Gelada genomes highlight events of gene flow, hybridisation and local adaptation that track past climatic changes.

Theropithecus gelada, the last surviving species of this genus, occupy a unique and highly specialised ecological niche in the Ethiopian highlands. A subdivision into three geographically defined populations (Northern, Central and Southern) has been tentatively proposed for this species on the basis of genetic analyses, but genomic data have been investigated only for two of these groups (Northern and Central). Here we combined newly generated whole genome sequences of individuals sampled from the population living south of the East Africa Great Rift Valley with available data from the other two gelada populations to reconstruct the evolutionary history of the species. Integrating genomic and paleoclimatic data we found that gene-flow across populations and with Papio species tracked past climate changes. The isolation and climatic conditions experienced by Southern geladas during the Holocene shaped local diversity and generated diet-related genomic signatures.

Anthropogenic events and responses to environmental stress are shaping the genomes of Ethiopian indigenous goats.

Anthropological and biophysical processes have shaped livestock genomes over Millenia and can explain their current geographic distribution and genetic divergence. We analyzed 57 Ethiopian indigenous domestic goat genomes alongside 67 equivalents of east, west, and north-west African, European, South Asian, Middle East, and wild Bezoar goats. Cluster, ADMIXTURE (K = 4) and phylogenetic analysis revealed four genetic groups comprising African, European, South Asian, and wild Bezoar goats. The Middle Eastern goats had an admixed genome of these four genetic groups. At K = 5, the West African Dwarf and Moroccan goats were separated from East African goats demonstrating a likely historical legacy of goat arrival and dispersal into Africa via the coastal Mediterranean Sea and the Horn of Africa. FST, XP-EHH, and Hp analysis revealed signatures of selection in Ethiopian goats overlaying genes for thermo-sensitivity, oxidative stress response, high-altitude hypoxic adaptation, reproductive fitness, pathogen defence, immunity, pigmentation, DNA repair, modulation of renal function and integrated fluid and electrolyte homeostasis. Notable examples include TRPV1 (a nociception gene); PTPMT1 (a critical hypoxia survival gene); RETREG (a regulator of reticulophagy during starvation), and WNK4 (a molecular switch for osmoregulation). These results suggest that human-mediated translocations and adaptation to contrasting environments are shaping indigenous African goat genomes.

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.

Integrative functional genomic analyses identify genetic variants influencing skin pigmentation in Africans.

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.

Whole-genome resource sequences of 57 indigenous Ethiopian goats.

Domestic goats are distributed worldwide, with approximately 35% of the one billion world goat population occurring in Africa. Ethiopia has 52.5 million goats, ~99.9% of which are considered indigenous landraces deriving from animals introduced to the Horn of Africa in the distant past by nomadic herders. They have continued to be managed by smallholder farmers and semi-mobile pastoralists throughout the region. We report here 57 goat genomes from 12 Ethiopian goat populations sampled from different agro-climates. The data were generated through sequencing DNA samples on the Illumina NovaSeq 6000 platform at a mean depth of 9.71x and 150 bp pair-end reads. In total, ~2 terabytes of raw data were generated, and 99.8% of the clean reads mapped successfully against the goat reference genome assembly at a coverage of 99.6%. About 24.76 million SNPs were generated. These SNPs can be used to study the population structure and genome dynamics of goats at the country, regional, and global levels to shed light on the species' evolutionary trajectory.

Genetic diversity of Mycobacterium tuberculosis isolates from the central, eastern and southeastern Ethiopia.

Introduction: The population structure of Mycobacterium tuberculosis complex (MTBC) in Ethiopia is diverse but dominated by Euro-American (Lineage 4) and East-African-Indian (Lineage 3) lineages. The objective of this study was to describe the genetic diversity of MTBC isolates in Central, Eastern and Southeastern Ethiopia. Methods: A total of 223 MTBC culture isolates obtained from patients referred to Adama and Harar TB reference laboratories were spoligotyped. Demographic and clinical characteristics were collected. Results: Six major lineages: Euro-American (Lineage 4), East-African-Indian (Lineage 3), East Asian (Lineage 2), Indo-Oceanic (Lineage 1), Mycobacterium africanum (Lineage 5 and Lineage 6) and Ethiopian (Lineage 7) were identified. The majority (94.6 %) of the isolates were Euro-American and East-African-Indian, with proportions of 75.3 % and 19.3 %, respectively. Overall, 77 different spoligotype patterns were identified of which 42 were registered in the SITVIT2 database. Of these, 27 spoligotypes were unique, while 15 were clustered with 2-49 isolates. SIT149/T3_ETH (n = 49), SIT53/T1 (n = 33), SIT21/CAS1_Kili (n = 24) and SIT41/Turkey (n = 11) were the dominant spoligotypes. A rare Beijing spoligotype pattern, SIT541, has also been identified in Eastern Ethiopia. The overall clustering rate of sub-lineages with known SIT was 71.3 %. Age group (25-34) was significantly associated with clustering. Conclusion: We found a heterogeneous population structure of MTBC dominated by T and CAS families, and the Euro-American lineage. The identification of the Beijing strain, particularly the rare SIT541 spoligotype in Eastern Ethiopia, warrants a heightened surveillance plan, as little is known about this genotype. A large-scale investigation utilizing a tool with superior discriminatory power, such as whole genome sequencing, is necessary to gain a thorough understanding of the genetic diversity of MTBC in the nation, which would help direct the overall control efforts.

Global genetic diversity, introgression, and evolutionary adaptation of indicine cattle revealed by whole genome sequencing.

Indicine cattle, also referred to as zebu (Bos taurus indicus), play a central role in pastoral communities across a wide range of agro-ecosystems, from extremely hot semiarid regions to hot humid tropical regions. However, their adaptive genetic changes following their dispersal into East Asia from the Indian subcontinent have remained poorly documented. Here, we characterize their global genetic diversity using high-quality whole-genome sequencing data from 354 indicine cattle of 57 breeds/populations, including major indicine phylogeographic groups worldwide. We reveal their probable migration into East Asia was along a coastal route rather than inland routes and we detected introgression from other bovine species. Genomic regions carrying morphology-, immune-, and heat-tolerance-related genes underwent divergent selection according to Asian agro-ecologies. We identify distinct sets of loci that contain promising candidate variants for adaptation to hot semi-arid and hot humid tropical ecosystems. Our results indicate that the rapid and successful adaptation of East Asian indicine cattle to hot humid environments was promoted by localized introgression from banteng and/or gaur. Our findings provide insights into the history and environmental adaptation of indicine cattle.

A review on characterization of BCR - ABL transcript variants for molecular monitoring of chronic myeloid leukemia phenotypes.

Chronic myeloid leukemia (CML) is a clonal myeloproliferative growth of human pluripotent stem cells which is estimated to occur at a rate of 1/100000 populations every year worldwide. A characteristic feature of this disease is the presence of the Philadelphia chromosome genotype, which results from the reciprocal translocation between human chromosomes 9 and 22. Two types of major genotypes are involved, which consequently result in two major types of expressed fusion mRNA transcripts: b3a2 and b2a2, i.e. major breakpoint segments (happening after exon 13 & after exon 14) of the BCR gene on chromosome 22 fuze with the ABL1 gene breakpoint (happening after exon 2) on chromosome 9, forming two genotypes coding for two transcripts: b3a2 (e14a2) and b2a2 (e13a2). The protein 'p210 BCR-ABL1', a protein which characteristically exhibits a high tyrosine kinase activity which is followed by the activation of various cellular processes that lead to increased cellular proliferation and cancer, is coded by both major BCR - ABL1 mRNA transcripts. Recent developments in the treatment of CML through molecular monitoring of the disease have managed to reduce patient morbidity and mortality. Advanced molecular techniques are aimed at detecting BCR-ABL1 transcript levels to monitor treatment response. Transcript typing is necessary to detect minimal residual disease and to achieve molecular response by helping to provide selective therapy based on the type of transcript identified, as transcript type is correlated with the disease course.The purpose of this review is to discuss: the role of the BCR-ABL1 fusion gene in the pathogenesis of CML; the role of BCR-ABL1 transcript characterization in the molecular monitoring of CML therapy; the association of BCR - ABL1 transcript types with different CML phenotypes, molecular responses, and treatment responses; and the laboratory techniques employed to detect and characterize BCR - ABL1 transcripts.

Diverse African genomes reveal selection on ancient modern human introgressions in Neanderthals.

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 ∼250 kya, and subsequent admixture with Neanderthals, resulting in ∼6% 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.

Genome-wide diversity and admixture of five indigenous cattle populations from the Tigray region of northern Ethiopia.

The Tigray region, where we found around eight per cent of the indigenous cattle population of Ethiopia, is considered as the historic centre of the country, with the ancient pre-Aksumite and Aksumite civilisations in contact with the civilisations of the Fertile Crescent and the Indian subcontinent. Here, we used whole genome sequencing data to characterise the genomic diversity, relatedness, and admixture of five cattle populations (Abergelle, Arado, Begait, Erob, and Raya) indigenous to the Tigray region of Ethiopia. We detected 28 to 29 million SNPs and 2.7 to 2.9 million indels in each population, of which 7% of SNPs and 34% of indels were novel. Functional annotation of the variants showed around 0.01% SNPs and 0.22%-0.27% indels in coding regions. Enrichment analysis of genes overlapping missense private SNPs revealed 20 significant GO terms and KEGG pathways that were shared by or specific to breeds. They included important genes associated with morphology (SCN4A, TAS1R2 and KCNG4), milk yield (GABRG1), meat quality (MMRN2, VWC2), feed efficiency (PCDH8 and SLC26A3), immune response (LAMC1, PCDH18, CELSR1, TLR6 and ITGA5), heat resistance (NPFFR1 and HTR7) and genes belonging to the olfactory gene family, which may be related to adaptation to harsh environments. Tigray indigenous cattle are very diverse. Their genome-wide average nucleotide diversity ranged from 0.0035 to 0.0036. The number of heterozygous SNPs was about 0.6-0.7 times higher than homozygous ones. The within-breed average number of ROHs ranged from 777.82 to 1000.45, with the average sum of the length of ROHs ranging from 122.01 Mbp to 163.88 Mbp. The genomic inbreeding coefficients differed among animals and breeds, reaching up to 10% in some Begait and Raya animals. Tigray indigenous cattle shared a common ancestry with Asian indicine (85.6%-88.7%) and African taurine (11.3%-14.1%) cattle, with very small, if any, European taurine introgression. This study identified high within-breed genetic diversity representing an opportunity for breeding improvement programs and, also, significant novel variants that could increase the number of known cattle variants, an important contribution to the knowledge of domestic cattle genetic diversity.

Profile and Frequency of Mutations Conferring Drug-Resistant Tuberculosis in the Central, Southeastern and Eastern Ethiopia.

Purpose: Advances in molecular tools that assess genes harboring drug resistance mutations have greatly improved the detection and treatment of drug-resistant tuberculosis (DR-TB). This study was conducted to determine the frequency and type of mutations that are responsible for resistance to rifampicin (RIF), isoniazid (INH), fluoroquinolones (FLQs) and second-line injectable drugs (SLIDs) in Mycobacterium tuberculosis (MTB) isolates obtained from culture-positive pulmonary tuberculosis (TB) patients in the central, southeastern and eastern Ethiopia. Patients and Methods: In total, 224 stored culture-positive MTB isolates from pulmonary TB patients referred to Adama and Harar regional TB laboratories between August 2018 and January 2019 were assessed for mutations conferring RIF, INH, FLQs and SLIDs resistance using GenoType®MTBDRplus (MTBDRplus) and GenoType®MTBDRsl (MTBDRsl). Results: RIF, INH, FLQs and SLIDs resistance-conferring mutations were identified in 88/224 (39.3%), 85/224 (38.0%), 7/77 (9.1%), and 3/77% (3.9%) of MTB isolates, respectively. Mutation codons rpoB S531L (59.1%) for RIF, katG S315T (96.5%) for INH, gyrA A90V (42.1%) for FLQs and WT1 rrs (100%) for SLIDs were observed in the majority of the isolates tested. Over a 10th of rpoB mutations detected in the current study were unknown. Conclusion: In this study, the most common mutations conferring drug resistance to RIF, INH, FLQs were identified. However, a significant proportion of RIF-resistant isolates manifested unknown rpoB mutations. Similarly, although few in number, all SLID-resistant isolates had unknown rrs mutations. To further elucidate the entire spectrum of mutations, tool such as whole-genome sequencing is imperative. Furthermore, the expansion of molecular drug susceptibility testing services is critical for tailoring patient treatment and preventing disease transmission.

Genomic characterization of HLA class I and class II genes in ethnically diverse sub-Saharan African populations: A report on novel HLA alleles.

HLA allelic variation has been well studied and documented in many parts of the world. However, African populations have been relatively under-represented in studies of HLA variation. We have characterized HLA variation from 489 individuals belonging to 13 ethnically diverse populations from rural communities from the African countries of Botswana, Cameroon, Ethiopia, and Tanzania, known to practice traditional subsistence lifestyles using next generation sequencing (Illumina) and long-reads from Oxford Nanopore Technologies. We identified 342 distinct alleles among the 11 HLA targeted genes: HLA-A, -B, -C, -DRB1, -DRB3, -DRB4, -DRB5, -DQA1, -DQB1, -DPA1, and -DPB1, with 140 of those alleles containing novel sequences that were submitted to the IPD-IMGT/HLA database. Sixteen of the 140 alleles contained novel content within the exonic regions of the genes, while 110 alleles contained novel intronic variants. Four alleles were found to be recombinants of already described HLA alleles and 10 alleles extended the sequence content of already described alleles. All 140 alleles include complete allelic sequence from the 5' UTR to the 3' UTR that are inclusive of all exons and introns. This report characterizes the HLA allelic variation from these individuals and describes the novel allelic variation present within these specific African populations.

Whole-genome sequencing reveals a complex African population demographic history and signatures of local adaptation.

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 ∼12 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.

The genetic and evolutionary basis of gene expression variation in East Africans.

BACKGROUND: Mapping of quantitative trait loci (QTL) associated with molecular phenotypes is a powerful approach for identifying the genes and molecular mechanisms underlying human traits and diseases, though most studies have focused on individuals of European descent. While important progress has been made to study a greater diversity of human populations, many groups remain unstudied, particularly among indigenous populations within Africa. To better understand the genetics of gene regulation in East Africans, we perform expression and splicing QTL mapping in whole blood from a cohort of 162 diverse Africans from Ethiopia and Tanzania. We assess replication of these QTLs in cohorts of predominantly European ancestry and identify candidate genes under selection in human populations. RESULTS: We find the gene regulatory architecture of African and non-African populations is broadly shared, though there is a considerable amount of variation at individual loci across populations. Comparing our analyses to an equivalently sized cohort of European Americans, we find that QTL mapping in Africans improves the detection of expression QTLs and fine-mapping of causal variation. Integrating our QTL scans with signatures of natural selection, we find several genes related to immunity and metabolism that are highly differentiated between Africans and non-Africans, as well as a gene associated with pigmentation. CONCLUSION: Extending QTL mapping studies beyond European ancestry, particularly to diverse indigenous populations, is vital for a complete understanding of the genetic architecture of human traits and can reveal novel functional variation underlying human traits and disease.

Genomic adaptation of Ethiopian indigenous cattle to high altitude.

The mountainous areas of Ethiopia represent one of the most extreme environmental challenges in Africa faced by humans and other inhabitants. Selection for high-altitude adaptation is expected to have imprinted the genomes of livestock living in these areas. Here we assess the genomic signatures of positive selection for high altitude adaptation in three cattle populations from the Ethiopian mountainous areas (Semien, Choke, and Bale mountains) compared to three Ethiopian lowland cattle populations (Afar, Ogaden, and Boran), using whole-genome resequencing and three genome scan approaches for signature of selection (iHS, XP-CLR, and PBS). We identified several candidate selection signature regions and several high-altitude adaptation genes. These include genes such as ITPR2, MB, and ARNT previously reported in the human population inhabiting the Ethiopian highlands. Furthermore, we present evidence of strong selection and high divergence between Ethiopian high- and low-altitude cattle populations at three new candidate genes (CLCA2, SLC26A2, and CBFA2T3), putatively linked to high-altitude adaptation in cattle. Our findings provide possible examples of convergent selection between cattle and humans as well as unique African cattle signature to the challenges of living in the Ethiopian mountainous regions.

Ecological niche modelling as a tool to identify candidate indigenous chicken ecotypes of Tigray (Ethiopia).

The Tigray region is an ancient entry route for the domestic chickens into Africa. The oldest African chicken bones were found in this region at Mezber, a pre-Aksumite rural farming settlement. They were dated to around 800-400 BCE. Since then, the farming communities of the region have integrated chicken into their livelihoods. The region is also recognised for its high chicken-to-human population ratio and diverse and complex geography, ranging from 500 to 4,000 m above sea level (m.a.s.l.). More than 15 agro-ecological zones have been described. Following exotic chicken introductions, the proportion of indigenous chicken is now 70% only in the region. It calls for the characterisation of indigenous Tigrayan chicken ecotypes and their habitats. This study reports an Ecological Niche Modelling using MaxEnt to characterise the habitats of 16 indigenous village chicken populations of Tigray. A total of 34 ecological and landscape variables: climatic (22), soil (eight), vegetation, and land cover (four), were included. We applied Principal Component Analysis correlation, and MaxentVariableSelection procedures to select the most contributing and uncorrelated variables. The selected variables were three climatic (bio5 = maximum temperature of the warmest month, bio8 = mean temperature of the wettest quarter, bio13 = precipitation of the wettest month), three vegetation and land cover (grassland, forest land, and cultivated land proportional areas), and one soil (clay content). Following our analysis, we identified four main chicken agro-ecologies defining four candidates indigenous Tigrayan chicken ecotypes. The study provides baseline information for phenotypic and genetic characterisation as well as conservation interventions of indigenous Tigrayan chickens.

Antimicrobial Resistance and Associated Risk Factors of Gram-Negative Bacterial Bloodstream Infections in Tikur Anbessa Specialized Hospital, Addis Ababa.

Background: Bloodstream infections (BSIs) are significant causes of morbidity and mortality in Ethiopia and worldwide. Alarming is the rapid global spread of antimicrobial resistance (AMR) in bacteria. Objective: To determine the microbial profile, antimicrobial susceptibility pattern, and associated risk factors for bloodstream infections in Tikur Anbessa Specialized Hospital (TASH) Addis Ababa Ethiopia. Methods: A cross-sectional study was conducted between September 2018 and March 2019. Blood collected twice from each septicemia suspected patient were processed following standard bacteriological procedures. AST was performed by using the disk diffusion test according to CLSI 2017 and 2018 guidelines. Data captured in Epidata were cleaned and analyzed by SPSS version 21 software. Results: The prevalence of BSI was 28.06% and a higher proportion of pathogene detected were gram-negative bacteria (GNB) (54.5%) and gram-positive bacteria (GPB) (45.43%). The most abundant bacterial species were Klebsiella pneumoniae 17.6%, CoNS 15.2%, and Acinetobacter spp 11.0%. Culture positivity was associated with age below 6 years, neonates AOR p=<0.001, infants AOR p=<0.001, Pre-school P=0.002, ICU admission COR p=<0.001, length of admission >5 days COR P=0.016, temperature greater than 38°C, AOR p=0.013, instrument usage during medical care AOR, p=<0.001, chronic illness AOR p=0.027, and neonatal incubation AOR p=0.013. GNB average drug resistance rate was 57.9% of the commonly used antibiotics and the most efficient and inefficient drugs were amikacin (10.8%) and ampicillin (94.6%). The gram-negative isolates showed a 95.3% rate of multi-drug resistance; and MDR, XDR, and PDR were observed at 55.8%, 32.2%, and 7.3%, of isolates respectively. This finding shows children especially neonates were highly affected by drug resistant BSI. Conclusion: Pediatric patients and ICU patients are more affected by BSI, and drug-resistant bacteria are a major problem. Therefore, appropriate intervention approaches need to be implemented.

Signatures of Convergent Evolution and Natural Selection at the Alcohol Dehydrogenase Gene Region are Correlated with Agriculture in Ethnically Diverse Africans.

The alcohol dehydrogenase (ADH) family of genes encodes enzymes that catalyze the metabolism of ethanol into acetaldehyde. Nucleotide variation in ADH genes can affect the catalytic properties of these enzymes and is associated with a variety of traits, including alcoholism and cancer. Some ADH variants, including the ADH1B*48His (rs1229984) mutation in the ADH1B gene, reduce the risk of alcoholism and are under positive selection in multiple human populations. The advent of Neolithic agriculture and associated increase in fermented foods and beverages is hypothesized to have been a selective force acting on such variants. However, this hypothesis has not been tested in populations outside of Asia. Here, we use genome-wide selection scans to show that the ADH gene region is enriched for variants showing strong signals of positive selection in multiple Afroasiatic-speaking, agriculturalist populations from Ethiopia, and that this signal is unique among sub-Saharan Africans. We also observe strong selection signals at putatively functional variants in nearby lipid metabolism genes, which may influence evolutionary dynamics at the ADH region. Finally, we show that haplotypes carrying these selected variants were introduced into Northeast Africa from a West-Eurasian source within the last ∼2,000 years and experienced positive selection following admixture. These selection signals are not evident in nearby, genetically similar populations that practice hunting/gathering or pastoralist subsistence lifestyles, supporting the hypothesis that the emergence of agriculture shapes patterns of selection at ADH genes. Together, these results enhance our understanding of how adaptations to diverse environments and diets have influenced the African genomic landscape.

Impact of natural selection on global patterns of genetic variation and association with clinical phenotypes at genes involved in SARS-CoV-2 infection.

Human genomic diversity has been shaped by both ancient and ongoing challenges from viruses. The current coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has had a devastating impact on population health. However, genetic diversity and evolutionary forces impacting host genes related to SARS-CoV-2 infection are not well understood. We investigated global patterns of genetic variation and signatures of natural selection at host genes relevant to SARS-CoV-2 infection (angiotensin converting enzyme 2 [ACE2], transmembrane protease serine 2 [TMPRSS2], dipeptidyl peptidase 4 [DPP4], and lymphocyte antigen 6 complex locus E [LY6E]). We analyzed data from 2,012 ethnically diverse Africans and 15,977 individuals of European and African ancestry with electronic health records and integrated with global data from the 1000 Genomes Project. At ACE2, we identified 41 nonsynonymous variants that were rare in most populations, several of which impact protein function. However, three nonsynonymous variants (rs138390800, rs147311723, and rs145437639) were common among central African hunter-gatherers from Cameroon (minor allele frequency 0.083 to 0.164) and are on haplotypes that exhibit signatures of positive selection. We identify 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 compared with the chimpanzee genome. Genetic variants that are targets of natural selection are associated with clinical phenotypes common in patients with COVID-19. Our study provides insights into global variation at host genes related to SARS-CoV-2 infection, which have been shaped by natural selection in some populations, possibly due to prior viral infections.