Category: Genetics

Categories : GeneticsTags :

Polygenic Risk Scores are not That Useful, Study Finds

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Polygenic risk scores, which estimate a person’s disease risk based on thousands or millions of common genetic variants, perform poorly in screening and prediction of common diseases such as heart disease, according to a new study led by UCL (University College London) researchers. An extremely high number of individuals would need to be screened for each potential intervention, creating a significant burden on healthcare, while producing numerous false positive results.

It has been claimed that polygenic risk scores are set to transform the prediction and prevention of common diseases, with companies already set up to sell polygenic risk score testing services.

The new study, published in BMJ Medicine, examined 926 polygenic risk scores for 310 diseases. It found that, on average, only 11% of individuals who develop disease are identified, while at the same time 5% of people who do not develop the disease test positive. Unaffected people usually outnumber those affected which results in far more false than true positive predictions.

Lead author Professor Aroon Hingorani said: “Strong claims have been made about the potential of polygenic risk scores in medicine, but our study shows that this is not justified.

“We found that, when held to the same standards as employed for other tests in medicine, polygenic risk scores performed poorly for prediction and screening across a range of common diseases.”

For the new study, researchers looked at data available in an open-access database, the Polygenic Score Catalog, to determine what the detection rate and false positive rate of the scores would be if used in screening.

For breast cancer and coronary artery disease, the risk scores identified only 10% and 12% of eventual cases respectively, using a cut-off that resulted in 5% of unaffected individuals testing positive.

The researchers also investigated how polygenic risk scores would perform if used alongside conventional screening methods.

They found that, if used alongside conventional risk factors, several thousand people would need to have a polygenic risk score done to guide statin prescriptions to prevent one additional heart attack or stroke. The researchers noted that using age alone as a guide to statin prescription would be simpler and more effective at preventing heart attacks and strokes without the need for genetic testing.

They also found that adding polygenic risk scores as first stage screening to determine who should be prioritised for mammography would miss most women who later develop breast cancer and generate many false positives, adding to the burden on healthcare systems.

Co-author Professor Sir Nicholas Wald said: “It has been suggested that polygenic risk scores could be introduced early on to help prevent breast cancer and heart disease but, in the examples we looked at, we found that the scores contributed little, if any, health benefit while adding cost and complexity.”

In the paper, the researchers suggest regulation of commercial genetic tests based on polygenic risk scores to “protect the public from unrealistic expectations and already stretched public health systems from becoming overburdened by the management of false positive results”.

The researchers said consumers of commercial polygenic risk score tests should be informed of the detection rate and false positive rate of the polygenic risk scores as well as the absolute risk with and without a polygenic score result so they can better judge whether the test is useful.

Co-author Dr Jasmine Gratton said: “Polygenic risk scores seem attractive because genotyping is now inexpensive, the same for all diseases and is performed only once because a person’s genotype does not change. However, these features are irrelevant if the test is not useful.”

Professor Sir Nick Wald said: “Our results build on evidence that indicates that polygenic risk scores do not have a role in public health screening programmes.”

The researchers said the performance of polygenic risk scores was unlikely to change much as the variants with the strongest effect had already been identified.

Polygenic risk scores should not be confused with genetic testing for certain single gene mutations such as BRCA1 and BRCA2 which have an important role in screening for breast and ovarian cancer.

Discovering variants that are associated with a higher risk of disease is still crucial for drug development, the team emphasised, as the variants encode proteins that can be targeted with drugs that would be useful for everyone regardless of their genetic makeup.

Polygenic risk score testing is also one of the aims of the UK’s nationwide Our Future Health project.

Source: EurekAlert!

Categories : Genetics Pain ManagementTags :

Neanderthal Gene Variants Associated with Greater Sensitivity to Some Types of Pain

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Source: Pixabay CC0

People who carry three gene variants that have bene inherited from Neanderthals are more sensitive to some types of pain, according to a new study co-led by UCL researchers. The findings, published in Communications Biology, are the latest findings to show how past interbreeding with Neanderthals has influenced the genetics of modern humans.

The researchers found that people carrying three so-called Neanderthal variants in the gene SCN9A, which is implicated in sensory neurons, are more sensitive to pain from skin pricking after prior exposure to mustard oil.

Previous research has identified three variations in the SCN9A gene – known as M932L, V991L, and D1908G – in sequenced Neanderthal genomes and reports of greater pain sensitivity among humans carrying all three variants. However, prior to this study the specific sensory responses affected by these variants was unclear.

An international team measured the pain thresholds of 1963 people from Colombia in response to a range of stimuli.

The SCN9A gene encodes a sodium channel that is expressed at high levels in sensory neurons that detect signals from damaged tissue. The researchers found that the D1908G variant of the gene was present in around 20% of chromosomes within this population and around 30% of chromosomes carrying this variant also carried the M932L and V991L variants.

The authors found that the three variants were associated with a lower pain threshold in response to skin pricking after prior exposure to mustard oil, but not in response to heat or pressure. Additionally, carrying all three variants was associated with greater pain sensitivity than carrying only one.

When they analysed the genomic region including SCN9A using genetic data from 5971 people from Brazil, Chile, Colombia, Mexico and Peru, the authors found that the three Neanderthal variants were more common in populations with higher proportions of Native American ancestry, such as the Peruvian population, in which the average proportion of Native American ancestry was 66%.

The authors propose that the Neanderthal variants may sensitise sensory neurons by altering the threshold at which a nerve impulse is generated. They speculate that the variants may be more common in populations with higher proportions of Native American ancestry as a result of random chance and population bottlenecks that occurred during the initial occupation of the Americas. Although acute pain can moderate behaviour and prevent further injury, the scientists that say additional research is needed to determine whether carrying these variants and having greater pain sensitivity may have been advantageous during human evolution.

Diagram comparing the nose shape of a Neanderthal with that of a modern human by Dr Macarena Fuentes-Guajardo.

Previous research by co-corresponding author Dr Kaustubh Adhikari (UCL Genetics, Evolution & Environment and The Open University) has shown that humans also inherited some genetic material from Neanderthals affecting the shape of our noses.

Dr Adhikari commented: “In the last 15 years, since the Neanderthal genome was first sequenced, we have been learning more and more about what we have inherited from them as a result of interbreeding tens of thousands of years ago.

“Pain sensitivity is an important survival trait that enables us to avoid painful things that could cause us serious harm. Our findings suggest that Neanderthals may have been more sensitive to certain types of pain, but further research is needed for us to understand why that is the case, and whether these specific genetic variants were evolutionarily advantageous.”

First author Dr Pierre Faux (Aix-Marseille University and University of Toulouse) said: “We have shown how variation in our genetic code can alter how we perceive pain, including genes that modern humans acquired from the Neanderthals. But genes are just one of many factors, including environment, past experience, and psychological factors, which influence pain.”

Source: University College London

Categories : Genetics NeurologyTags :

CRISPR Untangles the Connections between Genome Organisation and Autism

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Photo by Peter Burdon on Unsplash

Using CRISPR gene editing, stem cells and human neurons, researchers have isolated the impact of a gene that is commonly mutated in autism. This new study, published today in The American Journal of Human Genetics, ties mutations in the gene CHD8 with a broad spectrum of molecular and cellular defects in human cortical neurons.

Autism is a highly heritable disorder with a recent increase in incidence – approximately 1 in 40 children in the US are diagnosed with autism. Over the past decade, sequencing studies have found many genes associated with autism but it has been challenging to understand how mutations in certain genes drive complex changes in brain activity and function.

The team, led by researchers at the New York Genome Center and New York University (NYU) and the Broad Institute, team developed an integrated approach to understand how mutations in the CHD8 gene alter genome regulation, gene expression, neuron function, and are tied to other key genes that play a role in autism. 

For more than a decade, it has been known that individuals with mutations in the CHD8 gene tend to have many similar ailments, such as autism, an abnormally large head size, digestive issues and difficulty sleeping. The CHD8 gene is a regulator of proteins called chromatin that surround the DNA but it is unclear how this particular gene might relate to major alterations in neural development and, in turn, result in autism. 

The research team identified numerous changes in physical state of DNA, which makes the genome more accessible to regulators of gene expression, and, in turn, drives aberrant expression of hundreds of genes. These molecular defects resulted in clear functional changes in neurons that carry the CHD8 mutation. These neurons are much less talkative: They are activated less often and send fewer messages across their synapses. 

The study authors initially observed these changes using human cortical neurons differentiated from stem cells where CRISPR was used to insert a CHD8 mutation. These findings were further bolstered by similar reductions in neuron and synapse activity when examining neurons from mice with a CHD8 mutation. These substantial defects in neuron function were circumvented when extra CHD8 was added to the cell using a gene therapy approach. In this case, extra copies of a healthy CHD8 gene without any mutation were added using a viral vector. Upon differentiation, the team found that the neurons rescued by the treatment returned to a normal rate of activity and synaptic communication, indicating that this gene therapy approach may be sufficient to restore function.

Lastly, when examining disrupted genes, the authors found that the CHD8 mutation seemed to specifically alter other genes that have been implicated in autism or intellectual disability, but not genes associated with unrelated disorders like cardiovascular disease. This suggest that CHD8 might influence selectively those genes that tend to be involved in neurodevelopmental disorders, providing an explanation for some of the particular characteristics of individuals carrying a CHD8 mutation.

Source: EurekAlert!

Categories : Diet and Nutrition GeneticsTags :

Going Vegetarian may be Down to Genetics

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A person’s genetic makeup plays a role in determining whether they can stick to a strict vegetarian diet, a new study has found. The findings, published in PLOS ONE, open the door to further studies that could have important implications regarding dietary recommendations and the production of meat substitutes. It is the first fully peer-reviewed and indexed study to look at the association between genetics and strict vegetarianism.

“Are all humans capable of subsisting long term on a strict vegetarian diet? This is a question that has not been seriously studied,”said corresponding study author Dr. Nabeel Yaseen, professor emeritus of pathology at Northwestern University Feinberg School of Medicine.

A large proportion (about 48 to 64%) of self-identified “vegetarians” report eating fish, poultry and/or red meat, which Yaseen said suggests environmental or biological constraints override the desire to adhere to a vegetarian diet.

“It seems there are more people who would like to be vegetarian than actually are, and we think it’s because there is something hard-wired here that people may be missing.”

Several genes involved in lipid metabolism, brain function

To determine whether genetics contribute to one’s ability to adhere to a vegetarian diet, the scientists compared UK Biobank genetic data from 5 324 strict vegetarians (consuming no fish, poultry or red meat) to 329 455 controls. All study participants were white Caucasian to attain a homogeneous sample and avoid confounding by ethnicity.

The study identified three genes that are significantly associated with vegetarianism and another 31 genes that are potentially associated. Several of these genes, including two of the top three (NPC1 and RMC1), are involved in lipid (fat) metabolism and/or brain function, the study found.

“One area in which plant products differ from meat is complex lipids,” Yaseen said. “My speculation is there may be lipid component(s) present in meat that some people need. And maybe people whose genetics favor vegetarianism are able to synthesize these components endogenously. However, at this time, this is mere speculation and much more work needs to be done to understand the physiology of vegetarianism.”

Why do most people eat meat?

Religious and moral considerations have been major motivations behind adopting a vegetarian diet, and recent research has provided evidence for its health benefits. And although vegetarianism is increasing in popularity, vegetarians remain a small minority of people worldwide. For example, in the US, vegetarians comprise approximately 3 to 4% of the population. In the UK, 2.3% of adults and 1.9% of children are vegetarian.

This raises the question of why most people still prefer to eat meat products. The driving factor for food and drink preference is not just taste, but also how an individual’s body metabolises it, Yaseen said. For example, when trying alcohol or coffee for the first time, most people would not find them pleasurable, but over time, one develops a taste because of how alcohol or caffeine makes them feel.

“I think with meat, there’s something similar,” Yaseen said. “Perhaps you have a certain component – I’m speculating a lipid component – that makes you need it and crave it.”

If genetics influence whether someone chooses to be a vegetarian, what does that mean for those who don’t eat meat for religious or moral reasons?

“While religious and moral considerations certainly play a major role in the motivation to adopt a vegetarian diet, our data suggest that the ability to adhere to such a diet is constrained by genetics,” Yaseen said. “We hope that future studies will lead to a better understanding of the physiologic differences between vegetarians and non-vegetarians, thus enabling us to provide personalized dietary recommendations and to produce better meat substitutes.”

Source: Northwestern University

Categories : GeneticsTags :

A Gene for ‘Explosive’ Cell Death Drives Runaway Inflammation

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Australian researchers at Walter and Eliza Hall Institute have found that a genetic change that increases the risk of inflammation, through necroptosis, a process described as ‘explosive’ cell death, is carried by up to 3% of the global population.

The study, which is published in Nature Communications, may explain why some people have an increased chance of developing conditions like inflammatory bowel disease or suffer more severe reactions to infections with bacteria like Salmonella.

Immune power of ‘explosive’ cell death

Programmed cell death is a normal part of the body’s immune system and maintenance, removing unwanted, damaged or dangerous cells, and preventing the spread of viruses, bacteria, and even cancer.

First author WEHI’s Dr Sarah Garnish is first author on the paper and said that while there are various types of cell death, necroptosis is distinguished by its ferocity – the cells essentially explode, which sounds an alarm for other cells in the body to respond.

“This is a good thing in the case of a viral infection, where necroptosis not only kills the infected cells but instructs the immune system to respond, clean things up, and start a more specific, long lived immune response,” Dr Garnish said.

“But when necroptosis is uncontrolled or excessive, the inflammatory response can actually trigger disease.”

Genetic brakes

The gatekeeper of necroptosis is the gene MLKL. When the body needs to trigger a cell death response with plenty of firepower, the cellular brakes that normally keep MLKL in-check are released. However, some of us make a form of MLKL with flimsy brakes.

Dr Garnish and her co-authors have been able to quantify this at a population level for the first time.

“For most of us, MLKL will stop when the body tells it to stop, but 2-3% of people have a form of MLKL that is less responsive to stop signals,” Dr Garnish said.

“While 2-3% doesn’t seem like much, when you consider the global population, this adds up to many millions of people carrying a copy of this gene variant.”

Project leader Dr Joanne Hildebrand said the research proposes that a common genetic change like this can combine with a person’s lifestyle, infection history and broader genetic makeup to increase the risk of inflammatory diseases and severe reactions to infections.

This is known as polygenic risk, the combined influence of multiple genes on developing a certain trait or condition.

“Taking Type 2 diabetes as an example, it’s rare that just one gene change determines whether someone will develop the condition,” Dr Hildebrand said.

“Instead many different genes play a role, as do environmental factors, like diet and smoking.”

Dr Hildebrand said it’s not as simple as directly connecting this difference in the MLKL gene with the chance of someone developing a specific condition.

“We haven’t tagged this MLKL gene variant to any one particular disease yet, but we see real potential for it to combine with other gene variants, and other environmental cues, to influence the intensity of our inflammatory response.”

Towards personalised medicine

Our understanding of MLKL has come a long way since it surfaced by chance in a WEHI lab more than 20 years ago. Today’s research opens the door for future tests and screening to determine disease risks.

Genome sequencing is becoming cheaper and more readily accessible. As more genomic data becomes available to researchers, it increases the likelihood that they can link common genetic variants, like the one described for MLKL, with disease.

In the future researchers hope to pinpoint the genetic changes that might mean someone is more likely to have a severe case of COVID-19, or less likely to bounce back after chemotherapy.

“Every piece of information like this helps us make personalised medicine more of a reality,” said Dr Garnish.

The WEHI team is also investigating whether uncontrolled necroptosis could be beneficial in some circumstances. For example, could people with the MLKL gene variant have a stronger cellular defensive response to certain viruses?

“Gene changes like this don’t usually accumulate in the population over time unless there is a reason for it – they generally get passed on because they do something good,” said Dr Garnish.

“We’re looking at the downsides of having this gene change, but we’re looking for the upsides as well.”

Source: Walter and Eliza Hall Institute

Categories : Allergies GeneticsTags :

Can We Predict the Severity of Food Allergies Using Genetics?

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Photo by Sangharsh Lohakare on Unsplash

Researchers have discovered that a genetic biomarker may be able to help predict the severity of food allergy reactions. Currently there is no reliable or readily available clinical biomarker that accurately distinguishes patients with food allergies who are at risk for severe life-threatening reactions versus more mild symptoms. The researchers reported their findings in the Journal of Allergy and Clinical Immunology.

The researchers, led by Ann & Robert H. Lurie Children’s Hospital of Chicago, found that the presence of an enzyme isoform called α-tryptase, which is encoded by the TPSAB1 gene, correlates with increased prevalence of anaphylaxis or severe reaction to food as compared to subjects without any α-tryptase.

“Determining whether or not a patient with food allergies has α-tryptase can easily be done in clinical practice using a commercially available test to perform genetic sequencing from cheek swabs,” said lead author Abigail Lang, MD, MSc, attending physician and researcher at Lurie Children’s and Assistant Professor of Pediatrics at Northwestern University Feinberg School of Medicine. “If the biomarker is detected, this may help us understand that the child is at a higher risk for a severe reaction or anaphylaxis from their food allergy and should use their epinephrine auto-injector if exposed to the allergen. Our findings also open the door to developing an entirely new treatment strategy for food allergies that would target or block α-tryptase. This is an exciting first step and more research is needed.”

Tryptase is found mainly in mast cells, which become activated during allergic reactions. Increased TPSAB1 copy number which leads to increased α-tryptase is already known to be associated with severe reactions in adults with Hymenoptera venom allergy (or anaphylaxis following a bee sting).

Dr Lang’s study included 119 participants who underwent TPSAB1 genotyping, 82 from an observational food allergy cohort at the National Institute of Allergy and Infectious Diseases (NIAID) and 37 from a cohort of children who reacted to peanut oral food challenge at Lurie Children’s.

“We need to validate our preliminary findings in a much larger study, but these initial results are promising,” says Dr Lang. “We also still need a better understanding of why and how α-tryptase makes food allergy reactions more severe in order to pursue this avenue for potential treatment.”

Source: Ann & Robert H. Lurie Children’s Hospital of Chicago

Categories : Genetics PaediatricsTags :

Genetics can Make Paediatric Medicines Taste Sweeter

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Paediatric medicines often come in a sweetened liquid form for compliance in ingesting it, but if it’s too palatable, a child may empty an entire bottle and poison themselves. But children can perceive taste in different ways. A new study published in the International Journal of Molecular Sciences uncovers genetic variations in how sweetness of medicine is perceived, with adult participants of African descent finding it than those of European descent.

A multidisciplinary research group specialising in paediatrics, genetics, and psychophysics, co-led by Julie A. Mennella, PhD, Principal Investigator at the Monell Chemical Senses Center, has identified wide variation in the sensory perception of a paediatric formulation of ibuprofen. Some were tied to genetic ancestry, and some were not. These findings indicate that a range of factors come into play in determining how a medicine tastes to an individual. Their work is the first in a series of studies funded by the National Institutes of Health to look at variation in the taste of medicines.

“Taste is personal and determining how individuals differ and why is critical to understanding medication adherence and personal risks,” said Mennella. Bitter taste and irritating sensations in the throat are the top reasons for non-compliance, as a child (or adult) is less likely to ingest a medicine that is unpleasant (or tastes bad). However, if a child finds the medicine bottle uncapped and finds it tastes sweet like candy, they may ingest too much. Discovering how individuals differ in sensory perception is especially key when it comes to liquid ibuprofen, which accounts for many unintentional poison exposures among children younger than six years old in the US, according to the US Poison Centers.

“Sweetening medicines like ibuprofen is a delicate balance between having it taste good enough that kids take it, but bitter enough that, should they get unguarded access to it, it’s irritating enough that they stop drinking it and don’t poison themselves,” said Mennella. “We found genetic markers, both ancestry-related and independent of it, that could predict if someone would find a medication irritating or pleasantly sweet. If we get to the point of tailor-making medications in the future, knowing these associations could help us design taste specifically for each child in the not-so-distant future.”

The study included 154 adult panellists from Philadelphia, who represented the diversity of their city. According to a genome-wide association study, 63 had African ancestry, 51 European, 13 South Asian, seven East Asian, and seven American. They underwent training in sensory methods and then rated the sweetness, irritation, bitterness, and palatability of a paediatric formulation of a berry-flavoured ibuprofen after swallowing, and also after just tasting it without swallowing.

Researchers found that panellists of African genetic ancestry had fewer chemaesthetic sensations such as tingling or an urge to cough, rated the medicine as tasting sweeter and more palatable than those of European genetic ancestry. Researchers also found a novel association between the TRPA1rs1198875 genetic variation and tingling sensations, independent of ancestry. This is significant as TRPA1 is a family of neuron receptors that are involved in sensory neural response to a variety of chemical irritants found in foodstuff and other medicines.

Discovering both an ancestry-related link and non-ancestry-related genetic variation to taste and irritation perception shows that who perceives a medicine as palatable or not is a complicated picture and must consider a variety of factors.

This first study was conducted with adults because the sensory measures were complex and included several hour-long test sessions. That does not mean future tests should not include children, Mennella said, adding that this is just the first in a line of studies on the taste of paediatric medicines and methods need to be developed to measure sensory irritation in children. “This is a small study, but it is the first step in showing how research on diverse populations is needed to be able to unravel the genetic, cultural, dietary, and developmental paths that underlie medicine adherence and also risk for poisoning,” said Mennella. “It’s looking at both sides of the same, very important coin.”

Findings from this research will affect how sensory tests can be designed in the future. Since participants did both swallow and sip-and-spit tests, the team was able to determine that just tasting medicine allowed predictions and perceptions after swallowing, which could simplify future studies in different age groups. Other studies as part of this National Institutes of Health grant are ongoing, including determining the variation and acceptance of medicines in children.

Source: Monell Chemical Senses Center

Categories : Cancer GeneticsTags :

New Genes, Natural Toxins Offer Hope for Patients with Head and Neck Cancer – and Maybe Others

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Photo by National Cancer Institute on Unsplash

Research led by Queen Mary University of London and published in Molecular Cancer has revealed two new genes that cause head and neck cancer patients to be resistant to chemotherapy. The study also shows that silencing either gene can make cancer cells that were previously unresponsive chemotherapy subsequently respond to it.

The two genes discovered actively ‘work’ in most human cancer types, meaning the findings could potentially extend to other cancers with elevated levels of the genes.

The researchers also looked through a chemical library, commonly used for drug discovery, and found two substances that could target the two genes specifically and make resistant cancer cells almost 30 times more sensitive to a common chemotherapy drug called cisplatin. They do this by reducing the levels of the two genes and could be given alongside existing chemotherapy treatment such as cisplatin. One of these substances is a fungal toxin – Sirodesmin A – and the other – Carfilzomib – comes from a bacterium. This shows that there may be existing drugs that can be repurposed to target new causes of disease, which can be cheaper than having to develop and produce new ones.

The research is the first evidence for the genes NEK2 and INHBA causing chemoresistance in head and neck squamous cell carcinoma (HNSCC) and gene silencing of either gene overturning chemoresistance to multiple drugs.

The scientists first used a method known as data mining to identify genes that may be affecting tumour responsiveness to drug therapy. They tested 28 genes on 12 strains of chemoresistant cancer cell lines, finding 4 ‘significant’ genes that were particularly responsive that they then investigated further and tested multidrug-resistance.

Senior study author Dr Muy-Teck Teh, from Queen Mary University of London, said: “These results are a promising step towards cancer patients in the future receiving personalised treatment based on their genes and tumour type that give them a better survival rate and treatment outcome.

“Unfortunately, there are lots of people out there who do not respond to chemotherapy or radiation. But our study has shown that in head and neck cancers at least it is these two particular genes that could be behind this, which can then be targeted to fight against chemoresistance.

“Treatment that doesn’t work is damaging both for the NHS and patients themselves. There can be costs associated with prolonged treatment and hospital stays, and it’s naturally extremely difficult for people with cancer when their treatment doesn’t have the results they are hoping for.”

90% of all head and neck cancers are caused by HNSCCs, with tobacco and alcohol use being key associations. In the UK, there are 12 422 new cases of head and neck cancer each year, and the overall 5-year survival rate of patients with advanced HNSCC is less than 25%. A major cause of poor survival rates of HNSCC is because of treatment failure that stems from resistance to chemotherapy and/or radiotherapy.

Unlike lung and breast cancer patients, all HNSCC patients are treated with almost the same combinations of treatment irrespective of the genetic makeup of their cancer.

Source: Queen Mary University of London

Categories : Genetics Respiratory DiseasesTags :

Fathers Who Smoked as Young Teens Pass Epigenetic Changes to Offspring

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A new study suggests boys who smoke in their early teens risk damaging the genes of their future children, increasing their chances of developing asthma, obesity and low lung function.

This research, published in Clinical Epigenetics, is the first human study to reveal the biological mechanism behind the impact of fathers’ early teenage smoking on their children.

Researchers from the University of Southampton and the University of Bergen in Norway investigated the epigenetic profiles of 875 people, aged 7 to 50, and the smoking behaviours of their fathers.

They found epigenetic changes at 19 sites mapped to 14 genes in the children of fathers who smoked before the age of 15. These changes in the way DNA is packaged in cells (methylation) regulate gene expression (switching them on and off) and are associated with asthma, obesity and wheezing.

“Our studies in the large international RHINESSA, RHINE and ECRHS studies have shown that the health of future generations depends on the actions and decisions made by young people today – long before they are parents – in particular for boys in early puberty and mothers/grandmothers both pre-pregnancy and during pregnancy,” says Professor Cecilie Svanes from the University of Bergen and Research Director of the RHINESSA study. “It is really exciting that we have now been able to identify a mechanism that explains our observations in the cohorts.”

‘Unique markers’

“Changes in epigenetic markers were much more pronounced in children whose fathers started smoking during puberty than those whose fathers had started smoking at any time before conception,” says co-lead author of the paper Dr Negusse Kitaba, Research Fellow at the University of Southampton. “Early puberty may represent a critical window of physiological changes in boys. This is when the stem cells are being established which will make sperm for the rest of their lives.”

The team also compared the paternal preconception smoking profiles with people who smoked themselves and those whose mothers smoked before conception.

“Interestingly, we found that 16 of the 19 markers associated with fathers’ teenage smoking had not previously been linked to maternal or personal smoking,” says Dr Gerd Toril Mørkve Knudsen from the University of Bergen and co-lead author of the study. “This suggests these new methylation biomarkers may be unique to children whose fathers have been exposed to smoking in early puberty.”

Teenage vaping ‘deeply worrying’

The number of young people smoking has fallen in the UK in recent years. But co-author Professor John Holloway, from the University of Southampton and the NIHR Southampton Biomedical Research Centre, is concerned about children taking up vaping.

“Some animal studies suggest that nicotine may be the substance in cigarette smoke that is driving epigenetic changes in offspring,” says Professor Holloway. “So it’s deeply worrying that teenagers today, especially teenage boys, are now being exposed to very high levels of nicotine through vaping.

“The evidence from this study comes from people whose fathers smoked as teenagers in the 60s and 70s, when smoking tobacco was much more common. We can’t definitely be sure vaping will have similar effects across generations, but we shouldn’t wait a couple of generations to prove what impact teenage vaping might have. We need to act now.”

The new findings have significant implications for public health. They suggest a failure to address harmful exposures in young teenagers today could damage the respiratory health of future generations, further entrenching health inequalities for decades to come.

Source: University of Southampton

Categories : Diseases, Syndromes and Conditions GeneticsTags :

Scientists Snip Muscular Dystrophy Gene, Yielding Shorter but Now-functional Proteins

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CRISPR-Cas9 is a customisable tool that lets scientists cut and insert small pieces of DNA at precise areas along a DNA strand. This lets scientists study our genes in a specific, targeted way. Credit: Ernesto del Aguila III, National Human Genome Research Institute, NIH

The most common inherited muscular disorder and one of the most severe, Duchenne muscular dystrophy (DMD) results from mutations of the dystrophin gene. In the journal Stem Cell Reports, researchers used a dual CRISPR RNA method to restore dystrophin protein function in stem cells derived from DMD patients. By removing large sections of the dystrophin gene, the cells were able skip faulty or misaligned sections of the genetic code, yielding shortened but still functional proteins for a wide variety of mutation patterns associated with DMD.

“Dual CRISPR-Cas3 is a promising tool to induce a gigantic genomic deletion and restore dystrophin protein via multi-exon skipping induction,” says senior author Akitsu Hotta of Kyoto University. “We expect this study to enlighten new ways to treat DMD patients and other genetic disorders that require extensive deletions.”

Due to significant variations in the mutation patterns affecting the dystrophin gene, deleting a small section of the gene can only be used for a limited number of DMD patients. For example, the most common mono-exon skipping of exons 51, 53, and 45 can be applied to 13%, 8%, and 8% of DMD patients, respectively.

Multi-exon skipping (MES) has broad applicability to various DMD mutation patterns. By targeting the mutation hotspots in the dystrophin gene, MES from exon 45 to 55 was estimated to benefit more than 60% of DMD patients. Unfortunately, few techniques are available to induce a large deletion to cover the target exons spread over several hundred kilobases.

To overcome this hurdle, Hotta and his team used CRISPR-Cas3 to induce a deletion of up to 340 kilobases at the dystrophin exon 45-55 region in various DMD mutation patterns. Because it was rare to observe a deletion of more than a hundred kilobases using a single CRISPR RNA – which helps to locate the correct segment of DNA – the researchers used a pair of CRISPR RNAs inwardly sandwiching the target genomic region.

Limitations of the dual CRISPR RNA system include is variation in the deletion pattern, and the precise start and end points of the deletion cannot be fully controlled. This could be a drawback when a large but precise deletion is required. The study also did not demonstrate the functionality of the recovered dystrophin protein. Future research should aim to improve the overall genome editing efficiency of the Cas3 system.

“Our dual-Cas3 system might apply to future gene therapies once we’re able to deliver the dual-Cas3 components in vivo to skeletal muscle tissues safely and efficiently,” says Hotta. “The ability to induce several hundred kilobases of DNA deletion itself also has broad applicability for basic research when a large deletion is needed.”

Source: Science Daily