H3Africa Consortium Primes A Continent For Large-Scale Genomics Research

By Deborah Borfitz

February 2, 2021 | The Human Heredity and Health in Africa (H3Africa) Consortium is endeavoring to foster collaborative research on the world’s second-most populous continent, having spent the past decade bolstering the genomics research capacity here with 48 projects across 34 countries. Clinical geneticist and physician-scientist Neil Hanchard, M.D., Ph.D., through his academic position at Baylor College of Medicine, has, for example, been involved in a H3Africa-sponsored genomic study in children coinfected with HIV and tuberculosis whose principal investigator is based in Botswana.

Most recently, Hanchard was one of the senior authors on an H3Africa-sponsored study published in Nature (DOI: 10.1038/s41586-020-2859-7) showcasing the continent’s complex and vast diversity of genetic variation, which will be supporting research for decades to come. Only a fraction of the genetic diversity among African individuals had previously been surveyed, he says, even by large-scale efforts such as the 1000 Genomes Project.

The high level of genetic diversity vis-à-vis other continents makes anthropological sense given that people have lived in Africa, the birthplace of modern humans, longer than anywhere else on earth, says Hanchard. From that perspective, it could be considered unsurprising that the research team identified evidence for natural selection in and around 62 previously unreported genes.

The newly discovered variants were predominantly found in genes associated with viral immunity, DNA repair, and metabolism, Hanchard says. “We think most of those genetic signatures are relatively recent and likely to have some impact upon healthcare in persons of African ancestry.”

Researchers also observed complex patterns of ancestral mixing within and between populations, alongside evidence that Zambia was a likely intermediate site in the Bantu migration route to the south and east of the continent. The ancestry of people in one central Nigerian group was highly suggestive of historic in-migration from East Africa.

Whole-genome sequencing analyses was done on 426 individuals across 13 African countries. Participants represented 50 ethnolinguistic groups, including previously unsampled populations.

More than 100 areas of the genome had probably been under natural selection, the researchers concluded, a sizable proportion of which were associated with immunity-related genes. They believe viral infections, in addition to better-known insect-transmitted diseases like malaria and sleeping sickness, likely helped shape genomic differences across local geographies where people adopted certain dietary habits and were exposed to unique pathogens.

All told, researchers discovered over 3 million novel variants by comparing more than 1,000 African and 100,000 other genomes in public repositories (Exome Aggregation Consortium and Genome Aggregation Database) and most of them were found among the newly sampled ethnolinguistic groups. Even populations from the same country showed a great deal of variation among themselves, an observation wholly unsurprising—at least to the people living there, Hanchard says.

The implication is that many more novel genetic variants await discovery by sequencing African populations, Hanchard says. Notably, the research was conducted predominantly by local African researchers using local computational facilities, signaling that the continent now has the requisite infrastructure and analytic skills for large-scale genomics research.

Diversity Matters

Locals are keenly aware of differences between Bantu-speaking groups tracing back to sub-Saharan Africa and those of Nilo-Saharan ancestry rooted more in East Africa, although both reside in Uganda, says Hanchard. Similarly, Nigeria’s population includes individuals with very different lineages than those speaking the predominant Niger-Congo languages who are represented in existing databases.

Better characterization of the genomic diversity of African individuals could aid efforts to improve disease risk models developed mainly with data from European or Western populations. Cardiovascular genetic risk models, for example, have not translated well into African populations or populations of African ancestry, Hanchard notes. More advanced risk prediction models may ultimately be required to home in on the variants of concern in different subpopulations.

Clinical geneticists using sequencing in hopes of arriving at a diagnosis need to know which variants are rare and thus more likely to be causing a disease, Hanchard says. Databases encompassing the level of diversity seen across Africa are going to be vital to the diagnosis of rare diseases, particularly among individuals with African ancestry.

Hanchard says the research team for the H3Africa study will be adding the newly identified variants to existing databases, as well as developing a standalone, Africa-specific database. Sequencing data will be accessible to other scientists who want to interrogate their own datasets, and the sharing will happen in accordance with a framework established by the H3Africa Consortium.

Members of the H3Africa Consortium who contributed to the Nature study comprise 24 institutions across Africa, including the Sydney Brenner Institute for Molecular Bioscience at Wits University in Johannesburg. The study was co-led by Zané Lombard, associate professor in the division of human genetics in the faculty of health sciences at Wits and at the National Health Laboratory Service.

Research-Ready

The H3Africa Consortium has sought to empower researchers on the ground in Africa, flipping the historic paradigm of outsiders coming in to conduct studies without leaving behind any kind of redevelopment, says Hanchard. The consortium has been collaborating with groups in the U.S. and U.K. to enable sustainable genomic and genetic studies on the continent, which is good for the economy as well as the healthcare of its populace. 

Data generated by H3Africa-sponsored projects was used to develop a microarray genotyping chip that has already been used in genome-wide association studies on well over 70,000 individuals across the continent, Hanchard says. Over time, the chip will become an increasingly better proxy of the most meaningful genetic variants to look for in the African population.

The H3Africa Consortium is being funded through 2021 by the National Institutes of Health, the Wellcome Trust, and the African Academy of Sciences, and many large-scale research projects have already been completed, says Hanchard. The projects range from the burden of type 2 diabetes in sub-Saharan Africa and risk factors for cardiometabolic syndrome to the impact of immunoglobin gene diversity on antibody function in people with HIV infection and the genetics of hearing loss.

Research also extends to the mental health arena, including intergenerational epigenomics of trauma and post-traumatic stress disorder in Rwanda and the role of infant gene expression on the transgenerational effects of exposure to prenatal maternal psychological stress.

On the human resources side, projects of the H3Africa Consortium all involve master’s and Ph.D. students who are educated on the genetic research process, says Hanchard. The training extends to ethics and the informed consent process.

The physical resources provided include facilities for genotype microarrays in South Africa and the availability of larger sequencers in Nigeria and Uganda, he adds, which have proven useful during previous Ebola outbreaks and the current COVID-19 pandemic.