Sequencing of African population to enhance genomic dataset for disease diagnosis

Worldwide, the promise of precision medicine is gaining traction, but some populations continue to be hampered by a lack of data, infrastructure, and a very small skilled workforce.

In 2020, about 3.4 million distinct gene variants were reported in an analysis of about 400 human genomes from 50 ethnic groups in 15 African countries. However, despite the growth of data in genomic repositories, many variants from African populations remain unrecorded, according to another study in Biomed Central.

Michèle Ramsay, Director of the Sydney Brenner Institute for Molecular Bioscience at the University of the Witwatersrand (Wits), South Africa, says the African genomic gap remains huge. “As the rest of the world forges ahead with large genomics projects, the relative proportion of continental African studies and databases with genomic data are getting smaller and smaller.”

Zané Lombard, from the Division of Human Genetics at Wits, says: “Less than 2% of human genomes analysed so far have been those of Africans. Only about 22% of participants in genomics research are not of European ancestry, and most available genetic data comes from the UK (40%), US (19%) and Iceland (12%).”

“We need large and diverse datasets. We know that African genomes harbour the most diversity in the world. The best approach would be to produce whole genome sequencing on a large group of individuals from across Africa”, says Lombard.

A Nature article suggests at least 3 million African genomes should be sequenced. But Ramsay says “We still do not know how different the populations are and what the impact is on their health. Often genetic variation does not work in isolation, and one variant can have different effects depending on its interaction with other variants or with the environment.

These differences can vary even within a country between different populations. It is therefore critical to study each population, before the next step to diagnostics and precision medicine can be taken.

With regards to diagnostics, Ramsay says when genetic tests are developed, they include the mutations which are known, mostly from European patients. We do not have enough data on African patients to properly inform the tests for an African setting. If the tests do not detect the mutations, then diseases will be misdiagnosed or not diagnosed at all..

An article in Nature Reviews Genetics explains how African researchers have made considerable contributions to the detection, surveillance and identification of novel pathogen genomes in the field of infectious diseases. This is not yet the case for non-communicable diseases such as cancer, diabetes, stroke, hypertension, mental health, and asthma.

The gap and opportunities The huge opportunities in ramping up efforts within the continent may be lost unless proactive efforts are made to address a number of challenges from manpower to infrastructure. For Ramsay “as we delay our exploration of African genomes and associated data, the gap towards precision medicine will continue to widen. To really apply precision medicine for non-communicable diseases you need a lot of data from each population.”

Though diagnosing rare diseases is a global issue, it is further compounded in Africa for a variety of reasons. First, is the lack of genetic services on the continent. There are very few trained genetic experts and very few job opportunities for those who are trained, making it difficult for patients with rare diseases to access treatment.

Africa does not yet have a critical mass of skilled bio-informaticists and genomics scientists and the absence of funded job opportunities and career paths has led to an exodus of talented researchers. The technical infrastructure also remains scarce and the costs of doing research are higher due to the need to import consumables and equipment.

“We need well-funded positions for mid-career and senior investigators in Africa to contribute to training the next generation of genomic researchers and finding solutions toward sustainable genomics in Africa,” says Ramsay explains. Also in many countries, there are no or inadequate genetic testing facilities available, which makes it impossible to offer comprehensive genetic testing such as whole exome or genome sequencing.

The data gap makes it very difficult to interpret genetic data if you do not have an appropriate African-based reference dataset to compare your patient’s DNA to. When analysing a rare disease patient’s DNA, you are looking for variation that could potentially explain the disease in question, Ramsay adds.

“One key consideration is that such a variant would likely not be present in the genomes of many (or any) healthy individuals, and therefore would be more likely to cause a rare disease. However, sometimes a variant seems to be rare or absent, just because you are looking for it in a reference dataset that is not very diverse, leading to a conclusion that it is likely disease-causing. This could result in false conclusions.”

A ray of hope is in the Human Heredity and Health in Africa (H3Africa) Research Initiative, encompassing 51 projects, all led by African scientists and involving researchers from more than 30 African countries. This has resulted in 50,000 samples being genotyped and nearly 700 papers being published.

Funds for H3Africa will cease this year, according to a recent Nature comment. The authors write: “Thanks to H3Africa and other genomics initiatives, such as the Nigerian 100K Genome Project African genomics is now poised to improve the health of millions of people worldwide, including those across the continent and the African diaspora.

“But building on the discoveries made so far — and especially applying findings to the clinic — will require several systemic changes, including a major shift in how genomics research in Africa is funded.”