What is genetic diversity?
Genetic diversity refers to the combined differences in the genetic code or DNA of all individuals in a population [1]. All humans are 99.9% identical in their genetic make-up, but the remaining 0.1% differ and, more importantly, hold important clues to health and disease, as they can help a population adapt to changing environmental conditions, resist disease, and secure long-term survival. Between populations, genetic diversity is influenced by factors such as the exchange of genetic material through migration, the occurrence of mutations and selective environmental pressures that shape the traits passed on from one generation to the next [2].
Lack of diversity in genetic studies hinders global progress on rare diseases
To date, the vast majority of genetic data available worldwide are from populations of European ancestry [3]. The underrepresentation of ethnically diverse populations in genetic studies challenges our ability to understand the genetic architecture of diseases across populations. This is critical in the case of rare diseases, as many of the genetic associations that have been identified in populations of European ancestry may not necessarily be generalizable to African populations [3]. This could have an impact on diagnostic tests being less accurate, but also on therapeutics. Gene therapy and future personalized medicine are currently being developed on the basis of results obtained largely from patients of European descent and, as a consequence, this could increase the health gap for rare disease patients in other populations.
Embracing African genetic diversity for rare diseases
Africa is considered to be the most genetically diverse continent because it has the longest continuous history of human habitation. Modern humans (Homo sapiens) are believed to have originated in Africa about 200,000 years ago. African populations are believed to have a complex history of migration, admixture and assimilation with repeated population expansions and bottlenecks that, in the presence of genetic drift, including natural selection, are believed to have largely shaped their genetic diversity [4, 5]. At some point, a small group of these early modern humans left Africa and migrated to other parts of the world, in what is known as the "Out of Africa" migration" around 65,000 years ago, eventually spreading across the globe and replacing other human species such as Neanderthals in Europe and Homo erectus in Asia [6]. Consistent with the human origins theory, it is highly unlikely that the current genetic databases, made mostly of individuals of European ancestry, reflect the full spectrum of genetic variation relevant to rare genetic diseases.
How is SENEGENE contributing to tackle the rare diseases health gap?
Relatively little research has explored this diversity in the context of monogenic (single gene) diseases and our knowledge remains very limited [7]. SENEGENE is one of the first studies in sub-Saharan Africa to analyze in detail the genomic and phenotypic architecture of rare genetic diseases, in particular neuromuscular and neurogenetic disorders, which make a high proportion of all rare genetic diseases. SENEGENE aims to contribute to unlocking the potential of the African genome by creating an anonymized genomic and phenotypic database from Senegal, which will be serve as a resource to the wider scientific and medical community to promote rare disease research in sub-Saharan Africa. Our study will share all data generated via peer-reviewed journals and the RD-Connect GPAP platform. Some of our aims are detailed below.
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Improve our understanding of the epidemiological and genetic makeup of rare diseases in West-African populations, particularly in Senegal. For instance, we still do not know which genetic diseases are more common in Sub-Saharan Africa, and why some genetic diseases commonly seen in Europeans (e.g., myotonic dystrophy, FSHD, etc.) are non-reported or rarely seen in people of African descent.
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Understand the genetic variations that exist within different populations to improve diagnosis accuracy for rare disease patients in Africa and around the world. if databases do not include sufficient data from ethnically-diverse populations, we may mistakenly infer that a benign genetic variant is pathogenic just because it is rare in populations of European descent.
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To help ensure that the development of personalized medical treatments and therapies is also tailored to the specific needs of patients with rare diseases of African descent.
References
1. 1000 Genomes Project Consortium. A global reference for human genetic variation. Nature. 2015 Oct 1;526(7571):68-74.
2. Schlebusch CM, Jakobsson M. Tales of Human Migration, Admixture, and Selection in Africa. Annu Rev Genomics Hum Genet. 2018 Aug 31;19:405-428.
3. Sirugo G, Williams SM, Tishkoff SA. The Missing Diversity in Human Genetic Studies. Cell. 2019 May 2;177(4):1080.
4. Gurdasani D, Carstensen T, Tekola-Ayele F, Pagani L, Tachmazidou I, Hatzikotoulas K, et al. The African Genome Variation Project shapes medical genetics in Africa. Nature. 2015 Jan 15;517(7534):327-32.
5. Campbell MC, Tishkoff SA. African genetic diversity: implications for human demographic history, modern human origins, and complex disease mapping. Annu Rev Genomics Hum Genet. 2008;9:403-33.
6. Quintana-Murci L, Semino O, Bandelt HJ,et al. Genetic evidence of an early exit of Homo sapiens sapiens from Africa through eastern Africa. Nat Genet. 1999 Dec;23(4):437-41.
7. Lumaka A, Carstens N, Devriendt K, et al; as members of the Rare Disease Working Group of the H3Africa Consortium. Increasing African genomic data generation and sharing to resolve rare and undiagnosed diseases in Africa: a call-to-action by the H3Africa rare diseases working group. Orphanet J Rare Dis. 2022 Jun 16;17(1):230.