Mapping African genetic diversity for better health

The contribution of the Sydney Brenner Institute for Molecular Bioscience to the field of human genomics is rewriting history on the African continent.

DELIA DU TOIT CHANTÉ SCHATZ

When the Human Genome Project finished in 2003, scientists had the ability, for the first time, to read nature’s complete genetic blueprint for building a human being. And now, it’s becoming clear that one single reference genome is inadequate – humans, after eons of evolution in different environments, are simply too diverse. This is especially the case on the African continent, and the Sydney Brenner Institute for Molecular Bioscience (SBIMB) at Wits has taken massive strides to illuminate African genomes since its founding in 2014.

Genetics is the scientific study of genes and heredity – of how certain qualities or traits are passed from parents to offspring because of changes in DNA sequence. Genomics is the study of all an individual’s genes (the genome), including scientific research into complex diseases such as heart disease, asthma, diabetes and cancer, because these diseases are typically caused more by a combination of genetic and environmental factors than by individual genes.

DNA, DATA AND AFRICA

In 2017, the SBIMB led the publication of the pilot study of the first African government-funded Human Genome Project of 24 whole human genomes, involving the efforts of scientists in seven South African institutions.

In 2020, under the banner of the Human Heredity and Health in Africa Consortium, researchers from the Institute were lead authors in a study involving the analysis of whole genome sequences of 426 African individuals, depicted in African beads and featured on the cover of the journal Nature. The study identified marks of natural selection in several genes associated with viral immunity, DNA repair and metabolism, demonstrating adaptation to new geographies, diets and pathogens.

“The central premise of the research at the SBIMB is to create a better understanding of African genetic diversity and how that impacts on health or drug response,” says Professor Michèle Ramsay, Director of the SBIMB. “Africa is so diverse in terms of genetics, climate and culture that you can’t think of the populations on the continent as one group of people.”

Ramsay has been involved in the Human Genome Project since its start in the 1990s. “It’s incredible that, over the span of a few decades, we’ve moved from not having a genome sequence to now having a reference human genome, access to so much data, and the ability to immediately identify DNA sequences and where they come from on the genome map. When I started my career, we had to build those maps to understand where the DNA sequences were that we were working on. We’ve come so far.”

DIVERSITY IN DISEASE

“Africa is so diverse in terms of genetics, climate and culture, that you can’t think of the populations on the continent as one group of people.”

Bantu-language speaking South Africans, including 5 000 people from all the major language groups. “Until now it was considered that all South African populations are more or less genetically equivalent. But we found several differences that are significant in terms of disease susceptibility and drug response and contributed to the country’s history by showing how groups of people migrated and interacted with other populations.”

Impactful as this work is, it’s still in its infancy in many ways, says Professor Scott Hazelhurst, whose work at the SBIMB focuses on building computational capacity as well as pharmacogenomics – particularly how genes impact drug efficacy and safety. “The Institute’s work in Africa is clinically significant, as most drugs are developed in European populations for Europeans. When these drugs are then deployed here, there are potential issues because of the differences in the genetic diversity between African populations and other world populations. We’ve been spending the last three years cataloguing that diversity and giving some insight into potential drug effects.”

TOWARDS PRECISION MEDICINE

Hazelhurst says that to get the complete picture, we need the “sequencing of every human being in Africa, and on the planet. Only then will we have precision medicine that considers individual variability in genes, environment and lifestyle for each person.”

Though this is, at least for now, a castle in the sky, it makes it clear why more data, more capacity, more funding and more expertise is critical, says Ramsay. “The models for analysing genomes are so complex so there are still very few people on the continent who can analyse the data. We’re not near critical mass yet when it comes to developing this expertise.”

However, study by study, things are changing. The SBIMB currently has 17 PhD students and eight postdoctoral fellows. Many of these students are nested in the Africa Wits-INDEPTH partnership for genomics studies in Africans. Though the partnership is now in its tenth year and the grant is coming to an end, its projects and related research will continue – using data and stored samples on around 12 000 people in four African countries. “Possibly the most rewarding part of our jobs is to oversee the development of future leaders in the field. Many of these younger researchers are already growing their own research programmes,” says Ramsay.

And the future looks bright. The Institute recently received funding to study at least 1 000 whole human genomes from under-investigated African populations. Another project is using machine learning to extract new information from data collected from several projects over the past 20 years and to analyse it to provide health planning and treatment insights into multimorbidity in populations in South Africa and Kenya.

Yet another study will look at the effect of genetic variants in African individuals and develop algorithms to predict where a person falls on a spectrum of risk for a particular disease. The SBIMB also has active cancer genomics and pharmacogenomics programmes. Its scientists work collaboratively with researchers locally, regionally and globally, across a range of disciplines.

The Institute today has data and stored samples on over 17 000 Africans and 200 whole African genomes – taking up close to two petabytes of storage. “All those samples in the biobank means we are building resources for the future, too. Mining the data for interesting findings will form the basis for future generations of study,” concludes Ramsay. C