Closing the Gaps in Genomic Research
Authors: Cesar Fortes-Lima, Carina Schlebusch
Journal: Trends in Genetics (2020)

Despite Africa's central role in the origin of our species, our knowledge of the genomic diversity in Africa is remarkably sparse. A recent publication by Choudhury . underscores the scientific imperative for a broader characterisation of African genomic diversity to better understand demographic history and improve global human health. Despite Africa's central role in the origin of our species, our knowledge of the genomic diversity in Africa is remarkably sparse. A recent publication by Choudhury . underscores the scientific imperative for a broader characterisation of African genomic diversity to better understand demographic history and improve global human health. Human populations are known to harbour the greatest genetic diversity in Africa, from where modern humans originated. Therefore, studying genomic patterns of diversity in Africa presents remarkable opportunities to gain a better understanding about our deep population history and the underlying genetic basis of human adaptation and disease [1.Schlebusch C.M. Jakobsson M. Tales of human migration, admixture, and selection in Africa.Annu. Rev. Genomics Hum. Genet. 2018; 19: 405-428Crossref PubMed Scopus (43) Google Scholar]. However, in comparison to populations of European or Asian ancestry, African populations are largely under-represented in genomic research, exacerbating health inequalities [2.Sirugo G. et al.The missing diversity in human genetic studies.Cell. 2019; 177: 1080Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar]. Heavily biased genetic databases often lead scientists and medical doctors to diagnose conditions or prescribe treatments that might be relevant to people with European ancestry, but not for people from other genetic backgrounds. To investigate the genomic diversity across the African continent, a recent paper by Choudhury et al. [3.Choudhury A. et al.High-depth African genomes inform human migration and health.Nature. 2020; 586: 741-748Crossref PubMed Scopus (88) Google Scholar] analysed whole-genome sequencing data of 426 individuals representing 50 ethnolinguistic groups in Africa (Figure 1). This ground-breaking study represents an important step in addressing existing biases in available data for genetic research, which hamper the study of human health problems in populations from Africa and the African Diaspora. The study was led by the Human Heredity and Health in Africa (H3Africa) Consortiumi [4.H3Africa Consortium et al.Research capacity. Enabling the genomic revolution in Africa.Science. 2014; 344: 1346-1348Crossref PubMed Scopus (250) Google Scholar], funded by the US National Institutes of Health (NIH) and the Wellcome Sanger Institute, to redress the long-standing scarcity of genomic research in African populations and to support African institutions conducting genomic research. The high coverage of the newly available African genomes (with an average depth of coverage between 10x and 30x) allowed the authors to better examine rare genetic variants in an accurate and quantifiable way. Choudhury et al. [3.Choudhury A. et al.High-depth African genomes inform human migration and health.Nature. 2020; 586: 741-748Crossref PubMed Scopus (88) Google Scholar] uncovered more than three million novel variants, mostly found in newly sampled ethnolinguistic groups from Botswana and Mali (over 18 700 and 13 300 novel variants per individual, respectively) and identified 33 loci with strong evidence of selection that have not been reported previously in African [5.Gurdasani D. et al.Uganda genome resource enables insights into population history and genomic discovery in Africa.Cell. 2019; 179: 984-1002Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar] or world-wide populations [6.Bergström A. et al.Insights into human genetic variation and population history from 929 diverse genomes.Science. 2020; 367eaay5012Crossref PubMed Scopus (194) Google Scholar]. As expected, the results reflected the long history and rich genomic diversity across the continent and further evidenced the enormous scope for identifying novel variants in future genomic studies in Africa. This is one of the largest studies of high-depth-sequenced African genomes reported to date, and samples were analysed from 13 African countries (Figure 1); however, coverage remains notably incomplete in some African regions. Certain ethnolinguistic groups that are crucial for population history inferences were not included in this study, such as hunter–gatherer groups, whose genetic heritage represents early (prefarming) African history, due to their deep continuities in their respective regions. This poses an important limitation for producing accurate inferences regarding deep population history and historical mass migration in Africa and future research will need to include more geographically and linguistically diverse populations to be able to test different hypotheses. For instance, Southern African hunter–gatherers (San) and herders (Khoekhoe), known collectively as Khoe-San speaking people, have more genomic diversity than other African and non-African groups and represent the deepest population divergence within Homo sapiens, supported by a recent study [7.Schlebusch C.M. et al.Khoe-San genomes reveal unique variation and confirm the deepest population divergence in Homo sapiens.Mol. Biol. Evol. 2020; 37: 2944-2954Crossref PubMed Scopus (26) Google Scholar] of high-coverage whole-genomes of five Khoe-San populations (with an average depth of coverage 50x). Likewise, hunter–gatherer groups from the Central African rainforest and East Africa are other crucial populations to include in future genomic studies [8.Fan S. et al.African evolutionary history inferred from whole genome sequence data of 44 indigenous African populations.Genome Biol. 2019; 20: 82Crossref PubMed Scopus (56) Google Scholar]. Long-distance migrations played a pivotal role in shaping the genomic landscape in the African continent, particularly migrations of people speaking Bantu languages. The broad dispersion of Bantu-speaking people has been ascribed to a series of migrations across sub-Saharan Africa over the past 5000 years, supported by genome-wide studies [9.Patin E. et al.Dispersals and genetic adaptation of Bantu-speaking populations in Africa and North America.Science. 2017; 356: 543-546Crossref PubMed Scopus (117) Google Scholar,10.Semo A. et al.Along the Indian Ocean coast: genomic variation in Mozambique provides new insights into the Bantu expansion.Mol. Biol. Evol. 2020; 37: 406-416Crossref PubMed Scopus (16) Google Scholar]. Choudhury et al. [3.Choudhury A. et al.High-depth African genomes inform human migration and health.Nature. 2020; 586: 741-748Crossref PubMed Scopus (88) Google Scholar] observed complex genomic patterns of ancestral mixing within and between populations and suggested that Zambia was a likely intermediate site along the routes of expansion of Bantu-speaking populations to both East and South Africa. However, these findings need to be interpreted with caution and more Bantu-speaking populations representing South, East, and Central Africa will be needed to confirm and refine these findings, as well as the use of haplotype-based methods, model-testing approaches, and well-defined hypothesis-driven research. The Bantu-expansion was likely a complex movement of multiple waves of populations interacting with and replacing each other [1.Schlebusch C.M. Jakobsson M. Tales of human migration, admixture, and selection in Africa.Annu. Rev. Genomics Hum. Genet. 2018; 19: 405-428Crossref PubMed Scopus (43) Google Scholar] and fine-scale data from modern and ancient individuals across sub-Saharan Africa will be crucial to disentangle the complex history behind this huge expansion. In order to generalise the discoveries from genetic studies of complex diseases and to provide opportunities for new understanding of disease aetiology and potential therapeutic strategies, it is crucial to investigate genetic variation in world-wide populations, particularly in non-European populations. The study by Choudhury et al. [3.Choudhury A. et al.High-depth African genomes inform human migration and health.Nature. 2020; 586: 741-748Crossref PubMed Scopus (88) Google Scholar] contributes significantly to an increasingly global context of medically relevant genetic variation and uncovers the genomic landscape of loci associated with chronic noncommunicable diseases in Africa (e.g., cardiometabolic diseases). Furthermore, it facilitates future studies exploring the relevance of genetic variants in disease burden among the African populations. An example is the APOL1 variants (Figure 1) that provide protection against specific Trypanosoma species in African populations from endemic regions like West Africa, but also increase susceptibility to nephropathy in populations from non-trypanosomiasis endemic areas in Africa or from the African Diaspora. The study also identifies new evidence for natural selection in 62 genes associated with immune-related functions (for viral and bacterial infection), involved in DNA maintenance and carbohydrate and lipid metabolism. The researchers additionally teased out signals of selection within each population, for example, genes involved in metabolism were under selection among individuals from Botswana. Among the selection signals detected in Botswana, the authors also found evidence for preferential gene-flow from Khoe-San ancestry, highlighting adaptive introgression in Southern Africa. The study presented by Choudhury et al. [3.Choudhury A. et al.High-depth African genomes inform human migration and health.Nature. 2020; 586: 741-748Crossref PubMed Scopus (88) Google Scholar] is also a major milestone in African genomics research capacity, as it was led predominantly by local researchers using local infrastructure and resources for large-scale genomics research in Africa. Collectively, their results refine our current understanding of human migration, patterns of admixture, and strong drivers of selection across the African continent. The study also points out the extent of uncatalogued genomic variation across the continent and the need for future genomic studies of the many diverse under-represented populations in Africa. C.F-L. and C.S. were funded by the European Research Council (ERC StG AfricanNeo, grant no. 759933 to C.S.). C.F-L. was funded by the Marcus Borgström Foundation for Genetic Research, the Sven and Lilly Lawski's Foundation, and the Royal Physiographic Society of Lund (Nilsson-Ehle Endowments). ihttps://h3africa.org/