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.”
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 journalCell 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.”
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.”
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.
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.
As an adult-onset psychiatric disorder, schizophrenia is thought to be triggered by some combination of environmental factors and genetics, although the exact cause remains unclear. In a study published in the journal Cell Genomics, researchers find a correlation between schizophrenia and somatic copy-number variants, a type of mutation that occurs early in development but after genetic material is inherited. This study is one of the first to rigorously describe the relationship between somatic genetic mutations and schizophrenia risk.
“We originally thought of genetics as the study of inheritance. But now we know that genetic mechanisms go way beyond that,” says senior author Chris Walsh, an investigator at the Howard Hughes Medical Institute and chief of genetics and genomics at Boston Children’s Hospital. “We’re looking at mutations that are not inherited from the parents.”
The researchers analysed genotype-marker data from over 20,000 blood samples of people with or without schizophrenia from the Psychiatric Genomics Consortium. They ultimately identified two genes, NRXN1 and ABCB11, that correlated with schizophrenia cases when disrupted in utero. NRXN1, a gene that helps transmit signals throughout the brain, has been associated with schizophrenia before. However, this is the first study to associate somatic, not inherited, NRXN1 mutations with schizophrenia.
Unlike inherited mutations, which are present in all the cells of the body, somatic mutations are only present in a fraction of cells based on when and where a mutation occurred. If a mutation occurs early in development, it is expected that the variant is present throughout the body in a mosaic pattern. On the basis of this principle, researchers can identify somatic mutations that occurred early in development and are present not only in the brain but also in a fraction of cells in the blood.
“If a mutation occurs after fertilisation when there are only two cells, the mutation will be present in half of the cells of the body,” says Walsh. “If it occurs in one of the first four cells, it will be present in about a quarter of the cells of the body, and so on.”
The second gene the researchers identified, ABCB11, is most known to encode a liver protein. “That one came out of nowhere for us,” says Eduardo Maury, a student in Harvard-MIT’s MD-PhD program. “There have been some studies associating mutations in this gene with treatment-resistant schizophrenia, but it hasn’t been strongly implicated in schizophrenia per se.”
When the team investigated further, they found that ABCB11 is also expressed in very specific subsets of neurons that carry dopamine from the brainstem to the cerebral cortex. Most schizophrenia drugs are thought to act on these cells to decrease an individual’s dopamine levels, so this might explain why the gene is associated with treatment resistance.
Next, the team is working towards identifying other acquired mutations that might be associated with schizophrenia. Given that the study analysed blood samples, it will be important to look at more brain-specific mutations that might have been too subtle or recent in a patient’s life for this analysis to detect. In addition, somatic deletions or duplications might be an under-investigated risk factor associated with other disorders.
“With this study, we show that it is possible to find somatic variants in a psychiatric disorder that develops in adulthood,” says Maury. “This opens up questions about what other disorders might be regulated by these kinds of mutations.”
An international team of researchers has developed a new method to deliver drugs into the inner ear, according to a new study in Science Translational Medicine. The discovery was possible by harnessing the natural flow of fluids in the brain and employing a little-understood backdoor into the cochlea. When combined to deliver a gene therapy that repairs inner ear hair cells, the researchers were able to restore hearing in deaf mice.
“These findings demonstrate that cerebrospinal fluid transport comprises an accessible route for gene delivery to the adult inner ear and may represent an important step towards using gene therapy to restore hearing in humans,” says lead author Barbara Canlon, professor at Karolinska Institutet.
The number of people worldwide predicted to have mild to complete hearing loss is expected to grow to around 2.5 billion by mid-century. The primary cause is the death or loss of function of hair cells found in the cochlea – which relay sounds to the brain – due to mutations of critical genes, aging, noise exposure, and other factors.
While hair cells do not naturally regenerate in humans and other mammals, gene therapies have shown promise and in separate studies have successfully repaired the function of hair cells in neo-natal and very young mice.
“However, as both mice and humans age, the cochlea, already a delicate structure, becomes enclosed in the temporal bone. At this point, any effort to reach the cochlea and deliver gene therapy via surgery risks damaging this sensitive area and altering hearing,” says Barbara Canlon.
In the new study, the researchers describe a little-understood passage into the cochlea called the cochlear aqueduct. The cochlear aqueduct is a thin boney channel no larger than several strands of hair.
Channel for spinal fluid
A new study shows that the cochlear aqueduct acts as a conduit between the cerebrospinal fluid found in the inner ear and the rest of the brain.
Scientists are developing a clearer picture of the mechanics of the glymphatic system, the brain’s unique process of removing waste. Because the glymphatic system pumps cerebrospinal fluid deep into brain tissue to wash away toxic proteins, researchers have been eyeing it as a potential new way to deliver drugs into the brain, a major challenge in developing drugs for neurological disorders.
The new study represented an opportunity to put the drug delivery potential of the glymphatic system to the test, while at the same time targeting a previously unreachable part of the auditory system.
Employing several imagining and modeling technologies, the researchers were able to develop a detailed portrait of how fluid from other parts of the brain flows through the cochlear aqueduct and into the inner ear.
The team then injected an adeno-associated virus into the cisterna magna, a large reservoir of cerebrospinal fluid found at the base of the skull.
The virus found its way into the inner ear via the cochlear aqueduct and delivered a gene therapy that expresses a protein called vesicular glutamate transporter-3, which enables the hair cells to transmit signals and rescue hearing in adult deaf mice.
“This new delivery route into the ear may not only serve the advancement of auditory research but also prove useful when translated to humans with progressive genetic-mediated hearing loss,” says Barbara Canlon.
Researchers have identified how pathogenic genes in some Providencia spp., which have gained attention as causes of food poisoning as well as enterohaemorrhagic Escherichia coli. O157 and Salmonella, are transferred within bacterial cells. Their findings are expected to provide new insights into the identification of infection routes of Providencia spp. and the establishment of preventive methods for food poisoning.
Recently, Providencia spp. which have been detected in patients with gastroenteritis, and similar to enterohemorrhagic Escherichia coli. O157 and Salmonella spp., have been attracting attention as causative agents of food poisoning. For children with low immunity, food poisoning can be lethal as it causes severe symptoms such as diarrhoea and dehydration, so clarifying the source of infection and pathogenic factors of Providencia spp., and establishing preventive methods are urgent issues worldwide.
A joint research group led by Professor Shinji Yamasaki, Dr Sharda Prasad Awasthi, a Specially Appointed Lecturer, and graduate student Jayedul Hassan from the Graduate School of Veterinary Science, Osaka Metropolitan University, determined how the pathogenic genes in some Providencia spp. such as Providencia alcalifaciens and Providencia rustigianii are transferred within bacterial cells of genus Providencia. The group has also elucidated that the pathogenic genes of Providencia rustigianii are also transferred to other bacterial cells belonging to Enterobacteriaceae.
Professor Yamasaki concluded, “This achievement is expected to provide new insights into the identification of infection routes of Providencia spp. and the establishment of preventive methods for food poisoning.”
South African scientists – notably, the team headed by Professor Tulio de Oliveira – were thrown into the global spotlight through their pivotal role in detecting and monitoring the emergence of new variants of SARS-CoV-2 – the Beta variant in 2020 and Omicron in 2021. De Oliveira is now at the University of Stellenbosch, but for much of the pandemic headed the KwaZulu-Natal Research Innovation and Sequencing Platform (KRISP).
The country’s advanced genomic sequencing capabilities and proactive surveillance efforts allowed for the early identification of the variants and the discoveries played a crucial role in alerting the global scientific community to the potential for viral mutations and the need for enhanced monitoring.
Now, scientists worldwide believe it is critical to continue investing in genomics to support disease control in public health in South Africa and the broader continent.
What is genomics?
The World Health Organization (WHO) defines genomic surveillance as “the process of constantly monitoring pathogens and analysing their genetic similarities and differences”. It is done through a method known as whole genome sequencing, which determines the entire genetic makeup of specific organisms or cell types. This method is also able to detect changes in areas of genomes, which can help scientists to establish how specific diseases form. The results of genomic sequencing can also be used in diagnosing and treating diseases.
Genomic sequencing enables scientists to read the DNA and RNA of pathogens and understand what they are and how they spread between people – and to develop vaccines and other measures to deal with them.
The US Centers for Disease Control (CDC) explains, “All organisms (bacteria, vegetable, mammal) have a unique genetic code, or genome that is composed of nucleotide bases (A, T, C, and G). If you know the sequence of the bases in an organism, you have identified its unique DNA fingerprint or pattern. Determining the order of bases is called sequencing. Whole genome sequencing is a laboratory procedure that determines the order of bases in the genome of an organism in one process.
“Scientists conduct whole genome sequencing by following these four main steps:
DNA shearing: Scientists begin by using molecular scissors to cut the DNA, which is composed of millions of bases (A’s, C’s, T’s, and G’s), into pieces that are small enough for the sequencing machine to read.
DNA barcoding: Scientists add small pieces of DNA tags, or bar codes, to identify which piece of sheared DNA belongs to which bacteria. This is similar to how a bar code identifies a product at a grocery store.
DNA sequencing: The bar-coded DNA from multiple bacteria is combined and put in a DNA sequencer. The sequencer identifies the A’s, C’s, T’s, and G’s, or bases, that make up each bacterial sequence. The sequencer uses the bar code to keep track of which bases belong to which bacteria.
Data analysis: Scientists use computer analysis tools to compare sequences from multiple bacteria and identify differences. The number of differences can tell the scientists how closely related the bacteria are, and how likely it is that they are part of the same outbreak…”
Time to expand
At a recent conference held at Stellenbosch University’s new state-of-the-art Biomedical Medical Research Institute, de Oliveira stressed that African and other experts should now build on their success in COVID-19 genomics to expand to other pathogens such as influenza, H5N1, and climate-amplified pathogens.
John Sillitoe, the Director of the Genomic Surveillance Unit at the Wellcome Sanger Institute in the United Kingdom, agreed.
“It is important now to focus on endemic diseases so we can improve our understanding and control of endemic diseases. We should also be looking at TB, particularly with the increased prevalence in drug resistance and reduced response to drugs. For other African countries, malaria should be a key focus area. We know that drug resistance now is spreading into Africa from South East Asia and understanding the right combination of drugs to use is something that is easily identifiable through genomic surveillance.”
But surveillance is also about being ready for the next pandemic.
“There’s that classic line that, ‘diseases take no notice of national borders’,” Sillitoe said in an interview. “So, it is really important that we can get as wide a picture of surveillance as possible to identify something new emerging as soon as possible.”
Marco Salemi, Professor of Experimental Pathology at the Department of Pathology, Immunology, and Laboratory Medicine at the University of Florida College of Medicine, said Africa and the world need to be “proactive, rather than reactive” in the battle against future epidemics. He said the world is currently focused on monitoring the COVID-19 pandemic. “But we forget this is this huge reservoir of pathogens out there which we know so little about and which can become more and more of a threat, especially because of climate change – so we need to understand more about all these pathogens in the wild, in animals, and their potential to jump to humans, especially with the rate of globalisation on the planet … Events of zoonotic transmissions will become more and more frequent. We need to face it.”
Building capacity
De Oliveira is of the view that Africa could, in the next few years, potentially, “leapfrog over the rest of the world” in genomic surveillance, thanks to its success in COVID-19 genomics and its experience in using genomics to monitor other pathogens over the past 20 years.
We won’t be starting from scratch.
The use of genomics in infectious diseases started in the mid-eighties during the HIV epidemic, when scientists realised HIV was a complex virus that existed in many different sub-types. Scientists around the world started using genomic tools to sequence the HIV virus, track its origin, and trace the way the virus disseminated.
Genomics has, however, changed dramatically since the 1980s.
“There have been many attempts… to use genomics for public health purposes, but the key factor that was always missing was the ability to generate DNA sequencing in real-time,” said Salemi. “Real-time means there is an epidemic, with cases happening today – and we need to generate sequences within one or two days and then to analyse the genomic data and then to have actionable information that can be immediately transmitted to the public health authorities so that they can act within a few days.”
“Now the technological and computational limitations of the past few years have been overcome, and, as was clearly shown during the COVID-19 pandemic, we have machines that can generate literally thousands of sequences, like coronavirus sequences, in less than one day, or even within a few hours. At the same time, we have high-performance computer clusters, and super calculators that are capable of analysing this data in a very short time,” he said.
These technical advances would, of course, be of little value without people to use them and develop them further.
“Investment has been made on the continent in infectious disease surveillance and genomics surveillance specifically, and so we have lots of experts on the continent who know a lot about infectious diseases and how viruses work, and why it’s important to look at the genomics to trace when there is going to be a new outbreak,” says Professor Zané Lombard, Principal Medical Scientist in the Division of Human Genetics at the University of the Witwatersrand. “South Africa’s role during COVID-19 showcased what can happen quickly and effectively for public health interventions if you have the right experts with the right platform and expertise and infrastructure in place to do that kind of surveillance.”
De Oliveira and his team have worked closely with the Africa Centres for Disease Control and Prevention (Africa CDC) to scale genomic surveillance on the continent and have actively collaborated with other African countries to share expertise, resources, and genetic data in a bid to foster a continent-wide approach to genomic surveillance.
They have also helped set up large genomics facilities in Zimbabwe, Mozambique, and Botswana.
The Africa CDC, through its Pathogen Genomics Initiative (Africa PGI), has, for the past few years, been building a continent-wide genomic disease surveillance network. In 2019, when the PGI started its work, only seven of the African Union’s 55 member states had public health institutions with the equipment and staff to do genetic sequencing. Today, 31 African nations are able to do genetic sequencing for surveillance of COVID, malaria, cholera, Ebola, and other diseases.
De Oliveira said the continent’s experience in genomic surveillance of pathogens in Africa evolved to “unheard-of” levels during COVID. “We’ve been trying to advance genomic surveillance in Africa for the past two decades, and when the pandemic came, we had the right expertise to deal with viruses and respiratory pathogens such as tuberculosis, so we were able to pivot for SARS-CoV-2. In the end, South Africa and Africa became an example to follow for the whole world.
“All the investments we have made in genomic surveillance for COVID can now be leveraged and advanced to other areas of genomics in Africa… including for rare diseases, for cancer diagnostics, and human genomics. Finally, we have the tools and the equipment, as well as the support, to do advanced genomics in Africa, as we have dreamt of doing for the last twenty years.”
What it means in practical terms
Asked what it means, practically, to build capacity for genomics research, Lombard said one aspect is the establishment of strong laboratories. “Historically, if infrastructure was not available locally, researchers would partner with international labs and send their samples to have their sequencing done there. The problem with that was that expertise in using [that] technique was not being built locally,” she said. “It is really important to train the right people who know how to do the laboratory experiments but also to interpret the data correctly.
“It’s not only about building the infrastructure in the labs but also about training the individuals and making sure there are job opportunities locally for them,” she said.
Turning to the machines used in genomics, Lombard said, “The most popular machine these days is called a next-generation sequencer. These can read the whole DNA sequence of a virus.”
Salemi added, “Some of these sequencers are very large and some are even little portable boxes. Some can sequence thousands of samples at a time, while others are capable of sequencing a few dozen samples at a time. The samples, depending on the virus (or pathogen) being tested for, are taken from blood samples, nasal swabs, or sputum from patients, from faeces, urine, or from the skin.
“The BMRI (at Stellenbosch University) – which has the largest sample storage capacity in the southern hemisphere – can store five million samples at minus 80 degrees. If someone wants to build a lab that includes top-of-the-line computational capacity, it will cost anything from $40 million (over 700 million), but to start a small operation to do a few hundred sequences of a virus every week, $100 000 to $200 000 (roughly R17 million to R34 million) is enough, which has been done in many different African countries during the pandemic.”
Training is key
While all the scientists interviewed agreed that laboratories are important in building capacity for genomics research, they stressed that what is really needed is to train more individuals.
“More people need to be trained in genomics but also in bioinformatics, which is a really important component of this work. The technology component is becoming very smart and automated, but the data being generated is becoming more and more complex, with bigger data sets. Dealing with these,” Lombard said, “requires special data analysis skills and bioinformatics skills. The field of bioinformatics will need investment so that we can deal with the deluge of data that will come out.”
She said South African and other African universities are taking this skills need seriously, with many initiatives to offer undergraduate and post-graduate training programmes in these areas.
Salami agreed. “The most important part of building capacity is the human training. I find it naïve and sad when I hear politicians talking about building top-of-the-line laboratories, when, what they really need to do is to start building human capacity. Africa is an amazing reservoir (from which to build these skills) because 50 percent of the continent [are] people who are less than 30 years old. There are about 27 excellent laboratories all over Africa. We need to start creating a strong next generation of scientists.”
In support of this, de Oliveira is trying to raise 100 million dollars to implement real-time genomic research to enable the African continent to respond to new epidemics.
He said during COVID, the Network for Genomics Surveillance was founded and funded by the Department of Science and Innovation and the South African Medical Research Council (SAMRC). This funding was until 2021.
The Centre for Epidemic Response and Innovation, which is led by de Oliveira and forms part of the BMRI, is funded by the Africa CDC, the WHO, the Rockefeller Foundation, and the Elma Foundation. These funders support the work in South Africa and in other African countries, as well as the SA government. The BMRI was mostly funded by Stellenbosch University to the effect of R900 million, while the Department of Higher Education provided about R300 million. CERI occupies one floor of the BMRI.
In de Oliveira’s words, “This truly is the genome era for Africa.”
Diagram comparing the nose shape of a Neanderthal with that of a modern human by Dr Macarena Fuentes-Guajardo.
Neanderthal genes comprise some 1 to 4% of the genome of present-day humans whose ancestors migrated out of Africa, and new research has shown that their lingering presence shapes the immune systems and metabolism of people of non-African ancestry. Some of these genetics changes are detrimental, but are slowly being replaced by human versions.
A multi-institution research team including Cornell University has developed a new suite of computational genetic tools to address the genetic effects of interbreeding between humans of non-African ancestry and Neanderthals that took place some 50 000 years ago. (The study applies only to descendants of those who migrated from Africa before Neanderthals died out, and in particular, those of European ancestry.)
In a study published in eLife, the researchers reported that some Neanderthal genes are responsible for certain traits in modern humans, including several with a significant influence on the immune system. Overall, however, the study shows that modern human genes are winning out over successive generations.
“Interestingly, we found that several of the identified genes involved in modern human immune, metabolic and developmental systems might have influenced human evolution after the ancestors’ migration out of Africa,” said study co-lead author April (Xinzhu) Wei, an assistant professor of computational biology in the College of Arts and Sciences. “We have made our custom software available for free download and use by anyone interested in further research.”
Using a vast dataset from the UK Biobank consisting of genetic and trait information of nearly 300 000 British people of non-African ancestry, the researchers analysed more than 235 000 genetic variants likely to have originated from Neanderthals. They found that 4303 of those differences in DNA are playing a substantial role in modern humans and influencing 47 distinct genetic traits, such as how fast someone can burn calories or a person’s natural immune resistance to certain diseases.
Unlike previous studies that could not fully exclude genes from modern human variants, the new study leveraged more precise statistical methods to focus on the variants attributable to Neanderthal genes.
While the study used a dataset of almost exclusively white individuals living in the United Kingdom, the new computational methods developed by the team could offer a path forward in gleaning evolutionary insights from other large databases to delve deeper into archaic humans’ genetic influences on modern humans.
“For scientists studying human evolution interested in understanding how interbreeding with archaic humans tens of thousands of years ago still shapes the biology of many present-day humans, this study can fill in some of those blanks,” said senior investigator Sriram Sankararaman, an associate professor at the University of California, Los Angeles. “More broadly, our findings can also provide new insights for evolutionary biologists looking at how the echoes of these types of events may have both beneficial and detrimental consequences.”
