Most genotyping arrays available at the time the array was designed (2015) did not have adequate representation of African genomic variation. Additionally, most reference panels for imputation were based on data from primarily Caucasian populations, included only a limited number of African ancestry samples and did not accurately reflect African genomic structure; therefore, H3Africa designed a more appropriate array and also generated a more useful imputation reference panel.
There were three sources of whole genome sequence data from African populations that were used:
For the African Genome Variation Project, the secondary data analysis form described the use of these data for the design of the H3Africa genotyping array
The H3Africa array has a dense tag-SNP coverage of genome variation in multiple African population groups and includes some novel common African variants. It also contains a comprehensive set of SNPs of potential clinical and pharmacogenomics significance derived from relevant public databases and disease-associated variants nominated for inclusion by H3Africa researchers. The performance of the array was evaluated computationally to assess coverage and imputation accuracy. The H3Africa array was shown to outperform currently available arrays of similar size in terms of genomic coverage and imputation accuracy for African populations. The array will provide researchers in Africa with a better tool for genetic research on African populations and those with high African admixture. It is a research tool and should not be used in clinical settings.
The array is being used for research, mostly by the H3Africa consortium, to study the association of genomic variants with various health and disease states in order to understand risk factors for these diseases specifically in African and African-ancestry populations. The hope is that the findings of these studies will help scientists to eventually develop African-appropriate diagnostics, interventions, treatments, and even cures.
Illumina was chosen based on their track record in developing consortium arrays with other research networks, price-point for manufacture and service, ability to include all the custom content requested by the consortium in the time-frame needed, and their commitment to increasing capacity for genomics research in Africa. As part of this commitment they have already contributed to establishing a genotyping service on the continent and intend to support others.
While the array is considered an H3Africa consortium product, Illumina may sell this array at cost to others who are engaged in genomic research to benefit Africans.
This array was designed by scientists for scientists and developed so that African scientists can do better science to ultimately benefit the people of Africa. No group, person or data provider associated with H3Africa who worked on the project has any commercial interest in the array or will receive any financial reward whatsoever from the array design, or sale of any arrays.
In order to manufacture the array, we had to engage a commercial partner with capacity to manufacture high quality arrays at reasonable prices. As explained above, Illumina was chosen as the technology partner. Through H3Africa negotiation with Illumina, competitive pricing was agreed for the array for African scientists. A standard consortium agreement was established and signed in order to give H3Africa members and other African scientists access to the array as a research tool at low cost. Illumina has provided a free array scanner for African use, and covered costs of sample shipping for genotyping for H3Africa researchers. Any profit that Illumina makes is a reasonable and appropriate profit for the manufacture of the array rather than the content of the array.
As with all genotyping arrays, the IP is contained in the technology and the probes to detect the variants and not in the variant data or content itself. Illumina does not own any IP on the content. None of the underlying individual level data has been provided to Illumina, only the reference information needed to generate the probes, which include a subset of common variants present in multiple populations derived from aggregated data. Current understanding and legal opinion are that sequence data does not contain IP (see: https://ghr.nlm.nih.gov/primer/testing/genepatents).
The array contains two sets of probes: (1) Probes for SNPs which researchers specifically asked for; and (2) Probes for SNPs that were chosen because of the allele frequency in African or global populations, taking into account the linkage disequilibrium structure of different populations. The result of the design process was only the list of probes that should be included in the array. Not only was no individual-level data made available to Illumina, no frequency or linkage disequilibrium data was provided nor any reason for why the probe was selected or in which population the SNP had been found. Any IP that might subsist in this sequence data therefore has not been affected by the array design process.
This project is called the Human Heredity and Health in Africa, and designated H3Africa.
Organized to enable African researchers to carry out large-scale studies on African populations, H3Africa will make use of state-of-the art genomic technologies, in combination with clinical and environmental analyses, with the aim of understanding the interaction of genes and the environment in health and disease. As part of this H3Africa will create new research capabilities in Africa by enhancing infrastructure and supporting pan- African collaborations, as well as collaborations with researchers in the United States and Europe when appropriate.
In the last few years there have been a number of studies which have looked at variation in the human genome and identified genetic risk factors for common diseases such as diabetes and obesity. To date these have mainly focused on North American and European populations, but studies such as the International HapMap Project, have shown that African populations carry the oldest, most diverse set of human genes. The studies which H3Africa will support will relate genetic variation in these populations to clinical findings and environmental information, Understanding this variation is key to informing strategies for prevention and treatment, both at the individual and population level.
Initially, H3Africa will support two pilot studies. The role of genetic variability in infectious diseases is not fully understood, so one set of studies will focus on the interactions between disease-causing micro-organisms and human hosts. The second will investigate a non-communicable disease, such as hypertension, stroke, heart disease, diabetes or cancer, all of which are becoming widespread in Africa populations. H3Africa will seek to understand the interaction between genetic susceptibilities and environmental changes — such as diet — that may be leading to the increased incidence of these diseases.
H3Africa will support studies investigating the effects of potential gene-environment interactions on health. This will inform public health policies and guidelines. Environmental factors under study could include nutrition, pollutants and lifestyle factors.
H3Africa will support multidisciplinary research teams comprised of a range of experts, including geneticists, clinicians, physiologists, bioinformaticians and social scientists. Genomic tools will likely include genotyping chips used in genome-wide association studies, sequencing of all the genes in the human genome (called exome sequencing) and eventually, whole genome sequencing; the data produced will be analyzed by state-of-the-art bioinformatics tools. Accurate clinical diagnosis will be critical, and where appropriate detailed information on lifestyle and environmental exposures will be obtained.
Although H3Africa is intended to build capacity in Africa, it may be that early studies will rely on existing genome facilities in Africa, the United States and the United Kingdom. As the project moves forward, we expect that adequate genotyping and sequencing capacity will be developed in Africa.
H3Africa is funded by a partnership between the U.S. National Institutes of Health, an agency of the U.S. Department of Health and Human Services, and the Wellcome Trust, a global charity based in London, U.K. NIH has committee $5 million a year for five years starting in fiscal year 2011, a total of $25 million. Wellcome Trust will contribute $12 million over that period.
The African Society of Human Genetics will participate as a non-funding partner. It has served an organizing role for H3Africa and will continue to provide an educational and organizational forum for the project among genetic scientists in Africa.
NIH and the Wellcome Trust are still working on the managerial aspects of the partnership.
Both NIH and the Wellcome Trust have established mechanisms for awarding grants, contracts and cooperative agreements between the funding institutions and individual researchers or groups of researchers. Existing mechanisms will be employed to ensure a fair and transparent competition process for awarding research funding.
The African Society of Human Genetics (AfSHG) has played an essential organizing role that led to the development of H3Africa. AfSHG is a professional society of genetic researchers and health care providers across the continent and it serves as a convener for meetings to organize the genetic research community. In 2007 and 2009, AfSHG organized two meetings, in Egypt and Cameroon, to advance the idea of a project that evolved into H3Africa.
Researchers will be expected to engage in community consultation with those in the study, especially in studies with cohorts that will be revisited often. The goal is to help communities understand that H3Africa is here for the long term and that it will have an impact on their health, but it is unlikely that the consultation will be as extensive as that for HapMap.
Developing plans envision H3Africa eventually creating a bio-repository somewhere in Africa for biological samples collected from populations in Africa. Until sufficient infrastructure is created to both manage and analyze samples, they may be sent for processing and analyses elsewhere. But the samples only will leave Africa for the purposes of collaboration with other researchers; African researchers will always be involved and will retain responsibility for the samples. Samples will not simply be collected and shipped out for others to use.