Category: Genetics

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.

Categories : GeneticsTags :

African Genetic Data Needed to Complete the DNA Picture

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A $4.5 billion initiative to gather genomic data from African populations has been put forward to help fill the gaps in understanding the human genome.

Genome Wide Assay Studies (GWAS) have yielded a huge amount of insight into genetic associations with disease and roles in bodily function, transforming medicine. But the picture is still incomplete, and there are large gaps remaining.

While the genomes of Europeans and Americans has been well mapped, the genomes of Africans remain virtually a blank state despite having far more genetic diversity than any other region. Genome mapping has come a long way in the two decades since the first genome was sequenced, falling in cost from $3 billion to around $1000.

“Most genomic research on the African continent over the last two decades has largely been driven by agendas defined more by European and American investigators,” Ambroise Wonkam, a medical genetics professor and deputy dean of research at the University of Cape Town’s Faculty of Health Sciences, told AFP.

“The Three Million African Genomes (3MAG) project would require sequencing individuals carefully selected across Africa to cover ethnolinguistic, regional and other groups,” Prof Wonkam said. A similar study to map the genomes of 100 000 Asian people is underway. 

The continent’s enormous genetic diversity no doubt holds a great number of surprises and important discoveries. Making his case in a comment in Nature, Prof Wonkam said that having access to such a diverse database would make it much easier to track down mutations.

“The aim is to capture the full scope of Africa’s genetic variation—for the benefit of all human populations and to ensure equitable access to genetic medicine.”

For example, a variant of the PCSK9 gene that is correlated with dyslipidaemia only came to light because it was 200 times more common in African Americans than Europeans.

Citing another example, Prof Wonkam said, “The inclusions of even a small number of black Americans in control cohorts probably would have prevented the misclassification of benign variants as causing cardiomyopathy.”

The relatively few GWAS of African populations that have been done also revealed a genetic susceptibility to type-2 diabetes that had previously gone unreported, and up to half of African populations have a gene variant associated with severe side effects to the HIV drug efavirenz.

When the genomes of 910 people of African descent were sequenced, it revealed large gaps in the ‘reference genome’ used by researchers around the world, Jesse Gillis, a researcher at the Stanley Institute for Cognitive Genomics in New York, noted in a study in BMC.

“Approximately 10 percent of DNA sequences—some 300 million base pairs—from these genomes were ‘missing’,” he stated.

Prof Wonkam has said that the study should mostly be funded by African governments, but international organisations should help foot the bill too. 

Source: Medical Xpress

Journal information: Comment: Sequence three million genomes across Africa, Nature (2021). DOI: 10.1038/d41586-021-00313-7 , www.nature.com/articles/d41586-021-00313-7

Categories : GeneticsTags :

Study Reveals the Genetics of Daytime Napping

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Genes play a role in how often, if at all, people take daytime naps, research has revealed.

Identifying dozens of genetic regions associated with napping, a team of researchers from Massachusetts General Hospital (MGH) and the University of Murcia in Spain conducted the largest study of its kind. Additionally, they discovered genetic links to cardiometabolic health. 

“Napping is somewhat controversial,” said Hassan Saeed Dashti, PhD, RD, of the MGH Center for Genomic Medicine, co-lead author of the report. Dashti noted that some countries (such as Spain) which featured daytime napping in their culture now discourage it. Conversely, some companies in the United States now promote napping as a productivity. “It was important to try to disentangle the biological pathways that contribute to why we nap,” said Dashti.

In a Genome-Wide Association Study, the MGH researchers used genomic data obtained from the UK Biobank, which holds the genomes of 452 633 people. They replicated their findings using data from the company 23andMe which has obtained data from 541 333 people. The participants had rated their daytime napping habits, and a subset wore accelerometers to provide objective verification of resting behaviour. A number of the genes analysed were also already known to be associated with sleep.

The GWAS identified 123 genetic areas associated with napping. On further investigation, the researchers identified three factors which promote napping:

Sleep propensity: Some people require more sleep than others.
Disrupted sleep: Daytime napping can make up for poor sleep the previous night.
Early morning awakening: People who wake up too early can ‘get back’ some sleeping` time.

“This tells us that daytime napping is biologically driven and not just an environmental or behavioural choice,” said Dashti. Some of these subtypes were linked to cardiometabolic health concerns, such as waist circumference.

“Future work may help to develop personalised recommendations for siesta,” concluded Garaulet.

A number of the genes related to napping were already associated with orexin, a neuropeptide involved in wakefulness, as well as a number of other areas such as mood and feeding behaviour. This pathway is known to be associated with narcolepsy, but the findings suggested that smaller perturbations seem to be associated with napping.

Source: Medical Xpress

Journal information: Dashti, H.S., Daghlas, I., Lane, J.M. et al. Genetic determinants of daytime napping and effects on cardiometabolic health. Nat Commun 12, 900 (2021). doi.org/10.1038/s41467-020-20585-3 , www.nature.com/articles/s41467-020-20585-3

Categories : GeneticsTags :

New Study Finds Critical Flaw in Blood-brain Model

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The wrong kind of cells have been used to make in vitro models of the blood-brain barrier, which now throws a decade’s worth of research into question.

The present in vitro human blood-brain barrier model was developed in 2012. By inducing differentiated adult cells, such as skin cells, into developing into stem cells, the pluripotent stem cells obtained from the process are then transformed into nearly any type of mature cell. This includes the type of endothelial cell that lines brain and spinal cord blood vessels, and making a unique barrier that acts as a gatekeeper, restricting potentially dangerous substances, antibodies, and immune cells from entering the brain from the bloodstream.

“The blood-brain barrier is difficult to study in humans and there are many differences between the human and animal blood-brain barrier. So it’s very helpful to have a model of the human blood-brain barrier in a dish,” said co-study leader Dritan Agalliu, PhD, associate professor at Columbia University Vagelos College of Physicians and Surgeons.

Agalliu had noticed that these endothelial cells produced in this manner, did not behave like normal endothelial cells in the human brain. “This raised my suspicion that the protocol for making the barrier’s endothelial cells may have generated cells of the wrong identity,” said Agalliu.
“At the same time the Weill Cornell Medicine team had similar suspicions, so we teamed up to reproduce the protocol and perform bulk and single-cell RNA sequencing of these cells.”

Upon analysis, the researchers discovered that the supposed human brain endothelial cells were missing several key proteins found in natural endothelial cells and had more in common with epithelial cells, which is not usually found in the brain.

The team also identified three genes that, when activated within induced pluripotent cells, lead to the creation of cells that behave more like actual endothelial cells. More work is still needed, Agalliu says, to create endothelial cells that produce a reliable model of the human blood-brain barrier. His team is working to address this problem.

“The misidentification of human brain endothelial cells may be an issue for other types of cells made from induced pluripotent cells such as astrocytes or pericytes that form the neurovascular unit,” said Agalliu. The protocols to produce these cells were drawn up prior to the advent of single-cell technologies that are better at identifying cells.

“Cell misidentification remains a major problem that needs to be addressed in the scientific community in order to develop cells that mirror those found in the human brain. This will allow us to use these cells to study the role of genetic risk factors for neurological disorders and develop drug therapies that target the correct cells that contribute to the blood-brain barrier.”

Source: Medical Xpress

Categories : Genetics New Compounds and TreatmentsTags :

Embracing Ethnic Genetic Diversity in Drug Design

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Although human beings have a great deal of genetic similarity, small genetic differences can nonetheless lead to very different results in drug effects.

Pharmacologist Namandje Bumpus, PhD—who recently became the first African American woman to head a Johns Hopkins University School of Medicine department, and is the only African American woman leading a pharmacology department in the country—explains why certain drugs can have different effects between distinct populations. Warfarin, for example, is known to be less effective in people of African descent.  

As new vaccines and treatments are developed to fight the COVID pandemic, which have disproportionately affected certain ethnic groups. According to APM Research Lab, in the US as of 2 Feb, Pacific Islanders are 2.7 times as likely to die from COVID as whites (adjusted for age), compared to 0.9 times for Asian Americans.

In light of these differences, Bumpus laid out a four-part plan to improve the equity of drug development.

Merely increasing the representation of races in drug trials is insufficient. Her plan includes: laboratory research to study genetic variability; diversifying the scientific workforce; diversity requirements for funding agencies; and diversity reporting requirements on clinical trial demographics in published articles.

Bumpus said that with genetic technology, animals can be engineered to “bolster predictability of drug outcomes and provide a mechanistic foundation for understanding disparities.”

Genetic variations linked to drug response are often associated with a family of enzymes, cytochromes P450. In humans this enzyme family processes about 75% of clinically available drugs. Subtle genetic differences can however lead to altered enzymes in humans, and these are more common in certain ethnic groups. 

This framework, Bumpus said, could compel the drug development field to move toward a future where “treatments are most likely to work for all people” and “existing health disparities are not further exacerbated.”

Source: Medical Xpress

Journal information: Namandjé N. Bumpus, “For better drugs, diversify clinical trials,” Science  05 Feb 2021: Vol. 371, Issue 6529, pp. 570-571. DOI: 10.1126/science.abe2565