Tag: genetics

Categories : Diseases, Syndromes and ConditionsTags :

Why Some Infections Can Be so Persistent

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C. difficile bacteria. Source: CDC

University of Utah researchers have discovered a novel mechanism that infectious bacteria use to rapidly adapt to environmental stress, which could help explain why certain types of common infections such as sepsis can be so persistent.

The mechanism, described in the journal Nucleic Acids Research, alters the precision with which the bacteria make the proteins that carry out most of the work in cells. These changes may improve the bacteria’s chance for survival.

“Understanding how pathogens survive stressful situations can reveal new targets for development of anti-microbial drugs and vaccines,” said the study’s senior author, Professor Matthew Mulvey.

Adapt or die
Bacteria infecting a host are exposed to stresses such as acidity or antibiotics. If even one of the bacteria’s key pathways for survival is crippled, the entire population could die off.

However, bacteria can adapt, an ability that relies on a slight twist to basic principles of biology.

Traditionally, each gene is thought to carry instructions for making a single kind of protein. A molecule called transfer RNA (tRNA) then uses these instructions to oversee protein production in the cell. In times of stress, though, random changes to the tNRA-mediated process can be an especially quick way to alter a cell’s array of proteins. This can generate useful new proteins that help the organism to thrive.

“There is a growing appreciation that a little bit of noise in the system can be good,” Prof Mulvey said.

Shifting expectations
A graduate student in the lab happened to stumbled onto a bacterial enzyme, MiaA, which turned out to be both sensitive to environmental stress and key to regulating protein expression. In one experiment, he created a version of an especially pathogenic bacteria that lacked the gene that encodes MiaA.

“Every kind of stress we exposed the MiaA-deficient strain to seemed to cause problems,” said the study’s co-first author Matthew Blango, PhD, who is now a junior research group leader at the Leibniz Institute for Natural Product Research and Infection Biology in Jena, Germany. “So, we really thought that this protein might be playing an important role in gene regulation.”

Bacteria lacking MiaA did not thrive and did not cause urinary tract infections or sepsis in mice. This same effect also occurred with bacteria manipulated into expressing too much MiaA. “There appears to be a Goldilocks zone, where just the right amount of MiaA allows the optimal stress response,” Dr Blango said.

Seeing how badly things went when MiaA levels were out of balance, Brittany Fleming, PhD, the study’s co-first author, investigated further. She discovered that knocking out MiaA caused random ‘frameshifting’ – an error where tRNA delivers three-letter genetic codes to be translated into proteins that are off by one letter. For example, a genetic code of “CAT CAT GTA” might read as “ATC ATG TA…” when frameshifted. In the bacteria, the result of such a shift was impaired production of important proteins and production of unexpected proteins.

Another co-first author, graduate student Alexis Rousek, showed that changing levels of MiaA could alter the availability of key metabolites that feed into other important stress response pathways within the bacteria. These findings implicate MiaA as a key player within a web of pathways that can impact pathogen stress resistance

Prof Mulvey says his lab’s next step is learning how environmental stress alters MiaA levels within bacteria.

The implications for this research may extend beyond infection control. Humans express a version of MiaA that is linked to certain cancers and metabolic diseases. “What we learned about how MiaA works is likely to be relevant to research on cancer and other non-infectious human diseases,” Mulvey said.

Source: University of Utah

Categories : Diseases, Syndromes and ConditionsTags :

Candida Glabrata Genome Yields Secrets of Virulence and Drug Resistance

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Genetics
Source: Pixabay

A project sequencing the Candida glabrata genome has revealed insights into the pathogenic fungus’s virulence and resistance, which researchers found to have been enhanced by transmission through humans as they travel between continents. The project’s findings appear in Genetics. 

C. glabrata is an opportunistic human fungal pathogen that causes superficial mucosal and life-threatening bloodstream infections in individuals with a compromised immune system. It most commonly affects the urinary tract, genitals, mouth, and the bloodstream. If it is not caught, these infections can become deadly.  It is also very resistant to certain antifungal drugs, so understanding why resistance occurs is key to knowing how to treat it effectively. 

Using samples from eight hospitals in Scotland to sequence the genome of C. glabrata, new insights on the species were made. This includes information on how it reproduces and its genetic diversity. Genes increasing its infectivity also confer an advantage for survival, and the drug-resistance genes often evolve within patients.

These findings provide scientists with an advantage in treating fungus, allowing research to focus in ways that were not possible before. It also helps aid understanding on how the pathogen spreads, which is important to identifying infections.

Dr Rhys Farrer, one of the Principal Investigators at the MRC Centre for Medical Mycology at the University of Exeter, said: “Our study sheds new light on the genetic diversity of Candida glabrata. We have demonstrated that this deadly human fungal pathogen is being spread between continents, probably by humans, and recombining to form new populations, which is likely contributing to its high virulence and increasing drug resistance.”

Source: University of Exeter

Categories : Cardiovascular Disease GeneticsTags :

Prevalence of Cardiac Arrhythmia Risk Genes Greater Than Believed

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By sequencing genes linked to cardiac arrhythmia risk in more than 20 000 people without an indication for genetic testing, scientists were able to identify possible pathogenic variants in 0.6% of individuals, according to a study published in Circulation.

This rate is higher than those previously reported, according to Carlos G. Vanoye, PhD, research associate professor of Pharmacology and a co-author of the study.

“This study suggests the prevalence of genetic susceptibility to cardiac arrhythmia may be underestimated,” Dr Vanoye said.

The American College of Genetics and Genomics (ACMG) currently recommends that incidentally discovered pathogenic or likely pathogenic variants in 73 Mendelian disease genes be reported back to patients. This includes many genetic variants associated with congenital cardiac arrhythmias, causing irregular heartbeats which can lead to stroke or sudden cardiac death.

However, the pathogenicity of many genetic variants in these known arrhythmia genes is uncertain, and classification of these variants is still in the early stages.

“A person can carry a disease-causing gene variant but exhibit no obvious signs or symptoms of the disease,” Dr Vanoye said. “Because the genes we studied are associated with sudden death, which may have no warning signs, discovery of a potentially life-threatening arrhythmia gene variant can prompt additional clinical work-up to determine risks and guide preventive therapies.”

The current study used data from the Electronic Medical Records and Genomics sequencing (eMERGEIII) study. The eMERGEIII study investigated the feasibility of population genomic screening by sequencing 109 genes implicated across the spectrum of Mendelian (single inherited gene mutation) diseases in over 20 000 individuals, returning variant results to the participants, and using Electronic Health Record (EHR) and follow-up clinical data to ascertain patient phenotypes.

In the current study, investigators analysed 10 arrhythmia-associated genes in individuals without an indication for genetic testing.

The researchers determined the functional consequences of these variants of uncertain significance and used the data to refine the assessment of pathogenicity. In the end, they reclassified 11 of these variants: three that were likely benign and eight that were likely pathogenic.

In all, 0.6% of the studied population had a variant that increases risk for potentially life-threatening arrhythmia and there was overrepresentation of arrhythmia phenotypes among these patients. This is a rate higher than previously known for genetic arrhythmia syndromes (approximately 1 in 2000) and illustrates the potential for population genomic screening, Dr Vanoye said.

“Population genomic screening can positively affect public health. Many rare, disease-associated variants can be found this way which can then help determine the disease-risk of the carriers of these variants,” Dr Vanoye said. “Although the costs of genomic screening may be currently high, assessing patient risk followed up by clinical care would reduce the financial and emotional cost of the disease.”

Source: Northwestern Medicine

Categories : CancerTags :

Genetic Underpinnings of Acne Uncovered by Study

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Photo by cottonbro from Pexels

A study into the genetics of acne revealed 29 regions of the genome that underpin the condition, which could offer potential new treatment targets and may also help clinicians identify individuals at high risk of severe disease.

A common skin condition, acne is estimated to affect 80% of adolescents, with common features including spots and cysts, pigment changes and scarring. The face is the most common site, with the chest and back also frequently involved. The negative psychological consequences of acne are seen in all ages, but are of particular concern for many adolescents.

The research, published in Nature Communications, analysed nine genome wide association study datasets from patients around the world. These studies involved scanning the whole genomes of 20 165 people with acne and 595 231 without. The study identified 29 new genetic variants that are more common in people with acne. It also confirmed 14 of the 17 variants already known to be associated with the condition, which brings the total number of known variants to 46.

Professor Catherine Smith at St John’s Institute of Dermatology at Guy’s and St Thomas’ said: “Despite major treatment advances in other skin conditions, progress in acne has been limited. As well as suffering from the symptoms of acne, individuals describe consequent profound, negative impacts on their psychological and social wellbeing. It’s exciting that this work opens up potential avenues to find treatments for them.”

A number of genes associated with acne were identified, and are also linked to other skin and hair conditions. The team believe this will help to understand the causes of acne, which could be a mix of factors.

“We know that the causes of acne are complicated, with a mix of biological factors such as genetics and hormones, and environmental factors,” said Professor Michael Simpson at King’s College London. “Understanding the genetics of the condition will help us to disentangle some of these causes, and find the best way to treat the condition. This is a really promising area for further study, and opens up a lot of avenues for research.”

The study also uncovered a link between the genetic risk of acne and disease severity. Individuals with the highest genetic risk are more likely to have severe disease. While further research is required, this finding raises the potential to identify individuals at risk of severe disease for early intervention.

Source: NIHR Biomedical Research Centre at Guy’s and St Thomas’ and King’s College London

Categories : Antibiotics Diseases, Syndromes and ConditionsTags :

Signs of Antibiotic ‘Pre-resistance’ Identified for the First Time

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Drug-resistant, Mycobacterium tuberculosis bacteria, the pathogen responsible for causing the disease tuberculosis (TB). A 3D computer-generated image. Credit: CDC

In a first of its kind study, researchers have spotted signs of antibiotic ‘pre-resistance’ in bacteria for the first time, indicating that they have the potential to develop drug resistance in the future.

The findings, published in Nature Communications, will allow doctors in the future to select the best treatments for bacterial infections.

Mycobacterium tuberculosis (TB) was the second leading infectious cause of death after COVID in 2020, killing 1.5m people. It can be cured if treated with the right antibiotics, but treatment is lengthy and many people most at risk lack access to adequate healthcare. Drug-resistant TB can develop when people do not finish their full course of treatment, or when drugs are not available or are of poor quality.

Multi-drug resistant TB represents a huge, unsustainable burden and totally drug resistant strains have been detected in a handful of countries. As health systems struggle to cope with the pandemic, progress on TB treatment globally has slowed.

To better understand TB for developing new drugs, this study has identified for the first time how to pre-empt drug resistance mutations before they have occurred. Dubbed ‘pre-resistance’ when a pathogen has a greater inherent risk of developing resistance to drugs in the future.

By analysing thousands of bacterial genomes, the study has potential application to other infectious diseases and paves the way towards personalised pathogen ‘genomic therapy’ – which chooses drugs according to the pathogen, preventing drug resistance.

The culmination of 17 years’ work, the study built up a TB bacterial ‘family tree’  from 3135 different tuberculosis samples. Computational analysis identified the ancestral genetic code of bacteria that then went on to develop drug resistance. The team identified the key changes associated with the development of resistance by looking through the ‘branches’ of the family tree to see which had the most potential for developing drug resistance.

Variations in the TB genome predicted that a particular branch would likely become drug resistant, and then validated their findings in an independent global TB data set.

Dr Grandjean, senior author of the study, said: “We’re running out of options in antibiotics and the options we have are often toxic – we have to get smarter at using what we have to prevent drug resistance.

“This is the first example of showing that we can get ahead of drug resistance. That will allow us in the future to use the pathogen genome to select the best treatments.”

Source: EurekAlert!

Categories : Addiction Mental HealthTags :

Use of Electronic Devices Linked to Depression and Anxiety

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Photo by Tracy le Blanc from Pexels
Photo by Tracy le Blanc from Pexels

In a study published in Addiction Biology, researchers uncovered significant associations between use of electronic devices and signs of depression and anxiety, as well as cigarette smoking and alcohol drinking. The team also found certain genetic variants that were linked with these traits.

A review of studies on smartphone addiction found that anxiety and depression were commonly mediated mental health problems. A wide range of physical health sequelae was also associated with smartphone addiction. Furthermore, there was an association between smartphone addiction and neurological disorders.

The study included data on hundreds of thousands of individuals from the UK Biobank. Three indicators of use of electronic devices were included in the study: TV watching, computer using, and computer playing.

Their findings suggested that electronic devices use was associated with common mental traits and provided new clues for understanding genetic architecture of mental traits.

The authors wrote that the study’s findings suggest that reducing time spent using electronic devices may help reduce mental health burdens. 

Source: Wiley

Categories : Genetics Immune SystemTags :

Differences in Influenza Responses According to Genetic Ancestries

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Photo by Andrea Piacquadio on Unsplash

Researchers have uncovered differences in immune pathway activation to influenza infection between individuals of European and African genetic ancestry, according to a study published in Science. Many of the genes that were associated with these immune response differences to influenza are also enriched among genes associated with COVID disease severity. 

“The lab has been interested in understanding how individuals from diverse populations respond differently to infectious diseases,” said first author Haley Randolph, a graduate student at the University of Chicago. “In this study, we wanted to look at the differences in how various cell types respond to viral infection.”

The researchers examined gene expression patterns in peripheral mononuclear blood cells, a diverse set of specialised immune cells that play important roles in the body’s response to infection. These cells were gathered from men of European and African ancestry and then exposed the cells to flu in a laboratory setting. This let the team examine the gene signatures of a variety of immune cell types, and observe how the flu virus affected each cell type’s gene expression.

The results showed that individuals of European ancestry showed an increase in type I interferon pathway activity during early influenza infection.

“Interferons are proteins that are critical for fighting viral infections,” said senior author Luis Barreiro, PhD, Associate Professor of Medicine at UChicago. “In COVID-19, for example, the type I interferon response has been associated with differences in the severity of the disease.”

This increased pathway activation hindered the replication of the virus more and limited viral replication later on. “Inducing a strong type I interferon pathway response early upon infection stops the virus from replicating and may therefore have a direct impact on the body’s ability to control the virus,” said Barreiro. “Unexpectedly, this central pathway to our defense against viruses appears to be amongst the most divergent between individuals from African and European ancestry.”

The researchers saw a variety of differences in gene expression across different cell types, suggesting a constellation of cells that work together to fight disease.

Such a difference in immune pathway activation could explain influenza outcome disparities between different racial groups; Non-Hispanic Black Americans are more likely to be hospitalised due to the flu than any other racial group.

However, these results are not evidence for genetic differences in disease susceptibility, the researchers point out. Rather, possible differences in environmental and lifestyle between racial groups could be influencing gene expression, and affecting the immune response.

“There’s a strong relationship between the interferon response and the proportion of the genome that is of African ancestry, which might make you think it’s genetic, but it’s not that simple,” said Barreiro. “Genetic ancestry also correlates with environmental differences. A lot of what we’re capturing could be the result of other disparities in our society, such as systemic racism and healthcare inequities. Although some of the differences we show in the paper can be linked to specific genetic variation, showing that genetics do play some role, such genetic differences are not enough to fully explain the differences in the interferon response.”

These differences in viral susceptibility may not be confined to just influenza. Comparing a list of genes associated with differences in COVID severity, the researchers found that many of the same genes showed significant differences in their expression after flu infection between individuals of African and European ancestry.

“We didn’t study COVID patient samples as part of this study, but the overlap between these gene sets suggests that there may be some underlying biological differences, influenced by genetic ancestry and environmental effects, that might explain the disparities we see in COVID outcomes,” said Barreiro.

As they explore this further, the researchers hope to figure out which factors contribute to the differences in the interferon response, and immune responses more broadly, to better predict individual disease risk.

Source: EurekAlert!

Categories : Genetics NeurologyTags :

Scientists Identify A New Recessive Neurodevelopmental Disorder

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Image source: Pixabay

In the Journal of Clinical Investigation, researchers have reported a rare neurodevelopmental condition characterised by intellectual disability, ataxia with cerebellar hypoplasia and delayed puberty with hypogonadotropic hypogonadism (HH).

Patients with this unusual combination of conditions were referred to Mehul Dattani (UCL), and affected individuals were found to carry the same homozygous mutation in the PRDM13 gene, which encodes a chromatin modifying factor that contributes to regulating cell fate. Intriguingly, an unaffected heterozygous carrier of this mutation was identified by screening 42 unaffected individuals in the Maltese population, suggesting that this mutation is present at low levels in the population.

The researchers set out to model this condition and identify the underlying causes using a PRDM13-deficient mouse model. The researchers found evidence that both the cerebellar hypoplasia and reproductive phenotypes resulted from defects in the specification of specific populations of GABAergic neuronal progenitors in the developing cerebellum and hypothalamus, respectively.

The results indicate that this condition results from abnormal cell fate specification during development. Consequently, the hypoplastic cerebellum is deficient in molecular layer interneurons, which play critical roles in regulating cerebellar circuits. In the hypothalamus, fewer Kisspeptin neurons, which are important regulators of gonadotropin releasing hormone and puberty, were present in PRDM13 mutant mice.

Together, these findings identify PRDM13 as a critical regulator of neuronal cell fate in the cerebellum and hypothalamus, providing a mechanistic explanation for the co-occurrence of hypogonadism and cerebellar hypoplasia in this syndrome.

Source: King’s College London

Categories : COVIDTags :

Scientist Identify the Gene Responsible for Doubling Severe COVID Risk

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Image source: Pixabay

Scientists at Oxford University have identified the gene responsible for doubling the risk of respiratory failure from COVID. Some 60% of people of South Asian descent carry the high-risk genetic signal, partly explaining the impact of COVID in the Indian subcontinent and the excess deaths seen in some UK communities.

Prior research already identified a stretch of DNA on chromosome 3 which doubled the COVID mortality risk of adults under 65. However, scientists did not know how this genetic signal worked to increase the risk, nor the exact genetic change that was responsible.

In a study published in Nature Genetics, an Oxford University team used cutting edge technology to work out which gene was causing the effect, and how it was doing so.

Study co-lead Jim Hughes, Professor of Gene Regulation, said: “The reason this has proved so difficult to work out, is that the previously identified genetic signal affects the ‘dark matter’ of the genome. We found that the increased risk is not because of a difference in gene coding for a protein, but because of a difference in the DNA that makes a switch to turn a gene on. It’s much harder to detect the gene which is affected by this kind of indirect switch effect.”

The team trained an artificial intelligence algorithm to analyse huge quantities of genetic data from hundreds of types of cells from all parts of the body, to show that the genetic signal is likely to affect cells in the lung. Then the researchers used a newly developed precision technique to zero in on the DNA at the genetic signal. This examines the way that the billions of DNA letters fold up to fit inside a cell to locate the specific gene that was being controlled by the sequence that increases severe COVID risk.

Dr Damien Downes, who led laboratory work, said: “Surprisingly, as several other genes were suspected, the data showed that a relatively unstudied gene called LZTFL1 causes the effect.”

The researchers found that the higher risk version of the gene probably prevents the cells lining airways and the lungs from responding to the virus properly. But importantly it doesn’t affect the immune system, so the researchers expect people carrying this version of the gene to respond normally to vaccines.

The researchers are also hopeful that drugs and other therapies could target the pathway preventing the lung lining from transforming to less specialised cells, raising the possibility of new treatments customised for those most likely to develop severe symptoms.

Study co-lead Professor James Davies, Associate Professor of Genomics at Oxford University, said: “The genetic factor we have found explains why some people get very seriously ill after coronavirus infection. It shows that the way in which the lung responds to the infection is critical. This is important because most treatments have focussed on changing the way in which the immune system reacts to the virus.”

About 60% of people with South Asian ancestry carried this higher-risk version of the gene compared to 15% of those with European ancestry – explaining in part the higher death rates and hospitalisations in the former group. The study also found that 2% of people with Afro-Caribbean ancestry carried the higher risk genotype, meaning that this genetic factor does not completely explain the higher death rates reported for black and minority ethnic communities.

Prof Davies explained: “The higher risk DNA code is found more commonly in some black and minority ethnic communities but not in others. Socioeconomic factors are also likely to be important in explaining why some communities have been particularly badly affected by the COVID pandemic.

“Although we cannot change our genetics, our results show that the people with the higher risk gene are likely to particularly benefit from vaccination. Since the genetic signal affects the lung rather than the immune system, it means that the increased risk should be cancelled out by the vaccine.”

Source: Oxford University

Categories : GeneticsTags :

The Need for an African Genetic Library

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Source: Mart Production on Pexels

Earlier this year, UCT professor Ambroise Wonkam published the Three Million African Genomes (3MAG) project in Nature, which he said started with a “crazy idea”. Now, it looks like his vision is starting to take shape.

The idea of creating a huge library of genetic information about the population of Africa emerged from his work on how genetic mutations among Africans contribute to conditions like sickle-cell disease and hearing impairments.

African genes contain great genetic variation, more than that seen outside of Africa. As he explained, “We are all African but only a small fraction of Africans moved out of Africa about 20–40 000 years ago and settled in Europe and in Asia.”

Another concern for Prof Wonkam is equity, saying: “Too little of the knowledge and applications from genomics have benefited the global south because of inequalities in health-care systems, a small local research workforce and lack of funding.”

Thus far only about 2% of genomes mapped are African, a good proportion of which are African American. This stes from a lack of prioritising funding, policies and training infrastructure, he says, but it also means the understanding of genetic medicine as a whole is lopsided. By studying African genomes, injustics can be corrected, such as finding that genetic risk profiles based on Europeans could be misleading for those of African descent.

To address these disparities, Prof Wonkam and other scientists are speaking to governments, companies and professional bodies across Africa and internationally, in order to build up capacity over the next decade to make the vision a reality.

He expects three million is the number needed to accurately map genetic variations across Africa. The project will take a decade, he says, costing around $450m per year, with industry already showing interest. 

Biotech firms welcome prospects of new data
The Centre for Proteomic and Genomic Research (CPGR) in Cape Town works with biotech firm Artisan Biomed on a variety of diagnostic tests. Gaps in the applicability of genetic data to the local population are a challenge for the firm, it said.

A genetic mutation in someone could be found but it would be uncertain if that variation is associated with a disease, especially as a marker for that particular population.

“The more information you have at that level, the better the diagnosis, treatment and eventually care can be for any individual, regardless of your ethnicity,” said Dr Lindsay Petersen, the company’s chief operations officer.

Artisan Biomed says the data it collects feeds back into CPGR’s research – allowing them to design a better diagnostic toolkit that is better suited to African populations, for instance.

Dr Judith Hornby Cuff said that the 3MAG project would help streamline processes and improve research, and one day could provide cheaper, more effective and more accessible health care, particularly in the strained South African system.

Prof Wonkam acknowledged that while the costs are huge, the project will “improve capacity in a whole range of biomedical disciplines that will equip Africa to tackle public-health challenges more equitably”.

“We have to be ambitious when we are in Africa. You have so many challenges you cannot see small, you have to see big – and really big,” he said.

Source: BBC News