Tag: genetics

A Blindness Gene That Also Increases Intelligence

DNA repair
Source: Pixabay/CC0

A new study published in Brain shows that a genetic mutation which causes blindness in humans also increases intelligence, possibly through an increase in synaptic activity between the very same neurons damaged by the mutation.

The present study came about when Professors Tobias Langenhan and Manfred Heckmann, came across a paper on a mutation that damages a synaptic protein. The mutation caused patients to go blind, but then doctors noticed that the patients were also of above-average intelligence, something which piqued the two neurobiologists’ interest. “It’s very rare for a mutation to lead to improvement rather than loss of function,” said Prof Langenhan.

The two neurobiologists have been using fruit flies to analyse synaptic functions for many years. “Our research project was designed to insert the patients’ mutation into the corresponding gene in the fly and use techniques such as electrophysiology to test what then happens to the synapses. It was our assumption that the mutation makes patients so clever because it improves communication between the neurons which involve the injured protein,” explained Prof Langenhan. “Of course, you can’t conduct these measurements on the synapses in the brains of human patients. You have to use animal models for that.”

“75 per cent of genes that cause diseases in humans also exist in fruit flies”

Professor Tobias Langenhan

First, in collaboration with Oxford researchers, the scientists showed that the fly protein called RIM looks molecularly identical to that of humans. This was essential in order to be able to study the changes in the human brain in the fly. In the next step, the neurobiologists inserted the genetic mutation into flies. They then took electrophysiological measurements of synaptic activity. “We actually observed that the animals with the mutation showed a much increased transmission of information at the synapses. This amazing effect on the fly synapses is probably found in the same or a similar way in human patients, and could explain their increased cognitive performance, but also their blindness,” concludes Professor Langenhan.

The scientists also found out how the increased transmission at the synapses occurs: the molecular components in the transmitting nerve cell that trigger the synaptic impulses move closer together as a result of the mutation effect and lead to increased release of neurotransmitters. A novel method, super-resolution microscopy, was one of the techniques used in the study. “This gives us a tool to look at and even count individual molecules and confirms that the molecules in the firing cell are closer together than they normally are,” said Prof Langenhan.

“The project beautifully demonstrates how an extraordinary model animal like the fruit fly can be used to gain a very deep understanding of human brain disease. The animals are genetically highly similar to humans. It is estimated that 75% of the genes involving disease in humans are also found in the fruit fly,” explained Professor Langenhan, pointing to further research on the topic: “We have started several joint projects with human geneticists, pathologists and the team of the Integrated Research and Treatment Center (IFB) Adiposity Diseases; based at Leipzig University Hospital, they are studying developmental brain disorders, the development of malignant tumours and obesity. Here, too, we will insert disease-causing mutations into the fruit fly to replicate and better understand human disease.”

Source: Universität Leipzig

Genetic Risk Score for Hip or Knee Replacements

A Monash University-led research team has developed a risk score based on individuals’ genetic data to predict their likelihood of needing hip or knee replacement surgery for osteoarthritis. The team validated the score’s predictive ability in a study published in Arthritis & Rheumatology.  

The score incorporates 10 genetic sequence variants for predicting a person’s risk of needing knee replacement surgery and 37 genetic sequence variants for predicting the risk of needing hip replacement surgery.  

Among 12093 individuals of European genetic descent aged 70 years or older, 1422 (11.8%) had knee replacements and 1,297 (10.7%) had hip replacements. Participants with high risk scores had a 1.44-times higher odds of knee replacement and a 1.88-times higher odds of hip replacement, compared with those with low risk scores.   

 “Genetic scores, such as the one we developed, do not change over a person’s life. They provide an individual  with further information about their risk of severe osteoarthritis in later life and have the potential to improve prevention of severe knee and hip osteoarthritis by identifying those who may benefit from early intervention,” said senior author Flavia Cicuttini, PhD, of Monash University.  

Source: Wiley

People with Blue Eyes Share a Single Ancestor

Source: Daniil Kuzelev on Unsplash

New research published in Human Genetics shows that people with blue eyes trace their ancestry back to a single individual. Researchers tracked down a genetic mutation which took place 6–10 000 years ago and is the cause of the eye colour of all blue-eyed humans without albinism alive on the planet today.

While blue eyes evolved only once, blonde hair has evolved at least twice: in Melanesian populations, blonde hair evolved independently to European populations, involving a mutation in a different gene.

“Originally, we all had brown eyes,” said Professor Hans Eiberg from the University of Copenhagen. “But a genetic mutation affecting the OCA2 gene in our chromosomes resulted in the creation of a ‘switch’, which literally ‘turned off’ the ability to produce brown eyes.” The OCA2 gene codes for the P protein, which is involved melanin production. This ‘switch’, located in the gene next to OCA2, does not completely shut off production but instead is limited to reducing the production of melanin in the iris, effectively ‘diluting’ brown eyes to blue. The switch’s effect on OCA2 is very specific therefore. If the OCA2 gene is completely destroyed or turned off, albinism would be the result.

Eye colours from brown to green depend on the amount of melanin in the iris, but blue-eyed individuals only have a small degree of variation in the amount of melanin in their eyes. “From this we can conclude that all blue-eyed individuals are linked to the same ancestor,” said Professor Eiberg. “They have all inherited the same switch at exactly the same spot in their DNA.” Brown-eyed individuals, by contrast, have considerable individual variation in the area of their DNA that controls melanin production.

Professor Eiberg and his team studied mitochondrial DNA and compared the eye colour of blue-eyed individuals in countries as diverse as Jordan, Denmark and Turkey. His research stretches back to 1996, when he first implicated the OCA2 gene as being responsible for eye colour.

The mutation of brown to blue eyes does not confer any evolutionary advantage, as with others such as hair colour.

As Professor Eiberg explained, “it simply shows that nature is constantly shuffling the human genome, creating a genetic cocktail of human chromosomes and trying out different changes as it does so.”

Source: University of Copenhagen

Rare COVID Vaccine Blood Clots May Result from Genetics

Photo by Spencer Davis on Unsplash

Scientists have discovered that the rare blood clot side-effect associated with some COVID vaccines could be the result of a specific gene variant, which could make a genetic screening test possible.

Vaccine-induced thrombotic thrombocytopenia (VITT), a rare disorder causing thrombosis and thrombocytopenia (low blood platelet counts), was linked to AstraZeneca’s COVID vaccine in early 2021, leading some countries to pause or restrict its use. It is also associated with the Johnson & Johnson vaccine, which also uses a viral vector.

Now, a new study may help to explain what’s causing the rare side effect. The study by Flinders University and SA Pathology is now available on the medRxiv preprint server and is awaiting peer review.

Examining five unrelated individuals who all had the clotting complication after vaccination, the researchers found that all of the patients had unusually structured antibodies against a protein called platelet factor 4 (PF4), which is involved in blood clotting.

In addition, all five shared a specific version of a gene responsible for producing these antibodies.

“We knew previously that PF4 was directly involved in the clotting disorder, and we knew that aberrant antibodies against PF4 are responsible, but what we don’t know is how and why some people develop them,” explained lead author Dr Jing Jing Wang.

The antibodies were all found to be derived from the same amino acid sequence. The researchers then found that all of the patients carried a specific variant of one gene, called IGLV3-21*02, most commonly occurring in people of European descent.

“The other specific amino acid sequences of these antibodies from each patient were derived from separate basic sequences but had all evolved to carry very similar properties, making them very potent attackers of the PF4 protein,” explained research team leader Professor Tom Gordon.

“Together, this suggests that it is the combination of a variant in a gene and the evolution of this antibody towards targeting the PF4 protein in a destructive manner, which is leading to this harmful side-effect.”

Though why the antibody is found in such a tiny number of vaccine recipients remains unknown, the identification of the gene could enable a genetic screening tool to identify patients who are at risk of this severe complication.

“It also provides a unique opportunity for targeted, specific therapy development aimed at neutralising this highly damaging but very specific antibody,” said Dr Wang.

Source: Flinders University

Why Some Infections Can Be so Persistent

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

Candida Glabrata Genome Yields Secrets of Virulence and Drug Resistance

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

Prevalence of Cardiac Arrhythmia Risk Genes Greater Than Believed

Source: Pixabay/CC0

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

Genetic Underpinnings of Acne Uncovered by Study

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

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

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!

Use of Electronic Devices Linked to Depression and Anxiety

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