Tag: gene sequencing

Categories : Diseases, Syndromes and ConditionsTags :

Gene Mutation in Young Girl May Finally Yield Lupus Treatment

On By ModernMedia
Facial rash characteristic of lupus. Credit: Statpearls

A study published in Nature has identified mutations in an X chromosome gene that senses viral RNA, as a cause of the autoimmune disease lupus, a finding which may explain why the disease is far more common in females, and which might lead to new treatments.

In the study, whole genome sequencing was performed on the DNA of a Spanish child named Gabriela, who was diagnosed with severe lupus at age 7. Such a severe case with early onset of symptoms is rare and suggests a single genetic cause.

In their genetic analysis, the researchers discovered a single point mutation in the TLR7 gene. Referrals from other institutions, they were able to identify other cases of severe lupus where this gene was also mutated.

To confirm that the mutation causes lupus, the team inserted the gene into mice, which went on to develop the disease and showed similar symptoms. The mouse model and the mutation were both named ‘kika’ by Gabriela, the young girl central to this discovery.

Carola Vinuesa, senior author and principal investigator said: “It has been a huge challenge to find effective treatments for lupus, and the immune-suppressors currently being used can have serious side effects and leave patients more susceptible to infection. There has only been a single new treatment approved by the FDA in about the last 60 years.

“This is the first time a TLR7 mutation has been shown to cause lupus, providing clear evidence of one way this disease can arise.”

Professor Nan Shen, co-director of CACPI adds: “While it may only be a small number of people with lupus who have variants in TLR7 itself, we do know that many patients have signs of overactivity in the TLR7 pathway. By confirming a causal link between the gene mutation and the disease, we can start to search for more effective treatments.”

The mutation identified by the researchers makes TLR7 protein bind more readily guanosine and become more active. This in turn increases the sensitivity of the immune cell, making it more likely to incorrectly target healthy tissue.

Interestingly, other studies have shown mutations that cause TLR7 to become less active are associated with some cases of severe COVID infection, highlighting the delicate balance of a healthy immune system.

The findings could also explain why lupus is 10 times more common in females than in males. Because TLR7 is located on the X chromosome, females have two copies of the gene while males have one. Usually, in females one of the X chromosomes is inactive, but in this section of the chromosome, silencing of the second copy is often incomplete. This means females with a mutation in this gene can have two functioning copies.

Study co-author Dr Carmen de Lucas Collantes, said: “Identification of TLR7 as the cause of lupus in this unusually severe case ended a diagnostic odyssey and brings hope for more targeted therapies for Gabriela and other lupus patients likely to benefit from this discovery.”

Gabriela, now a teenager, remains in touch with the research team. She said, “I hope this finding will give hope to people with lupus and make them feel they are not alone in fighting this battle. Hopefully the research can continue and end up in a specific treatment that can benefit so many lupus warriors who suffer from this disease.”

The researchers are now investigating the repurposing of existing treatments which target the TLR7 gene. By targeting this gene, they hope to be able to also help patients with related conditions.

Carola added: “There are other systemic autoimmune diseases, like rheumatoid arthritis and dermatomyositis, which fit within the same broad family as lupus. TLR7 may also play a role in these conditions.”

Source: Francis Crick Institute

Categories : GeneticsTags :

Whole Genome Sequencing Yields Diagnoses for Rare Diseases

On By ModernMedia

With the integration of whole genome sequencing in Swedish healthcare, some 1200 individuals with rare diseases have received a diagnosis, with novel disease genes discovered in the process.

“We’ve established a way of working where hospital and university collaborate on sequencing each patients’ entire genome in order to find genetic explanations for different diseases,” said first author Henrik Stranneheim, researcher at the Department of Molecular Medicine and Surgery, Karolinska Institutet. “This is an example of how precision medicine can be used to make diagnoses and tailor treatments to individual patients.”

The technology of large-scale whole genome sequencing to yield a person’s entire DNA, is not yet widely used in hospitals despite the technology becoming much more accessible over the last ten years. Whole genome sequencing has uncovered a great genetic variety among different populations, such as in South Africa, where a pilot study uncovered a high rate of novel variants in African populations.

Karolinska University Laboratory and the Clinical Genomics facility at SciLifeLab launched the Genomic Medicine Centre Karolinska-Rare Diseases (GMCK-RD) five years ago. Since then, the centre has sequenced the genomes of 3219 patients, which led to molecular diagnoses for 40% of them with rare diseases.

In addition to these, the researchers found pathogenic mutations in more than 750 genes and discovered 17 novel disease genes. 

“Clinical whole genome sequencing has had huge implications for the area of rare diseases,” explained corresponding author Anna Wedell, professor at the Department of Molecular Medicine and Surgery, Karolinska Institutet. “Used in the right way, targeted at each patient’s specific clinical situation, new groups of patients can receive the right diagnosis and treatment in a way that hasn’t been possible before.”

Whole genome sequencing is challenging in part due to having to manage and interpret the millions of variations that exist within each invidual’s genome. In order to overcome this difficulty, the centre came up with a model that directs the initial analysis to pathogenic variants in genes relevant for that patient’s clinical symptomsIn this way, doctors play an important role in choosing which genetic analyses to run first.
Should the first assessment fail, the analyses are then broadened to more gene panels, which has uncovered new disease genes.

“For us to succeed with precision medicine, a multidisciplinary collaboration between health care and academia is essential,” said second corresponding author Anna Lindstrand, professor at the Department of Molecular Medicine and Surgery, Karolinska Institutet and consultant at Karolinska University Hospital’s Department of Clinical Genetics. “Through these initiatives we combine clinical expertise with bioinformatic tools and together deliver accurate diagnoses and individualised treatments.”

Source: Medical Xpress

Journal information: “Integration of whole genome sequencing into a health care setting: High diagnostic rates across multiple clinical entities in 3219 rare disease patients,” Genome Medicine (2021). DOI: 10.1186/s13073-021-00855-5

Categories : COVID GeneticsTags :

Bat Coronavirus 94.5% Similar to SARS-CoV-2 Found

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Researchers in China and Australia have reported the discovery of novel bat coronaviruses with a similarity of up to 94.5% to SARS-CoV-2. 

This finding further illuminates the diversity and complex evolutionary history of these viruses. A pre-print version of the research paper is available on the bioRxiv server.

Now, Weifeng Shi from Shandong First Medical University & Shandong Academy of Medical Sciences in Taian, China and colleagues have conducted a meta-transcriptomic analysis of samples collected from 23 bat species in Yunnan province in China during 2019 and 2020.  

Using a combination of genome sequencing and sampling studies, researchers identified a number of SARS-CoV-2-related coronaviruses in wildlife species that together pointed to underestimation of the phylogenetic and genomic diversity of coronaviruses.

“Our study highlights both the remarkable diversity of bat viruses at the local scale and that relatives of SARS-CoV-2 and SARS-CoV circulate in wildlife species in a broad geographic region of Southeast Asia and southern China,” said the team.

Bats are hosts to a broad range of viruses that can infect humans, and four of the seven known human coronaviruses have zoonotic origins.  They are also host to many coronaviruses, but sometimes “intermediate” hosts such as dromedary camels (MERS-CoV) are involved in the jump to humans.

Retrospective genome sequencing and sampling studies identified a number of SARS-CoV-2-related coronaviruses in wildlife species. These included the RaTG13 virus, which is the closest known relative of SARS-CoV-2,  found in the Rhinolophus affinis bat. SARS-CoV-2-related viruses have also been identified in various other Rhinolophid bats across Asia.

“Collectively, these studies indicate that bats across a broad swathe of Asia harbour coronaviruses that are closely related to SARS-CoV-2 and that the phylogenetic and genomic diversity of these viruses has likely been underestimated,” said Shi and colleagues.

Notably, one of these novel bat coronaviruses – RpYN06 – exhibited 94.5% sequence identity to SARS-CoV-2 across the whole genome, with key similarities in certain genes. Low genopmic sequence identity in the spike gene made RpYN06 the second closest relative of SARS-CoV-2, next to RaTG13. This is far more similar than seen in other SARS-CoV-2-like viruses identified in wildlife species.

Indeed, while the other three SARS-CoV-2-related viruses identified here were almost identical in sequence, the spike protein sequences formed an independent lineage that was separated from known sarbecoviruses (a  viral subgenus or the coronaviruses that  includesSARS-CoV-2)   by a relatively long branch.

“Collectively, these results highlight the extremely high, and likely underestimated, genetic diversity of the sarbecovirus spike proteins, which likely reflects their adaptive flexibility,” wrote Shi and colleagues.

The researchers say studies have previously shown that host switching of coronaviruses among bats is a frequent occurrence.

Source: News-Medical.Net

Journal information: Shi W, et al. Identification of novel bat coronaviruses sheds light on the evolutionary origins of SARS-CoV-2 and related viruses. bioRxiv. 2021. doi: https://doi.org/10.1101/2021.03.08.434390

Categories : Diseases, Syndromes and Conditions GeneticsTags :

Excessive False Positives from SNP Testing in Very Rare Diseases

On By ModernMedia

A widely-used genetic testing technology has a very high rate of false positives for extremely rare genetic diseases, a study has found.

Single nucleotide polymorphism (SNP) chips are DNA microarrays which test genetic variation at hundreds of thousands of specific genome locations. They were initially developed to study common genetic variations, and are excellent tools for tracing ancestry and aso detecting predisposition to common multifactorial diseases such as type 2 diabetes.

Prompted by accounts of women scheduling surgery because of wrongly being informed they had variations in the BRCA1 gene that could lead to very high risks of breast disease, a team from the University of Exeter set out to test the technology. Using data from 50 000 individuals, they found that the majority of rare disease detections were false.

“SNP chips are fantastic at detecting common genetic variants, yet we have to recognise that tests that perform well in one scenario are not necessarily applicable to others,” said senior author Caroline Wright, Professor in Genomic Medicine at the University of Exeter Medical School. “We’ve confirmed that SNP chips are extremely poor at detecting very rare disease-causing genetic variants, often giving false positive results that can have profound clinical impact. These false results had been used to schedule invasive medical procedures that were both unnecessary and unwarranted.”

The team compared data from the SNP chips to data from the UK Biobank which was sequenced with better technology, plus 21 volunteers sharing their consumer genetic data.

They found a false positive rate of 84% for variants that were 1 in 100 000. From the consumer data, 20 of the 21 had at least one false positive for a disease-causing variation.

Co-author Dr Leigh Jackson, Lecturer in Genomic Medicine at the University of Exeter, said the number of such false positives on SNP chips was “shockingly high.”

“To be clear: a very rare, disease-causing variant detected using a SNP chip is more likely to be wrong than right,” said Dr Jackson. “Although some consumer genomics companies perform sequencing to validate important results before releasing them to consumers, most consumers also download their ‘raw’ SNP chip data for secondary analysis, and this raw data still contain these incorrect results. The implications of our findings are very simple: SNP chips perform poorly for detecting very rare genetic variants and the results should never be used to guide a patient’s medical care, unless they have been validated.”

Source: Medical Xpress

Journal information: BMJ (2021). www.bmj.com/content/372/bmj.n214

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Genetic Basis for Why Lithium is Effective for Only Some

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Lithium was the first effective mood stabiliser for bipolar disorder (BD) and still the first-line treatment, but it is effective only in about 30% of patients, while the remainder are unresponsive. A new study implicates the decreased activation of a certain gene.

The study shows that decreased activation of a gene called LEF1 disrupts ordinary neuronal function and promotes hyperexcitability in brain cells—a hallmark of BD. The findings could lead to development of a new drug target for BD as well as a biomarker for lithium nonresponsiveness.

“Only one-third of patients respond to lithium with disappearance of the symptoms,” says Renata Santos, co-first author on the study. “We were interested in the molecular mechanisms behind lithium resistance, what was blocking lithium treatment in nonresponders. We found that LEF1 was deficient in neurons derived from nonresponders. We were excited to see that it was possible to increase LEF1 and its dependent genes, making it a new target for therapeutic intervention in BD.”

The study built on a previous one which discovered differences in the neurons of those with lithium unresponsiveness.

Using stem cell technology, the team grew neurons sampled from patients’ blood, who had BD and were responsive or unresponsive to lithium, and from normal patients. They compared the genetic characteristics and behaviour of those neurons.Lithium enables beta-catenin to pair with LEF1 to promote neural regulation in the normal controls and lithium responders.

Administration of valproic acid, a typical treatment for non-responders, increased LEF1 levels as well as activation of related genes. Silencing the LEF1 gene also deactivated related genes.”When we silenced the LEF1 gene, the neurons became hyperexcitable,” says Shani Stern, co-first author on the study. “And when we used valproic acid, expression of LEF1 increased, and we lowered the hyperexcitability. That shows there is a causative relationship, and that’s why we think LEF1 may be a possible target for drug therapy.”

The team wants to look at other types of cells, such as astrocytes, to better understand the role of LEF1 in the bipolar neural network.”LEF1 works in various ways in different parts of the body, so you can’t just turn it on everywhere,” said  co-corresponding author Carol Marchettor. “You want to be more specific, either activating LEF1 on a targeted basis or activating downstream genes that are relevant for lithium nonresponsiveness.”

Source: Medical Xpress

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Discovery of New Genetic Targets for Endometriosis Treatment

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Endometriosis can be a debilitatingly painful disease which can lead to infertility, and has few treatment options for more severe forms – but new treatment options are unfolding as genetic targets for drugs are discovered.

Jake Reske, a graduate student in the MSU Genetics and Genome Sciences Program, explains: “There haven’t been many successful nonhormonal therapies for this form of endometriosis that have made it to the bedside yet.”

Some severe forms of endometriosis involve a gene called ARID1A. A mutation in this gene triggers “super-enhancer” DNA which in turn allows cells to run rampant and set up outside the uterus, causing great pelvic pain.

The researchers aim to implement a novel treatment, “epigenetic therapy”, to prevent the cells from running rampant. 

“It can seriously impact women’s quality of life and their ability to have a family and work,” said study supervisor Ronald Chandler, an assistant professor of obstetrics, gynaecology and reproductive biology. “It’s not easy to treat, and it can become resistant to hormone therapy. The most clinically impactful thing we found is that targeting super-enhancers might be a new treatment for this deeply invasive form of the disease.”

The compound they used targeted protein called P300, which suppressed the super-enhancers and relieving the effects of the  ARID1A mutation. This could also possibly be applied to other forms of endometriosis. The researchers plan to look for more compounds that can also target the P300 protein.  

Source: News-Medical.Net

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Study Reconstructs Original SARS-CoV-2 “Progenitor” Genome

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Medical Xpress reports on a study which managed to make a reconstruction of the original SARS-CoV-2 genome that infected patient zero.

No genome could have possibly been sampled in the early days when the virus made the jump to humans while the world was still unaware of the disease; thus, it has to be reconstructed by working backwards through all the mutations recorded. This study was led by Sudhir Kumar, director of the Institute for Genomics and Evolutionary Medicine, Temple University, and sifted through 30 000 complete SARS-CoV-2 genomes, searching for what they called the “progenitor genome”.

Previous attempts to reach the same goal because the focus was to build an evolutionary tree, said Kumar. “This coronavirus evolves too slow, the number of genomes to analyze is too large, and the data quality of genomes is highly variable. I immediately saw parallels between the properties of these genetic data from coronavirus with the genetic data from the clonal spread of another nefarious disease, cancer,” Kumar said.

The research has already yielded intriguing insights; a protein that made the virus more infectious apparently appeared early on, before many of the other mutations that took place, but this protein was not in the progenitor genome.

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COVID DNA of White House “Superspreader Event” Analysed

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On September 26, numerous high-profile individuals, contracted COVID at a large official White House gathering. This White House “superspreader event” as it was known became something of a case study in how COVID can spread in large groups of people.

Although President Trump contracted the virus, it is not known if this was a result of attending that event. The event, which had over a dozen guests, resulted in 34 individuals including White House staff testing positive for COVID by October 7.

Whilst contact tracing is difficult with COVID, genome sequencing offers a chance for insights into its development and spread. The researchers analysed SARS-CoV-2 genomes from nasal swabs taken from the patients at the White House superspreader event, and analysed it, looking for mutations. They found two variants, WH-2 and WH-2. They determined that these viruses descended from those widely in circulation in Florida, New York, Texas, Connecticut, and Washington – as well as certain countries such as  New Zealand.

Source: News-Medical.Net