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We conduct high coverage (>30×) whole-genome sequencing of 180 individuals from 12 indigenous African populations. We identify millions of unreported variants, many predicted to be functionally important. We observe that the ancestors of southern African San and central African rainforest hunter-gatherers (RHG) diverged from other populations >200 kya and maintained a large effective population size. We observe evidence for ancient population structure in Africa and for multiple introgression events from "ghost" populations with highly diverged genetic lineages. Although currently geographically isolated, we observe evidence for gene flow between eastern and southern Khoesan-speaking hunter-gatherer populations lasting until â¼12 kya. We identify signatures of local adaptation for traits related to skin color, immune response, height, and metabolic processes. We identify a positively selected variant in the lightly pigmented San that influences pigmentation in vitro by regulating the enhancer activity and gene expression of PDPK1.
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Aclimatación , Pigmentación de la Piel , Humanos , Secuenciación Completa del Genoma , Densidad de Población , África , Proteínas Quinasas Dependientes de 3-FosfoinosítidoRESUMEN
Leukocyte telomere length (LTL) varies significantly across human populations, with individuals of African ancestry having longer LTL than non-Africans. However, the genetic and environmental drivers of LTL variation in Africans remain largely unknown. We report here on the relationship between LTL, genetics, and a variety of environmental and climatic factors in ethnically diverse African adults (n = 1,818) originating from Botswana, Tanzania, Ethiopia, and Cameroon. We observe significant variation in LTL among populations, finding that the San hunter-gatherers from Botswana have the longest leukocyte telomeres and that the Fulani pastoralists from Cameroon have the shortest telomeres. Genetic factors explain â¼50% of LTL variation among individuals. Moreover, we observe a significant negative association between Plasmodium falciparum malaria endemicity and LTL while adjusting for age, sex, and genetics. Within Africa, adults from populations indigenous to areas with high malaria exposure have shorter LTL than those in populations indigenous to areas with low malaria exposure. Finally, we explore to what degree the genetic architecture underlying LTL in Africa covaries with malaria exposure.
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Malaria Falciparum , Telómero , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , África del Sur del Sahara/epidemiología , Población Negra/etnología , Población Negra/genética , Enfermedades Endémicas , Leucocitos/metabolismo , Malaria Falciparum/genética , Malaria Falciparum/epidemiología , Malaria Falciparum/parasitología , Plasmodium falciparum/genética , Plasmodium falciparum/patogenicidad , Pueblo Africano Subsahariano , Telómero/genética , Homeostasis del Telómero/genética , Botswana , Tanzanía , Camerún , Pueblo del Sur de ÁfricaRESUMEN
Gene-editing research is a complex science and foreign in most communities including Botswana. Adopting a qualitative deliberative framework with 109 participants from 7 selected ethnic communities in Botswana, we explored the perceptions of local communities on cultural values, norms, and beliefs that may motivate or deter likely participation in the use of gene-editing related research. What emerged as the ethnic community's motivators for research participation include the potential for gene-editing technologies to promote access to individualized medications, and the possibility of protecting family members from genetic related diseases. Deterrents for research participation include cultural values such as implications of lineage for chieftainship, trust, fear or anxiety, uncertainty, and sensitivity on the use of gene-editing. Findings of our study have implications for continuous engagement with local communities to explore potential ways of addressing cultural sensitivities that can further deter their participation in future gene-editing related research.
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Populations in sub-Saharan Africa have historically been exposed to intense selection from chronic infection with falciparum malaria. Interestingly, populations with the highest malaria intensity can be identified by the increased occurrence of endemic Burkitt Lymphoma (eBL), a pediatric cancer that affects populations with intense malaria exposure, in the so called "eBL belt" in sub-Saharan Africa. However, the effects of intense malaria exposure and sub-Saharan populations' genetic histories remain poorly explored. To determine if historical migrations and intense malaria exposure have shaped the genetic composition of the eBL belt populations, we genotyped ~4.3 million SNPs in 1,708 individuals from Ghana and Northern Uganda, located on opposite sides of eBL belt and with ≥ 7 months/year of intense malaria exposure and published evidence of high incidence of BL. Among 35 Ghanaian tribes, we showed a predominantly West-Central African ancestry and genomic footprints of gene flow from Gambian and East African populations. In Uganda, the North West population showed a predominantly Nilotic ancestry, and the North Central population was a mixture of Nilotic and Southern Bantu ancestry, while the Southwest Ugandan population showed a predominant Southern Bantu ancestry. Our results support the hypothesis of diverse ancestral origins of the Ugandan, Kenyan and Tanzanian Great Lakes African populations, reflecting a confluence of Nilotic, Cushitic and Bantu migrations in the last 3000 years. Natural selection analyses suggest, for the first time, a strong positive selection signal in the ATP2B4 gene (rs10900588) in Northern Ugandan populations. These findings provide important baseline genomic data to facilitate disease association studies, including of eBL, in eBL belt populations.
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Linfoma de Burkitt/genética , Flujo Génico , Malaria Falciparum/genética , Selección Genética , Adolescente , África del Sur del Sahara , Anciano , Linfoma de Burkitt/epidemiología , Estudios de Casos y Controles , Niño , Preescolar , Enfermedades Endémicas , Femenino , Genética de Población , Estudio de Asociación del Genoma Completo , Ghana/epidemiología , Migración Humana , Humanos , Incidencia , Lactante , Recién Nacido , Malaria Falciparum/epidemiología , Masculino , Persona de Mediana Edad , Modelos Genéticos , ATPasas Transportadoras de Calcio de la Membrana Plasmática/genética , Polimorfismo de Nucleótido Simple , Uganda/epidemiologíaRESUMEN
Skin color is highly variable in Africans, yet little is known about the underlying molecular mechanism. Here we applied massively parallel reporter assays to screen 1,157 candidate variants influencing skin pigmentation in Africans and identified 165 single-nucleotide polymorphisms showing differential regulatory activities between alleles. We combine Hi-C, genome editing and melanin assays to identify regulatory elements for MFSD12, HMG20B, OCA2, MITF, LEF1, TRPS1, BLOC1S6 and CYB561A3 that impact melanin levels in vitro and modulate human skin color. We found that independent mutations in an OCA2 enhancer contribute to the evolution of human skin color diversity and detect signals of local adaptation at enhancers of MITF, LEF1 and TRPS1, which may contribute to the light skin color of Khoesan-speaking populations from Southern Africa. Additionally, we identified CYB561A3 as a novel pigmentation regulator that impacts genes involved in oxidative phosphorylation and melanogenesis. These results provide insights into the mechanisms underlying human skin color diversity and adaptive evolution.
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Albinismo Oculocutáneo , Melaninas , Pigmentación de la Piel , Humanos , Pigmentación de la Piel/genética , Melaninas/genética , Alelos , Genómica , Pigmentación/genética , Polimorfismo de Nucleótido Simple/genética , Proteínas Represoras/genéticaRESUMEN
While the evaluation of learning development interventions needs to be considered carefully and included at the curriculum design stage, there is limited literature on the actual design of interventions, especially on how these designs evolve and improve over time. This paper describes the evolution of a learning development program intended to support first-year medical students adjusting to a problem-based learning curriculum. We used a design-based research approach, articulating our theoretical grounding and incorporating students' voices to develop an "optimal" intervention for the specific challenges in our context. We describe lessons learned around four aspects: students' growth and development, teachers' professional growth and development, program design principles, and the emergent components of a learning development program. Overall, our students describe the Learning Success Program as adding value by enabling the adoption of a repertoire of skills and strategies for learning management. Additionally, the incremental nature of design-based research allowed for the development of a context-specific program that considers students' voices through needs assessment and feedback on the program offerings. It has also provided an opportunity for the professional development of teachers through feedback from classroom practice, reflection, and the literature. Supplementary Information: The online version contains supplementary material available at 10.1007/s40670-023-01790-3.
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Comparisons of Neanderthal genomes to anatomically modern human (AMH) genomes show a history of Neanderthal-to-AMH introgression stemming from interbreeding after the migration of AMHs from Africa to Eurasia. All non-sub-Saharan African AMHs have genomic regions genetically similar to Neanderthals that descend from this introgression. Regions of the genome with Neanderthal similarities have also been identified in sub-Saharan African populations, but their origins have been unclear. To better understand how these regions are distributed across sub-Saharan Africa, the source of their origin, and what their distribution within the genome tells us about early AMH and Neanderthal evolution, we analyzed a dataset of high-coverage, whole-genome sequences from 180 individuals from 12 diverse sub-Saharan African populations. In sub-Saharan African populations with non-sub-Saharan African ancestry, as much as 1% of their genomes can be attributed to Neanderthal sequence introduced by recent migration, and subsequent admixture, of AMH populations originating from the Levant and North Africa. However, most Neanderthal homologous regions in sub-Saharan African populations originate from migration of AMH populations from Africa to Eurasia â¼250 kya, and subsequent admixture with Neanderthals, resulting in â¼6% AMH ancestry in Neanderthals. These results indicate that there have been multiple migration events of AMHs out of Africa and that Neanderthal and AMH gene flow has been bi-directional. Observing that genomic regions where AMHs show a depletion of Neanderthal introgression are also regions where Neanderthal genomes show a depletion of AMH introgression points to deleterious interactions between introgressed variants and background genomes in both groups-a hallmark of incipient speciation.
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Hombre de Neandertal , Humanos , Animales , Hombre de Neandertal/genética , Genoma Humano , Flujo Génico , Genómica , África del Sur del SaharaRESUMEN
We investigated global patterns of genetic variation and signatures of natural selection at host genes relevant to SARS-CoV-2 infection (ACE2, TMPRSS2, DPP4, and LY6E). We analyzed novel data from 2,012 ethnically diverse Africans and 15,997 individuals of European and African ancestry with electronic health records, and integrated with global data from the 1000GP. At ACE2, we identified 41 non-synonymous variants that were rare in most populations, several of which impact protein function. However, three non-synonymous variants were common among Central African hunter-gatherers from Cameroon and are on haplotypes that exhibit signatures of positive selection. We identify strong signatures of selection impacting variation at regulatory regions influencing ACE2 expression in multiple African populations. At TMPRSS2, we identified 13 amino acid changes that are adaptive and specific to the human lineage. Genetic variants that are targets of natural selection are associated with clinical phenotypes common in patients with COVID-19.
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We investigated global patterns of genetic variation and signatures of natural selection at host genes relevant to SARS-CoV-2 infection ( ACE2, TMPRSS2, DPP4 , and LY6E ). We analyzed novel data from 2,012 ethnically diverse Africans and 15,997 individuals of European and African ancestry with electronic health records, and integrated with global data from the 1000GP. At ACE2 , we identified 41 non-synonymous variants that were rare in most populations, several of which impact protein function. However, three non-synonymous variants were common among Central African hunter-gatherers from Cameroon and are on haplotypes that exhibit signatures of positive selection. We identify strong signatures of selection impacting variation at regulatory regions influencing ACE2 expression in multiple African populations. At TMPRSS2 , we identified 13 amino acid changes that are adaptive and specific to the human lineage. Genetic variants that are targets of natural selection are associated with clinical phenotypes common in patients with COVID-19.
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Despite the wide range of skin pigmentation in humans, little is known about its genetic basis in global populations. Examining ethnically diverse African genomes, we identify variants in or near SLC24A5, MFSD12, DDB1, TMEM138, OCA2, and HERC2 that are significantly associated with skin pigmentation. Genetic evidence indicates that the light pigmentation variant at SLC24A5 was introduced into East Africa by gene flow from non-Africans. At all other loci, variants associated with dark pigmentation in Africans are identical by descent in South Asian and Australo-Melanesian populations. Functional analyses indicate that MFSD12 encodes a lysosomal protein that affects melanogenesis in zebrafish and mice, and that mutations in melanocyte-specific regulatory regions near DDB1/TMEM138 correlate with expression of ultraviolet response genes under selection in Eurasians.
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Población Negra/genética , Evolución Molecular , Flujo Génico , Sitios Genéticos , Melaninas/genética , Pigmentación de la Piel/genética , África Oriental , Animales , Antiportadores/genética , Proteínas de Unión al ADN/genética , Etnicidad/genética , Genoma Humano , Estudio de Asociación del Genoma Completo , Humanos , Melaninas/biosíntesis , Melaninas/metabolismo , Melanocitos/metabolismo , Proteínas de la Membrana/genética , Ratones , Polimorfismo de Nucleótido Simple , Exposición a la Radiación , Supresión Genética , Rayos UltravioletaRESUMEN
BACKGROUND: Sub-Saharan Africa has a greater share of the global burden of disease, poverty, and inadequate human resources for health compared with other regions of the world. Botswana, as other regional countries, is failing to successfully recruit and retain academics at its medical school. OBJECTIVES: To document the medical school's staff recruitment and retention trends and challenges, and to propose possible solutions. METHODS: This was a descriptive research study involving review and analysis of the University of Botswana medical school's staff number targets, actual numbers on post, and other relevant publicly available university documents. The numbers and country of origin of staff recruited from 2008 to 2013 were recorded. Net staff gain or loss per year was then calculated. Student numbers were analysed and related to staff availability. As there was a multilevel change in university management in 2011, the periods and events before and after April 2011 were analysed. Publicly available University of Botswana documents about the university's organisational structure, policies, and processes were reviewed. RESULTS: Over a 5-year period, the school recruited 74 academics worldwide; 30 of them left the school. Retention was a greater challenge than recruitment. The school had difficulty recruiting locals and senior academics, regardless of specialty. It appears that staff loss occurred regardless of country of origin. CONCLUSION: The authors suggest that multilevel change in management was one of the most likely contributors to the school's recruitment and retention challenges. The University of Botswana must comprehensively address these.