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African genomics needed for genetic medicine

As part of the 20th anniversary of Nature Reviews Genetics, Professor Ambroise Wonkam from the University of Cape Town has provided his thoughts on the necessity of African genomics to advance genetic medicine in the coming years.

Poor diversity

There is an abundance of evidence demonstrating the disproportionate effects of COVID-19 on minority communities. Furthermore, a recent report by the AACR highlighted substantial differences in cancer burden within certain groups across the United States. Investigating these disparities is critical, but cannot be done without understanding these populations. It is globally recognised that diversity within population studies is poor, with the majority involving individuals of European descent. To uncover the true potential of global precision medicine, research into genomic variation across all populations is imperative.

A recent assembly of a pan-genome from 910 individuals of African descent revealed at least 300 million genetic variants that were not present in the current human reference. Furthermore, current GWAS and polygenic risk scores that aim to predict individual risk for specific diseases are met with bias due to their incorporation of largely European ancestry. As a result, this has caused concern about the usability and transferability of inferences from these means across different populations. For example, a large GWAS meta-analysis for 34 complex traits conducted in 14,345 Africans revealed several loci that had limited transferability across cohorts. In other words, several functionally important signals were found to be driven by African-specific variants. This reinforces that genomic variation among Africans is higher compared to other populations. Importantly, this genomic variation has been shown to provide more power in detecting genotype-phenotype relationships.

Genomic history

Although complex, the ‘Out of Africa’ model proposes that all anatomically modern humans outside of Africa descended from populations of Homo sapiens that left East Africa around 70,000 years ago. Reconstructing this divergence and expansion has largely been based on evidence from genetics. For example, investigation of specific haplogroups (e.g. mitochondrial DNA haplogroups) within populations can trace geographical migration. African populations are characterised by greater levels of genetic diversity and less linkage disequilibrium compared to non-African populations. This improves fine mapping and identification of causative variants.

Modern Europeans and East Asians have inherited ~2% of their genome from Neanderthals. These regions are enriched for variation that is involved in dermatological phenotypes, neuropsychiatric disorders and immunological functions. Previously, researchers believed that Africans lacked Neanderthal DNA. However, recent evidence suggests that ~0.3% of their genome is actually Neanderthal. Researchers hypothesise that this was obtained when Europeans migrated back to Africa over 20,000 years ago. Wonkam suggests that when technical challenges in sequencing poor-quality DNA are overcome, investigations into the genomic contributions of African archaic populations will be refined. In turn, associations between variants in ancient African DNA and human traits or diseases will be discovered. This could provide key insights that could benefit modern-day humans.

Inform and increase discovery

Greater availability and accessibility of African genomes will help improve our understanding of genomic variation and disease. The discovery of a single African origin of the sickle cell disease (SCD) mutation, ~5,000-7,000 years ago, illustrated migration and admixture events but also developed our understanding of the impact of genetic variation on haemoglobinopathies. Wonkam suggests that having an in-depth knowledge of an individual’s variation can impact secondary prevention and treatment strategies for SCD. For example, variants in APOL1 and HMOX1 and co-inheritance of α-thalassaemia are associated with kidney dysfunctions. Wonkam believes that SCD in Africa can act as a model for understanding the impact of variation on common monogenic traits and the multiple layers of genomic medicine implementation.

Importantly, exploring the genomic diversity in African genomes can increase the discovery of novel variants and genes. For example, evidence suggests that novel variants in hearing impairment-associated genes are more likely to be found in African populations than in European or Asian. In addition, higher fertility rate, consanguinity practices and regional genetic bottlenecks could help improve novel gene discovery for monogenic disorders in Africa. 

Specific ecology

The African continent lies along the North-South axis which is linked with variable climates and biodiversity. The frequency of variants within populations is shaped by natural evolutionary selection due to adaptation to environmental pressures. Africa’s specific ecology has shaped its genetic variation, which can have both a detrimental and positive impact on health. The most prominent example is in SCD. Individuals that are heterozygous for the mutation are found to be protected against malaria. Another example is APOL1 variants. Variants in this gene can protect against trypanosomes (parasites that cause sleeping sickness) yet can also increase susceptibility to chronic kidney disease. Understanding variants that have been selected under environmental pressures and how they interact with each other will be key for genetic medicine. Wonkam notes that immunogenetic studies among Africans will also be important to understand natural selection and responses to emerging infectious diseases like COVID-19.


Most African countries are being left behind within the genomic revolution. If this is not urgently addressed, we are at risk of genomics contributing to the widening inequalities within healthcare. Studying African genomic variation is key for genetic medicine as it provides insight into ancestry, ecology and disease. Importantly, it will help enhance genetic knowledge and practice in Africa. Nonetheless, integrating genomics in Africa will present challenges of overburdened and under-resourced healthcare systems as well as the absence of ethical, legal and social frameworks. Wonkam emphasises that an African genomics workforce must be developed to meet these needs. He refers to recent initiatives, such as H3Africa, that have laid the foundation for further endeavours. Equitable access for Africans is vital to ensure the true potential of genetic medicine can be seen globally. We must go back to our beginnings to understand our present.

Make sure you catch-up on our recent webinar that explored how the first North African genome was assembled and annotated!

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Diversity / Equity / Population Genetics

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