Category: Genetics

Categories : GeneticsTags :

Refining the Genetic Heritage of South Africans for Better Medicine

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A new study from Wits University challenges the idea that all South-Eastern-Bantu speaking groups are a single genetic group.

The South-Eastern-Bantu (SEB) language family includes isiZulu, isiXhosa, siSwati, Xitsonga, Tshivenda, Sepedi, Sesotho and Setswana. Almost 80% of South Africans speak one of these as their first language and their origins can be traced to West-Central Africa farmers whose descendants over the past two millennia southwards, finally reaching Southern Africa.

Since then, settling and population movements and interaction with Khoe and San communities, as other SEB speakers, ultimately resulted in distinct Southern African languages such as isiZulu, isiXhosa and Sesotho. But despite these linguistic differences, these groups of people are treated as one group in genetic studies.

Genetic disease studies rely on understanding the genetic diversity of population. If two genetically distinct populations are treated as one, errors could occur when finding disease genes, especially for complex diseases like hypertension and diabetes.

Dr Dhriti Sengupta  and Dr  Ananyo Choudhury in the Sydney Brenner Institute for Molecular Bioscience (SBIMB) at Wits University were joint lead authors of the paper published in Nature Communications. 

“South Eastern Bantu-speakers have a clear linguistic division – they speak more than nine distinct languages – and their geography is clear: some of the groups are found more frequently in the north, some in central, and some in southern Africa. Yet despite these characteristics, the SEB groups have so far been treated as a single genetic entity,” said Dr Choudhury.

The study found that SEB speaking groups are too different to be treated as a single genetic unit.

“So if you are treating say, Tsonga and Xhosa, as the same population – as was often done until now – you might get a completely wrong gene implicated for a disease,” said Sengupta.

The study aimed to find out whether the SEB speakers are indeed a single genetic entity or if they have enough genetic differences to be grouped into smaller units.

Genetic data from more than 5000 participants speaking eight different southern African languages were generated and analysed. Participants were recruited from research sites in Gauteng, Mpumalanga, and Limpopo province.

The study detected major variations in genetic contribution from the Khoe and San into SEB speaking groups; some groups have received a lot of genetic influx from Khoe and San people, while others have had a very little genetic exchange with these groups.

This variation ranged on average from about 2% in Tsonga to more than 20% in Xhosa and Tswana, suggesting that  SEB speaking groups are too different to be treated as a single genetic unit.

“The study showed that there could be substantial errors in disease gene discovery and disease risk estimation if the differences between South-Eastern-Bantu speaking groups are not taken into consideration,” said Dr Sengupta.

The genetic data also show major differences in the history of these groups over the last 1000 years, with genetic exchanges occurring at different points in time. These genetic differences are distinctive enough to affect the outcomes of biomedical genetic research.

Dr Sengupta cautioned that ethnolinguistic identities are complex and broad conclusions extrapolated should not from the findings regarding genetic differences.

“Although genetic data showed differences [separation] between groups, there was also a substantial amount of overlap [similarity]. So while findings regarding differences could have huge value from a research perspective, they should not be generalised,” she said.

A common approach to identify if a genetic variant causes or predisposes a disease is to compare occurrence of many genetic variants in individuals with a disease (eg, hypertension or diabetes) against healthy individuals. If there is a difference in frequency in a variant between two sets, the genetic variant is assumed to be perhaps linked to the disease.

“However, this approach depends entirely on the underlying assumption that the two groups consist of genetically similar individuals. One of the major highlights of our study is the observation that Bantu-speakers from two geographic regions – or two ethnolinguistic groups – cannot be treated as if they are the same when it comes to disease genetic studies,” said Dr Choudhury.

Future studies, especially those testing a small number of variants, need to be more nuanced and have balanced ethnolinguistic and geographic representation, he said.

Professor Michèle Ramsay, director of the SBIMB and corresponding author of the study, says: “The in-depth analysis of several large African genetic datasets has just begun. We look forward to mining these datasets to provide new insights into key population histories and the genetics of complex diseases in Africa”.

Source: Wits University

Journal reference: Sengupta, D., et al. (2021) Genetic substructure and complex demographic history of South African Bantu speakers. Nature Communications.doi.org/10.1038/s41467-021-22207-y.

Categories : Ethics and Law GeneticsTags :

Human-monkey Chimeric Embryos Set off Ethics Debate

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Blastocyst. Source: Wikimedia Commons.

A study published in the journal Cell has announced the creation of human-monkey chimeric embryos, igniting renewed debate over ethics.

The embryos are known as chimeras, organisms whose cells come from two or more “individuals”, and in this case, different species: a long-tailed macaque and a human. The research confirmed that the cells can survive and multiply.

Natural human chimeras do exist, and can involve humans cells from two embryos in the same womb fusing to produce a single individual, or a combination of maternal and foetal cells, or monozygotic twins sharing blood cells from a shared placenta.

Previously, researchers had produced pig or sheep embryos that contained human cells, in an effort to one day develop a way to grow human organs for transplant inside the animals.

The researchers, led by Prof Juan Carlos Izpisua Belmonte from the Salk Institute in the US, said that the results shed new light on the communications pathways between cells of different species. This could help with future efforts to engineer chimeras using more distantly related species.

“These results may help to better understand early human development and primate evolution and develop effective strategies to improve human chimerism in evolutionarily distant species,” the authors wrote.

In 2019, the Spanish newspaper El País reported on rumours that a team of researchers led by Belmonte had created monkey-human chimeras.

Specific human foetal cells called fibroblasts were reprogrammed to become stem cells, and were then introduced into 132 embryos of long-tailed macaques, six days after fertilisation.

“Twenty-five human cells were injected and on average we observed around 4% of human cells in the monkey epiblast,” said Dr Jun Wu, a co-author of the research, and now at the University of Texas Southwestern Medical Center.

The embryos were grown in petri dishes and were terminated 19 days after the stem cells were injected. The human cells were engineered with a fluorescent protein to enable identification.

The researchers reported that 132 embryos contained human cells on day seven after fertilisation. However, the proportion containing human cells fell over time.

“We demonstrated that the human stem cells survived and generated additional cells, as would happen normally as primate embryos develop and form the layers of cells that eventually lead to all of an animal’s organs,” Belmonte said.

The researchers also found differences in intercellular interactions between human and monkey cells within chimeric embryos, compared to the normal monkey embryos.

The researchers hoped the research would help develop “transplantable human tissues and organs in pigs to help overcome the shortages of donor organs worldwide”, said Wu.

Prof Robin Lovell-Badge, a developmental biologist from the Francis Crick Institute in London, said at the time of the El País report he was not concerned about the ethics of the experiment, noting the team had only produced a ball of cells. But he noted conundrums could arise in the future should the embryos be allowed to develop further.

While not the first attempt at making human-monkey chimeras – another group reported such experiments last year – the new study has reignited such concerns. Prof Julian Savulescu, the director of the Oxford Uehiro Centre for Practical Ethics and co-director of the Wellcome Centre for Ethics and Humanities at the University of Oxford, said the research had raised all sorts of ethical concerns.

“These embryos were destroyed at 20 days of development but it is only a matter of time before human-nonhuman chimeras are successfully developed, perhaps as a source of organs for humans,” he said, and added that a key ethical concern was the moral status of such organisms.

“Before any experiments are performed on live-born chimeras, or their organs extracted, it is essential that their mental capacities and lives are properly assessed. What looks like a nonhuman animal may mentally be close to a human,” he said. “We will need new ways to understand animals, their mental lives and relationships before they are used for human benefit.”

Others were less concerned, and rather pointed out that all the study found was that the creation of such chimera was simply ineffective.

Dr Alfonso Martinez Arias, an affiliated lecturer in the department of genetics at the University of Cambridge, said: “I do not think that the conclusions are backed up by solid data. The results, in so far as they can be interpreted, show that these chimeras do not work and that all experimental animals are very sick.

“Importantly, there are many systems based on human embryonic stem cells to study human development that are ethically acceptable and in the end, we shall use this rather than chimeras of the kind suggested here.”

Source: The Guardian

Categories : Genetics Medical Research & TechnologyTags :

New Bioluminescent System Illuminates Biological Processes

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Scientists at the Federal University of São Carlos (UFSCar) have developed a new bioluminescent system that can enable greatly improved imaging of biological and pathological processes in organisms.

Luciferases are enzymes that catalyse the oxidation of luciferins present in organisms such as fireflies, which results in bioluminescence in the visible light spectrum. Images of cell cultures and live animal models are made using the luciferin-luciferase system found in fireflies. For example, this can show the structure and activity of tumours, or follow the viral process in cells, helping physicians develop treatments.

“We obtained a novel luciferin-luciferase system that produces far-red light at the wavelength of 650 nanometres and emits the brightest bioluminescence ever reported in this part of the spectrum,” said principal investigator Professor Vadim Viviani, biochemist at UFSCar. “It’s a highly promising result for bioluminescence imaging of biological and pathological processes in mammalian tissues.”

“Red bioluminescence is preferred when imaging biological or pathological processes in mammalian tissues because haemoglobin, myoglobin and melanin absorb little long-wavelength light. Detection is best of all in the far red and near-infrared bands, but bioluminescent systems that naturally emit far red light don’t exist,” Prof Viviani added.

“Some genetically modified forms of luciferase and synthetic analogs of natural luciferins are produced commercially. In conjunction, they produce light at wavelengths as long as 700 nanometers, but the light produced by these artificial systems is generally much weaker and more short-lived than light from natural bioluminescent systems.”

Prof Viviani and collaborators genetically modified luciferase from the Railroad worm Phrixothrix hirtus, the only luciferase that naturally emits red light, and combined with luciferin analogues synthesised by colleagues at the University of Electro-Communications in Tokyo. The resulting luciferin-luciferase generates a much more efficient far-red bioluminescence.

“Our best combination produces far-red at 650 nanometres, three times brighter than natural luciferin and luciferase, and roughly 1000 times brighter than the same luciferase with a commercial analog,” Viviani said.

“Besides the long-wavelength and intense brightness, our combination has better thermal stability and cell membrane penetrability. Above all, it produces more lasting continuous bioluminescence, taking at least an hour to decay and significantly facilitating the real-time imaging of biological and pathological processes.”

Source: News-Medical.Net

Journal information: Viviani, R. V, et al. (2021) A Very Bright Far-Red Bioluminescence Emitting Combination Based on Engineered Railroad Worm Luciferase and 6′-Amino-Analogs for Bioimaging Purposes. International Journal of Molecular Sciences. doi.org/10.3390/ijms22010303.

Categories : GeneticsTags :

Whole Genome Sequencing Yields Diagnoses for Rare Diseases

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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 :

Diphtheria Resurfacing as a Threat As it Evolves Antibiotic Resistance

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Diphtheria is resurfacing as a threat worldwide as it evolves antibiotic resistance and could escape vaccine containment, scientists warn.

Diphtheria cases in recent years have doubled what they were in previous decades, to 16 651 cases in 2018. Although babies are vaccinated against it in high-income countries, there is less coverage in middle- and low-income countries.

Diphtheria is mainly caused by Corynebacterium diphtheriae, spread by coughs and sneezes or close contact with the infected. Usually, the bacteria cause acute infections, driven by the diphtheria toxin—the main target of the vaccine. However, non-toxigenic C. diphtheria can also cause disease.

A team of researchers from the UK and India used genomics to map infections, including a subset from India, where more than half of the globally reported cases occurred in 2018.

Analysing the genomes of 61 bacteria isolated from patients and combining these with 441 publicly available genomes, the researchers were then able to understand how they spread. They also used this information to assess the presence of antimicrobial resistance (AMR) genes and assess toxin variation.

The researchers found clusters to genetically-similar bacteria isolated from different continents, most commonly Asia and Europe. This indicates that C. diphtheriae has been travelling with humans as they spread across the planet.

The diphtheria toxin ch is encoded by the tox gene, for which the researchers found 18 different variations, of which several had the potential to change the structure of the toxin.

Professor Gordon Dougan from the Cambridge Institute of Therapeutic Immunology and Infectious Disease (CITIID) said: “The diphtheria vaccine is designed to neutralise the toxin, so any genetic variants that change the toxin’s structure could have an impact on how effective the vaccine is. While our data doesn’t suggest the currently used vaccine will be ineffective, the fact that we are seeing an ever-increasing diversity of tox variants suggests that the vaccine, and treatments that target the toxin, need to be appraised on a regular basis.”

First author Robert Will, a PhD student at CITIID, said: “The C. diphtheriae genome is complex and incredibly diverse. It’s acquiring resistance to antibiotics that are not even clinically used in the treatment of diphtheria. There must be other factors at play, such as asymptomatic infection and exposure to a plethora of antibiotics meant for treating other diseases.”

Erythromycin and penicillin are commonly recommended to treat early-stage diphtheria, although there are other classes capable of it. Variants resistant to six of these classes in isolates from the 2010s were identified by the team.

Study leader Dr Ankur Mutreja from CITIID, said: “It’s more important than ever that we understand how diphtheria is evolving and spreading. Genome sequencing gives us a powerful tool for observing this in real time, allowing public health agencies to take action before it’s too late.
“We mustn’t take our eye off the ball with diphtheria, otherwise we risk it becoming a major global threat again, potentially in a modified, better adapted, form.”

Source: Medical Xpress

Journal information: Will, RC et al. Spatiotemporal persistence of multiple, diverse clades and toxins of Corynebacterium diphtheria. Nat Comms; 8 Mar 2021; DOI: 10.1038/s41467-021-21870-5

Categories : Gender GeneticsTags :

Health Conditions Driven By Evolution and Genetic Sex Differences

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A new study shows that the human genome has been subject to selection pressures favouring different characteristics in females and males, which makes males more susceptible to a variety of health conditions.

Genetic sex differences have long been known to have an impact on health. On balance, while females have certain conditions unique to them (eg, cervical cancer), or are more prone to (eg, multiple sclerosis), males are more prone to certain medical conditions, bringing down their average life expectancy compared to women.

Their research adds to a body of knowledge on genomic influences on health, which can map hereditary traits onto individuals and populations to guide healthcare. Looking at health conditions through the lens of genomics can help clinicians to better understand them and guide development of new treatments.  

“Our cells have memories and they carry the accumulation of all the changes our ancestors have experienced over millions of years,” said Rama Singh, a McMaster biology professor who wrote the paper with his son, Karun Singh, an associate professor of neuropathology at the University of Toronto, and Shiva Singh (no relation), a biology professor at Western University.

The researchers focussed on autism, which is a good example of the way men and women develop medical conditions differently; though they inherit the same sets of genes from the parents, the expression of those genes differs greatly by sex.

Though human behaviour regarding mate selection has changed, those genetic characteristics remain and continue to be expressed in the health and development of modern men.

The male genome has been shaped over millions of years, and favours reproduction in the early years of male maturity to pass on genes, at the expense of genetic well-being in the long term.

Women are less vulnerable to most health conditions, living longer than men because their genomes have evolved to protect against unhealthy traits in the male genome, resulting in better immunity and more longevity.

The same forces shaping human selection also apply to mental health, even though it is complex. Women are more prone to anxiety and depression, while men are more prone to anti-social disorders.

“If women and men were any more different, they would be different species,” joked corresponding author, Prof Karun Singh.

Male-female imbalance is especially pronounced in autism, with being up to four times more likely to have some form of autism, and are also more likely to have severe symptoms. Evolution has resulted in a higher threshold, protecting females from developing the condition.

Although autism is not solely the result of inherited characteristics, it does appear that boys are more likely to develop it as a result of other inhertied characteristics rendering them more vulnerable to environmental, developmental and other factors that give rise to autism.

“One of the reasons I think this is interesting is that it offers a perspective that is not well represented in the medical literature. This is a really good example of the perspective that geneticists and evolutionary biologists can add to health research,” said Prof Karun Singh.

Source: News-Medical.Net

Journal information: Singh, R. S., et al. (2021) Origin of Sex-Biased Mental Disorders: An Evolutionary Perspective. Journal of Molecular Evolution. doi.org/10.1007/s00239-021-09999-9.

Categories : GeneticsTags :

Study Reveals How Thyroid Subtly Regulates Metabolism

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Thyroid hormone appears to regulate metabolism by acting as a ‘dimmer switch’ as opposed to an ‘on/off’ switch, as reported by a new study from the University of Pennsylvania.

The thyroid hormone has long been known to be an important controller of the body’s metabolism, as well development, but how exactly this is achieved remains something of a mystery. Part of this problem was that the thyroid hormone worked inside the nucleus, activating some genes and deactivating others. Being able to observe this process has been extremely challenging.

“We were able in this study to show that thyroid hormone doesn’t just turn things on or off, as the canonical model suggests, but instead more subtly shifts the balance between the repression and enhancement of gene activity,” said principal investigator Mitchell Lazar, MD, PhD, at Penn Medicine. “Yet, as people with hypothyroidism know, the lack of thyroid hormone can have profound effects on the body.”

Knowing how thyroid hormone regulates the body’s metabolism would be a great boon for new drug development, especially to tackle obesity. For four decades, scientists have known that thyroid hormone acts on thyroid hormone receptors, but these special proteins exist in small quantities and marking where they are on DNA has proven difficult.
In the new study, the researchers developed a mouse model in which a special tag was added to TRβ, the main thyroid hormone receptor in the liver, which is where important metabolic effects of thyroid hormone occur. With this tag, they marked the thousands of locations on DNA where TRβ binds, both in states when thyroid hormone was present and could bind to TRβ and also when no hormone was present. In this way, the team came up with strong evidence that shows the unexpectedly subtle manner in which thyroid hormone works with TRβ.

When it binds to a DNA site, TRβ will promote or suppress nearby gene activity by forming complexes with other proteins called co-activators and co-repressors. When thyroid hormone is bound to TRβ, it can alter the balance of these co-regulator proteins towards more gene activation at some sites, and more gene repression at others. Prior models of thyroid hormone / TRβ function in which thyroid hormone has a more absolute, switch-like effect on gene activity.

The researchers acknowledged that more work is needed to discover just how genes are activated or repressed at the sites. However, this is a significant advancement towards treatments which can directly influence the body’s metabolism.

Source: Medical Xpress

Categories : Diseases, Syndromes and Conditions GeneticsTags :

Excessive False Positives from SNP Testing in Very Rare Diseases

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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

Categories : Genetics Injury & TraumaTags :

Plasma microRNAs as Biomarkers for Mild Brain Injury

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Plasma microRNA could serve as biomarkers for the detection and diagnosis of mild traumatic brain injury, a recent study from the University of Eastern Finland (UEF) has found.

Mild traumatic brain injury is extremely difficult to detect as it is almost invisible to most imaging techniques, and visible signs in daily life may be masked by compensation for increased task difficulty.

Blood biomarkers can satisfy the demand for timely, accurate, easily accessible and affordable tests for mild traumatic brain injury. They are minimally invasive and can provide molecular information about the injury on an ongoing basis.

MicroRNAs (miRNAs) are non-coding sections of RNA that play a key role in gene expression. The researchers sequenced DNA in blood plasma taken from animal models subjected to mild and severe traumatic brain injury. They selected the miRNAs which showed the greatest potential for use as biomarkers for further analysis with polymerase chain reaction (PCR). They wanted biomarkers that were both sensitive and specific to traumatic brain injury in an animal model.

Dr Noora Puhakka, A. Virtanen Institute for Molecular Sciences, UEF, said, “We have been developing a suitable analysis and measurement method especially for miRNAs that can be found in small amounts in plasma, and this method is based on digital droplet PCR.

“Humans and animals share many identical miRNAs, and this makes them excellent candidates for translational studies, where results achieved in animal models are sought to be applied in humans. However, it has proven challenging to reproduce results from different studies and different sets of data. This is why assessing the quality of measurement methods, and reproducibility, is an extremely important part of biomarker research.”
The study a pair of possible biomarker candidates to diagnose mild traumatic brain injury both in the animal model and in human patients.  

“We found two interesting biomarkers in the animal model, the plasma miRNAs miR-9a-3p and miR-136-3p, which we then decided to analyse in blood samples taken from patients with traumatic brain injury. Elevated levels of these biomarkers allowed us to identify some of the patients who had experienced a mild traumatic brain injury,” Dr Puhakka explained.

“Both of these miRNAs are more abundant in the brain than in other tissues, and their elevated levels in plasma could possibly be due to brain injury and the level of its seriousness. However, further research in larger patient cohorts is still needed.”

Source: News-Medical.Net

Journal information: Gupta, S. D., et al. (2021) Plasma miR-9-3p and miR-136-3p as Potential Novel Diagnostic Biomarkers for Experimental and Human Mild Traumatic Brain Injury. International Journal of Molecular Sciences. doi.org/10.3390/ijms22041563.