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1.
mSphere ; 5(5)2020 09 30.
Artigo em Inglês | MEDLINE | ID: mdl-32999084

RESUMO

The inaugural Black In Microbiology Week (#BlackInMicro) is 28 September 2020 through 4 October 2020. Its mission is to "showcase the presence and accomplishments of Black microbiologists from around the globe, connect Black microbiologists with one another and foster a sense of community among them, and provide a forum for the discussion of racial disparities in microbiology and its subfields." Participation in this event will happen primarily over Twitter through the hashtag #BlackInMicro and over Zoom through registration on the website https://blackinmicrobiology.org/ An additional mission of Black In Microbiology Week is to amplify black scientists. Today, mSphere does this by presenting two mSphere of Influence commentaries from Black In Microbiology co-lead organizers Ariangela J. Kozik ("mSphere of Influence: frameshift-a vision for human microbiome research" [mSphere 5:e00944-20, 2020, https://doi.org/10.1128/mSphere.00944-20]) and Kishana Taylor ("mSphere of Influence: that's racist-COVID-19, biological determinism, and the limits of hypotheses" [mSphere 5:e00945-20, 2020, https://doi.org/10.1128/mSphere.00945-20]).


Assuntos
Grupo com Ancestrais do Continente Africano/genética , Determinismo Genético , Racismo/prevenção & controle , Betacoronavirus , Infecções por Coronavirus/epidemiologia , Humanos , Microbiologia , Microbiota , Pandemias , Pneumonia Viral/epidemiologia
2.
Cell Transplant ; 29: 963689720968749, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33108902

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic. One open question is whether genetics could influence the severity of symptoms. Considering the limited data on cancer patients, we analyzed public data repositories limited to investigate angiotensin-converting enzyme 2 (ACE2) and the transmembrane serine protease 2 (TMPRSS2) expressions and genetic variants to identify the basis of individual susceptibility to SARS-CoV-2.Gene expression and variant data were retrieved from Tissue Cancer Genome Atlas, Genotype-Tissue Expression, and gnomAD. Differences in gene expression were tested with Mann-Whitney U-test. Allele frequencies of germline variants were explored in different ethnicities, with a special focus on ACE2 variants located in the binding site to SARS-CoV-2 spike protein.The analysis of ACE2 and TMPRSS2 expressions in healthy tissues showed a higher expression in the age class 20 to 59 years (false discovery rate [FDR] < 0.0001) regardless of gender. ACE2 and TMPRSS2 were more expressed in tumors from males than females (both FDR < 0.0001) and, opposite to the regulation in tissues from healthy individuals, more expressed in elderly patients (FDR = 0.005; FDR < 0.0001, respectively). ACE2 and TMPRSS2 expressions were higher in cancers of elderly patients compared with healthy individuals (FDR < 0.0001). Variants were present at low frequency (range 0% to 3%) and among those with the highest frequency, the variant S19P belongs to the SARS-CoV-2 spike protein binding site and it was exclusively present in Africans with a frequency of 0.2%.The mechanisms of ACE2 and TMPRSS2 regulation could be targeted for preventive and therapeutic purposes in the whole population and especially in cancer patients.Further studies are needed to show a direct correlation of ACE2 and TMPRSS2 expressions in cancer patients and the incidence of COVID-19.


Assuntos
Infecções por Coronavirus/patologia , Predisposição Genética para Doença , Neoplasias/patologia , Peptidil Dipeptidase A/genética , Pneumonia Viral/patologia , Serina Endopeptidases/genética , Adulto , Grupo com Ancestrais do Continente Africano/genética , Betacoronavirus/isolamento & purificação , Sítios de Ligação , Estudos de Casos e Controles , Infecções por Coronavirus/virologia , Bases de Dados Genéticas , Feminino , Frequência do Gene , Variação Genética , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Neoplasias/epidemiologia , Neoplasias/genética , Pandemias , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/virologia , Serina Endopeptidases/metabolismo , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/metabolismo , Adulto Jovem
3.
Am J Hum Genet ; 107(3): 379-380, 2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32888506

RESUMO

It is imperative for participation in genetics and genomics research to reflect humanity's diversity so that all people can enjoy its benefits. This will take a concerted effort by the research community and must include greater engagement with individuals and communities underrepresented in research. In engaging with vulnerable populations, it is essential that researchers guard against harm resulting from their participation.


Assuntos
Pesquisa Biomédica , Variação Genética/genética , Populações Vulneráveis , Grupo com Ancestrais do Continente Africano/genética , Grupo com Ancestrais do Continente Europeu/genética , Genoma Humano , Genômica , Genética Humana , Humanos
4.
PLoS One ; 15(9): e0239300, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32956418

RESUMO

BACKGROUND: Recent reports from small studies in West Africa suggest that Black children may have high rate of steroid sensitivity nephrotic syndrome (SSNS) contrary to long held knowledge. Herein, we determined the proportion of children with idiopathic nephrotic syndrome (INS) who achieved complete remission with steroid therapy and identified factors associated with complete remission. METHODS: We reviewed the medical records of 241 children with INS in two centres in Lagos from 2010 to 2019. We extracted demographic data, clinical features, laboratory values at the time of diagnosis, and receipt and response to steroids and other immunosuppressants. RESULTS: The median (interquartile range) age at diagnosis of INS was 5.1 (3.0-8.7) years and boys were 60.2% of the study population. Children with SSNS made up 85.9% (n = 207) of the study cohort. Among those aged 0-5 years, 92.6%were SSNS compared with 69.2% in those aged 11-17 years at the time of diagnosis. In addition, the proportion of children with SSNS increased from 73.8% between year 2010 and 2012 to 88.4% afterwards. Also, children with SSNS had lower serum creatinine (0.44 vs 0.70; p<0.001) and higher estimated glomerular filtration rate (101 vs 74.3 ml/min/1.73 m2; p = 0.008) at the time of diagnosis than those with steroid resistant nephrotic syndrome (SRNS). CONCLUSION: Among Black children in Lagos, the proportion with SSNS is comparable to proportions described in children of Asian and European descent. Furthermore, children with SSNS had lower serum creatinine and higher glomerular filtration rate than those with SRNS.


Assuntos
Síndrome Nefrótica/tratamento farmacológico , Esteroides/efeitos adversos , Adolescente , África Ocidental/epidemiologia , Grupo com Ancestrais do Continente Africano/genética , Criança , Pré-Escolar , Estudos Transversais , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Humanos , Lactente , Recém-Nascido , Masculino , Homens , Síndrome Nefrótica/epidemiologia , Síndrome Nefrótica/genética , Síndrome Nefrótica/patologia , Nigéria/epidemiologia , Esteroides/uso terapêutico
5.
PLoS One ; 15(8): e0237041, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32813691

RESUMO

INTRODUCTION: The Black population in the US is heterogeneous but is often treated as monolithic in research, with skin pigmentation being the primary indicator of racial classification. Objective: This paper examines the differences among Blacks by comparing genetic ancestry, skin color and social attainment of 259 residents across four US cities-Norman, Oklahoma; Cincinnati, Ohio; Harlem, New York; and Washington, District of Columbia. METHODS: Participants were recruited between 2004 and 2006 at community-based forums. Cross-sectional data were analyzed using chi-square tests, correlation analyses and logistic regression. RESULTS: There were variations in ancestry, melanin index and social attainment across some cities. Overall, men with darker skin color, and women with lighter skin color were significantly more likely to be married. Darker skin individuals with significantly more West African ancestry reported attainment of graduate degrees, and professional occupations than lighter skin individuals. CONCLUSIONS: Our findings suggest differences in skin pigmentation by geography and support regional variations in ancestry of US Blacks. Biomedical research should consider genetic ancestry and local historical/social context rather than relying solely on skin pigmentation as a proxy for race.


Assuntos
Afro-Americanos/genética , Melaninas/genética , Pigmentação da Pele/genética , Adulto , Grupo com Ancestrais do Continente Africano/genética , Cidades , Estudos Transversais , District of Columbia , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , New York , Ohio , Oklahoma , Classe Social
6.
Am J Hum Genet ; 107(3): 473-486, 2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32781046

RESUMO

Africa contains more human genetic variation than any other continent, but the majority of the population-scale analyses of the African peoples have focused on just two of the four major linguistic groups, the Niger-Congo and Afro-Asiatic, leaving the Nilo-Saharan and Khoisan populations under-represented. In order to assess genetic variation and signatures of selection within a Nilo-Saharan population and between the Nilo-Saharan and Niger-Congo and Afro-Asiatic, we sequenced 50 genomes from the Nilo-Saharan Lugbara population of North-West Uganda and 250 genomes from 6 previously unsequenced Niger-Congo populations. We compared these data to data from a further 16 Eurasian and African populations including the Gumuz, another putative Nilo-Saharan population from Ethiopia. Of the 21 million variants identified in the Nilo-Saharan population, 3.57 million (17%) were not represented in dbSNP and included predicted non-synonymous mutations with possible phenotypic effects. We found greater genetic differentiation between the Nilo-Saharan Lugbara and Gumuz populations than between any two Afro-Asiatic or Niger-Congo populations. F3 tests showed that Gumuz contributed a genetic component to most Niger-Congo B populations whereas Lugabara did not. We scanned the genomes of the Lugbara for evidence of selective sweeps. We found selective sweeps at four loci (SLC24A5, SNX13, TYRP1, and UVRAG) associated with skin pigmentation, three of which already have been reported to be under selection. These selective sweeps point toward adaptations to the intense UV radiation of the Sahel.


Assuntos
Adaptação Fisiológica/genética , Variação Genética/genética , Seleção Genética/genética , Pigmentação da Pele/genética , Grupo com Ancestrais do Continente Africano/genética , Antiporters/genética , Gerenciamento de Dados , Etiópia/epidemiologia , Feminino , Genética Populacional , Genoma Humano/genética , Haplótipos/genética , Humanos , Masculino , Glicoproteínas de Membrana/genética , Oxirredutases/genética , Polimorfismo de Nucleotídeo Único/genética , Nexinas de Classificação/genética , Proteínas Supressoras de Tumor/genética , Uganda/epidemiologia
7.
Am J Hum Genet ; 107(2): 265-277, 2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32707084

RESUMO

According to historical records of transatlantic slavery, traders forcibly deported an estimated 12.5 million people from ports along the Atlantic coastline of Africa between the 16th and 19th centuries, with global impacts reaching to the present day, more than a century and a half after slavery's abolition. Such records have fueled a broad understanding of the forced migration from Africa to the Americas yet remain underexplored in concert with genetic data. Here, we analyzed genotype array data from 50,281 research participants, which-combined with historical shipping documents-illustrate that the current genetic landscape of the Americas is largely concordant with expectations derived from documentation of slave voyages. For instance, genetic connections between people in slave trading regions of Africa and disembarkation regions of the Americas generally mirror the proportion of individuals forcibly moved between those regions. While some discordances can be explained by additional records of deportations within the Americas, other discordances yield insights into variable survival rates and timing of arrival of enslaved people from specific regions of Africa. Furthermore, the greater contribution of African women to the gene pool compared to African men varies across the Americas, consistent with literature documenting regional differences in slavery practices. This investigation of the transatlantic slave trade, which is broad in scope in terms of both datasets and analyses, establishes genetic links between individuals in the Americas and populations across Atlantic Africa, yielding a more comprehensive understanding of the African roots of peoples of the Americas.


Assuntos
Grupo com Ancestrais do Continente Africano/genética , Polimorfismo de Nucleotídeo Único/genética , África , América , Pessoas Escravizadas , Europa (Continente) , Feminino , Humanos , Masculino
8.
PLoS One ; 15(7): e0233808, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32673320

RESUMO

Similarly to other populations across the Americas, Argentinean populations trace back their genetic ancestry into African, European and Native American ancestors, reflecting a complex demographic history with multiple migration and admixture events in pre- and post-colonial times. However, little is known about the sub-continental origins of these three main ancestries. We present new high-throughput genotyping data for 87 admixed individuals across Argentina. This data was combined to previously published data for admixed individuals in the region and then compared to different reference panels specifically built to perform population structure analyses at a sub-continental level. Concerning the Native American ancestry, we could identify four Native American components segregating in modern Argentinean populations. Three of them are also found in modern South American populations and are specifically represented in Central Andes, Central Chile/Patagonia, and Subtropical and Tropical Forests geographic areas. The fourth component might be specific to the Central Western region of Argentina, and it is not well represented in any genomic data from the literature. As for the European and African ancestries, we confirmed previous results about origins from Southern Europe, Western and Central Western Africa, and we provide evidences for the presence of Northern European and Eastern African ancestries.


Assuntos
Grupo com Ancestrais do Continente Africano/genética , Grupo com Ancestrais do Continente Europeu/genética , Genoma Humano , Índios Sul-Americanos/genética , Casamento , Linhagem , Grupo com Ancestrais do Continente Africano/etnologia , Argentina , Colonialismo , DNA/genética , Escravização , Grupo com Ancestrais do Continente Europeu/etnologia , Marcadores Genéticos , Variação Genética , Genética Populacional , Genótipo , Migração Humana , Humanos , Índios Sul-Americanos/etnologia , Modelos Genéticos
9.
PLoS Genet ; 16(6): e1008867, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32555579

RESUMO

Recent research shows that introgression between closely-related species is an important source of adaptive alleles for a wide range of taxa. Typically, detection of adaptive introgression from genomic data relies on comparative analyses that require sequence data from both the recipient and the donor species. However, in many cases, the donor is unknown or the data is not currently available. Here, we introduce a genome-scan method-VolcanoFinder-to detect recent events of adaptive introgression using polymorphism data from the recipient species only. VolcanoFinder detects adaptive introgression sweeps from the pattern of excess intermediate-frequency polymorphism they produce in the flanking region of the genome, a pattern which appears as a volcano-shape in pairwise genetic diversity. Using coalescent theory, we derive analytical predictions for these patterns. Based on these results, we develop a composite-likelihood test to detect signatures of adaptive introgression relative to the genomic background. Simulation results show that VolcanoFinder has high statistical power to detect these signatures, even for older sweeps and for soft sweeps initiated by multiple migrant haplotypes. Finally, we implement VolcanoFinder to detect archaic introgression in European and sub-Saharan African human populations, and uncovered interesting candidates in both populations, such as TSHR in Europeans and TCHH-RPTN in Africans. We discuss their biological implications and provide guidelines for identifying and circumventing artifactual signals during empirical applications of VolcanoFinder.


Assuntos
Introgressão Genética , Genética Populacional/métodos , Genoma Humano/genética , Modelos Genéticos , Polimorfismo Genético , África ao Sul do Saara , Grupo com Ancestrais do Continente Africano/genética , Alelos , Antígenos/genética , Simulação por Computador , Europa (Continente) , Grupo com Ancestrais do Continente Europeu/genética , Evolução Molecular , Haplótipos , Humanos , Proteínas de Filamentos Intermediários/genética , Receptores da Tireotropina/genética , Proteínas S100/genética , Seleção Genética , Software
10.
J Biol Chem ; 295(33): 11742-11753, 2020 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-32587094

RESUMO

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has challenged the speed at which laboratories can discover the viral composition and study health outcomes. The small ∼30-kb ssRNA genome of coronaviruses makes them adept at cross-species spread while enabling a robust understanding of all of the proteins the viral genome encodes. We have employed protein modeling, molecular dynamics simulations, evolutionary mapping, and 3D printing to gain a full proteome- and dynamicome-level understanding of SARS-CoV-2. We established the Viral Integrated Structural Evolution Dynamic Database (VIStEDD at RRID:SCR_018793) to facilitate future discoveries and educational use. Here, we highlight the use of VIStEDD for nsp6, nucleocapsid (N), and spike (S) surface glycoprotein. For both nsp6 and N, we found highly conserved surface amino acids that likely drive protein-protein interactions. In characterizing viral S protein, we developed a quantitative dynamics cross-correlation matrix to gain insights into its interactions with the angiotensin I-converting enzyme 2 (ACE2)-solute carrier family 6 member 19 (SLC6A19) dimer. Using this quantitative matrix, we elucidated 47 potential functional missense variants from genomic databases within ACE2/SLC6A19/transmembrane serine protease 2 (TMPRSS2), warranting genomic enrichment analyses in SARS-CoV-2 patients. These variants had ultralow frequency but existed in males hemizygous for ACE2. Two ACE2 noncoding variants (rs4646118 and rs143185769) present in ∼9% of individuals of African descent may regulate ACE2 expression and may be associated with increased susceptibility of African Americans to SARS-CoV-2. We propose that this SARS-CoV-2 database may aid research into the ongoing pandemic.


Assuntos
Betacoronavirus/química , Betacoronavirus/genética , Infecções por Coronavirus/metabolismo , Bases de Dados de Proteínas , Simulação de Dinâmica Molecular , Pneumonia Viral/metabolismo , Proteoma , Grupo com Ancestrais do Continente Africano/genética , Sistemas de Transporte de Aminoácidos Neutros/química , Sistemas de Transporte de Aminoácidos Neutros/genética , Sistemas de Transporte de Aminoácidos Neutros/metabolismo , Infecções por Coronavirus/virologia , Predisposição Genética para Doença , Variação Genética , Interações Hospedeiro-Patógeno , Humanos , Masculino , Proteínas do Nucleocapsídeo/química , Proteínas do Nucleocapsídeo/metabolismo , Pandemias , Peptidil Dipeptidase A/química , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/virologia , Mapas de Interação de Proteínas , Processamento de Proteína Pós-Traducional , Homologia de Sequência de Aminoácidos , Serina Endopeptidases/química , Serina Endopeptidases/genética , Serina Endopeptidases/metabolismo , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/metabolismo
11.
Immunogenetics ; 72(5): 305-314, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32556499

RESUMO

Several genetic studies have implicated genes that encode for components of the innate immune response in tuberculosis (TB) susceptibility. The complement system is an early player in the innate immune response and provides the host with initial protection by promoting phagocytosis of apoptotic or necrotic cells. The C1q molecule is the first component of the classical pathway that leads to the activation of complement by binding to immune complexes and is encoded by the C1Q gene cluster. We investigated variants in this region to determine its association with TB susceptibility. Five single nucleotide polymorphisms (SNPs) (rs12033074, rs631090, rs172378, rs587585, and rs665691) were genotyped using TaqMan® SNP assays in 456 TB cases and 448 healthy controls and analysed by logistic regression models. The rs587585 variant showed a significant additive allelic association where the minor G allele was found more frequently in TB cases than in controls in both the discovery (p = 0.023; OR = 1.30; 95% CI, 1.04-1.64) and validation cohort (p = 0.038; OR = 1.31; 95% CI, 1.22-1.40). In addition, we detected increased C1qA expression when comparing cases and controls (p = 0.037) and linked this to a dosage effect of the G allele, which increased C1qA expression in TB cases. This is the first study to report the association of C1Q gene polymorphisms with progression to tuberculosis.


Assuntos
Complemento C1q/genética , Complemento C1q/metabolismo , Predisposição Genética para Doença/genética , Tuberculose/genética , Adulto , Grupo com Ancestrais do Continente Africano/genética , Alelos , Estudos de Casos e Controles , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Família Multigênica , Polimorfismo de Nucleotídeo Único , Tuberculose/imunologia , Adulto Jovem
12.
Hum Genet ; 139(11): 1471-1483, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32583022

RESUMO

Human growth is a complex trait determined by genetic factors in combination with external stimuli, including environment, nutrition and hormonal status. In the past, several genome-wide association studies (GWAS) have collectively identified hundreds of genetic variants having a putative effect on determining adult height in different worldwide populations. Theoretically, a valuable approach to better understand the mechanisms of complex traits as adult height is to study a population exhibiting extreme stature phenotypes, such as African Baka Pygmies. After phenotypic characterization, we sequenced the whole exomes of a cohort of Baka Pygmies and their non-Pygmies Bantu neighbors to highlight genetic variants associated with the reduced stature. Whole exome data analysis revealed 29 single nucleotide polymorphisms (SNPs) significantly associated with the reduced height in the Baka group. Among these variants, we focused on SNP rs7629425, located in the 5'-UTR of the Hyaluronidase-2 (HYAL2) gene. The frequency of the alternative allele was significantly increased compared to African and non-African populations. In vitro luciferase assay showed significant differences in transcription modulation by rs7629425 C/T alleles. In conclusion, our results suggested that the HYAL2 gene variants may play a role in the etiology of short stature in Baka Pygmies population.


Assuntos
Grupo com Ancestrais do Continente Africano/genética , Moléculas de Adesão Celular/genética , Proteínas Ligadas por GPI/genética , Transtornos do Crescimento/genética , Hialuronoglucosaminidase/genética , Polimorfismo de Nucleotídeo Único/genética , Adulto , Alelos , Estatura/genética , Exoma/genética , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino
13.
Am J Respir Crit Care Med ; 202(7): 962-972, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32459537

RESUMO

Rationale: Puerto Ricans have the highest childhood asthma prevalence in the United States (23.6%); however, the etiology is uncertain.Objectives: In this study, we sought to uncover the genetic architecture of lung function in Puerto Rican youth with and without asthma who were recruited from the island (n = 836).Methods: We used admixture-mapping and whole-genome sequencing data to discover genomic regions associated with lung function. Functional roles of the prioritized candidate SNPs were examined with chromatin immunoprecipitation sequencing, RNA sequencing, and expression quantitative trait loci data.Measurements and Main Results: We discovered a genomic region at 1q32 that was significantly associated with a 0.12-L decrease in the lung volume of exhaled air (95% confidence interval, -0.17 to -0.07; P = 6.62 × 10-8) with each allele of African ancestry. Within this region, two SNPs were expression quantitative trait loci of TMEM9 in nasal airway epithelial cells and MROH3P in esophagus mucosa. The minor alleles of these SNPs were associated with significantly decreased lung function and decreased TMEM9 gene expression. Another admixture-mapping peak was observed on chromosome 5q35.1, indicating that each Native American ancestry allele was associated with a 0.15-L increase in lung function (95% confidence interval, 0.08-0.21; P = 5.03 × 10-6). The region-based association tests identified four suggestive windows that harbored candidate rare variants associated with lung function.Conclusions: We identified common and rare genetic variants that may play a critical role in lung function among Puerto Rican youth. We independently validated an inflammatory pathway that could potentially be used to develop more targeted treatments and interventions for patients with asthma.


Assuntos
Grupo com Ancestrais do Continente Africano/genética , Asma/genética , Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 5/genética , Volume Expiratório Forçado/genética , Índios Norte-Americanos/genética , Pulmão/fisiopatologia , Adolescente , Asma/fisiopatologia , Brônquios/citologia , Estudos de Casos e Controles , Linhagem Celular , Criança , Imunoprecipitação da Cromatina , Mapeamento Cromossômico , Mucosa Esofágica/metabolismo , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Expressão Gênica , Humanos , Desequilíbrio de Ligação , Pulmão/fisiologia , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Miócitos de Músculo Liso , Mucosa Nasal/metabolismo , Polimorfismo de Nucleotídeo Único , Porto Rico , Locos de Características Quantitativas , Análise de Sequência de RNA , Sequenciamento Completo do Genoma , Adulto Jovem
14.
Cancer Res ; 80(13): 2956-2966, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32393663

RESUMO

Although prostate cancer is the leading cause of cancer mortality for African men, the vast majority of known disease associations have been detected in European study cohorts. Furthermore, most genome-wide association studies have used genotyping arrays that are hindered by SNP ascertainment bias. To overcome these disparities in genomic medicine, the Men of African Descent and Carcinoma of the Prostate (MADCaP) Network has developed a genotyping array that is optimized for African populations. The MADCaP Array contains more than 1.5 million markers and an imputation backbone that successfully tags over 94% of common genetic variants in African populations. This array also has a high density of markers in genomic regions associated with cancer susceptibility, including 8q24. We assessed the effectiveness of the MADCaP Array by genotyping 399 prostate cancer cases and 403 controls from seven urban study sites in sub-Saharan Africa. Samples from Ghana and Nigeria clustered together, whereas samples from Senegal and South Africa yielded distinct ancestry clusters. Using the MADCaP array, we identified cancer-associated loci that have large allele frequency differences across African populations. Polygenic risk scores for prostate cancer were higher in Nigeria than in Senegal. In summary, individual and population-level differences in prostate cancer risk were revealed using a novel genotyping array. SIGNIFICANCE: This study presents an Africa-specific genotyping array, which enables investigators to identify novel disease associations and to fine-map genetic loci that are associated with prostate and other cancers.


Assuntos
Grupo com Ancestrais do Continente Africano/genética , Predisposição Genética para Doença , Neoplasias/epidemiologia , Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/genética , Estudos de Casos e Controles , Estudos de Coortes , Loci Gênicos , Genética Populacional , Estudo de Associação Genômica Ampla , Humanos , Masculino , Neoplasias/classificação , Neoplasias da Próstata/classificação , Fatores de Risco , África do Sul/epidemiologia
15.
Mol Genet Genomics ; 295(5): 1079-1089, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32440765

RESUMO

Population substructure within human populations is globally evident and a well-known confounding factor in many genetic studies. In contrast, admixture mapping exploits population stratification to detect genotype-phenotype correlations in admixed populations. Southern Africa has untapped potential for disease mapping of ancestry-specific disease risk alleles due to the distinct genetic diversity in its populations compared to other populations worldwide. This diversity contributes to a number of phenotypes, including ancestry-specific disease risk and response to pathogens. Although the 1000 Genomes Project significantly improved our understanding of genetic variation globally, southern African populations are still severely underrepresented in biomedical and human genetic studies due to insufficient large-scale publicly available data. In addition to a lack of genetic data in public repositories, existing software, algorithms and resources used for imputation and phasing of genotypic data (amongst others) are largely ineffective for populations with a complex genetic architecture such as that seen in southern Africa. This review article, therefore, aims to summarise the current limitations of conducting genetic studies on populations with a complex genetic architecture to identify potential areas for further research and development.


Assuntos
Grupo com Ancestrais do Continente Africano/genética , Predisposição Genética para Doença/genética , Genética Populacional/métodos , África Austral , Variação Genética , Genoma Humano , Humanos , Estudos Prospectivos
17.
PLoS One ; 15(5): e0230815, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32379818

RESUMO

Smoking is a potentially causal behavioral risk factor for type 2 diabetes (T2D), but not all smokers develop T2D. It is unknown whether genetic factors partially explain this variation. We performed genome-environment-wide interaction studies to identify loci exhibiting potential interaction with baseline smoking status (ever vs. never) on incident T2D and fasting glucose (FG). Analyses were performed in participants of European (EA) and African ancestry (AA) separately. Discovery analyses were conducted using genotype data from the 50,000-single-nucleotide polymorphism (SNP) ITMAT-Broad-CARe (IBC) array in 5 cohorts from from the Candidate Gene Association Resource Consortium (n = 23,189). Replication was performed in up to 16 studies from the Cohorts for Heart Aging Research in Genomic Epidemiology Consortium (n = 74,584). In meta-analysis of discovery and replication estimates, 5 SNPs met at least one criterion for potential interaction with smoking on incident T2D at p<1x10-7 (adjusted for multiple hypothesis-testing with the IBC array). Two SNPs had significant joint effects in the overall model and significant main effects only in one smoking stratum: rs140637 (FBN1) in AA individuals had a significant main effect only among smokers, and rs1444261 (closest gene C2orf63) in EA individuals had a significant main effect only among nonsmokers. Three additional SNPs were identified as having potential interaction by exhibiting a significant main effects only in smokers: rs1801232 (CUBN) in AA individuals, rs12243326 (TCF7L2) in EA individuals, and rs4132670 (TCF7L2) in EA individuals. No SNP met significance for potential interaction with smoking on baseline FG. The identification of these loci provides evidence for genetic interactions with smoking exposure that may explain some of the heterogeneity in the association between smoking and T2D.


Assuntos
Glicemia/análise , Fumar Cigarros/genética , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/genética , Jejum/sangue , Genótipo , Adulto , Grupo com Ancestrais do Continente Africano/genética , Idoso , Fumar Cigarros/etnologia , Estudos de Coortes , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/etnologia , Grupo com Ancestrais do Continente Europeu/genética , Estudos de Viabilidade , Feminino , Loci Gênicos , Estudo de Associação Genômica Ampla , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Risco
18.
PLoS Genet ; 16(3): e1008552, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32150539

RESUMO

The genetic diversity of humans, like many species, has been shaped by a complex pattern of population separations followed by isolation and subsequent admixture. This pattern, reaching at least as far back as the appearance of our species in the paleontological record, has left its traces in our genomes. Reconstructing a population's history from these traces is a challenging problem. Here we present a novel approach based on the Multiple Sequentially Markovian Coalescent (MSMC) to analyze the separation history between populations. Our approach, called MSMC-IM, uses an improved implementation of the MSMC (MSMC2) to estimate coalescence rates within and across pairs of populations, and then fits a continuous Isolation-Migration model to these rates to obtain a time-dependent estimate of gene flow. We show, using simulations, that our method can identify complex demographic scenarios involving post-split admixture or archaic introgression. We apply MSMC-IM to whole genome sequences from 15 worldwide populations, tracking the process of human genetic diversification. We detect traces of extremely deep ancestry between some African populations, with around 1% of ancestry dating to divergences older than a million years ago.


Assuntos
Fluxo Gênico/genética , Genoma Humano/genética , Grupo com Ancestrais do Continente Africano/genética , Variação Genética/genética , Haplótipos/genética , Migração Humana , Humanos , Modelos Genéticos , Densidade Demográfica , Sequenciamento Completo do Genoma/métodos
20.
Cardiovasc J Afr ; 31(4): 180-184, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32159583

RESUMO

BACKGROUND: Isolated left ventricular non-compaction (ILVNC), dilated cardiomyopathy (DCMO) and hypertrophic cardiomyopathy (HCM) are diseases that may be present in family members of patients with ILVNC. The primary aim of this study was to identify the prevalence and spectrum of cardiomyopathy in first-degree relatives of patients with ILVNC. A secondary aim was to compare a strategy of clinical screening, utilising only a clinical assessment and electrocardiogram (ECG), compared to one that included echocardiography for screening of family members of patients with ILVNC. METHODS: Eighty-three close relatives of 38 unrelated patients from the ILVNC clinic at the Chris Hani Baragwanath Hospital underwent a detailed clinical history, physical examination, ECG and echocardiogram. RESULTS: Echocardiographic screening revealed unexplained left ventricular (LV) dysfunction in 10 (12.05%) relatives. Nine out of the 10 individuals satisfied the criteria for diagnosis of DCMO. No cases of HCM or LVNC were identified. A strategy of clinical assessment and ECG had a sensitivity of 76% and a specificity of 42% versus the gold standard of echocardiographic screening. CONCLUSIONS: Echocardiographic screening detected DCMO in 10.8% of subjects. A strategy of clinical screening that included electrocardiography was sub-optimal as a screening strategy compared to echocardiographic screening.


Assuntos
Cardiomiopatia Dilatada/diagnóstico , Cardiomiopatia Hipertrófica/diagnóstico , Ecocardiografia , Eletrocardiografia , Frequência Cardíaca , Miocárdio Ventricular não Compactado Isolado/diagnóstico , Função Ventricular Esquerda , Adolescente , Adulto , Grupo com Ancestrais do Continente Africano/genética , Cardiomiopatia Dilatada/etnologia , Cardiomiopatia Dilatada/genética , Cardiomiopatia Dilatada/fisiopatologia , Cardiomiopatia Hipertrófica/etnologia , Cardiomiopatia Hipertrófica/genética , Cardiomiopatia Hipertrófica/fisiopatologia , Feminino , Predisposição Genética para Doença , Frequência Cardíaca/genética , Hereditariedade , Humanos , Miocárdio Ventricular não Compactado Isolado/etnologia , Miocárdio Ventricular não Compactado Isolado/genética , Miocárdio Ventricular não Compactado Isolado/fisiopatologia , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Valor Preditivo dos Testes , Prevalência , Estudos Retrospectivos , África do Sul/epidemiologia , Função Ventricular Esquerda/genética , Adulto Jovem
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