Researchers have found that previous studies analysing the genomes of people with European ancestry may have reported inaccurate results by not fully accounting for population structure. By considering mixed genetic lineages, researchers at the National Human Genome Research Institute (NHGRI) demonstrated that previously inferred links between a genomic variant for lactase and traits such as a person’s height and low-density lipoprotein cholesterol (LDL-C) level may not be valid.
The study, published in Nature Communications, shows that people with European ancestry, who were previously treated as a genetically homogenous group in large-scale genetic studies, have clear evidence of mixed genetic lineages, known as admixture. As such, the results from previous genome-wide association studies that do not account for admixture in their examinations of people with European ancestry should be re-evaluated.
“By reading population genetics papers, we realised that the pattern of genetic makeup in Europe is too detailed to be viewed on a continental level,” said Daniel Shriner, PhD, staff scientist in the NIH Center for Research on Genomics and Global Health and senior author of the study. “What is clear based on our analysis, is when data from genetic association studies of people of European ancestry are evaluated, researchers should adjust for admixture in the population to uncover true links between genomic variants and traits.”
To look at European genetic ancestry, the researchers collated data in published genetic association studies and generated a reference panel of genomic data that included 19 000 individuals of European ancestry across 79 populations in Europe and European Americans in the US, capturing ancestral diversity not seen in other large catalogues of human genomic variation.
As an example, the researchers investigated the lactase gene, which encodes a protein that helps digest lactose and is highly varied across Europe. Using the new reference panel, they analysed how a genomic variant of the lactase gene is related to traits such as height, body mass index and LDL-C.
When the researchers considered the genetic admixture of the European population in their analysis, they found that the genomic variant of the lactase gene is not linked to height or LDL-C level. In contrast, the same variant does influence body mass index.
“The findings of this study highlight the importance of appreciating that the majority of individuals in populations around the world have mixed ancestral backgrounds and that accounting for these complex ancestral backgrounds is critically important in genetic studies and the practice of genomic medicine,” says Charles Rotimi, PhD, NIH Distinguished Investigator, director of the Center for Research on Genomics and Global Health and senior author of the study.
While the lactase gene is one example of a gene that may be incorrectly linked to some traits based on previous analyses, the researchers say it’s likely that there are other false associations in the literature and that some true associations are yet to be found. Information about how genomic variants are related to different traits helps researchers estimate polygenic risk scores and may give clues about a person’s ability to respond safely to drug treatments.
While the differences in any two people’s genomes are less than 1%, the small percentage of genomic variation can give clues about where a person’s ancestors might have come from and how different families might be related. Information about who a person is biologically descended from, known as genetic ancestry, can give important clues about genetic risks for common diseases.
“Finding true genetic associations will help researchers be more efficient and careful with how further research is conducted,” said first author Mateus Gouveia, PhD, research fellow in the Center for Research on Genomics and Global Health. “We hope that by accounting for mixed ancestries in future genomic analyses, we can improve the predictive value of polygenic risk scores and facilitate genomic medicine.”
The reference panel generated in this study is available to the scientific community for use in other studies, with additional information provided in the paper.
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.”
