Tag: genetics

Categories : GeneticsTags :

African Genetic Data Needed to Complete the DNA Picture

On By ModernMedia

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

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

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

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

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

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

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

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

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

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

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

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

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

Source: Medical Xpress

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

Categories : GeneticsTags :

Study Reveals the Genetics of Daytime Napping

On By ModernMedia

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

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

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

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

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

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

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

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

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

Source: Medical Xpress

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

Categories : Cancer Immune SystemTags :

Immune Cells in Prostate Tumours Boost Survival with Immunotherapy

On By ModernMedia

A new Northwestern Medicine study discovered the reason why black men are more likely to survive prostate cancer when given immunotherapy. 

Black men die more often from prostate cancer, yet are more likely to respond to immunotherapy. The increased presence of a type of immune cell in the tumours of black men appears to be related to their increased odds of survival with immunotherapy. The findings will be published on February 10 in Nature Communications.

A research team by Dr Edward Schaeffer, chair of urology at Northwestern University Feinberg School of Medicine and Northwestern Medicine, found that men who survive prostate cancer with immunotherapy have been found to have more plasma cells. Plasma cells are a type of specially differentiated B cell, which secrete antibodies and play a key role in the adaptive immune response.

“If a man’s prostate cancer has numerous plasma cells, we found he had improved cancer survival,” Schaeffer said. “Our study suggests plasma cells are important in the body’s response to cancer.”

Recent studies have shown that black men with advanced prostate cancer have on average better response to immunotherapy than white men. However, there has been no way to determine which individuals would have a better response, regardless of race.

Schaeffer’s team went through the genomics of 1300 tumour samples classified to genetic ancestry or self-identified race, and found more plasma cells in the tumours of black men than those of white men. However, the finding was not unique to black men alone, as elevated plasma cells in all men raised the odds of cancer-free survival after surgery.

“The finding comes at a time as researchers are discovering plasma cells may play a greater role in cancer immunotherapy than previously thought,” said first author Dr. Adam Weiner, a Northwestern Medicine urology resident. “Testing for plasma cells in prostate cancer may help identify men who will benefit from immune-based treatments.”

Source: Medical Xpress

Categories : GeneticsTags :

New Study Finds Critical Flaw in Blood-brain Model

On By ModernMedia

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

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

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

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

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

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

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

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

Source: Medical Xpress

Categories : Genetics New Compounds and TreatmentsTags :

Embracing Ethnic Genetic Diversity in Drug Design

On By ModernMedia

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

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

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

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

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

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

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

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

Source: Medical Xpress

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

Categories : Gender Mental HealthTags :

Protein ‘Flavours’ Cause Gender Difference in Psychiatric Drug Responses

On By ModernMedia

A new study has shown that different isoforms or ‘flavours’ of key proteins have different effects in males and females, causing psychiatric drugs to function well in one gender and in others to be ineffective or a have host of side effects.

“The ultimate goal is to find the kink in the armor of mental illness—the proteins in the brain that we can specifically target without impacting other organs and causing side effects,” explained Charles Hoeffer, an assistant professor of integrative physiology at the Institute for Behavioral Genetics. “Personalisation is also key. We need to stop hitting every mental illness with the same hammer.

AKT was discovered in the 1970s and known as a gene which resulted in cancer when mutation was present. It is now known to play a role in “synaptic plasticity”, where synaptic connections between neurons are strengthened to encode memories.

“Let’s say you see a shark and you’re scared and your brain wants to form a memory. You have to make new proteins to encode that memory,” explained Hoeffer.

Different isoforms have different functions in the brain; AKT1 together with AKT2 in the prefrontal cortex is important for making new memories.
“These subtle differences could be really important if you wanted to personalise treatments for people,” explained Marissa Ehringer, an associate professor of integrative physiology who partnered with Hoeffer on some of the research.

The researchers spent six years examining the brains of male and female animals, and the role the loss of AKT played. For example, male mice with functioning AKT1 were much better than those without AKT1 when it came to “extinction learning”—replacing an old memory, or association that is no longer needed. However, in female mice, not having AKT1 did not make much difference.

“We found the difference between males and females to be so great it became the focus of our work,” Hoeffer said. “It was like night and day.”

Although there is much still to be learned, Hoeffer suspects that there are many other such key proteins having different effects or purposes in males and females.  

“To help more people suffering from mental illness we need much more knowledge about the difference between male and female brains and how they could be treated differently,” Hoeffer said. “This study is an important step in that direction.”

Source:Medical Xpress
Journal information: Helen Wong et al. Isoform-specific roles for AKT in affective behavior, spatial memory, and extinction related to psychiatric disorders, eLife (2020). DOI: 10.7554/eLife.56630

Categories : Cancer GeneticsTags :

New Method to Pick up Mutations Behind Colorectal Cancer Risks

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University of Michigan researchers have developed a method to detect mutations which give rise to colorectal cancer.

Colorectal cancer is the third most common cancer type, and the second most common cause of cancer-related deaths in the United States. Although most cases occur sporadically, some 5 to 10% of cases are hereditary, the most common cause of which is Lynch syndrome. Lynch syndrome results in an 80% increase in the lifetime risk of developing colorectal cancer. Those with a family history of colorectal cancer are advised to start screening before age 45. However, genetic testing for cancer risk does not always provide useful information for those with family history.  

To address this, a new method of genetic testing was developed by Jacob Kitzman, PhD, of the Department of Human Genetics at Michigan Medicine plus together with other colleagues. Since mutations are rare in the human population, determining which one is responsible is difficult, and simply studying one in the lab is too time consuming to be practical.
With deep mutational scanning, the researchers measured the effect of MSH2 mutations, which is one major cause of Lynch syndrome

They deleted the normal copy of MSH2 from human cells with CRISPR-Cas, replacing it with a library of every possible mutation in the MSH2 gene. Each cell in the mix then carried a unique MSH2 mutation. Chemotherapy then killed off only the cells that had a functional variant of MSH2.

The counterintuitive idea, noted Kitzman, is that the surviving cells do not have functioning MSH2—which have mutations that are most likely to cause disease.

“We were basically trying to sit down and make the mutations we could so they could serve as a reference for ones that are newly seen or are amongst the thousands of variants of unknown significance identified in people from clinical testing,” says Kitzman. “Until now, geneticists could not be sure whether these are benign or pathogenic.”

It is hoped that with other patient-specific information, some of these variants could be reclassified, and those individuals advised to undergo more intense screening.

Kitzman said: “One of the next areas that will need some focus in the field of human genetics is to create these sorts of maps for many different genes where there is a clinical connection, so we can be more predictive when variants are found in an individual.”

Source: Medical Xpress

Journal information: Xiaoyan Jia et al, Massively parallel functional testing of MSH2 missense variants conferring Lynch syndrome risk, The American Journal of Human Genetics (2020). DOI: 10.1016/j.ajhg.2020.12.003

Categories : AntibioticsTags :

Prevalence of Antibiotic Resistance is Underestimated

On By ModernMedia

Antibiotic resistance to pathogenic bacteria in humans has spread farther than expected, as it has been discovered that bacteria can swap DNA far more readily than thought possible.

A growing threat, antibiotic resistance has emerged faster than thought possible. Some 33 000 deaths have occurred to antibiotic resistant infections in Europe alone, and finding new antibiotics or even alternatives are a top research priority. Totally different strains of bacteria can swap genetic information through the use of containers called plasmids. Plasmids are small containers of DNA which are kept outside of their chromosomes. When two bacteria come into contact, they can copy plasmids to one another in a process called conjugation (also known as “bacterial sex“). This is the most important means by which bacteria spread antibiotic resistance.

“In recent years, we’ve seen that resistance genes spread to human pathogens to a much greater degree than anyone expected,” said Jan Zrimec, a researcher in systems and synthetic biology at the Chalmers University of Technology. “Many of the genes appear to have originated in a wide array of bacterial species and environments, such as soil, water, and plant bacteria.

“This has been difficult to explain because although conjugation is very common, we’ve thought that there was a distinct limitation for which bacterial species can transfer plasmids to each other. Plasmids belong to different mobility groups or MOB groups, so they can’t transfer between just any bacterial species.”

Among his developments, he has written an algorithm that can sift through substantial amounts of plasmid DNA to pick out sections of DNA which are necessary for conjugation (known as oriT regions, where the enzyme relaxase can bind to and snip out DNA). This algorithm can then sort the plasmids into groups based on their oriT regions. His new method differs from the standard one because it analyses oriT regions by their physiochemical properties instead of searching DNA for the enzyme sequence for relaxase, or the point where it can bind to. This method is less time-consuming and resource intensive than the standard one.

Previously, it was thought that a plasmid had to have both the relaxase enzyme and the oriT sequence to bind to, but a bacterial cell can have an oriT region for conjugation to occur. With his new algorithm, he has been able to explore the DNA of 4600 plasmids from different bacteria found in nature.
– There may be eight times as many oriT regions than those discovered with standard methods.
– There may be twice as many mobile plasmids as previously known.
– There also may be twice as many bacterial species with mobile plasmids as previously known.
– More than half the plasmids have an oriT group matching to an enzyme for conjugation from a plasmid that already been classified in a different MOB group. This means that they could be transferred from a different plasmid in the same cell.

The last finding suggests that there may be far greater interchange between bacteria than had been previously been believed.

“This has been a major limitation of the research field up to now,” Zrimec said. “I hope that the methods will be able to benefit large parts of the research into antibiotic resistance, which is an extremely interdisciplinary and fragmented area. The methods can be used for studies aiming to develop more effective limitations to antibiotic use, instructions for how antibiotics are to be used, and new types of substances that can prevent the spread of resistance genes at the molecular level.”

Source: News-Medical.Net

Journal information: Zrimec, J. (2021) Multiple plasmid origin‐of‐transfer regions might aid the spread of antimicrobial resistance to human pathogens. MicrobiologyOpen.doi.org/10.1002/mbo3.1129.

Categories : Mental HealthTags :

Autism Theory Treats its Characteristic Traits as Favoured by Society

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For decades, scientists have fruitlessly sought a unifying aetiology for autism and an explanation for its prevalence, but now a new theoretical model describes the condition as a combination of traits that are common in autism and which are socially valued, combined with co-occurring disabilities.

An estimated 1 in 54 people have autism, which has been on the increase in developed countries. TA Meridian McDonald, PhD, a research instructor in Neurology at Vanderbilt University Medical Center, said: “Up until now there have been a lot of theories about the possible causes of autism but none of those theories account for the majority of autism cases. There are also a lot of theories as to why the prevalence of autism has been increasing in the population but, to date, there hasn’t been a theory that provides an explanatory model that accounts for all of those phenomena, including the genetics, social history, or characteristics of autism.”

She has worked on autism for 25 years, culminating in a theory called, “The Broader Autism Phenotype Constellation-Disability Matrix Paradigm (BAPCO-DMAP) Theory”, a focuses on the genetic basis of autism in line with current science but shifts the emphasis to positive traits selected for by events occurring over the past century.”The BAPCO-DMAP theory describes how people are attracted to other people who are very similar. They are attracted to certain traits that are very common in the population, and this leads to offspring who are more likely to have certain traits, as well as a greater intensity of traits,” said McDonald.

“The [BAPCO] traits are not what people expect. They expect the traits to be about challenges or difficulties, but instead there are six main traits—increased attention, increased memory, a preference for the object world vs. the social world and their environment, increased nonconformity, increased differences in sensory and perception, as well as systemising.”

These BAPCO traits are thus not necessarily negative, and can be combined with social skills. Counterintuitively, babies with increased memory and attention spans learn language later, because babies normally rely on their tiny attention span to break words down into their simplest sounds. With greater memory and attention spans, infants engage in echolalia, speaking long phrases without understanding them.

“You can often see children with autism engaging in sense-making activities, such as watching the same show over and over and memorising information,” McDonald said.The BAPCO traits are not by themselves significant impediments, but when combined with a disability such as an information processing disorder, then the combination leads to greater difficulties.

According to McDonald, the increased prevalence of autism in developed countries is due to men and women with BAPCO traits being able to pursue similar careers and passions, as opposed to being limited by circumstance, and results in relationships. This effectively concentrates BAPCO traits in any children they have.Since the BAPCO traits are socially valued, there simply is no “cure” for them, according to McDonald.”When we talk about autism we need to address the developmental disabilities that these individuals are experiencing but also find way to support and enhance their broader autism trait constellations,” she concluded.

Source: Medical Xpress

Journal information: T.A. Meridian McDonald, The broader autism phenotype constellations–disability matrix paradigm: Theoretical model for autism and the broader autism phenotype, Medical Hypotheses (2020). DOI: 10.1016/j.mehy.2020.110456

Categories : GeneticsTags :

Not Quite Mirror Images: DNA of Identical Twins Differs Slightly

On By ModernMedia

The popular depiction of identical twins is that they are exactly that – individuals from a single zygote that are identical because their DNA is identical. But new research has shown that there can be a surprisingly large amount of mutations that differentiate one twin from another.

Twin studies have been popular in identifying the genetic basis of traits and conditions, such as vulnerabilities to disease, as well as in psychological studies examining the effects of genetic “nature” versus environmental “nurture”.

Sequencing the DNA of 387 pairs of identical twins, along with their parents, children and spouses, scientists in Iceland were able to find small numbers of early mutations between twins.Identical twins have an average of about 5.2 mutations between them, but in 15%, there were as many as 100 mutations. Such a number of genetic mutations could influence height differences or susceptibility to cancer.

Jan Dumanski, a geneticist at Uppsala University in Sweden, who was not involved in the new paper, said of the results, “The implication is that we have to be very careful when we are using twins as a model” for discerning the influences of nature and nurture.

The study went beyond previous ones that had already discovered small mutations between twins, to include parents, spouses and children, enabling them to pinpoint mutations in two kinds of cell: those present in just one individual and those passed on to their children. In addition, they found mutations occuring before the zygote split into two embryos.

Study co-author Kari Stefansson, a geneticist at the University of Iceland and the company deCODE genetics, said that his team had discovered cases where pairs of twins had mutations that were present in all cells of one twin, but not found in the other twin at all. However, “sometimes the second twin may show the mutation in some cells, but not all cells,” he said.

Source: Medical Express

Journal information: Hakon Jonsson et al. Differences between germline genomes of monozygotic twins, Nature Genetics (2021). DOI: 10.1038/s41588-020-00755-1