Tag: genetics

Categories : COVID GeneticsTags :

SARS-CoV-2 Does Not Alter Human DNA

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Image source: Pixabay

Despite controversial claims, the SARS-CoV-2 virus likely does not integrate its genetic material into the genes of humans, according to a study published in the Journal of Virology.

A prior study reported the virus’s genetic material was found to have integrated into human DNA in cells in petri dishes, though the scientists conducting the newer research now say this was resulted from genetic artefacts in the testing.

Study co-lead author Majid Kazemian, a Purdue University assistant professor of biochemistry and computer science, said that this finding has two important implications.

“Relatively little is known about why some individuals persistently test positive for the virus even long after clearing the infection,” he explained. “This is important because it’s not clear whether such individuals have been re-infected or whether they continue to be infectious to others. So-called ‘human genome invasion’ by SARS-CoV-2 has been suggested as an explanation for this observation, but our data do not support this case.

“If the virus was able to integrate its genetic material into the human genome, that could have meant that any other mRNA could do the same. But because we have shown that this is not supported by current data, this should allay any concerns about the safety of mRNA vaccines,” he concluded.

It is indeed possible for virus genetic material to be incorporated into the DNA of humans and other animals, which are referred to as ‘chimeric events’. These have happened over many millions of years; human DNA contains approximately 100 000 pieces of ‘fossil DNA’ from viruses that have been accumulated throughout our evolution, accounting for nearly 10% of the genetic material in our cells. Some viral fragments even play a role in diseases such as cancer.

Recent scientific journal articles have raised controversy by claiming that the SARS-CoV-2 virus can also cause these chimeric events. Even before this study demonstrated it was not the case, the researchers suspected it was unlikely, said co-lead author Dr Ben Afzali, an Earl Stadtman Investigator of the National Institutes of Health’s National Institute of Diabetes and Digestive and Kidney Diseases.

“While an earlier study suggested that, in cells infected with SARS-CoV-2, genetic material from the virus copied and pasted itself into human DNA, our group thought this seemed unlikely,” Dr Afzali said. “SARS-CoV-2, like HIV, has its genetic material in the form of RNA but, unlike HIV, does not have the machinery to convert the RNA into DNA. SARS-CoV-2 is unlikely to paste itself into the genome and coronaviruses, in general, does not go near human DNA. As our study shows, we find it highly improbable that SARS-CoV-2 could integrate into the human genome.”

Christiane Wobus, associate professor of microbiology and immunology at the University of Michigan Medical School, another co-lead author on the study, said that the collective understanding of RNA viruses is that SARS-CoV-2 integrating into the human genome was extremely unlikely, it was still worth asking the question.

“Unexpected findings in science—when confirmed independently—lead to paradigm shifts and propel fields forward. Therefore, it is good to be open-minded and examine unexpected results carefully, which I believe we did in our study,” she said. “However, we did not find conclusive evidence for SARS-CoV-2 integration, but instead showed that during the RNA sequencing methodology, chimeras are produced at a very low level as an artifact of the laboratory technique.”

To examine any possible integration event, the researchers came up with a novel technique involving extraction the genetic material from infected cells and then boosting the amount of the genetic material 30-fold. With any chimeric events in the host cell DNA, these bits of genetic material from SARS-CoV-2 would have also increased those by 30. The data did not show this.

“We found the frequency of host-virus chimeric events was, in fact, not greater than background noise,” Kazemian stated. “When we enriched the SARS-CoV-2 sequences from the bulk RNA of infected cells, we found that the chimeric events are, in all likelihood, artifacts. Our work does not support the claim that SARS-CoV-2 fuses or integrates into human genomes.”

Source: Medical Xpress

Journal information: Bingyu Yan et al, Host-virus chimeric events in SARS-CoV2 infected cells are infrequent and artifactual, Journal of Virology (2021). DOI: 10.1128/JVI.00294-21

Categories : Cancer GeneticsTags :

New Study Finds Genetic Switch Role in Melanoma

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The ability of cancer cells to move and spread depends on actin-rich core structures such as the podosomes (yellow) shown here in melanoma cells. Cell nuclei (blue), actin (red), and an actin regulator (green) are also shown. Source: National Cancer Institute
Metastatic melanoma cells

A study published in the journal Cell Reports reveals that a genetic switch that could potentially be targeted to develop new treatments for melanoma by keeping the switch turned off.

Melanoma causes the majority of skin cancer-related deaths, despite only making up roughly 1 percent of skin cancers. The incidence of malignant melanoma is rapidly increasing around the world, and this increase is occurring at a faster rate than that of any other cancer except lung cancer in women. Treatments exist for this serious disease, but the effectiveness of these drugs can vary depending on the individual.

“We’ve been able to correlate the activity of this genetic switch to melanin production and cancer,” said Salk study corresponding author Marc Montminy, a professor in the Clayton Foundation Laboratories for Peptide Biology.

Melanoma develops when melanocytes, the pigment-producing skins in the cell, mutate and begin to multiply out of control. These mutations can cause proteins such as CRTC3 to prompt the cell to produce an abnormal amount of pigment, or to migrate and be more invasive.

While it was known that the CRTC family of proteins (CRTC1, CRTC2, and CRTC3) is involved in pigmentation and melanoma, obtaining precise details about the individual proteins has proven difficult. “This is a really interesting situation where different behaviours of these proteins, or genetic switches, can actually give us specificity when we start thinking about therapies down the road,” said first author Jelena Ostojic, a former Salk staff scientist and now a principal scientist at DermTech.

When the researchers deleted the CRTC3 gene in mice caused a color change in the animal’s coat color, demonstrating that the protein is needed for melanin production. They also found that when melanoma cells lacked the protein, they migrated and invaded less, meaning they were less aggressive, suggesting that inhibiting the protein could help treat the disease.

The team also described the connection between two cellular signalling systems that work on the CRTC3 protein in melanocytes. These two systems tell the cell to either proliferate or make the pigment melanin. Montminy likens this process to a relay race: essentially, a baton (chemical message) is passed from one protein to another until it reaches the CRTC3 switch, either turning it on or off.

“The fact that CRTC3 was an integration site for two signaling pathways—the relay race—was most surprising,” says Montminy, who holds the J.W. Kieckhefer Foundation Chair. “CRTC3 makes a point of contact between them that increases specificity of the signal.”

Next, the team plans to further investigate the mechanism of how CTRC3 impacts the balance of melanocyte differentiation to develop a better understanding of its role in cancer.

Source: Salk Institute

Categories : GeneticsTags :

Muscle Atrophy Gene Identified from Mice Sent into Space

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Dragon cargo capsule arriving at the International Space Station. Image by SpaceX-Imagery from Pixabay

Researchers from the University of Tsukuba have found a new gene involved in muscle atrophy when they sent mice into space to explore effects of weightlessness on skeletal muscles.

Extended periods of skeletal muscle inactivity or mechanical unloading (bed rest, immobilisation, spaceflight and reduced step) can result in a significant loss of muscle mass and strength which ultimately lead to muscle atrophy. Spaceflight is one of the leading models of understanding muscle atrophy from disuse.

As the molecular and cellular mechanisms involved in disuse skeletal muscle atrophy have been studied, several different signaling pathways have been studied to understand their regulatory role in this process. However, large gaps exist in the understanding of the regulatory mechanisms involved, as well as their functional significance.

Prior studies examining the effects of reduced gravity on muscle mass and function have used a ground control group which cannot be directly compared to the space experimental group. Researchers from the University of Tsukuba set out to explore the effects of gravity in mice subjected to the same housing conditions, such as the stresses of launch, landing and cosmic radiation. “In humans, spaceflight causes muscle atrophy and can lead to serious medical problems after return to Earth” says senior author Professor Satoru Takahashi. “This study was designed based on the critical need to understand the molecular mechanisms through which muscle atrophy occurs in conditions of microgravity and artificial gravity.”

Two groups of six mice each were housed onboard the International Space Station for 35 days. One group was subjected to artificial gravity (1g) and the other was left in microgravity. All mice were returned to Earth aboard a Dragon capsule and the team compared the effects of the different onboard environments on skeletal muscles. “To understand what was happening inside the muscles and cells, at the molecular level, we examined the muscle fibers. Our results show that artificial gravity prevents the changes observed in mice subjected to microgravity, including muscle atrophy and changes in gene expression,” explained Prof Takahashi. 

Transcriptional analysis of gene expression showed that the artificial gravity environment prevented altered expression of atrophy-related genes, and also identified other genes possibly associated with atrophy. Specifically, a gene called Cacng1 was identified as possibly having a functional role in myotube atrophy, which previously had no known function, and was shown to have increased activity when muscle atrophy was present.

When muscle fibres were cultured in vitro, ones which had Cacng1 expression upregulated were decreased in diameter by 27.5%. A similar effect was seen in newborn mice with upregulated Cacng1.

This work validated the use of 1g artificial gravity environments in spaceflight for examining the effects of microgravity in muscles. These studies add to the body of knowledge surrounding the mechanisms of muscle atrophy, possibly improving the treatment of related diseases.

Source: Tsukuba University

Journal information: Okada, R., et al. (2021) Transcriptome analysis of gravitational effects on mouse skeletal muscles under microgravity and artificial 1 g onboard environment. Scientific Reports. doi.org/10.1038/s41598-021-88392-4.

Categories : Cancer GeneticsTags :

Oesophageal Cancer Unleashes ‘Fossil Viruses’ Hidden in Human DNA

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Colorectal cancer cells. Photo by National Cancer Institute on Unsplash.

Scientists have discovered that many oesophageal cancers turn on ancient viral DNA that was embedded in our genome hundreds of millions of years ago.

“It was surprising,” said principal investigator Adam Bass, MD, the Herbert and Florence Irving Professor of Medicine at Columbia University Vagelos College of Physicians and Surgeons and Herbert Irving Comprehensive Cancer Center. 

“We weren’t specifically searching for the viral elements, but the finding opens up a huge new array of potential cancer targets that I think will be extremely exciting as ways to enhance immunotherapy.”

The idea that bits of ancient retroviruses within the human genome—known as endogenous retroviral elements, or ERVs—play a role in cancer is not new. About 8% of our genome is made up of these remnants of viral infections that have accumulated over the last 100 million years. While ERV sequences have degraded over the aeons and cannot produce viral particles, the viral fossils sometimes wind up inside other genes, disrupting their normal activities, or act as switches that turn on cancer-causing genes.

Recent research however shows that ERVs may also have a cancer fighting role if they are transcribed into strands of RNA.

“When cells activate lots of ERVs, a lot of double-stranded RNA is made and gets into the cell cytoplasm,” Dr Bass explained. “That creates a state that’s like a viral infection and can cause an inflammatory response. In that way, ERVs may make the cancer more susceptible to immunotherapy, and many researchers are working on ways to trick cancer cells into activating ERVs.”

In the new study, Bass and colleagues created organoids of oesophageal mouse tissue to follow the development of cancer from normal cells to malignancy.

With these organoids, Bass discovered that a specific cancer-promoting gene in oesophageal cancers called SOX2 triggers the expression of many ERVs.  

As ERV expression and the accumulation of double-stranded RNAs that can result can be toxic to cells, the researchers found that there is a specific enzyme called ADAR1 that rapidly degrades these double-stranded RNAs.

ADAR1 has been implicated in oesophageal cancer by other researchers, although its role had been unclear. Levels of ADAR1 are known to correlate with poor survival. “The cancers are dependent on ADAR1 to prevent an immune reaction that can be very toxic to the cells,” Bass says.

Some patients with oesophageal cancer are currently treated with immunotherapy, which has been shown to increase survival by several months. “We have a lot of enthusiasm that blocking ADAR1 may both have direct efficacy for oesophageal cancers and that ADAR1 inhibition may have even great effects by enhancing the efficacy of cancer immunotherapy in patients with oesophageal cancer,” Bass said.

Beyond the results regarding ADAR1 and ERVs, the process of modelling the development of oesophageal cancer via genomic engineering of organoids also uncovered a variety of other processes in oesophageal cancer that could help develop new therapies.

“The way we used organoids to build cancers up from the normal cell is a powerful system for uncovering cancer-causing activities and testing therapeutic targets,” said Bass. “By making individual genome alterations in these models one at a time, we can see which combinations of genetic alterations lead to cancer and then determine specific mechanisms of tumor formation.”

In this study, the organoids started with overexpression of the SOX2 gene, a commonly amplified factor that promotes the development of squamous cancers.

In the study, Dr Bass’ team built a panel of organoids emulating conditions ranging from normal oesophagus to fully transformed cancer.

By comparing normal and cancerous organoids, the team could dissect how the activity of SOX2 differs in normal and cancerous tissues. “It’s important to understand the difference, since potential treatments need to target the cancer functions but have lesser impact upon normal tissue,” he says. “It’s relatively easy to kill cancer cells. The problem is, how do you kill cancer cells but spare other cells?”

Results from the organoids showed that when SOX2 is overactive—and two tumour suppressors are inactivated—SOX2 interacts with other factors, activating an array of cancer-causing genes in addition to their effects upon induction of ERVs.  

“These findings reveal new vulnerabilities in SOX2 oesophageal cancers,” Bass said, “that will now allow us to begin developing therapies that can precisely target the cancer cell and improve the treatment of patients.”

Source: Columbia University Irving Medical Center

Journal information: Zhong Wu, et al. Reprogramming of the esophageal squamous carcinoma epigenome by SOX2 promotes ADAR1 dependence. Nature Genetics, 2021; DOI: 10.1038/s41588-021-00859-2

Categories : COVID Gender GeneticsTags :

Severe COVID and Male Balding Gene Linked

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Photo by Brett Sayles from Pexels

While COVID has been long known to be more dangerous in men than women, research which is still in its early stages shows that some of this increased risk could be from having a gene for male balding. 

A team of researchers in the US first suspected the link when they noticed that men with a common form of hormone-sensitive hair loss, known as androgenetic alopecia, were also more likely to be hospitalised with COVID.  They presented their findings May 6 at the virtual spring meeting of the European Academy of Dermatology and Venereology (EADV).

“Among hospitalized men with COVID-19, 79% presented with androgenetic alopecia compared to 31%-53% that would be expected in a similar aged match population,” said researchers led by Dr Andy Goren, chief medical officer at Applied Biology Inc in California. 

The researchers noted that androgenetic alopecia is due to the activity of the androgen receptor (AR) gene, which can lead to balding in some men. An enzyme called TMPRSS2, key to COVID infection, is also androgen-sensitive, and might be affected by the AR gene as well, explained Dr Goren’s group.

One key segment on the AR gene seems to affect both COVID severity and male balding.

In the new study, the Irvine group enrolled 65 men hospitalised with COVID, and conducted a genetic analysis on them. The results showed that participants with certain structural differences in the AR gene were at greater risk of developing severe COVID. Speaking in a meeting press release, Goren said the AR gene anomaly “could be used as a biomarker to help identify male COVID-19 patients most at risk for ICU admissions.”

He added that he believes that “the identification of a biomarker connected with the androgen receptor is another piece of evidence highlighting the important role of androgens [male hormones] in COVID-19 disease severity.”

Dr Teresa Murray Amato  has seen many severe cases of COVID. She is chair of emergency medicine at Long Island Jewish Forest Hills in New York City. Though not connected to the new research, but said it “did show a significant correlation between a higher number of androgen receptors and a higher incidence of ICU admissions for patients infected with COVID-19.”

Dr Amato added that, “While the study is small and the exact association is not completely understood, it may show at least one answer to why men were more likely to be admitted to ICU and have overall higher morality with COVID-19 infections.”

According to Amato, further investigations are necessary to determine whether “medications that block androgen receptors will be useful in treating a subset of [COVID-19] patients.”

Since the findings were presented at a medical meeting, they should be considered preliminary until published in a peer-reviewed journal.

Source: Medical Xpress

Categories : Skeletal SystemTags :

Unique Genetic Profile of Bone Cells Mapped

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X-ray of a wrist. Photo by Cara Shelton on Unsplash

Pioneering new research has charted the unique genetic profile of the skeleton’s ‘master regulator’ cells, known as osteocytes.

The study led by the Garvan Institute of Medical Research was published in Nature Communications. The study describes the genes that are switched on or off in osteocytes, a multifunctional type of bone cell that regulates how bone material is grown or broken down in order to maintain healthy skeletons.

“This new information provides a kind of genetic shortlist we can look to when diagnosing bone diseases that have a genetic component,” said the study’s first author Dr Scott Youlten, Research Officer in the Bone Biology Lab. “Identifying this unique genetic pattern will also help us find new therapies for bone disease and better understand the impacts of current therapies on the skeleton.”

Far from static, the skeleton is a highly dynamic structure that is constantly remodelled throughout a person’s life. Though osteocytes are the most common cell type in bone, they have been hard to study as they are embedded within the skeleton’s hard mineral structure.

Osteocytes form a network inside bones on a scale and complexity which mirrors the neurons in the brain (42 billion osteocytes with over 23 trillion connections between them), which monitors bone health and responds to ageing and damage by signalling other cells to either add more bone or break down old bone. Osteoporosis, rare genetic skeletal disorders and other bone diseases arise from an imbalance in these processes.

To understand what genes are involved in controlling bone build-up or breakdown, the researchers isolated bone samples from different skeletal sites of experimental models in order to measure the average gene activity in osteocytes. In so doing, they found an osteocyte ‘signature’ of 1239 genes that are switched on. Of these genes, 77% had no previously known role in the skeleton, and many were completely novel and unique to osteocytes.

“Many of the genes we saw enriched in osteocytes are also found in neurons, which is interesting given these cells share similar physical characteristics and may suggest they are more closely related than we previously thought,” explained Dr Youlten.

Comparing the osteocyte signature genes with human genetic association studies of osteoporosis could identify new genes that may be associated with susceptibility to this common skeleton disease. Additionally, a number of these osteocyte genes were also shown to be responsible for rare bone diseases.

“Mapping the osteocyte transcriptome could help clinicians and researchers more easily establish whether a rare bone disease has a genetic cause, by looking through the ‘shortlist’ of genes known to play an active role in controlling the skeleton,” said Dr Youlten.

Co-senior author Professor Peter Croucher, Deputy Director of the Garvan Institute and Head of the Bone Biology Lab, said that “the osteocyte transcriptome map gives researchers a picture of the whole landscape of genes that are switched on in osteocytes for the first time, rather than just a small glimpse”.

“The majority of genes that we’ve found to be active within osteocytes had no previously known role in bones. This discovery will help us understand what controls the skeleton, which genes are important in rare and common skeletal diseases and help us identify new treatments that can stop development of bone disease and also restore lost bone.”

Source: Medical Xpress

Journal information: Nature Communications (2021). DOI: 10.1038/s41467-021-22517-1

Categories : Genetics Obstetrics & GynaecologyTags :

Foetal Genetics Drive Birth Defects and Pregnancy Loss

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Pregnant belly with ultrasound image superimposed. Image by Rudy and Peter Skitterians from Pixabay

A study by Yale researchers has shown that the genetics of the foetus and placenta drive developmental abnormalities, including those that lead to pregnancy loss and autism.

In the US, a birth defect is diagnosed in about 3% of children born every year, according to the Centers for Disease Control and Prevention. Birth defects also occur in most cases of pregnancy loss, and also result in many deaths in the first year of life. The causes are thought to be a complex interplay of environmental and biological factors.

“Mothers often feel that they are responsible for these defects,” explained senior author Dr Harvey Kliman,  Research Scientist at the Department of Obstetrics, Gynecology & Reproductive Services, Yale School of Medicine. “But it’s not their fault. This new research points to the genetics of these children as being the most important cause.”

Dr Kliman and his team examined placental data for nearly 50 sets of identical and non-identical twins. They discovered identical twins had similar numbers of abnormal cell growths called trophoblast inclusions (TIs), which are markers for a number of developmental abnormalities, while non-identical twins showed a markedly different TI count.

While identical twins share the same DNA, non-identical twins only share half of their DNA. Identical twins were found to often have the same number of TIs or were within one of having the same TI count. Non-identical twins had TI counts that differed by four or five on average.

“This work suggests that developmental abnormalities are much more likely to be due to the genetics of the child, and not the mother’s fault,” Dr Kliman explained.

The findings were reported in the journal Placenta.  

First author Julia Katz, a former Yale undergraduate and now medical student at Hofstra University, provided the inspiration for the study.

Katz and her brother, Jesse, who was born underweight and with several congenital abnormalities, are non-identical twins. “I had a lot of guilt, growing up, about why my twin had certain conditions that I didn’t,” Katz explained. “I think mothers also tend to blame themselves.”

After a lecture,  Katz approached Dr Kliman and asked him what causes babies to be born undersized, a conversation which led to a discussion about developmental abnormalities and Katz’s desire to find out more about her and her twin’s genetics — including looking at her own placental slides from birth.

It also led Dr Kliman, Katz, and co-author Parker Holzer, a graduate student in the Yale Department of Statistics and Data Science, to conduct the new study.

“Julia’s need to resolve this burden is what propelled our study,” Dr Kliman said. “Hopefully, this finding will help many other people, as well.”

“This experience has shown me that if you have a question, ask it,” Katz added. “And if you don’t get an answer, try to answer it yourself.”

Source: News-Medical.Net

Journal information: Katz, J., et al. (2021) Genetics, not the uterine environment, drive the formation of trophoblast inclusions: Insights from a twin study. Placenta. doi.org/10.1016/j.placenta.2021.04.010.

Categories : GeneticsTags :

Refining the Genetic Heritage of South Africans for Better Medicine

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A new study from Wits University challenges the idea that all South-Eastern-Bantu speaking groups are a single genetic group.

The South-Eastern-Bantu (SEB) language family includes isiZulu, isiXhosa, siSwati, Xitsonga, Tshivenda, Sepedi, Sesotho and Setswana. Almost 80% of South Africans speak one of these as their first language and their origins can be traced to West-Central Africa farmers whose descendants over the past two millennia southwards, finally reaching Southern Africa.

Since then, settling and population movements and interaction with Khoe and San communities, as other SEB speakers, ultimately resulted in distinct Southern African languages such as isiZulu, isiXhosa and Sesotho. But despite these linguistic differences, these groups of people are treated as one group in genetic studies.

Genetic disease studies rely on understanding the genetic diversity of population. If two genetically distinct populations are treated as one, errors could occur when finding disease genes, especially for complex diseases like hypertension and diabetes.

Dr Dhriti Sengupta  and Dr  Ananyo Choudhury in the Sydney Brenner Institute for Molecular Bioscience (SBIMB) at Wits University were joint lead authors of the paper published in Nature Communications. 

“South Eastern Bantu-speakers have a clear linguistic division – they speak more than nine distinct languages – and their geography is clear: some of the groups are found more frequently in the north, some in central, and some in southern Africa. Yet despite these characteristics, the SEB groups have so far been treated as a single genetic entity,” said Dr Choudhury.

The study found that SEB speaking groups are too different to be treated as a single genetic unit.

“So if you are treating say, Tsonga and Xhosa, as the same population – as was often done until now – you might get a completely wrong gene implicated for a disease,” said Sengupta.

The study aimed to find out whether the SEB speakers are indeed a single genetic entity or if they have enough genetic differences to be grouped into smaller units.

Genetic data from more than 5000 participants speaking eight different southern African languages were generated and analysed. Participants were recruited from research sites in Gauteng, Mpumalanga, and Limpopo province.

The study detected major variations in genetic contribution from the Khoe and San into SEB speaking groups; some groups have received a lot of genetic influx from Khoe and San people, while others have had a very little genetic exchange with these groups.

This variation ranged on average from about 2% in Tsonga to more than 20% in Xhosa and Tswana, suggesting that  SEB speaking groups are too different to be treated as a single genetic unit.

“The study showed that there could be substantial errors in disease gene discovery and disease risk estimation if the differences between South-Eastern-Bantu speaking groups are not taken into consideration,” said Dr Sengupta.

The genetic data also show major differences in the history of these groups over the last 1000 years, with genetic exchanges occurring at different points in time. These genetic differences are distinctive enough to affect the outcomes of biomedical genetic research.

Dr Sengupta cautioned that ethnolinguistic identities are complex and broad conclusions extrapolated should not from the findings regarding genetic differences.

“Although genetic data showed differences [separation] between groups, there was also a substantial amount of overlap [similarity]. So while findings regarding differences could have huge value from a research perspective, they should not be generalised,” she said.

A common approach to identify if a genetic variant causes or predisposes a disease is to compare occurrence of many genetic variants in individuals with a disease (eg, hypertension or diabetes) against healthy individuals. If there is a difference in frequency in a variant between two sets, the genetic variant is assumed to be perhaps linked to the disease.

“However, this approach depends entirely on the underlying assumption that the two groups consist of genetically similar individuals. One of the major highlights of our study is the observation that Bantu-speakers from two geographic regions – or two ethnolinguistic groups – cannot be treated as if they are the same when it comes to disease genetic studies,” said Dr Choudhury.

Future studies, especially those testing a small number of variants, need to be more nuanced and have balanced ethnolinguistic and geographic representation, he said.

Professor Michèle Ramsay, director of the SBIMB and corresponding author of the study, says: “The in-depth analysis of several large African genetic datasets has just begun. We look forward to mining these datasets to provide new insights into key population histories and the genetics of complex diseases in Africa”.

Source: Wits University

Journal reference: Sengupta, D., et al. (2021) Genetic substructure and complex demographic history of South African Bantu speakers. Nature Communications.doi.org/10.1038/s41467-021-22207-y.

Categories : Ethics and Law GeneticsTags :

Human-monkey Chimeric Embryos Set off Ethics Debate

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Blastocyst. Source: Wikimedia Commons.

A study published in the journal Cell has announced the creation of human-monkey chimeric embryos, igniting renewed debate over ethics.

The embryos are known as chimeras, organisms whose cells come from two or more “individuals”, and in this case, different species: a long-tailed macaque and a human. The research confirmed that the cells can survive and multiply.

Natural human chimeras do exist, and can involve humans cells from two embryos in the same womb fusing to produce a single individual, or a combination of maternal and foetal cells, or monozygotic twins sharing blood cells from a shared placenta.

Previously, researchers had produced pig or sheep embryos that contained human cells, in an effort to one day develop a way to grow human organs for transplant inside the animals.

The researchers, led by Prof Juan Carlos Izpisua Belmonte from the Salk Institute in the US, said that the results shed new light on the communications pathways between cells of different species. This could help with future efforts to engineer chimeras using more distantly related species.

“These results may help to better understand early human development and primate evolution and develop effective strategies to improve human chimerism in evolutionarily distant species,” the authors wrote.

In 2019, the Spanish newspaper El País reported on rumours that a team of researchers led by Belmonte had created monkey-human chimeras.

Specific human foetal cells called fibroblasts were reprogrammed to become stem cells, and were then introduced into 132 embryos of long-tailed macaques, six days after fertilisation.

“Twenty-five human cells were injected and on average we observed around 4% of human cells in the monkey epiblast,” said Dr Jun Wu, a co-author of the research, and now at the University of Texas Southwestern Medical Center.

The embryos were grown in petri dishes and were terminated 19 days after the stem cells were injected. The human cells were engineered with a fluorescent protein to enable identification.

The researchers reported that 132 embryos contained human cells on day seven after fertilisation. However, the proportion containing human cells fell over time.

“We demonstrated that the human stem cells survived and generated additional cells, as would happen normally as primate embryos develop and form the layers of cells that eventually lead to all of an animal’s organs,” Belmonte said.

The researchers also found differences in intercellular interactions between human and monkey cells within chimeric embryos, compared to the normal monkey embryos.

The researchers hoped the research would help develop “transplantable human tissues and organs in pigs to help overcome the shortages of donor organs worldwide”, said Wu.

Prof Robin Lovell-Badge, a developmental biologist from the Francis Crick Institute in London, said at the time of the El País report he was not concerned about the ethics of the experiment, noting the team had only produced a ball of cells. But he noted conundrums could arise in the future should the embryos be allowed to develop further.

While not the first attempt at making human-monkey chimeras – another group reported such experiments last year – the new study has reignited such concerns. Prof Julian Savulescu, the director of the Oxford Uehiro Centre for Practical Ethics and co-director of the Wellcome Centre for Ethics and Humanities at the University of Oxford, said the research had raised all sorts of ethical concerns.

“These embryos were destroyed at 20 days of development but it is only a matter of time before human-nonhuman chimeras are successfully developed, perhaps as a source of organs for humans,” he said, and added that a key ethical concern was the moral status of such organisms.

“Before any experiments are performed on live-born chimeras, or their organs extracted, it is essential that their mental capacities and lives are properly assessed. What looks like a nonhuman animal may mentally be close to a human,” he said. “We will need new ways to understand animals, their mental lives and relationships before they are used for human benefit.”

Others were less concerned, and rather pointed out that all the study found was that the creation of such chimera was simply ineffective.

Dr Alfonso Martinez Arias, an affiliated lecturer in the department of genetics at the University of Cambridge, said: “I do not think that the conclusions are backed up by solid data. The results, in so far as they can be interpreted, show that these chimeras do not work and that all experimental animals are very sick.

“Importantly, there are many systems based on human embryonic stem cells to study human development that are ethically acceptable and in the end, we shall use this rather than chimeras of the kind suggested here.”

Source: The Guardian

Categories : Cancer PaediatricsTags :

Blood Mutation Explains High Leukaemia Rates in Children with Down’s

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According to a new study by researchers at the Linda Crnic Institute for Down Syndrome, the reason that children with Down syndrome have a drastically elevated risk of leukaemia is due to a more prevalent condition increasing blood stem cell mutation.

Children with Down syndrome are 20-times more likely to develop acute lymphocytic leukaemia (ALL) and 150-times more likely to develop acute myeloid leukaemia (AML) compared to their typical peers. The researchers found that the reason for this is that they are more likely to present with clonal haematopoiesis (CH), a process in which a blood stem cell acquires a genetic mutation that promotes replication.  

The findings add to a growing body of evidence linking immune dysregulation to a very different disease spectrum, whereby people with Down syndrome are highly predisposed to certain diseases such as leukaemia and autoimmune disorders, while being highly protected from others, such as solid tumours.

“We found a higher-than expected rate of CH in individuals with Down syndrome between the age of one to 20 years old,” said study author Dr Alexander Liggett, who as a doctoral candidate led the study in the lab of Dr James DeGregori, Professor of Biochemistry and Molecular Genetics. “It is a surprising finding, as the phenomenon is typically only observed in elderly people.”

The researchers used an advanced sequencing technique that they had developed, called FERMI, to blood samples from the Crnic Institute Human Trisome Project Biobank. Mutations were more likely to be detected in Down’s syndrome and also more likely to be oncogenic. In elderly people, oncogenic mutations are commonly found in the genes DNMT3A, TET2, ASXL1, TP53, and JAK2. In people with Down’s syndrome, oncogenic CH was found to be dominated by mutations of the TET2 gene.

“Given the increased risk of leukaemia that accompanies clonal expansion of blood cells carrying oncogenic mutations, these expansions may become an important biomarker of cancer risk in the future,” said Dr Liggett.

The study also found that CH in Down syndrome is associated with immune dysregulation biosignatures linked to diseases co-occurring with Down’s syndrome, including thyroiditis, Alzheimer’s disease, and leukaemia. This discovery opens new avenues in understanding the way CH impacts an array of health outcomes in Down syndrome and how to potentially counteract its effects.

“This is truly transformative. This team has identified a new trait of Down syndrome that has strong implications for understanding the appearance of comorbidities more common in this population, such as leukaemia and premature ageing,” said Dr. Joaquin Espinosa, Executive Director of the Crnic Institute. “The next step is to define the long-term impacts of this precocious clonal hematopoiesis and how to prevent its harmful effects.”

Source: News-Medical.Net

Journal information: Liggett, L.A., et al. (2021) Precocious clonal hematopoiesis in Down syndrome is accompanied by immune dysregulation. Gut. doi.org/10.1182/bloodadvances.2020003858.