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1.
Nature ; 586(7831): 741-748, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33116287

RESUMO

The African continent is regarded as the cradle of modern humans and African genomes contain more genetic variation than those from any other continent, yet only a fraction of the genetic diversity among African individuals has been surveyed1. Here we performed whole-genome sequencing analyses of 426 individuals-comprising 50 ethnolinguistic groups, including previously unsampled populations-to explore the breadth of genomic diversity across Africa. We uncovered more than 3 million previously undescribed variants, most of which were found among individuals from newly sampled ethnolinguistic groups, as well as 62 previously unreported loci that are under strong selection, which were predominantly found in genes that are involved in viral immunity, DNA repair and metabolism. We observed complex patterns of ancestral admixture and putative-damaging and novel variation, both within and between populations, alongside evidence that Zambia was a likely intermediate site along the routes of expansion of Bantu-speaking populations. Pathogenic variants in genes that are currently characterized as medically relevant were uncommon-but in other genes, variants denoted as 'likely pathogenic' in the ClinVar database were commonly observed. Collectively, these findings refine our current understanding of continental migration, identify gene flow and the response to human disease as strong drivers of genome-level population variation, and underscore the scientific imperative for a broader characterization of the genomic diversity of African individuals to understand human ancestry and improve health.


Assuntos
Variação Genética , Genoma Humano/genética , Genômica , Saúde , Migração Humana , África/etnologia , Reparo do DNA/genética , Conjuntos de Dados como Assunto , Feminino , Fluxo Gênico , Genética Médica , Genética Populacional , Saúde/história , História Antiga , Migração Humana/história , Humanos , Imunidade/genética , Idioma , Masculino , Metabolismo/genética , Seleção Genética , Sequenciamento Completo do Genoma
3.
BMC Genomics ; 21(1): 289, 2020 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-32272904

RESUMO

BACKGROUND: Copy number variation is an important class of genomic variation that has been reported in 75% of the human genome. However, it is underreported in African populations. Copy number variants (CNVs) could have important impacts on disease susceptibility and environmental adaptation. To describe CNVs and their possible impacts in Africans, we sequenced genomes of 232 individuals from three major African ethno-linguistic groups: (1) Niger Congo A from Guinea and Côte d'Ivoire, (2) Niger Congo B from Uganda and the Democratic Republic of Congo and (3) Nilo-Saharans from Uganda. We used GenomeSTRiP and cn.MOPS to identify copy number variant regions (CNVRs). RESULTS: We detected 7608 CNVRs, of which 2172 were only deletions, 2384 were only insertions and 3052 had both. We detected 224 previously un-described CNVRs. The majority of novel CNVRs were present at low frequency and were not shared between populations. We tested for evidence of selection associated with CNVs and also for population structure. Signatures of selection identified previously, using SNPs from the same populations, were overrepresented in CNVRs. When CNVs were tagged with SNP haplotypes to identify SNPs that could predict the presence of CNVs, we identified haplotypes tagging 3096 CNVRs, 372 CNVRs had SNPs with evidence of selection (iHS > 3) and 222 CNVRs had both. This was more than expected (p < 0.0001) and included loci where CNVs have previously been associated with HIV, Rhesus D and preeclampsia. When integrated with 1000 Genomes CNV data, we replicated their observation of population stratification by continent but no clustering by populations within Africa, despite inclusion of Nilo-Saharans and Niger-Congo populations within our dataset. CONCLUSIONS: Novel CNVRs in the current study increase representation of African diversity in the database of genomic variants. Over-representation of CNVRs in SNP signatures of selection and an excess of SNPs that both tag CNVs and are subject to selection show that CNVs may be the actual targets of selection at some loci. However, unlike SNPs, CNVs alone do not resolve African ethno-linguistic groups. Tag haplotypes for CNVs identified may be useful in predicting African CNVs in future studies where only SNP data is available.


Assuntos
População Negra/genética , Variações do Número de Cópias de DNA , Genômica/métodos , África/etnologia , Bases de Dados Genéticas , Predisposição Genética para Doença , Genética Populacional , Genoma Humano , Haplótipos , Humanos
4.
Lancet ; 381(9861): 142-51, 2013 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-23103089

RESUMO

BACKGROUND: Reliable estimates of populations affected by diseases are necessary to guide efficient allocation of public health resources. Sickle haemoglobin (HbS) is the most common and clinically significant haemoglobin structural variant, but no contemporary estimates exist of the global populations affected. Moreover, the precision of available national estimates of heterozygous (AS) and homozygous (SS) neonates is unknown. We aimed to provide evidence-based estimates at various scales, with uncertainty measures. METHODS: Using a database of sickle haemoglobin surveys, we created a contemporary global map of HbS allele frequency distribution within a Bayesian geostatistical model. The pairing of this map with demographic data enabled calculation of global, regional, and national estimates of the annual number of AS and SS neonates. Subnational estimates were also calculated in data-rich areas. FINDINGS: Our map shows subnational spatial heterogeneities and high allele frequencies across most of sub-Saharan Africa, the Middle East, and India, as well as gene flow following migrations to western Europe and the eastern coast of the Americas. Accounting for local heterogeneities and demographic factors, we estimated that the global number of neonates affected by HbS in 2010 included 5,476,000 (IQR 5,291,000-5,679,000) AS neonates and 312,000 (294,000-330,000) SS neonates. These global estimates are higher than previous conservative estimates. Important differences predicted at the national level are discussed. INTERPRETATION: HbS will have an increasing effect on public health systems. Our estimates can help countries and the international community gauge the need for appropriate diagnoses and genetic counselling to reduce the number of neonates affected. Similar mapping and modelling methods could be used for other inherited disorders. FUNDING: The Wellcome Trust.


Assuntos
Traço Falciforme/epidemiologia , África Subsaariana/epidemiologia , Frequência do Gene , Saúde Global , Hemoglobina Falciforme/genética , Heterozigoto , Homozigoto , Humanos , Recém-Nascido , Dinâmica Populacional
5.
Parasite ; 31: 66, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39470326

RESUMO

Schistosomiasis is an endemic disease in Côte d'Ivoire. We compared the conventional Kato Katz (KK) test and a more sensitive but rarely used method, the point-of-care circulating cathodic antigen (POC-CCA), in order to contribute to the development of a more appropriate strategy for the control and elimination of intestinal schistosomiasis in western Côte d'Ivoire. A cross-sectional epidemiological survey was conducted in eight elementary schools in the Guémon and Cavally regions from February to December 2020. Selected schoolchildren provided stool and urine samples to detect the presence of Schistosoma mansoni eggs and parasite antigen using the KK and POC-CCA tests, respectively. A total of 554 schoolchildren were included in the study. The overall prevalence of intestinal schistosomiasis was 10% and 67% for KK and POC-CCA, respectively. The POC-CCA detected an infection rate of 100%, while the KK yielded a rate of 42%. In schools, prevalence ranged from 27 to 100% with POC-CCA and from 0 to 42% with KK. Swimming, fishing, washing clothes, and dishwashing were significantly associated with the onset of infection and high intensities. The epidemiological risk factors for intestinal schistosomiasis updated here using KK and POC-CCA diagnostic methods showed that prevalence was much higher than previously estimated using the KK. The POC-CCA is more sensitive and ways should be considered to improve its specificity in order to improve the diagnosis.


Title: Évaluation de la situation épidémiologique de la schistosomiase intestinale à l'aide du test antigénique parasitaire POC-CCA et du test de numération des œufs Kato-Katz chez les enfants d'âge scolaire de villages endémiques de l'ouest de la Côte d'Ivoire. Abstract: La schistosomiase est une maladie endémique en Côte d'Ivoire. Nous avons comparé le test conventionnel Kato Katz (KK) et une méthode plus sensible mais rarement utilisée, l'antigène cathodique circulant au point d'intervention (POC-CCA), afin de contribuer au développement d'une stratégie plus appropriée pour le contrôle et l'élimination de la schistosomiase intestinale dans l'ouest de la Côte d'Ivoire. Une enquête épidémiologique transversale a été menée dans huit écoles élémentaires des régions de Guémon et Cavally de février à décembre 2020. Des écoliers sélectionnés ont fourni des échantillons de selles et d'urine pour détecter la présence d'œufs de Schistosoma mansoni et d'antigène parasitaire à l'aide respectivement des tests KK et POC-CCA. Au total, 554 écoliers ont été inclus dans cette étude. La prévalence globale de la schistosomiase intestinale était respectivement de 10% et 67% pour KK et POC-CCA. Le POC-CCA a détecté un taux d'infection de 100%, tandis que le KK a donné un taux de 42%. Dans les écoles, la prévalence variait de 27 à 100% avec POC-CCA et de 0 à 42% avec KK. La natation, la pêche, la lessive et la vaisselle étaient associées de manière significative à l'apparition de l'infection et à des intensités élevées. La mise à jour ici des facteurs de risque épidémiologiques de la schistosomiase intestinale à l'aide des méthodes de diagnostic KK et POC-CCA a montré que la prévalence était beaucoup plus élevée que celle estimée précédemment à l'aide du KK. Le POC-CCA est plus sensible et des moyens devraient être envisagés pour améliorer sa spécificité afin de rendre un meilleur diagnostic.


Assuntos
Antígenos de Helmintos , Fezes , Contagem de Ovos de Parasitas , Schistosoma mansoni , Esquistossomose mansoni , Côte d'Ivoire/epidemiologia , Humanos , Criança , Esquistossomose mansoni/epidemiologia , Esquistossomose mansoni/diagnóstico , Esquistossomose mansoni/urina , Feminino , Masculino , Estudos Transversais , Prevalência , Fezes/parasitologia , Antígenos de Helmintos/urina , Animais , Schistosoma mansoni/imunologia , Schistosoma mansoni/isolamento & purificação , Doenças Endêmicas , Adolescente , Sensibilidade e Especificidade , Instituições Acadêmicas , Proteínas de Helminto/imunologia
6.
Hum Mutat ; 34(7): 937-44, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23568771

RESUMO

Warnings about the expected increase of the global public health burden of malaria-related red cell disorders are accruing. Past and present epidemiological data are necessary to track spatial and temporal changes in the frequencies of these genetic disorders. A number of open access biomedical databases including data on malaria-related red cell disorders have been launched over the last two decades. Here, we review the content of these databases, most of which focus on genetic diversity, and we describe a new epidemiological resource developed by the Malaria Atlas Project. To tackle upcoming public health challenges, the integration of epidemiological and genetic data is important. As many countries are considering implementing national screening programs, strategies to make such data more accessible are also needed.


Assuntos
Bases de Dados Factuais , Bases de Dados Genéticas , Hemoglobinopatias , Internet , Malária , Hemoglobinopatias/epidemiologia , Hemoglobinopatias/genética , Hemoglobinopatias/fisiopatologia , Humanos , Malária/epidemiologia , Malária/genética , Malária/fisiopatologia
7.
PLoS Med ; 9(11): e1001339, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23152723

RESUMO

BACKGROUND: Primaquine is a key drug for malaria elimination. In addition to being the only drug active against the dormant relapsing forms of Plasmodium vivax, primaquine is the sole effective treatment of infectious P. falciparum gametocytes, and may interrupt transmission and help contain the spread of artemisinin resistance. However, primaquine can trigger haemolysis in patients with a deficiency in glucose-6-phosphate dehydrogenase (G6PDd). Poor information is available about the distribution of individuals at risk of primaquine-induced haemolysis. We present a continuous evidence-based prevalence map of G6PDd and estimates of affected populations, together with a national index of relative haemolytic risk. METHODS AND FINDINGS: Representative community surveys of phenotypic G6PDd prevalence were identified for 1,734 spatially unique sites. These surveys formed the evidence-base for a Bayesian geostatistical model adapted to the gene's X-linked inheritance, which predicted a G6PDd allele frequency map across malaria endemic countries (MECs) and generated population-weighted estimates of affected populations. Highest median prevalence (peaking at 32.5%) was predicted across sub-Saharan Africa and the Arabian Peninsula. Although G6PDd prevalence was generally lower across central and southeast Asia, rarely exceeding 20%, the majority of G6PDd individuals (67.5% median estimate) were from Asian countries. We estimated a G6PDd allele frequency of 8.0% (interquartile range: 7.4-8.8) across MECs, and 5.3% (4.4-6.7) within malaria-eliminating countries. The reliability of the map is contingent on the underlying data informing the model; population heterogeneity can only be represented by the available surveys, and important weaknesses exist in the map across data-sparse regions. Uncertainty metrics are used to quantify some aspects of these limitations in the map. Finally, we assembled a database of G6PDd variant occurrences to inform a national-level index of relative G6PDd haemolytic risk. Asian countries, where variants were most severe, had the highest relative risks from G6PDd. CONCLUSIONS: G6PDd is widespread and spatially heterogeneous across most MECs where primaquine would be valuable for malaria control and elimination. The maps and population estimates presented here reflect potential risk of primaquine-associated harm. In the absence of non-toxic alternatives to primaquine, these results represent additional evidence to help inform safe use of this valuable, yet dangerous, component of the malaria-elimination toolkit. Please see later in the article for the Editors' Summary.


Assuntos
Antimaláricos/toxicidade , Frequência do Gene , Geografia Médica/métodos , Deficiência de Glucosefosfato Desidrogenase/epidemiologia , Glucosefosfato Desidrogenase/genética , Hemólise , Primaquina/toxicidade , Teorema de Bayes , Feminino , Mapeamento Geográfico , Glucosefosfato Desidrogenase/metabolismo , Humanos , Malária/epidemiologia , Masculino , Modelos Genéticos , Prevalência , Medição de Risco , Distribuição por Sexo
8.
Front Immunol ; 12: 613468, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33659002

RESUMO

Schistosomiasis remains the fourth most prevalent parasitic disease affecting over 200 million people worldwide. Control efforts have focussed on the disruption of the life cycle targeting the parasite, vector and human host. Parasite burdens are highly skewed, and the majority of eggs are shed into the environment by a minority of the infected population. Most morbidity results from hepatic fibrosis leading to portal hypertension and is not well-correlated with worm burden. Genetics as well as environmental factors may play a role in these skewed distributions and understanding the genetic risk factors for intensity of infection and morbidity may help improve control measures. In this review, we focus on how genetic factors may influence parasite load, hepatic fibrosis and portal hypertension. We found 28 studies on the genetics of human infection and 20 studies on the genetics of pathology in humans. S. mansoni and S. haematobium infection intensity have been showed to be controlled by a major quantitative trait locus SM1, on chromosome 5q31-q33 containing several genes involved in the Th2 immune response, and three other loci of smaller effect on chromosomes 1, 6, and 7. The most common pathology associated with schistosomiasis is hepatic and portal vein fibroses and the SM2 quantitative trait locus on chromosome six has been linked to intensity of fibrosis. Although there has been an emphasis on Th2 cytokines in candidate gene studies, we found that four of the five QTL regions contain Th17 pathway genes that have been included in schistosomiasis studies: IL17B and IL12B in SM1, IL17A and IL17F in 6p21-q2, IL6R in 1p21-q23 and IL22RA2 in SM2. The Th17 pathway is known to be involved in response to schistosome infection and hepatic fibrosis but variants in this pathway have not been tested for any effect on the regulation of these phenotypes. These should be priorities for future studies.


Assuntos
Variação Genética , Genoma Helmíntico , Hepatopatias/etiologia , Schistosoma/genética , Esquistossomose/parasitologia , Alelos , Animais , Mapeamento Cromossômico , Biologia Computacional/métodos , Gerenciamento Clínico , Genes de Helmintos , Ligação Genética , Estudo de Associação Genômica Ampla , Humanos , Hipertensão Portal/diagnóstico , Hipertensão Portal/etiologia , Hepatopatias/diagnóstico , Anotação de Sequência Molecular , Carga Parasitária , Fenótipo , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Schistosoma/imunologia , Esquistossomose/complicações , Esquistossomose/diagnóstico , Índice de Gravidade de Doença
9.
AAS Open Res ; 4: 36, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-35252746

RESUMO

Background: Approximately 25% of the risk of Schistosoma mansoni is associated with host genetic variation. We will test 24 candidate genes, mainly in the T h2 and T h17 pathways, for association with S. mansoni infection intensity in four African countries, using family based and case-control approaches. Methods: Children aged 5-15 years will be recruited in S. mansoni endemic areas of Ivory Coast, Cameroon, Uganda and the Democratic Republic of Congo (DRC). We will use family based (study 1) and case-control (study 2) designs. Study 1 will take place in Ivory Coast, Cameroon, Uganda and the DRC. We aim to recruit 100 high worm burden families from each country except Uganda, where a previous study recruited at least 40 families. For phenotyping, cases will be defined as the 20% of children in each community with heaviest worm burdens as measured by the circulating cathodic antigen (CCA) assay. Study 2 will take place in Uganda. We will recruit 500 children in a highly endemic community. For phenotyping, cases will be defined as the 20% of children with heaviest worm burdens as measured by the CAA assay, while controls will be the 20% of infected children with the lightest worm burdens. Deoxyribonucleic acid (DNA) will be genotyped on the Illumina H3Africa SNP (single nucleotide polymorphisms) chip and genotypes will be converted to sets of haplotypes that span the gene region for analysis. We have selected 24 genes for genotyping that are mainly in the Th2 and Th17 pathways and that have variants that have been demonstrated to be or could be associated with Schistosoma infection intensity.   Analysis: In the family-based design, we will identify SNP haplotypes disproportionately transmitted to children with high worm burden. Case-control analysis will detect overrepresentation of haplotypes in extreme phenotypes with correction for relatedness by using whole genome principal components.

10.
Sci Rep ; 3: 1671, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23591685

RESUMO

Haemoglobin C (HbC) is one of the commonest structural haemoglobin variants in human populations. Although HbC causes mild clinical complications, its diagnosis and genetic counselling are important to prevent inheritance with other haemoglobinopathies. Little is known about its contemporary distribution and the number of newborns affected. We assembled a global database of population surveys. We then used a Bayesian geostatistical model to create maps of HbC frequency across Africa and paired our predictions with high-resolution demographics to calculate heterozygous (AC) and homozygous (CC) newborn estimates and their associated uncertainty. Data were too sparse outside Africa for this methodology to be applied. The highest frequencies were found in West Africa but HbC was commonly found in other parts of the continent. The expected annual numbers of AC and CC newborns in Africa were 672,117 (interquartile range (IQR): 642,116-705,163) and 28,703 (IQR: 26,027-31,958), respectively. These numbers are about two times previous estimates.


Assuntos
Doença da Hemoglobina C/sangue , Doença da Hemoglobina C/epidemiologia , Hemoglobina C/análise , Modelos de Riscos Proporcionais , África/epidemiologia , Feminino , Humanos , Recém-Nascido , Masculino , Prevalência , Fatores de Risco
11.
Nat Commun ; 2: 266, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21468018

RESUMO

Blood group variants are characteristic of population groups, and can show conspicuous geographic patterns. Interest in the global prevalence of the Duffy blood group variants is multidisciplinary, but of particular importance to malariologists due to the resistance generally conferred by the Duffy-negative phenotype against Plasmodium vivax infection. Here we collate an extensive geo-database of surveys, forming the evidence-base for a multi-locus Bayesian geostatistical model to generate global frequency maps of the common Duffy alleles to refine the global cartography of the common Duffy variants. We show that the most prevalent allele globally was FY*A, while across sub-Saharan Africa the predominant allele was the silent FY*B(ES) variant, commonly reaching fixation across stretches of the continent. The maps presented not only represent the first spatially and genetically comprehensive description of variation at this locus, but also constitute an advance towards understanding the transmission patterns of the neglected P. vivax malaria parasite.


Assuntos
Sistema do Grupo Sanguíneo Duffy/genética , Malária Vivax/genética , Plasmodium vivax/fisiologia , África Subsaariana/epidemiologia , Alelos , Frequência do Gene , Humanos , Malária Vivax/sangue , Malária Vivax/epidemiologia
12.
Nat Commun ; 1: 104, 2010 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-21045822

RESUMO

It has been 100 years since the first report of sickle haemoglobin (HbS). More than 50 years ago, it was suggested that the gene responsible for this disorder could reach high frequencies because of resistance conferred against malaria by the heterozygous carrier state. This traditional example of balancing selection is known as the 'malaria hypothesis'. However, the geographical relationship between the transmission intensity of malaria and associated HbS burden has never been formally investigated on a global scale. Here, we use a comprehensive data assembly of HbS allele frequencies to generate the first evidence-based map of the worldwide distribution of the gene in a Bayesian geostatistical framework. We compare this map with the pre-intervention distribution of malaria endemicity, using a novel geostatistical area-mean comparison. We find geographical support for the malaria hypothesis globally; the relationship is relatively strong in Africa but cannot be resolved in the Americas or in Asia.

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