average, several years younger than women.
University of Virginia School of Medicine researcher Kenneth Walsh, PhD, says the new discovery suggests that men who suffer Y chromosome loss – estimated to include 40% of 70-year-olds – may particularly benefit from an existing drug that targets dangerous tissue scarring. The drug, he suspects, may help counteract the harmful effects of the chromosome loss – effects that may manifest not just in the heart but in other parts of the body as well.
On average, women live five years longer than men in the United States. The new finding, Prof Walsh estimates, may explain nearly four of the five-year difference.
“Particularly past age 60, men die more rapidly than women. It’s as if they biologically age more quickly,” said Prof Walsh. “There are more than 160 million males in the United States alone. The years of life lost due to the survival disadvantage of maleness is staggering. This new research provides clues as to why men have shorter lifespans than women.”
Many men begin to lose their Y chromosome in a fraction of their cells as they age, especially in smokers. The loss occurs predominantly in cells that undergo rapid turnover, such as blood cells. However, Y chromosome loss does not occur in male reproductive cells, so it is not inherited by the children of men who exhibit Y chromosome loss. It has been observed 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. This new research however is believed to be the first hard evidence that the chromosome loss harms men’s health.
Walsh and his team used CRISPR gene-editing technology to develop a special mouse model to better understand the effects of Y chromosome loss in the blood. The loss accelerated age-related diseases, made the mice more prone to heart scarring, leading to earlier death. But more than just the results of inflammation, there was complex series of responses in the immune system, leading to fibrosis throughout the body. This tug-of-war within the immune system, the researchers believe, may accelerate disease development.
The scientists also looked at the effects of Y chromosome loss in human 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. As chromosome loss increased, the scientists found, so did the risk of death.
The findings suggest that targeting the effects of Y chromosome loss could help men live longer, healthier lives. One treatment option might be a drug, pirfenidone, approved in the US for the treatment of idiopathic pulmonary fibrosis. The drug is also being tested for the treatment of heart failure and chronic kidney disease, two conditions for which tissue scarring is a hallmark. Based on his research, Walsh believes that men with Y chromosome loss could respond particularly well to this drug, and other classes of antifibrotic drugs that are being developed, though more research will be needed to determine that.
At the moment, doctors have no easy way to determine which men suffer Y chromosome loss. Prof Walsh’s collaborator Lars A. Forsberg, of Uppsala University in Sweden, has developed an inexpensive polymerase chain reaction (PCR) test that can detect Y chromosome loss, but the test is largely confined to his and Prof Walsh’s labs. Prof Walsh, however, can foresee that changing: “If interest in this continues and it’s shown to have utility in terms of being prognostic for men’s disease and can lead to personalised therapy, maybe this becomes a routine diagnostic test,” he said.
“The DNA of all our cells inevitably accumulate mutations as we age. 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,” said Walsh, a member of UVA’s Department of Biochemistry and Molecular Genetics. “Studies that examine Y chromosome loss and other acquired mutations have great promise for the development of personalised medicines that are tailored to these specific mutations.”
Around one in 500 men could be carrying an extra sex chromosome (X or Y), putting them at increased risk of diseases such as type 2 diabetes, atherosclerosis and thrombosis, according to a study published in Genetics in Medicine.
Researchers from the universities of Cambridge and Exeter analysed genetic data on 200 000 men aged 40 to 70 from UK Biobank. They found 356 men who carried either an extra X chromosome or an extra Y chromosome.
Some men have an extra X or Y chromosome – XXY or XYY, which is usually not obvious without a genetic test. Men with extra X chromosomes, a condition known as Klinefelter syndrome, are sometimes identified during investigations of delayed puberty and infertility; however, most are unaware that they have this condition. Men with an extra Y chromosome tend to be taller as boys and adults, but otherwise they have no distinctive physical features.
In today’s study, the researchers identified 213 men with an extra X chromosome and 143 men with an extra Y chromosome. As the participants in UK Biobank tend to be ‘healthier’ than the general population, this suggests that around one in 500 men may carry an extra X or Y chromosome.
Only a small minority of these men had a diagnosis of sex chromosome abnormality on their medical records or by self-report: fewer than one in four (23%) men with XXY and only one of the 143 XYY men (0.7%) had a known diagnosis.
By linking genetic data to routine health records, the team found that men with XXY have much higher chances of reproductive problems, including a three-fold higher risk of delayed puberty and a four-fold higher risk of being childless. These men also had significantly lower blood concentrations of testosterone. Men with XYY appeared to have a normal reproductive function.
Men with either XXY or XYY had higher risks of several other health conditions: a three-fold higher risk of developing type 2 diabetes, six-fold risk of venous thrombosis, three-fold risk of pulmonary embolism, and four-fold risk of chronic obstructive pulmonary disease (COPD).
It is unclear why an extra chromosome should increase the risk, said the researchers, or why the risks were so similar regardless of which sex chromosome was duplicated.
Yajie Zhao, a PhD student at the Medical Research Council (MRC) Epidemiology Unit at the University of Cambridge, the study’s first author, said: “Even though a significant number of men carry an extra sex chromosome, very few of them are likely to be aware of this. This extra chromosome means that they have substantially higher risks of a number of common metabolic, vascular, and respiratory diseases — diseases that may be preventable.”
Professor Ken Ong, also from the MRC Epidemiology Unit at Cambridge and joint senior author, added: “Genetic testing can detect chromosomal abnormalities fairly easily, so it might be helpful if XXY and XYY were more widely tested for in men who present to their doctor with a relevant health concern.
“We’d need more research to assess whether there is additional value in wider screening for unusual chromosomes in the general population, but this could potentially lead to early interventions to help them avoid the related diseases.”
Professor Anna Murray, at the University of Exeter, said: “Our study is important because it starts from the genetics and tells us about the potential health impacts of having an extra sex chromosome in an older population, without being biased by only testing men with certain features as has often been done in the past.”
Previous studies have found that around one in 1,000 females have an additional X chromosome, which can result in delayed language development and accelerated growth until puberty, as well as lower IQ levels compared to their peers.
