Making glaucoma genetic studies more diverse.

Although the blinding eye disease glaucoma is more common in people of African ancestry, previous genetic studies predominantly involved European subjects. In this issue of Cell, O'Brien et al. report a genome-wide association study for glaucoma in individuals of African ancestry, showing overlap with European studies and refining an African polygenic risk score.

A multi-cohort genome-wide association study in African ancestry individuals reveals risk loci for primary open-angle glaucoma.

Primary open-angle glaucoma (POAG), the leading cause of irreversible blindness worldwide, disproportionately affects individuals of African ancestry. We conducted a genome-wide association study (GWAS) for POAG in 11,275 individuals of African ancestry (6,003 cases; 5,272 controls). We detected 46 risk loci associated with POAG at genome-wide significance. Replication and post-GWAS analyses, including functionally informed fine-mapping, multiple trait co-localization, and in silico validation, implicated two previously undescribed variants (rs1666698 mapping to DBF4P2; rs34957764 mapping to ROCK1P1) and one previously associated variant (rs11824032 mapping to ARHGEF12) as likely causal. For individuals of African ancestry, a polygenic risk score (PRS) for POAG from our mega-analysis (African ancestry individuals) outperformed a PRS from summary statistics of a much larger GWAS derived from European ancestry individuals. This study quantifies the genetic architecture similarities and differences between African and non-African ancestry populations for this blinding disease.

Identifying and Interpreting Apparent Neanderthal Ancestry in African Individuals.

Admixture has played a prominent role in shaping patterns of human genomic variation, including gene flow with now-extinct hominins like Neanderthals and Denisovans. Here, we describe a novel probabilistic method called IBDmix to identify introgressed hominin sequences, which, unlike existing approaches, does not use a modern reference population. We applied IBDmix to 2,504 individuals from geographically diverse populations to identify and analyze Neanderthal sequences segregating in modern humans. Strikingly, we find that African individuals carry a stronger signal of Neanderthal ancestry than previously thought. We show that this can be explained by genuine Neanderthal ancestry due to migrations back to Africa, predominately from ancestral Europeans, and gene flow into Neanderthals from an early dispersing group of humans out of Africa. Our results refine our understanding of Neanderthal ancestry in African and non-African populations and demonstrate that remnants of Neanderthal genomes survive in every modern human population studied to date.

Uganda Genome Resource Enables Insights into Population History and Genomic Discovery in Africa.

Genomic studies in African populations provide unique opportunities to understand disease etiology, human diversity, and population history. In the largest study of its kind, comprising genome-wide data from 6,400 individuals and whole-genome sequences from 1,978 individuals from rural Uganda, we find evidence of geographically correlated fine-scale population substructure. Historically, the ancestry of modern Ugandans was best represented by a mixture of ancient East African pastoralists. We demonstrate the value of the largest sequence panel from Africa to date as an imputation resource. Examining 34 cardiometabolic traits, we show systematic differences in trait heritability between European and African populations, probably reflecting the differential impact of genes and environment. In a multi-trait pan-African GWAS of up to 14,126 individuals, we identify novel loci associated with anthropometric, hematological, lipid, and glycemic traits. We find that several functionally important signals are driven by Africa-specific variants, highlighting the value of studying diverse populations across the region.

Systems analysis and controlled malaria infection in Europeans and Africans elucidate naturally acquired immunity.

Controlled human infections provide opportunities to study the interaction between the immune system and malaria parasites, which is essential for vaccine development. Here, we compared immune signatures of malaria-naive Europeans and of Africans with lifelong malaria exposure using mass cytometry, RNA sequencing and data integration, before and 5 and 11 days after venous inoculation with Plasmodium falciparum sporozoites. We observed differences in immune cell populations, antigen-specific responses and gene expression profiles between Europeans and Africans and among Africans with differing degrees of immunity. Before inoculation, an activated/differentiated state of both innate and adaptive cells, including elevated CD161+CD4+ T cells and interferon-γ production, predicted Africans capable of controlling parasitemia. After inoculation, the rapidity of the transcriptional response and clusters of CD4+ T cells, plasmacytoid dendritic cells and innate T cells were among the features distinguishing Africans capable of controlling parasitemia from susceptible individuals. These findings can guide the development of a vaccine effective in malaria-endemic regions.

Common PIEZO1 Allele in African Populations Causes RBC Dehydration and Attenuates Plasmodium Infection.

Hereditary xerocytosis is thought to be a rare genetic condition characterized by red blood cell (RBC) dehydration with mild hemolysis. RBC dehydration is linked to reduced Plasmodium infection in vitro; however, the role of RBC dehydration in protection against malaria in vivo is unknown. Most cases of hereditary xerocytosis are associated with gain-of-function mutations in PIEZO1, a mechanically activated ion channel. We engineered a mouse model of hereditary xerocytosis and show that Plasmodium infection fails to cause experimental cerebral malaria in these mice due to the action of Piezo1 in RBCs and in T cells. Remarkably, we identified a novel human gain-of-function PIEZO1 allele, E756del, present in a third of the African population. RBCs from individuals carrying this allele are dehydrated and display reduced Plasmodium infection in vitro. The existence of a gain-of-function PIEZO1 at such high frequencies is surprising and suggests an association with malaria resistance.

An Unexpectedly Complex Architecture for Skin Pigmentation in Africans.

Approximately 15 genes have been directly associated with skin pigmentation variation in humans, leading to its characterization as a relatively simple trait. However, by assembling a global survey of quantitative skin pigmentation phenotypes, we demonstrate that pigmentation is more complex than previously assumed, with genetic architecture varying by latitude. We investigate polygenicity in the KhoeSan populations indigenous to southern Africa who have considerably lighter skin than equatorial Africans. We demonstrate that skin pigmentation is highly heritable, but known pigmentation loci explain only a small fraction of the variance. Rather, baseline skin pigmentation is a complex, polygenic trait in the KhoeSan. Despite this, we identify canonical and non-canonical skin pigmentation loci, including near SLC24A5, TYRP1, SMARCA2/VLDLR, and SNX13, using a genome-wide association approach complemented by targeted resequencing. By considering diverse, under-studied African populations, we show how the architecture of skin pigmentation can vary across humans subject to different local evolutionary pressures.

Gene Discovery for Complex Traits: Lessons from Africa.

The genetics of African populations reveals an otherwise "missing layer" of human variation that arose between 100,000 and 5 million years ago. Both the vast number of these ancient variants and the selective pressures they survived yield insights into genes responsible for complex traits in all populations.

Reconstructing Prehistoric African Population Structure.

We assembled genome-wide data from 16 prehistoric Africans. We show that the anciently divergent lineage that comprises the primary ancestry of the southern African San had a wider distribution in the past, contributing approximately two-thirds of the ancestry of Malawi hunter-gatherers ∼8,100-2,500 years ago and approximately one-third of the ancestry of Tanzanian hunter-gatherers ∼1,400 years ago. We document how the spread of farmers from western Africa involved complete replacement of local hunter-gatherers in some regions, and we track the spread of herders by showing that the population of a ∼3,100-year-old pastoralist from Tanzania contributed ancestry to people from northeastern to southern Africa, including a ∼1,200-year-old southern African pastoralist. The deepest diversifications of African lineages were complex, involving either repeated gene flow among geographically disparate groups or a lineage more deeply diverging than that of the San contributing more to some western African populations than to others. We finally leverage ancient genomes to document episodes of natural selection in southern African populations. PAPERCLIP.

Genetic Adaptation and Neandertal Admixture Shaped the Immune System of Human Populations.

Humans differ in the outcome that follows exposure to life-threatening pathogens, yet the extent of population differences in immune responses and their genetic and evolutionary determinants remain undefined. Here, we characterized, using RNA sequencing, the transcriptional response of primary monocytes from Africans and Europeans to bacterial and viral stimuli-ligands activating Toll-like receptor pathways (TLR1/2, TLR4, and TLR7/8) and influenza virus-and mapped expression quantitative trait loci (eQTLs). We identify numerous cis-eQTLs that contribute to the marked differences in immune responses detected within and between populations and a strong trans-eQTL hotspot at TLR1 that decreases expression of pro-inflammatory genes in Europeans only. We find that immune-responsive regulatory variants are enriched in population-specific signals of natural selection and show that admixture with Neandertals introduced regulatory variants into European genomes, affecting preferentially responses to viral challenges. Together, our study uncovers evolutionarily important determinants of differences in host immune responsiveness between human populations.

APOL1 risk variants in individuals of African genetic ancestry drive endothelial cell defects that exacerbate sepsis.

The incidence and severity of sepsis is higher among individuals of African versus European ancestry. We found that genetic risk variants (RVs) in the trypanolytic factor apolipoprotein L1 (APOL1), present only in individuals of African ancestry, were associated with increased sepsis incidence and severity. Serum APOL1 levels correlated with sepsis and COVID-19 severity, and single-cell sequencing in human kidneys revealed high expression of APOL1 in endothelial cells. Analysis of mice with endothelial-specific expression of RV APOL1 and in vitro studies demonstrated that RV APOL1 interfered with mitophagy, leading to cytosolic release of mitochondrial DNA and activation of the inflammasome (NLRP3) and the cytosolic nucleotide sensing pathways (STING). Genetic deletion or pharmacological inhibition of NLRP3 and STING protected mice from RV APOL1-induced permeability defects and proinflammatory endothelial changes in sepsis. Our studies identify the inflammasome and STING pathways as potential targets to reduce APOL1-associated health disparities in sepsis and COVID-19.

Genomic data in the All of Us Research Program.

Comprehensively mapping the genetic basis of human disease across diverse individuals is a long-standing goal for the field of human genetics1-4. The All of Us Research Program is a longitudinal cohort study aiming to enrol a diverse group of at least one million individuals across the USA to accelerate biomedical research and improve human health5,6. Here we describe the programme's genomics data release of 245,388 clinical-grade genome sequences. This resource is unique in its diversity as 77% of participants are from communities that are historically under-represented in biomedical research and 46% are individuals from under-represented racial and ethnic minorities. All of Us identified more than 1 billion genetic variants, including more than 275 million previously unreported genetic variants, more than 3.9 million of which had coding consequences. Leveraging linkage between genomic data and the longitudinal electronic health record, we evaluated 3,724 genetic variants associated with 117 diseases and found high replication rates across both participants of European ancestry and participants of African ancestry. Summary-level data are publicly available, and individual-level data can be accessed by researchers through the All of Us Researcher Workbench using a unique data passport model with a median time from initial researcher registration to data access of 29 hours. We anticipate that this diverse dataset will advance the promise of genomic medicine for all.

Atypical chemokine receptor 1 on nucleated erythroid cells regulates hematopoiesis.

Healthy individuals of African ancestry have neutropenia that has been linked with the variant rs2814778(G) of the gene encoding atypical chemokine receptor 1 (ACKR1). This polymorphism selectively abolishes the expression of ACKR1 in erythroid cells, causing a Duffy-negative phenotype. Here we describe an unexpected fundamental role for ACKR1 in hematopoiesis and provide the mechanism that links its absence with neutropenia. Nucleated erythroid cells had high expression of ACKR1, which facilitated their direct contact with hematopoietic stem cells. The absence of erythroid ACKR1 altered mouse hematopoiesis including stem and progenitor cells, which ultimately gave rise to phenotypically distinct neutrophils that readily left the circulation, causing neutropenia. Individuals with a Duffy-negative phenotype developed a distinct profile of neutrophil effector molecules that closely reflected the one observed in the ACKR1-deficient mice. Thus, alternative physiological patterns of hematopoiesis and bone marrow cell outputs depend on the expression of ACKR1 in the erythroid lineage, findings with major implications for the selection advantages that have resulted in the paramount fixation of the ACKR1 rs2814778(G) polymorphism in Africa.

Ancient DNA and deep population structure in sub-Saharan African foragers.

Multiple lines of genetic and archaeological evidence suggest that there were major demographic changes in the terminal Late Pleistocene epoch and early Holocene epoch of sub-Saharan Africa1-4. Inferences about this period are challenging to make because demographic shifts in the past 5,000 years have obscured the structures of more ancient populations3,5. Here we present genome-wide ancient DNA data for six individuals from eastern and south-central Africa spanning the past approximately 18,000 years (doubling the time depth of sub-Saharan African ancient DNA), increase the data quality for 15 previously published ancient individuals and analyse these alongside data from 13 other published ancient individuals. The ancestry of the individuals in our study area can be modelled as a geographically structured mixture of three highly divergent source populations, probably reflecting Pleistocene interactions around 80-20 thousand years ago, including deeply diverged eastern and southern African lineages, plus a previously unappreciated ubiquitous distribution of ancestry that occurs in highest proportion today in central African rainforest hunter-gatherers. Once established, this structure remained highly stable, with limited long-range gene flow. These results provide a new line of genetic evidence in support of hypotheses that have emerged from archaeological analyses but remain contested, suggesting increasing regionalization at the end of the Pleistocene epoch.

African-specific molecular taxonomy of prostate cancer.

Prostate cancer is characterized by considerable geo-ethnic disparity. African ancestry is a significant risk factor, with mortality rates across sub-Saharan Africa of 2.7-fold higher than global averages1. The contributing genetic and non-genetic factors, and associated mutational processes, are unknown2,3. Here, through whole-genome sequencing of treatment-naive prostate cancer samples from 183 ancestrally (African versus European) and globally distinct patients, we generate a large cancer genomics resource for sub-Saharan Africa, identifying around 2 million somatic variants. Significant African-ancestry-specific findings include an elevated tumour mutational burden, increased percentage of genome alteration, a greater number of predicted damaging mutations and a higher total of mutational signatures, and the driver genes NCOA2, STK19, DDX11L1, PCAT1 and SETBP1. Examining all somatic mutational types, we describe a molecular taxonomy for prostate cancer differentiated by ancestry and defined as global mutational subtypes (GMS). By further including Chinese Asian data, we confirm that GMS-B (copy-number gain) and GMS-D (mutationally noisy) are specific to African populations, GMS-A (mutationally quiet) is universal (all ethnicities) and the African-European-restricted subtype GMS-C (copy-number losses) predicts poor clinical outcomes. In addition to the clinical benefit of including individuals of African ancestry, our GMS subtypes reveal different evolutionary trajectories and mutational processes suggesting that both common genetic and environmental factors contribute to the disparity between ethnicities. Analogous to gene-environment interaction-defined here as a different effect of an environmental surrounding in people with different ancestries or vice versa-we anticipate that GMS subtypes act as a proxy for intrinsic and extrinsic mutational processes in cancers, promoting global inclusion in landmark studies.

Charting a landmark-driven path forward for population genetics and ancient DNA research in Africa.

Population history-focused DNA and ancient DNA (aDNA) research in Africa has dramatically increased in the past decade, enabling increasingly fine-scale investigations into the continent's past. However, while international interest in human genomics research in Africa grows, major structural barriers limit the ability of African scholars to lead and engage in such research and impede local communities from partnering with researchers and benefitting from research outcomes. Because conversations about research on African people and their past are often held outside Africa and exclude African voices, an important step for African DNA and aDNA research is moving these conversations to the continent. In May 2023 we held the DNAirobi workshop in Nairobi, Kenya and here we synthesize what emerged most prominently in our discussions. We propose an ideal vision for population history-focused DNA and aDNA research in Africa in ten years' time and acknowledge that to realize this future, we need to chart a path connecting a series of "landmarks" that represent points of consensus in our discussions. These include effective communication across multiple audiences, reframed relationships and capacity building, and action toward structural changes that support science and beyond. We concluded there is no single path to creating an equitable and self-sustaining research ecosystem, but rather many possible routes linking these landmarks. Here we share our diverse perspectives as geneticists, anthropologists, archaeologists, museum curators, and educators to articulate challenges and opportunities for African DNA and aDNA research and share an initial map toward a more inclusive and equitable future.

Toward building a comprehensive human pan-genome: The SEN-GENOME project.

The human reference genome (GRCh38), primarily sourced from individuals of European descent, falls short in capturing the vast genetic diversity across global populations. Efforts to diversify the reference genome face challenges in accessibility and representation, exacerbating the scarcity of African genomic data crucial for studying diseases prevalent in these populations. Sherman et al. proposed constructing reference genomes tailored to distinct human sub-populations. Their African Pan-Genome initiative highlighted substantial genetic variation missing from the GRCh38 human reference genome, emphasizing the necessity for population-specific genomes. In response, local initiatives like the Senegalese Genome project (SEN-GENOME) have emerged to document the genomes of historically overlooked populations. SEN-GENOME embodies community-driven decentralized research. With meticulous recruitment criteria and ethical practices, it aims to sequence 1,000 genomes from 31 ethnolinguistic groups, in the fourteen administrative regions of Senegal, fostering local genomic research tailored to the region. The key to SEN-GENOME's success is its commitment to local governance of data, capacity building, and integration with broader pan-genome projects in Africa. Despite the complexities of data harmonization and sharing, our collaborative efforts are aligned with common goals, ensuring steady progress toward a comprehensive human pan-genome. We invite and welcome collaboration with other research entities to achieve this shared vision. In summary, local initiatives such as SEN-GENOME are pivotal in bridging genomic disparities, offering pathways to equitable and inclusive genomic research. Collaborative endeavors guided by a collective vision for human health will propel us toward a more encompassing understanding of the human genome and better health through genomic medicine.

Association between telomere length and Plasmodium falciparum malaria endemicity in sub-Saharan Africans.

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 ∼50% 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.

African genetic diversity and adaptation inform a precision medicine agenda.

The deep evolutionary history of African populations, since the emergence of modern humans more than 300,000 years ago, has resulted in high genetic diversity and considerable population structure. Selected genetic variants have increased in frequency due to environmental adaptation, but recent exposures to novel pathogens and changes in lifestyle render some of them with properties leading to present health liabilities. The unique discoverability potential from African genomic studies promises invaluable contributions to understanding the genomic and molecular basis of health and disease. Globally, African populations are understudied, and precision medicine approaches are largely based on data from European and Asian-ancestry populations, which limits the transferability of findings to the continent of Africa. Africa needs innovative precision medicine solutions based on African data that use knowledge and implementation strategies aligned to its climatic, cultural, economic and genomic diversity.

Evolutionary history and adaptation from high-coverage whole-genome sequences of diverse African hunter-gatherers.

To reconstruct modern human evolutionary history and identify loci that have shaped hunter-gatherer adaptation, we sequenced the whole genomes of five individuals in each of three different hunter-gatherer populations at > 60× coverage: Pygmies from Cameroon and Khoesan-speaking Hadza and Sandawe from Tanzania. We identify 13.4 million variants, substantially increasing the set of known human variation. We found evidence of archaic introgression in all three populations, and the distribution of time to most recent common ancestors from these regions is similar to that observed for introgressed regions in Europeans. Additionally, we identify numerous loci that harbor signatures of local adaptation, including genes involved in immunity, metabolism, olfactory and taste perception, reproduction, and wound healing. Within the Pygmy population, we identify multiple highly differentiated loci that play a role in growth and anterior pituitary function and are associated with height.