Archaeogenomic distinctiveness of the Isthmo-Colombian area.

The recently enriched genomic history of Indigenous groups in the Americas is still meager concerning continental Central America. Here, we report ten pre-Hispanic (plus two early colonial) genomes and 84 genome-wide profiles from seven groups presently living in Panama. Our analyses reveal that pre-Hispanic demographic events contributed to the extensive genetic structure currently seen in the area, which is also characterized by a distinctive Isthmo-Colombian Indigenous component. This component drives these populations on a specific variability axis and derives from the local admixture of different ancestries of northern North American origin(s). Two of these ancestries were differentially associated to Pleistocene Indigenous groups that also moved into South America, leaving heterogenous genetic footprints. An additional Pleistocene ancestry was brought by a still unsampled population of the Isthmus (UPopI) that remained restricted to the Isthmian area, expanded locally during the early Holocene, and left genomic traces up to the present day.

Variation in CFHR3 determines susceptibility to meningococcal disease by controlling factor H concentrations.

Neisseria meningitidis protects itself from complement-mediated killing by binding complement factor H (FH). Previous studies associated susceptibility to meningococcal disease (MD) with variation in CFH, but the causal variants and underlying mechanism remained unknown. Here we attempted to define the association more accurately by sequencing the CFH-CFHR locus and imputing missing genotypes in previously obtained GWAS datasets of MD-affected individuals of European ancestry and matched controls. We identified a CFHR3 SNP that provides protection from MD (rs75703017, p value = 1.1 × 10-16) by decreasing the concentration of FH in the blood (p value = 1.4 × 10-11). We subsequently used dual-luciferase studies and CRISPR gene editing to establish that deletion of rs75703017 increased FH expression in hepatocyte by preventing promotor inhibition. Our data suggest that reduced concentrations of FH in the blood confer protection from MD; with reduced access to FH, N. meningitidis is less able to shield itself from complement-mediated killing.

Exome-wide association study to identify rare variants influencing COVID-19 outcomes: Results from the Host Genetics Initiative.

Host genetics is a key determinant of COVID-19 outcomes. Previously, the COVID-19 Host Genetics Initiative genome-wide association study used common variants to identify multiple loci associated with COVID-19 outcomes. However, variants with the largest impact on COVID-19 outcomes are expected to be rare in the population. Hence, studying rare variants may provide additional insights into disease susceptibility and pathogenesis, thereby informing therapeutics development. Here, we combined whole-exome and whole-genome sequencing from 21 cohorts across 12 countries and performed rare variant exome-wide burden analyses for COVID-19 outcomes. In an analysis of 5,085 severe disease cases and 571,737 controls, we observed that carrying a rare deleterious variant in the SARS-CoV-2 sensor toll-like receptor TLR7 (on chromosome X) was associated with a 5.3-fold increase in severe disease (95% CI: 2.75-10.05, p = 5.41x10-7). This association was consistent across sexes. These results further support TLR7 as a genetic determinant of severe disease and suggest that larger studies on rare variants influencing COVID-19 outcomes could provide additional insights.

Superspreading in the emergence of COVID-19 variants.

Superspreading and variants of concern (VOC) of the human pathogen severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are the main catalyzers of the coronavirus disease 2019 (COVID-19) pandemic. However, measuring their individual impact is challenging. By examining the largest database of SARS-CoV-2 genomes The Global Initiative on Sharing Avian Influenza Data [GISAID; n >1.2 million high-quality (HQ) sequences], we present evidence suggesting that superspreading has had a key role in the epidemiological predominance of VOC. There are clear signatures in the database compatible with large superspreading events (SSEs) coinciding chronologically with the worst epidemiological scenarios triggered by VOC. The data suggest that, without the randomness effect of the genetic drift facilitated by superspreading, new VOC of SARS-CoV-2 would have had more limited chance of success.

Contamination detection in sequencing studies using the mitochondrial phylogeny.

Within-species contamination is a major issue in sequencing studies, especially for mitochondrial studies. Contamination can be detected by analyzing the nuclear genome or by inspecting polymorphic sites in the mitochondrial genome (mtDNA). Existing methods using the nuclear genome are computationally expensive, and no appropriate tool for detecting sample contamination in large-scale mtDNA data sets is available. Here we present haplocheck, a tool that requires only the mtDNA to detect contamination in both targeted mitochondrial and whole-genome sequencing studies. Our in silico simulations and amplicon mixture experiments indicate that haplocheck detects mtDNA contamination accurately and is independent of the phylogenetic distance within a sample mixture. By applying haplocheck to The 1000 Genomes Project Consortium data, we further evaluate the application of haplocheck as a fast proxy tool for nDNA-based contamination detection using the mtDNA and identify the mitochondrial copy number within a mixture as a critical component for the overall accuracy. The haplocheck tool is available both as a command-line tool and as a cloud web service producing interactive reports that facilitates the navigation through the phylogeny of contaminated samples.

COVID vaccine-induced lupus nephritis: Case report and review of the literature.

Vaccines offer an effective strategy to prevent infectious diseases with minimal adverse effects. On rare occasions, vaccination can disrupt the immune response leading to induction of autoimmune diseases. We describe a case of new-onset lupus nephritis following COVID-19 vaccination with the first dose of the Pfizer vaccine. Her symptoms and lab values improved with steroids, hydroxychloroquine, and mycophenolate mofetil.

Short- and mid-term morbidity and primary-care burden due to infant respiratory syncytial virus infection: A Spanish 6-year population-based longitudinal study.

BACKGROUND: The morbidity burden of respiratory syncytial virus (RSV) in infants extends beyond hospitalization. Defining the RSV burden before implementing prophylaxis programs is essential for evaluating any potential impact on short- to mid-term morbidity and the utilization of primary healthcare (PHC) and emergency services (ES). We established this reference data using a population-based cohort approach. METHODS: Infants hospitalized for RSV from January 2016 to March 2023 were matched with non-hospitalized ones based on birthdate and sex. We defined the exposure as severe RSV hospitalization. The main study outcomes were as follows: (1) PHC and ES visits for RSV, categorized using the International Classification of Primary Care codes, (2) prescriptions for respiratory airway obstructive disease, and (3) antibacterial prescriptions. Participants were followed up from 30 days before hospitalization for severe RSV until the outcome occurrence or end of the study. Adjusted incidence rate ratios (IRRs) of the outcomes along with their 95% confidence intervals (CI) were estimated using Poisson regression models. Stratified analyses by type of PHC visit (nurse, pediatrician, or pharmacy) and follow-up period were undertaken. We defined mid-term outcomes as those taking place up to 24 months of follow-up period. RESULTS: The study included 6626 children (3313 RSV-hospitalized; 3313 non-hospitalized) with a median follow-up of 53.7 months (IQR = 27.9, 69.4). After a 3-month follow-up, severe RSV was associated with a considerable increase in PHC visits for wheezing/asthma (IRR = 4.31, 95% CI: 3.84-4.84), lower respiratory infections (IRR = 4.91, 95% CI: 4.34-5.58), and bronchiolitis (IRR = 4.68, 95% CI: 2.93-7.65). Severe RSV was also associated with more PHC visits for the pediatrician (IRR = 2.00, 95% CI: 1.96-2.05), nurse (IRR = 1.89, 95% CI: 1.75-1.92), hospital emergency (IRR = 2.39, 95% CI: 2.17-2.63), primary healthcare emergency (IRR: 1.54, 95% CI: 1.31-1.82), as well as with important increase in prescriptions for obstructive airway diseases (IRR = 5.98, 95% CI: 5.43-6.60) and antibacterials (IRR = 4.02, 95% CI: 3.38-4.81). All findings remained substantial until 2 years of post-infection. CONCLUSIONS: Severe RSV infection in infants significantly increases short- to mid-term respiratory morbidity leading to an escalation in healthcare utilization (PHC/ES attendance) and medication prescriptions for up to 2 years afterward. Our approach could be useful in assessing the impact and cost-effectiveness of RSV prevention programs.

Mapping genome variation of SARS-CoV-2 worldwide highlights the impact of COVID-19 super-spreaders.

The human pathogen severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the major pandemic of the twenty-first century. We analyzed more than 4700 SARS-CoV-2 genomes and associated metadata retrieved from public repositories. SARS-CoV-2 sequences have a high sequence identity (>99.9%), which drops to >96% when compared to bat coronavirus genome. We built a mutation-annotated reference SARS-CoV-2 phylogeny with two main macro-haplogroups, A and B, both of Asian origin, and more than 160 sub-branches representing virus strains of variable geographical origins worldwide, revealing a rather uniform mutation occurrence along branches that could have implications for diagnostics and the design of future vaccines. Identification of the root of SARS-CoV-2 genomes is not without problems, owing to conflicting interpretations derived from either using the bat coronavirus genomes as an outgroup or relying on the sampling chronology of the SARS-CoV-2 genomes and TMRCA estimates; however, the overall scenario favors haplogroup A as the ancestral node. Phylogenetic analysis indicates a TMRCA for SARS-CoV-2 genomes dating to November 12, 2019, thus matching epidemiological records. Sub-haplogroup A2 most likely originated in Europe from an Asian ancestor and gave rise to subclade A2a, which represents the major non-Asian outbreak, especially in Africa and Europe. Multiple founder effect episodes, most likely associated with super-spreader hosts, might explain COVID-19 pandemic to a large extent.

COVID-19 vaccine effectiveness in children by age groups. A population-based study in Galicia, Spain.

BACKGROUND: Studies on vaccine effectiveness (VE) against COVID-19 in the pediatric population are outgoing. We aimed to quantify VE against SARS-CoV-2 in two pediatric age groups, 5-11 and 12-17-year-old, while considering vaccine type, SARS-CoV-2 variant, and duration of protection. METHODS: A population-based test-negative control study was undertaken in Galicia, Spain. Children 5-11-year-old received the Comirnaty® (Pfizer, US) vaccine, while those aged 12-17-year-old received the Comirnaty® (Pfizer, US) or SpikeVax® (ModernaTX, Inc) vaccine. Participants were categorized into unvaccinated (0 doses or one dose with <14 days since vaccination), partially vaccinated (only one dose with ≥14 days, or two doses with <14 days after the second dose administration), and fully vaccinated (two doses with ≥14 days after the second injection). Adjusted odds ratios (OR) and their 95% confidence intervals (CI) were estimated using multiple logistic regression models. VE was calculated as (1-OR) * 100. Stratified and sensitivity analyses were performed. RESULTS: In the fully vaccinated 5-11-year-old children, VE against the Omicron variant was 44.1% (95% CI: 38.2%-49.4%). In the fully vaccinated 12-17-year-old individuals, VE was 83.4% (95% CI: 81.2%-85.3%) against Delta and 74.8% (95% CI: 58.5%-84.9%) against Omicron. Comirnaty® and SpikeVax® vaccines showed a similar magnitude of VE against Delta [Comirnaty® VE: 81.9% (95% CI: 79.3%-84.1%) and SpikeVax® VE: 85.3% (95% CI: 81.9%-88.1%)]. Comirnaty® (Pfizer, US; VE: 79.7%; 95% CI: 50.7%-92.4%) showed a slightly higher magnitude of protection against Omicron than SpikeVax® (ModernaTX, Inc), yet with an overlapping CI (VE: 74.3%; 95% CI: 56.6%-84.9%). VE was maintained in all age subgroups in both pediatric populations, but it declined over time. CONCLUSIONS: In Galicia, mRNA VE was moderate against SARS-CoV-2 infections in the 5-11-year-old populations, but high in older children. VE declined over time, suggesting a potential need for booster dose schedules.

CovidPhy: A tool for phylogeographic analysis of SARS-CoV-2 variation.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the pathogen responsible for the coronavirus disease 2019 (COVID-19) pandemic. SARS-CoV-2 genomes have been sequenced massively and worldwide and are now available in different public genome repositories. There is much interest in generating bioinformatic tools capable to analyze and interpret SARS-CoV-2 variation. We have designed CovidPhy (http://covidphy.eu), a web interface that can process SARS-CoV-2 genome sequences in plain fasta text format or provided through identity codes from the Global Initiative on Sharing Avian Influenza Data (GISAID) or GenBank. CovidPhy aggregates information available on the large GISAID database (>1.49 M genomes). Sequences are first aligned against the reference sequence and the interface provides different sources of information, including automatic classification of genomes into a pre-computed phylogeny and phylogeographic information, haplogroup/lineage frequencies, and sequencing variation, indicating also if the genome contains known variants of concern (VOC). Additionally, CovidPhy allows searching for variants and haplotypes introduced by the user and includes a list of genomes that are good candidates for being responsible for large outbreaks worldwide, most likely mediated by important superspreading events, indicating their possible geographic epicenters and their relative impact as recorded in the GISAID database.

A multi-tissue study of immune gene expression profiling highlights the key role of the nasal epithelium in COVID-19 severity.

Coronavirus Disease-19 (COVID-19) symptoms range from mild to severe illness; the cause for this differential response to infection remains unknown. Unravelling the immune mechanisms acting at different levels of the colonization process might be key to understand these differences. We carried out a multi-tissue (nasal, buccal and blood; n = 156) gene expression analysis of immune-related genes from patients affected by different COVID-19 severities, and healthy controls through the nCounter technology. Mild and asymptomatic cases showed a powerful innate antiviral response in nasal epithelium, characterized by activation of interferon (IFN) pathway and downstream cascades, successfully controlling the infection at local level. In contrast, weak macrophage/monocyte driven innate antiviral response and lack of IFN signalling activity were present in severe cases. Consequently, oral mucosa from severe patients showed signals of viral activity, cell arresting and viral dissemination to the lower respiratory tract, which ultimately could explain the exacerbated innate immune response and impaired adaptative immune responses observed at systemic level. Results from saliva transcriptome suggest that the buccal cavity might play a key role in SARS-CoV-2 infection and dissemination in patients with worse prognosis. Co-expression network analysis adds further support to these findings, by detecting modules specifically correlated with severity involved in the abovementioned biological routes; this analysis also provides new candidate genes that might be tested as biomarkers in future studies. We also found tissue specific severity-related signatures mainly represented by genes involved in the innate immune system and cytokine/chemokine signalling. Local immune response could be key to determine the course of the systemic response and thus COVID-19 severity. Our findings provide a framework to investigate severity host gene biomarkers and pathways that might be relevant to diagnosis, prognosis, and therapy.

Effectiveness of COVID-19 vaccine booster in the general population and in subjects with comorbidities. A population-based study in Spain.

BACKGROUND: Research on the effectiveness of COVID-19 booster-based vaccine schedule is ongoing and real-world data on vaccine effectiveness (VE) in comorbid patients are limited. We aimed to estimate booster dose VE against SARS-CoV-2 infection and COVID-19 severity in the general population and in comorbid patients. METHOD: A retrospective test-negative control study was undertaken in Galicia-Spain (December 2020-November 2021). VE and 95% confidence interval (CI) were estimated using multivariate logistic regression models. RESULTS: 1,512,415 (94.13%) negative and 94,334 (5.87%) positive SARS-CoV-2 test results were included. A booster dose of COVID-19 vaccine is associated with substantially higher protection against SARS-CoV-2 infection than vaccination without a booster [VEboosted = 87% (95%CI: 83%; 89%); VEnon-boosted = 66% (95%CI: 65%; 67%)]. The high VE was observed in all ages, but was more pronounced in subjects older than 65 years. VE against COVID-19 severity was analyzed in a mixed population of boosted and non-boosted individuals and considerable protection was obtained [VE: hospitalization = 72% (95%CI: 68%; 75%); intensive care unit administration = 83% (95%CI: 78%; 88%), in-hospital mortality = 66% (95%CI: 53%; 75%)]. Boosted comorbid patients are more protected against SARS-CoV-2 infection than those who were non-boosted. This was observed in a wide range of major diseases including cancer (81% versus 54%), chronic obstructive pulmonary disease (84% versus 61%), diabetes (84% versus 65%), hypertension (82% versus 65%) and obesity (91% versus 67%), among others. CONCLUSIONS: A booster dose of COVID-19 vaccine increases the protection against SARS-CoV-2 infection and COVID-19 severity in the general population and in comorbid patients.

A Timeframe for SARS-CoV-2 Genomes: A Proof of Concept for Postmortem Interval Estimations.

Establishing the timeframe when a particular virus was circulating in a population could be useful in several areas of biomedical research, including microbiology and legal medicine. Using simulations, we demonstrate that the circulation timeframe of an unknown SARS-CoV-2 genome in a population (hereafter, estimated time of a queried genome [QG]; tE-QG) can be easily predicted using a phylogenetic model based on a robust reference genome database of the virus, and information on their sampling dates. We evaluate several phylogeny-based approaches, including modeling evolutionary (substitution) rates of the SARS-CoV-2 genome (~10-3 substitutions/nucleotide/year) and the mutational (substitutions) differences separating the QGs from the reference genomes (RGs) in the database. Owing to the mutational characteristics of the virus, the present Viral Molecular Clock Dating (VMCD) method covers timeframes going backwards from about a month in the past. The method has very low errors associated to the tE-QG estimates and narrow intervals of tE-QG, both ranging from a few days to a few weeks regardless of the mathematical model used. The SARS-CoV-2 model represents a proof of concept that can be extrapolated to any other microorganism, provided that a robust genome sequence database is available. Besides obvious applications in epidemiology and microbiology investigations, there are several contexts in forensic casework where estimating tE-QG could be useful, including estimation of the postmortem intervals (PMI) and the dating of samples stored in hospital settings.

Phylogeography of Sub-Saharan Mitochondrial Lineages Outside Africa Highlights the Roles of the Holocene Climate Changes and the Atlantic Slave Trade.

Despite the importance of ancient DNA for understanding human prehistoric dispersals, poor survival means that data remain sparse for many areas in the tropics, including in Africa. In such instances, analysis of contemporary genomes remains invaluable. One promising approach is founder analysis, which identifies and dates migration events in non-recombining systems. However, it has yet to be fully exploited as its application remains controversial. Here, we test the approach by evaluating the age of sub-Saharan mitogenome lineages sampled outside Africa. The analysis confirms that such lineages in the Americas date to recent centuries-the time of the Atlantic slave trade-thereby validating the approach. By contrast, in North Africa, Southwestern Asia and Europe, roughly half of the dispersal signal dates to the early Holocene, during the "greening" of the Sahara. We elaborate these results by showing that the main source regions for the two main dispersal episodes are distinct. For the recent dispersal, the major source was West Africa, but with two exceptions: South America, where the fraction from Southern Africa was greater, and Southwest Asia, where Eastern Africa was the primary source. These observations show the potential of founder analysis as both a supplement and complement to ancient DNA studies.

The peopling of South America and the trans-Andean gene flow of the first settlers.

Genetic and archaeological data indicate that the initial Paleoindian settlers of South America followed two entry routes separated by the Andes and the Amazon rainforest. The interactions between these paths and their impact on the peopling of South America remain unclear. Analysis of genetic variation in the Peruvian Andes and regions located south of the Amazon River might provide clues on this issue. We analyzed mitochondrial DNA variation at different Andean locations and >360,000 autosomal SNPs from 28 Native American ethnic groups to evaluate different trans-Andean demographic scenarios. Our data reveal that the Peruvian Altiplano was an important enclave for early Paleoindian expansions and point to a genetic continuity in the Andes until recent times, which was only marginally affected by gene flow from the Amazonian lowlands. Genomic variation shows a good fit with the archaeological evidence, indicating that the genetic interactions between the descendants of the settlers that followed the Pacific and Atlantic routes were extremely limited.

Persistent Villous Atrophy in De Novo Adult Patients With Celiac Disease and Strict Control of Gluten-Free Diet Adherence: A Multicenter Prospective Study (CADER Study).

INTRODUCTION: A substantial proportion of adult patients with celiac disease on a gluten-free diet exhibit persistent villous atrophy, and inadvertent gluten exposure may be one of the causes. The aim of the present study was to evaluate villous atrophy persistence after 2 years on a gluten-free diet in de novo adult patients with celiac disease with strict control of gluten exposure. METHODS: Symptomatic de novo adult patients with celiac disease were prospectively included. Clinical visits and dietary surveillance were scheduled every 6 months during a 2-year follow-up period. At each visit, fecal samples were collected and stored at -20 °C until analysis for gluten immunogenic peptides (f-GIPs). A follow-up duodenal biopsy was performed at 2 years. We evaluated the variables associated with persistent villous atrophy. RESULTS: Seventy-six patients completed the study (36.5 ± 1.6 years, 73% women); persistent villous atrophy was observed in 40 (53%), whereas 72.5% were asymptomatic and 75% had negative serology. Detectable f-GIP >0.08 µg/g in at least 1 fecal sample was seen in 69% of patients. There were no significant differences in the median f-GIP at each visit and median area under the curve over the serial measurements between patients with persistent villous atrophy and those who recovered. On multivariate analysis, only older age was associated with persistent villous atrophy (32% for 16-30 years; 67% for >30 years; P = 0.016). DISCUSSION: The rate of persistent villous atrophy after 2 years was high in adult patients with celiac disease on an intentionally strict gluten-free diet. Low-level ongoing inadvertent gluten exposure could be a contributing factor to persistent villous atrophy.

Ancestry patterns inferred from massive RNA-seq data.

There is a growing body of evidence suggesting that patterns of gene expression vary within and between human populations. However, the impact of this variation in human diseases has been poorly explored, in part owing to the lack of a standardized protocol to estimate biogeographical ancestry from gene expression studies. Here we examine several studies that provide new solid evidence indicating that the ancestral background of individuals impacts gene expression patterns. Next, we test a procedure to infer genetic ancestry from RNA-seq data in 25 data sets where information on ethnicity was reported. Genome data of reference continental populations retrieved from The 1000 Genomes Project were used for comparisons. Remarkably, only eight out of 25 data sets passed FastQC default filters. We demonstrate that, for these eight population sets, the ancestral background of donors could be inferred very efficiently, even in data sets including samples with complex patterns of admixture (e.g., American-admixed populations). For most of the gene expression data sets of suboptimal quality, ancestral inference yielded odd patterns. The present study thus brings a cautionary note for gene expression studies highlighting the importance to control for the potential confounding effect of ancestral genetic background.

Origins and genetic legacies of the Caribbean Taino.

The Caribbean was one of the last parts of the Americas to be settled by humans, but how and when the islands were first occupied remains a matter of debate. Ancient DNA can help answering these questions, but the work has been hampered by poor DNA preservation. We report the genome sequence of a 1,000-year-old Lucayan Taino individual recovered from the site of Preacher's Cave in the Bahamas. We sequenced her genome to 12.4-fold coverage and show that she is genetically most closely related to present-day Arawakan speakers from northern South America, suggesting that the ancestors of the Lucayans originated there. Further, we find no evidence for recent inbreeding or isolation in the ancient genome, suggesting that the Lucayans had a relatively large effective population size. Finally, we show that the native American components in some present-day Caribbean genomes are closely related to the ancient Taino, demonstrating an element of continuity between precontact populations and present-day Latino populations in the Caribbean.

Identification of a Minimal 3-Transcript Signature to Differentiate Viral from Bacterial Infection from Best Genome-Wide Host RNA Biomarkers: A Multi-Cohort Analysis.

The fight against the spread of antibiotic resistance is one of the most important challenges facing health systems worldwide. Given the limitations of current diagnostic methods, the development of fast and accurate tests for the diagnosis of viral and bacterial infections would improve patient management and treatment, as well as contribute to reducing antibiotic misuse in clinical settings. In this scenario, analysis of host transcriptomics constitutes a promising target to develop new diagnostic tests based on the host-specific response to infections. We carried out a multi-cohort meta-analysis of blood transcriptomic data available in public databases, including 11 different studies and 1209 samples from virus- (n = 695) and bacteria- (n = 514) infected patients. We applied a Parallel Regularized Regression Model Search (PReMS) on a set of previously reported genes that distinguished viral from bacterial infection to find a minimum gene expression bio-signature. This strategy allowed us to detect three genes, namely BAFT, ISG15 and DNMT1, that clearly differentiate groups of infection with high accuracy (training set: area under the curve (AUC) 0.86 (sensitivity: 0.81; specificity: 0.87); testing set: AUC 0.87 (sensitivity: 0.82; specificity: 0.86)). BAFT and ISG15 are involved in processes related to immune response, while DNMT1 is related to the preservation of methylation patterns, and its expression is modulated by pathogen infections. We successfully tested this three-transcript signature in the 11 independent studies, demonstrating its high performance under different scenarios. The main advantage of this three-gene signature is the low number of genes needed to differentiate both groups of patient categories.

Genome-wide Ancestry and Demographic History of African-Descendant Maroon Communities from French Guiana and Suriname.

The transatlantic slave trade was the largest forced migration in world history. However, the origins of the enslaved Africans and their admixture dynamics remain unclear. To investigate the demographic history of African-descendant Marron populations, we generated genome-wide data (4.3 million markers) from 107 individuals from three African-descendant populations in South America, as well as 124 individuals from six west African populations. Throughout the Americas, thousands of enslaved Africans managed to escape captivity and establish lasting communities, such as the Noir Marron. We find that this population has the highest proportion of African ancestry (∼98%) of any African-descendant population analyzed to date, presumably because of centuries of genetic isolation. By contrast, African-descendant populations in Brazil and Colombia harbor substantially more European and Native American ancestry as a result of their complex admixture histories. Using ancestry tract-length analysis, we detect different dates for the European admixture events in the African-Colombian (1749 CE; confidence interval [CI]: 1737-1764) and African-Brazilian (1796 CE; CI: 1789-1804) populations in our dataset, consistent with the historically attested earlier influx of Africans into Colombia. Furthermore, we find evidence for sex-specific admixture patterns, resulting from predominantly European paternal gene flow. Finally, we detect strong genetic links between the African-descendant populations and specific source populations in Africa on the basis of haplotype sharing patterns. Although the Noir Marron and African-Colombians show stronger affinities with African populations from the Bight of Benin and the Gold Coast, the African-Brazilian population from Rio de Janeiro has greater genetic affinity with Bantu-speaking populations from the Bight of Biafra and west central Africa.