Category: 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 : GeneticsTags :

New Study Finds Critical Flaw in Blood-brain Model

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

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

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

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

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

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

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

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

Source: Medical Xpress

Categories : Genetics New Compounds and TreatmentsTags :

Embracing Ethnic Genetic Diversity in Drug Design

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 : Cancer GeneticsTags :

RNA Knockout Halts the Spread of Triple-negative Breast Cancer

On By ModernMedia

The University of Westminster has released a new study showing that taking out small chunks of human DNA called microRNA can reverse the spread of triple negative breast cancer cells.

The study also suggested that microRNAs could be targeted to spot and treat triple negative breast cancer. Breast cancer is the most common cancer in women, and triple negative breast cancer makes up 10-20% of cases.

MicroRNAs (miRs) have important roles in cellular functioning and signalling, and are heavily involved in the growth and metastasis of cancers. The researchers found that miR-21, a major breast cancer-related RNA, is increased in triple negative breast cancer and is also associated with metastasis.

Using CRISPR/Cas9, the researchers knocked out miR-21 from the cancer cells, and discovered that the cancer cells’ metastatic properties were reversed. They also observed that they released smaller vesicles, which release lipid blobs that play an important part in cancer spread. There was also less miR-21 carried in the vesicles, which also carry disease-related molecules to other cells.

Lead researcher Dr Pinar Uysal-Onganer of the University of Westminster, said: “This is an important study which contributes to better understanding of roles of miRs in aggressive cancer types such as triple negative breast cancer. We are now aiming to clarify the relationships between miR-21 and cancer drug resistance, which is another important factor that limits cancer cure.”

Source: Medical Xpress

Journal information: Elif Damla Arisan et al. MiR-21 is Required for the Epithelial–Mesenchymal Transition in MDA-MB-231 Breast Cancer Cells, International Journal of Molecular Sciences (2021). DOI: 10.3390/ijms22041557

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 : GeneticsTags :

Not Quite Mirror Images: DNA of Identical Twins Differs Slightly

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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

Categories : GeneticsTags :

Diet can Affect Sperm through Epigenetics

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A team of researchers have investigated the effect of adding nuts to a Western style diet on epigenetic effects of sperm quality.

The epigenetic effects are expressed through DNA methylation, where methyl groups are added to DNA sequences, altering their activity without changing the actual sequence.

A range of lifestyle and environmental factors have been investigated in the search for the cause in the drop of human sperm fertility observed over the pasty 70years. Specific sperm DNA methylation signatures are associated with sperm quality.

The researchers took data from 72 young non-smoking adults from the FERTINUTS trial. In the assigned nut-eating group, the participants’ sperm was found to have significantly sperm count, viability, motility, and morphology. Additionally, alterations in 36 specific DNA methylation regions were observed compared to the control group, and hypermethylation was seen in 97.2% of them.  

Albert Salas-Huetos, first author of the article stated that, “This work demonstrates that there are some sensitive regions of the sperm epigenome that respond to diet, and which can result in changes in sperm and in its ability to fertilise.”

Source: Science Daily

Categories : GeneticsTags :

“Elegant Chemo” Uses CRISPR Tools to Target Tumours

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New research from Tel Aviv University led by Prof Dan Peer, has developed a new system to directly slice DNA in cancer cells, effectively “deleting” them with molecular “scissors”, leaving no side effects, it is claimed. 

“This is the first study in the world to prove that the CRISPR genome editing system, which works by cutting DNA, can effectively be used to treat cancer in an animal,” said Peer.

The treatment increased survival by 30% for mice with gliboglioblastoma, one of the deadliest cancers, and 80% in disseminated ovarian tumours. 

When adapted for humans, the treatment would have to be customised for each individual based on a biopsy and then injected, either into the tumour or generally.

Peer explained that the injection consists of three components: a nanoparticle made from lipids, messenger RNA which “encodes” the “tiny scissor function” for cutting the DNA, and a system which “recognises” cancerous cells.   

Peer said, “When we first spoke of treatments with messenger RNA twelve years ago, people thought it was science fiction. I believe that in the near future, we will see many personalized treatments based on genetic messengers, for cancer and various genetic diseases.”

Source: Times of Israel

Categories : Genetics HIV T-cellsTags :

Long-term HIV Immunisation in Mice with Gene Technology

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While some COVID vaccines are entering the final phases of approval less than a year before the disease was first identified, HIV still has no vaccine after decades of research.

Now, engineered immune cells have elicited a response against HIV in mice, presenting an important first step forward in the quest for a vaccine. These broadly neutralising antibodies (bnabs) are effective against a variety of viruses and neutralise the glycan protecting HIV’s proteins.

Previous research had engineered B cells that produced the same antibodies as seen in rare HIV patients who are able to produce bnabs against HIV after many years. Now, this research has shown that it was possible to mature these into memory and plasma cells, conferring long-lasting protection and even showing improved antibodies can be produced, as in the immunisation process.

Principal investigator James Voss, PhD, of Scripps Research said, “This is the first time it has been shown that modified B cells can create a durable engineered antibody response in a relevant animal model.”

Currently it appears it would be an expensive therapy and a great barrier to many of the 38 million living with HIV around the world. A blood draw would be taken to the lab to engineer a vaccine for the patient, but Voss says that his team is looking to make the procedure inexpensive.

“People think of cell therapies as being very expensive,” Voss said. “We’re doing a lot of work towards trying to make the technology affordable as a preventative HIV vaccine or functional cure that would replace daily antiviral therapy.”

Source: Science Daily