Category: Genetics

Categories : Ageing GeneticsTags :

Mice Live Longer when Given a Longevity Gene from Naked Mole Rats

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CRISPR-Cas9 is a customisable tool that lets scientists cut and insert small pieces of DNA at precise areas along a DNA strand. This lets scientists study our genes in a specific, targeted way. Credit: Ernesto del Aguila III, National Human Genome Research Institute, NIH

In a ground-breaking advance in aging research, scientists have successfully transferred a longevity gene from naked mole rats to mice, resulting in improved health and an extension of the mouse’s lifespan.

Naked mole rats are known for their long lifespans and exceptional resistance to age-related diseases. By introducing a specific gene responsible for enhanced cellular repair and protection into mice, the researchers have opened exciting possibilities for unlocking the secrets of aging and extending human lifespan.

“Our study provides a proof of principle that unique longevity mechanisms that evolved in long-lived mammalian species can be exported to improve the lifespans of other mammals,” says Vera Gorbunova, professor at Rochester University. Gorbunova, along with Andrei Seluanov, a professor of biology, and their colleagues, report in a study published in Nature that they successfully transferred a gene responsible for making high molecular weight hyaluronic acid (HMW-HA) from a naked mole rat to mice. This led to improved health and an approximate 4.4 percent increase in median lifespan for the mice.

A unique mechanism for cancer resistance

Naked mole rats are mouse-sized rodents that have exceptional longevity for rodents of their size; they can live up to 41 years, nearly ten times as long as similar-size rodents. Unlike many other species, naked mole rats do not often contract age-related diseases such neurodegeneration, cardiovascular disease, arthritis, and cancer. Gorbunova and Seluanov have devoted decades of research to understanding the unique mechanisms that naked mole rats use to protect themselves against aging and diseases.

The researchers previously discovered that HMW-HA is one mechanism responsible for naked mole rats’ unusual resistance to cancer. Compared to mice and humans, naked mole rats have about ten times more HMW-HA in their bodies. When the researchers removed HMW-HA from naked mole rat cells, the cells were more likely to form tumours.

Gorbunova, Seluanov, and their colleagues wanted to see if the positive effects of HMW-HA could also be reproduced in other animals.

Transferring an HMW-HA-producing gene

The team genetically modified a mouse model to produce the naked mole rat version of the hyaluronan synthase 2 gene, which is the gene responsible for making a protein that produces HMW-HA. While all mammals have the hyaluronan synthase 2 gene, the naked mole rat version seems to be enhanced to drive stronger gene expression.

The researchers found that the mice that had the naked mole rat version of the gene had better protection against both spontaneous tumors and chemically induced skin cancer. The mice also had improved overall health and lived longer compared to regular mice. As the mice with the naked mole rat version of the gene aged, they had less inflammation in different parts of their bodies — inflammation being a hallmark of aging — and maintained a healthier gut.

While more research is needed on exactly why HMW-HA has such beneficial effects, the researchers believe it is due to HMW-HA’s ability to directly regulate the immune system.

A fountain of youth for humans?

“It took us 10 years from the discovery of HMW-HA in the naked mole rat to showing that HMW-HA improves health in mice,” Gorbunova says. “Our next goal is to transfer this benefit to humans.”

They believe they can accomplish this through two routes: either by slowing down degradation of HMW-HA or by enhancing HMW-HA synthesis.

“We already have identified molecules that slow down hyaluronan degradation and are testing them in pre-clinical trials,” Seluanov says. “We hope that our findings will provide the first, but not the last, example of how longevity adaptations from a long-lived species can be adapted to benefit human longevity and health.”

Source: University of Rochester

Categories : Gender GeneticsTags :

Scientists Finally Create an Accurate Map of the Y Chromosome

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Photo by Sangharsh Lohakare on Unsplash

Long overlooked by genetics, the Y chromosome is surprisingly quite challenging to sequence, and so its contributions to health and disease remain largely unknown. For the first time, the complete sequences of 43 human Y chromosomes from lineages from around the globe provides an essential step forward in understanding the roles of the Y chromosome in human evolution and biology. The researchers behind the effort published their findings in two papers in Nature.

Even as the field of human genomics forged ahead at an astonishing pace, the Y chromosome has long remained overlooked. It has been postulated that the human sex chromosomes once originated from a pair of structurally similar chromosomes, but subsequently one of the sex chromosomes, the ancestral Y chromosome, underwent significant degradation, losing 97%of its former complement of genes over many millions of years. This peculiar evolutionary trajectory has given rise to speculation that the human Y chromosomes might eventually disappear completely, albeit millions of years from now, and we already observe that some biological males do lose them in dividing cells as they age, with unclear health consequences.

In practical terms, the Y chromosome contains a large proportion of repetitive and heterochromatic (highly condensed, gene-poor and not transcribed to messenger RNA) sequences, making it exceptionally difficult to fully sequence. Using sequencing methods that can cover long, continuous sequences, the Telomere-to-Telomere (T2T) consortium has now published the first complete Y chromosome assembly from a single individual of European descent in Nature. At the same time, a team led by Jackson Laboratory (JAX) Professor and The Robert Alvine Family Endowed Chair Charles Lee, PhD, FACMG, has published, also in Nature, the assembled Y chromosomes from 43 unrelated males, with nearly half coming from African lineages. These two papers provide intriguing insights into human Y chromosomes, reveal the highly variable nature of Y chromosomes across individuals, and provide an important foundation for future studies on how they may be contributing to certain disorders and diseases.

The need for long reads

Standard short-read genomic sequencing technologies require breaking genomic DNA into short (~250-base-long) fragments. These fragments are then reassembled into the full genome of more than 3 billion base pairs across 46 chromosomes in humans. The method is very accurate and works well for most, but not all, of the genome. Almost all “complete” human genome sequences, including the current reference genome sequence (known as GRCh38), are actually only about 90% complete, because it is difficult to assemble the highly repetitive and other complex sections accurately. GRCh38 falls particularly short for the Y chromosome, as it barely assembles half of that chromosome.

As a result, while the much larger and gene-rich X chromosome has been extensively studied, the Y chromosome has been often overlooked outside of male-based fertility studies. In a significant step forward for the genomics field, scientists from JAX, including first author and JAX Associate Research Scientist, Pille Hallast, PhD, with collaborators from Clemson University, Heinrich Heine University (Germany) and more, have now revealed a full picture of the Y chromosome’s key characteristics and differences between individuals for the first time. Of note is the striking variation in size and structure across the 43 Y chromosomes sequenced that covered 180 000 years of human evolution and range from 45.2 million to 84.9 million base pairs in length.

The inclusion of 43 different individuals representing diverse Y lineages allowed the researchers to redefine inter-chromosomal region boundaries and identify large-scale variations at an unprecedented resolution and clarity. The study also revealed an unexpected degree of structural variation across the Y chromosomes. For example, half of the euchromatin (gene-rich region) of the sequenced chromosomes carries large recurrent inversions (segments that contain the same nucleotide sequences but oriented in the opposite direction) at a rate much higher than anywhere else in the genome. The study further identified regions of the Y chromosome that demonstrate little single nucleotide variation but show high gene copy number variation for specific gene families. Other gene families tended to maintain their copy numbers, however, consistent with their roles in fertility and normal development.

Role in overall health

“Having fully resolved Y chromosome sequences from multiple individuals is essential in order for us to begin to understand how this variation can affect function” says Hallast. “The degree of structural variation between individuals came as a big surprise to me, even though the nucleotide sequences within the Y chromosome genes are comparatively conserved. The variable gene copy numbers in certain gene families and extremely high inversion rates are almost certain to hold significant biological and evolutionary roles.”

The Y chromosome’s contributions to male health are poorly understood. Some unexpected indications of its importance to human health have recently come into focus in two new research studies that collectively implicate the Y chromosome in aggressive features of colorectal and bladder cancers in men. Indeed, one of the studies showed that tumors that had lost the Y chromosomes can more effectively evade T cell immunity, are infiltrated with higher numbers of dysfunctional CD8+ T cells, and are more responsive to anti-PD1 treatments compared to similar tumors retaining the Y chromosome.

“Research is emerging that shows proper Y chromosome gene function is incredibly important for the overall health of men,” says Lee, senior author on the paper. “Our study enables the inclusion of the full Y chromosome in all future studies when sequencing male genomes to understand health and disease.”

Source: Jackson Laboratory

Categories : Environmental Effects GeneticsTags :

Scientists Abuzz over a Genetic Way to Deafen Mosquitoes

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Specific receptors in the ears of mosquitoes have been revealed to modulate their hearing, finds a new study led by researchers at UCL and University of Oldenburg. Since male mosquitoes need to hear female mosquitoes is a crucial factor in their reproduction, this discovery could help develop new insecticides and control the spread of harmful diseases, such as malaria, dengue, and yellow fever.

In the study, published in Nature Communications, the researchers focused on a signalling pathway involving a molecule called octopamine. They demonstrated that it is key for mosquito hearing and mating partner detection, and so is a potential new target for mosquito control.

Male mosquitoes acoustically detect the buzz generated by females within large swarms that form transiently at dusk.

As swarms are potentially noisy, mosquitoes have developed highly sophisticated ears to detect the faint flight tone of females amid hundreds of mosquitoes flying together.

However, the molecular mechanisms by which mosquito males ‘sharpen their ears’ to respond to female flight tones during swarm time have been largely unknown.

The researchers looked at the expression of genes in the mosquito ear and found that an octopamine receptor specifically peaks in the male mosquito ear when mosquitoes swarm.

The study found that octopamine affects mosquito hearing on multiple levels. It modulates the frequency tuning and stiffness of the sound receiver in the male ear, and also controls other mechanical changes to boost the detection of the female.

The researchers demonstrated that the octopaminergic system in the mosquito ear can be targeted by insecticides. Mosquito mating is a bottleneck for mosquito survival, so identifying new targets to disrupt it is key to controlling disease-transmitting mosquito populations.

Source: University College London

Categories : Genetics TransplantsTags :

Pig-to-human Kidney Xenotransplant is the Longest Successful One Yet

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Photo by Natanael Melchor on Unsplash

Surgeons at NYU Langone Health have transplanted a genetically engineered pig kidney that continues to function well after 32 days in a man declared dead by neurologic criteria and maintained with a beating heart on ventilator support. This represents the longest period that a gene-edited pig kidney has functioned in a human, and the latest step toward the advent of an alternate, sustainable supply of organs for transplant.

Led by Robert Montgomery, MD, DPhil, the procedure was performed on July 24, 2023 and marks the fifth xenotransplant performed at NYU Langone. Observation is ongoing and the study will continue through mid-September 2023.

“This work demonstrates a pig kidney – with only one genetic modification and without experimental medications or devices – can replace the function of a human kidney for at least 32 days without being rejected,” said Dr Montgomery, who had previously performed the world’s first genetically modified pig kidney transplant into a human decedent in 2021.

Removing single troublesome gene

The first hurdle to overcome in xenotransplants is preventing so-called hyperacute rejection, which typically occurs just minutes after an animal organ is connected to the human circulatory system. By “knocking out” the gene that encodes the biomolecule known as alpha-gal, responsible for a rapid antibody-mediated rejection of pig organs by humans, immediate rejection has been avoided in all five xenotransplants at NYU Langone. Additionally, the pig’s thymus gland, which is responsible for educating the immune system, was embedded underneath the outer layer of the kidney to stave off novel, delayed immune responses. The combination of modifications has been shown to prevent rejection of the organ while preserving kidney function.

To ensure the body’s kidney function was sustained solely by the pig kidney, both of the transplant recipient’s native kidneys were surgically removed. One pig kidney was then transplanted and started producing urine immediately without any signs of hyperacute rejection. During the observation phase, intensive care clinical staff maintained the decedent on support while the pig kidney’s performance was monitored and sampled with weekly biopsies. Levels of creatinine, a bodily waste product found in the blood and an indicator of kidney function, were in the optimal range during the length of the study, and there was no evidence on biopsy of rejection.

The surgery was the latest in a larger study approved by a specific research ethics oversight board at NYU Langone and was performed after consultation with the New York State Department of Health. This important research, which study leaders say could save many lives in the future, was made possible by the family of a 57-year-old male who elected to donate his body after a brain death declaration and a circumstance in which his organs or tissues were not suitable for transplant.

A big leap toward a new organ source

“There are simply not enough organs available for everyone who needs one,” said Dr Montgomery, who received a hepatitis C-positive heart transplant himself in 2018. “Too many people are dying because of the lack of available organs, and I strongly believe xenotransplantation is a viable way to change that.”

The kidney and thymus gland used in this procedure were procured from a GalSafeTM pig, an animal engineered by Revivicor, Inc., a subsidiary of United Therapeutics Corporation. In December 2020, the U.S. Food and Drug Administration (FDA) approved the GalSafe pig as a potential source for human therapeutics as well as a food source for people with alpha-gal syndrome, a meat allergy caused by a tick bite.

Less may be more

While previous genetically engineered pig organ transplants have incorporated up to 10 genetic modifications, this latest study shows that a single-gene knockout pig kidney can still perform optimally for at least 32 days without rejection.

“We’ve now gathered more evidence to show that, at least in kidneys, just eliminating the gene that triggers a hyperacute rejection may be enough along with clinically approved immunosuppressive drugs to successfully manage the transplant in a human for optimal performance – potentially in the long-term,” said Dr Montgomery.

The NYU Langone team used standard transplant immunosuppression medications combined with enhanced screening of porcine cytomegalovirus (pCMV) in the donor pig to ensure safety. Recent studies have shown pCMV may affect organ performance and potentially trigger organ failure. No pCMV was detected after 32 days, and close surveillance of porcine endogenous retrovirus (PERV), along with six other viruses of interest, was performed.

Next steps

Monitoring of the pig kidney recipient will continue for another month with permission from the family, ethics committee approval and continued support from United Therapeutics. The additional data from the next several weeks will be analyzed further to develop a deeper understanding of this unique medical advance.

“We think using a pig already deemed safe by the FDA in combination with what we have found in our xenotransplantation research so far, gets us closer to the clinical trial phase,” said Dr Montgomery. “We know this has the potential to save thousands of lives, but we want to ensure the utmost safety and care as we move forward.”

Source: NYU Langone Health

Categories : Antibiotics GeneticsTags :

Genetic Mechanism Increases Resistance to the Antibiotic Albicidin by 1000-fold

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Photo by Sangharsh Lohakare on Unsplash

A new analysis shows that infectious bacteria exposed to the promising antibiotic albicidin rapidly develop up to a 1000-fold increase in resistance via a gene amplification mechanism. Mareike Saathoff of Freie Universität Berlin, Germany, and colleagues presented these findings in the open access journal PLOS Biology.

Bacterial resistance to antibiotics is a growing problem associated with millions of deaths around the world every year. Understanding how bacteria evolve resistance is key to developing more effective antibiotics and strategies for using them.

In recent years, albicidin has emerged as a promising antibiotic capable of killing a wide range of bacterial species by disrupting their DNA replication. Researchers are working to develop new albicidin-based medications; yet, despite its promise, some bacteria are able to develop resistance to albicidin.

To further investigate albicidin resistance mechanisms, Saathoff and colleagues conducted a suite of experiments employing a broad set of tools, including RNA sequencing, protein analysis, X-ray crystallography, and molecular modeling. They found that two bacteria often associated with human infection, Salmonella typhimurium and Escherichia coli, develop resistance to albicidin when exposed to increasingly higher concentrations of the compound. Their analysis narrowed down the source of this resistance to an increase in the number of copies of a gene known as STM3175 (YgiV) in the bacterial cells, which is amplified in each new generation of cells as they multiply. STM3175 encodes a protein that interacts with albicidin in such a way that protects the bacteria from it.

Further experiments showed that the same albicidin-resistance mechanism is widespread among both pathogenic and harmless bacteria, including the microbes Vibrio vulnificus, which can infect wounds, and Pseudomonas aeruginosa, which can cause pneumonia and other infections. These findings could help inform the ongoing development of albicidin-based antibiotic strategies.

The authors add, “Our study reveals a gene duplication and amplification-based mechanism of a transcriptional regulator in Gram-negative bacteria, that mediates resistance to the peptide antibiotic albicidin.”

Source: Science Daily

Categories : Genetics HIVTags :

Study of African-ancestry Genomes Reveals Defensive Gene Against HIV

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Photo by Ayo Ogunseinde on Unsplash

A study on almost 4000 people of African descent has identified a gene that acts as natural defence against HIV by limiting its replication in certain white blood cells. The findings were published in Nature. An international effort co-led by EPFL, Canada’s National Microbiology Laboratory, and Imperial College London, it paves the way for new treatment strategies.

“We searched for human genetic variation that associates with spontaneous control of HIV and identified a novel region in the genome that is only variable in populations of African ancestries,” says Professor Jacques Fellay at EPFL’s School of Life Sciences. “We used a combination of computational and experimental approaches to explore the biological mechanism behind the genetic association and provide evidence that the gene CHD1L acts to limit HIV replication in a subset of white blood cells.”

HIV is still a problem

Despite significant advances in treatment and access to therapy, the human immunodeficiency virus remains a global health challenge with almost 40 million affected individuals, no vaccine and no cure.

Although annual HIV infections have been declining because of widespread antiretroviral therapies, the trend has slowed substantially since 2005, and there are now alarming increases in the number of newly infected adults in some regions.

Genome-Wide Association Studies, or GWAS, analyse the entire genome of a large number of individuals to identify genetic variants associated with a clinical outcome, such as the ability to naturally control viral replication.

Measuring HIV replication control: not enough in African populations

The degree of viral infection is measured by the virus’ “setpoint viral load” (spVL), which refers to the relatively stable level of HIV replication in the body after the initial, acute phase of infection in untreated individuals.

A critical determinant of HIV infection progression and transmissibility, spVL is expressed as the number of viral copies/mL of plasma. The spVL of HIV varies widely in the infected population, depending on the ability of every individual’s immune system to control viral replication without antiretroviral drugs.

Although there have been large studies of spVL control in populations of European descent, much less has been done in populations of African ancestries, which have both a high genomic diversity and the greater burden of HIV.

A key gene for resistance to HIV replication in people of African ancestries

To address this disparity, a large international collaboration of scientists and clinicians has now performed large-scale GWAS using data from diverse populations of African ancestries. In total, the scientists analyzed the genomes from 3,879 individuals living with HIV-1. Using computational analysis and fine-mapping techniques, they identified a novel region in the genome that shows a strong association with spVL control.

This region corresponds to a gene known as CHD1L (for “Chromodomain Helicase DNA Binding Protein 1 Like”), which encodes a protein that helps DNA unwind after it has been damaged, allowing it to be repaired. But in this study, the CHD1L gene showed genetic variation specific to populations of African ancestries, and that was linked to the spontaneous control of the most common and virulent type of HIV, called HIV-1.

Having identified CHD1L as a potential modulator of HIV-1 infection, the researchers explored the biological mechanism behind the genetic association and determined that CHD1L plays a role in limiting HIV replication in a subset of white blood cells.

The study was co-led by Jacques Fellay at EPFL, Paul McLaren at the Public Health Agency of Canada’s National Microbiology Laboratory, and Manjinder Sandhu at Imperial College London.

The discovery of CHD1L’s role in limiting HIV replication could lead to improved treatment options for infected individuals. “Our findings provide insights into potential therapeutic targets, which are needed to continue the fight against HIV-1,” says Fellay. “In addition, our results underscore the importance of performing genomic studies in diverse ancestral populations to better address their specific medical needs and global health inequities.”

Source: Ecole Polytechnique Fédérale de Lausanne

Categories : Gender GeneticsTags :

Researchers Identify Sex-specific Genes for Obesity

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Source: CC0

Researchers have added several genes, which appear to affect obesity risk in certain sexes and ages, to the list of genes which influence weight gain. The study, published in the journal Cell Genomics, may shed light on new biological pathways that underlie obesity and highlight how sex and age contribute to health and disease.

“There are a million and one reasons why we should be thinking about sex, age, and other specific mechanisms rather than just lumping everyone together and assuming that disease mechanism works the same way for everyone,” says senior author John Perry, a geneticist and professor at the University of Cambridge. “We’re not expecting people to have completely different biology, but you can imagine things like hormones and physiology can contribute to specific risks.”

To untangle sex’s role in obesity risk, the research team sequenced the exome (the protein-coding part of the genome) of 414 032 adults from the UK Biobank study. They looked at variants, or mutations, within genes associated with body mass index (BMI) in men and women, respectively. Five genes influencing BMI in women and two in men were identified.

Among them, faulty variants of three genes – DIDO1, PTPRG, and SLC12A5 – are linked to higher BMI in women, up to nearly 8 kg/m² more, while having no effect on men. Over 80% of the women with DIDO1 and SLC12A5 variants had BMI-indicated obesity. Those carrying DIDO1 variants had stronger associations with higher testosterone levels and increased waist-to-hip ratio, both risk indicators for obesity-related complications like diabetes and heart disease. Others with SLC12A5 variants had higher odds of having type 2 diabetes compared with non-carriers. These findings highlight previously unexplored genes that are implicated in the development of obesity in women but not men.

Perry and his colleague then repeated their method to look for age-specific factors by searching for gene variants associated with childhood body size based on participants’ recollections. They identified two genes, OBSCN and MADD, that were not previously linked to childhood body size and fat. While carriers of OBSCN variants had higher odds of having higher weight as a child, MADD variant carriers were associated with smaller body sizes. In addition, the genetic variants acting on MADD had no association with adult obesity risk, highlighting age-specific effects on body size.

“What’s quite surprising is that if you look at the function of some of these genes that we identified, several are clearly involved in DNA damage response and cell death,” says Perry. Obesity is a brain-related disorder, whereas biological and environmental factors act to influence appetite. “There’s currently no well-understood biological paradigm for how DNA damage response would influence body size. These findings have given us a signpost to suggest variation in this important biological process may play a role in the aetiology of obesity.”

Next, the research team hopes to replicate the study in a larger and more diverse population. They also plan to study the genes in animals to peer into their function and relationship with obesity.

“We’re at the very earliest stages of identifying interesting biology,” says Perry. “We hope the study can reveal new biological pathways that may one day pave the way to new drug discovery for obesity.”

Source: Science Daily

Categories : Genetics Metabolic DisordersTags :

Abdominal Fat Accumulation may not be as Great a Diabetes Risk as Previously Thought

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Photo by Andres Ayrton on Pexels

Conventional wisdom holds that abdominal fat accumulation increases the risk for type 2 diabetes. But surprising new findings from the University of Virginia School of Medicine suggest that naturally occurring genetic variations in our genes can lead some people to store fat at the waist but also protect them from diabetes.

The unexpected discovery, which is published in eLife, provides a more nuanced view of the role of obesity in diabetes and related health conditions. It also could pave the way for more personalised medicine, such as prioritising weight loss for patients whose genes put them at increased risk but place less emphasis on it for patients with protective gene variants, the researchers say.

“There is a growing body of evidence for metabolically healthy obesity. In this condition, people who would normally be at risk for cardiovascular diseases and diabetes because they are obese are actually protected from adverse effects of their obesity. In our study, we found a genetic link that may explain how this occurs in certain individuals,” said researcher Mete Civelek, PhD, of UVA’s Center for Public Health Genomics. “Understanding various forms of obesity is important to tailor treatments for individuals who are at high risk for adverse effects of obesity.”

As medicine grows more sophisticated, understanding the role of naturally occurring gene variations will play an important role in ensuring patients get the best, most tailored treatments. The new work by Civelek and his team, for example, indicates that variants can simultaneously predispose some people to store fat at the abdomen, thought to put them at increased risk for metabolic syndrome, while also protecting them from type 2 diabetes. (Metabolic syndrome raises the risk for diabetes, stroke and other serious health issues.)

One of the metrics doctors use to determine if a patient has metabolic syndrome is abdominal obesity. This is often calculated by comparing the patient’s waist and hip measurements. But Civelek’s research suggest that, for at least some patients, it may not be that simple, with doctors using genetic testing to guide patients to good health.

“We found that among the hundreds of regions in our genomes which increase our propensity to accumulate excess fat in our abdomens, there are five which have an unexpected role,” said Yonathan Aberra, the lead author of the study and a PhD candidate at UVA’s Department of Biomedical Engineering, a joint program of the School of Medicine and School of Engineering. “To our surprise, these five regions decrease an individual’s risk for type 2 diabetes.”

In addition to producing surprising findings, Civelek’s research provides important new tools for his fellow researchers seeking to understand the complexities of gene variations. The sophisticated approach Civelek and his collaborators developed to identify the relevant variants and their potential effects will be useful for future research into metabolic syndrome and other conditions.

The tools could also prove invaluable in the development of new and better treatments for metabolic syndrome, the scientists say.

“We now need to expand our studies in more women and people from different genetic ancestries to identify even more genes that underlie the metabolically health obesity phenomenon,” Civelek said. “We plan to build on our findings to perform more experiments to potentially identify a therapeutic target.”

Source: University of Virginia Health System

Categories : Genetics Medical Research & TechnologyTags :

New CRISPR Discovery Targets Infected Cells

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CRISPR-Cas9 is a customisable tool that lets scientists cut and insert small pieces of DNA at precise areas along a DNA strand. This lets scientists study our genes in a specific, targeted way. Credit: Ernesto del Aguila III, National Human Genome Research Institute, NIH

German and US scientists have discovered a CRISPR system in cells that shuts them down entirely to protect against viral replication, instead of merely chopping out foreign DNA that it comes across. It does this by shredding any DNA or RNA it comes across, causing the cell to become senescent and not become a virus factory. The newly identified CRISPR system is described in two papers published in Nature.

“With this new system, known as Cas12a2, we’re seeing a structure and function unlike anything that’s been observed in CRISPR systems to date,” says Jackson, assistant professor in Utah State’s Department of Chemistry and Biochemistry.

CRISPR, (Clustered Regularly Interspaced Short Palindromic Repeats) has taken science by storm with its gene-editing potential. Study of CRISPR DNA sequences and CRISPR-associated (Cas) proteins, which are actually bacterial immune systems, is still a young field.

Identified as a distinct immune system within the last five years, the Class 2, type V Cas12a2 is somewhat similar to the better-known ‘molecular scissors’ of CRISPR-Cas9, which binds to target DNA and cuts it, effectively shutting off a targeted gene. But CRISPR-Cas12a2 binds a different target than Cas9, and that binding has a very different effect.

Using cryo-electron microscopy, the team captured the CRISPR-Cas12a2 in a naturally occurring defensive strategy called abortive infection, a natural resistance strategy used by bacteria and archaea to limit the spread of viruses and other pathogens by preventing replication in the cell.

The team observed Cas12a2 in the act of cutting double-stranded DNA, bending it 90° to expose the backbone of the helix to cut it, a phenomenon that a phenomenon that elicits audible gasps from fellow scientists,” Jackson says.

Since the difference between a healthy cell and a malignant cell or infected cell is genetic, if Cas12a2 could be harnessed, “the potential therapeutic applications are significant.”

“If Cas12a2 could be harnessed to identify, target and destroy cells at the genetic level, the potential therapeutic applications are significant,” he says.

Source: Utah State University

Categories : Diet and Nutrition GeneticsTags :

Obesity Genetic Risk Could be Curbed by Practising Restraint

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Photo by Jonathan Borba

Obesity risk genes make people feel hungrier and lose control over their eating, but practisng dietary restraint could counteract this, according to new research from University of Exeter. Published in the International Journal of Epidemiology, the study found that those with higher genetic risk of obesity can reduce the effects that are transmitted via hunger and uncontrolled eating by up to half through dietary restraint.

Lead author psychology PhD student, Shahina Begum said: “At a time when high calorie foods are aggressively marketed to us, it’s more important than ever to understand how genes influence BMI. We already know that these genes impact traits and behaviours such as hunger and emotional eating, but what makes this study different is that we tested the influence of two types of dietary restraint – rigid and flexible – on the effect of these behaviours. What we discovered for the first time was that increasing both types of restraint could potentially improve BMI in people genetically at risk; meaning that restraint-based interventions could be useful to target the problem.”

Genes linked to obesity increase BMI, with up to a quarter of this effect explained by increases in hunger and uncontrolled (including emotional) eating. There are over 900 genes that have so far been identified by researchers as being associated with BMI and several studies suggest these risk genes influence feelings of hunger and loss of control towards food.

This study examined 3780 adults aged between 22 and 92 years old from two UK cohorts: the Genetics of Appetite Study, and Avon Longitudinal Study of Parents and Children. Their weight and height were measured, and they provided a DNA sample via their blood to calculate an overall score for their genetic risk of obesity. They then completed questionnaires to measure 13 different eating behaviours, including disinhibition (a tendency to engage in binge or emotional eating) and over-eating due to hunger.

As expected, researchers found that a higher genetic risk score was associated with a higher BMI, partly due to increased disinhibition and hunger. However, results also found that those who had high levels of dietary restraint reduced those effects by almost half for disinhibition and a third for hunger, suggesting that restraint may counteract some of the effects of genetic risk.

There are different types of dietary restraint, including flexible strategies to rigid strategies, like calorie counting. The study tested the influence of both types of restraint for the first time and found both could potentially improve BMI in people genetically at risk.

Interventions to facilitate dietary restraint could include changing the food environment (by reducing the calorie content or portion size of food) or supporting individuals. To this end, members of the research team have developed a Food Trainer app (https://www.exeter.ac.uk/research/foodt/) to help achieve that. The app works as a game that trains people to repeatedly stop to high calorie food and research suggests this training may be particularly beneficial for those with a higher BMI.

Source: University of Exeter