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1.
Nat Commun ; 12(1): 2080, 2021 04 07.
Artículo en Inglés | MEDLINE | ID: mdl-33828095

RESUMEN

South Eastern Bantu-speaking (SEB) groups constitute more than 80% of the population in South Africa. Despite clear linguistic and geographic diversity, the genetic differences between these groups have not been systematically investigated. Based on genome-wide data of over 5000 individuals, representing eight major SEB groups, we provide strong evidence for fine-scale population structure that broadly aligns with geographic distribution and is also congruent with linguistic phylogeny (separation of Nguni, Sotho-Tswana and Tsonga speakers). Although differential Khoe-San admixture plays a key role, the structure persists after Khoe-San ancestry-masking. The timing of admixture, levels of sex-biased gene flow and population size dynamics also highlight differences in the demographic histories of individual groups. The comparisons with five Iron Age farmer genomes further support genetic continuity over ~400 years in certain regions of the country. Simulated trait genome-wide association studies further show that the observed population structure could have major implications for biomedical genomics research in South Africa.


Asunto(s)
Grupo de Ascendencia Continental Africana/genética , Demografía , Flujo Génico , Estudio de Asociación del Genoma Completo , Lenguaje , Cromosomas Humanos Y/genética , Grupos Étnicos , Femenino , Frecuencia de los Genes , Variación Genética , Genética de Población , Genómica , Geografía , Haplotipos , Humanos , Lingüística , Masculino , Filogenia , Sudáfrica
4.
Am J Phys Anthropol ; 174(4): 701-713, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33539553

RESUMEN

Previous studies show that the indigenous people of the southern Cape of South Africa were dramatically impacted by the arrival of European colonists starting ~400 years ago and their descendants are today mixed with Europeans and Asians. To gain insight on the occupants of the Vaalkrans Shelter located at the southernmost tip of Africa, we investigated the genetic make-up of an individual who lived there about 200 years ago. We further contextualize the genetic ancestry of this individual among prehistoric and current groups. From a hair sample excavated at the shelter, which was indirectly dated to about 200 years old, we sequenced the genome (1.01 times coverage) of a Later Stone Age individual. We analyzed the Vaalkrans genome together with genetic data from 10 ancient (pre-colonial) individuals from southern Africa spanning the last 2000 years. We show that the individual from Vaalkrans was a man who traced ~80% of his ancestry to local southern San hunter-gatherers and ~20% to a mixed East African-Eurasian source. This genetic make-up is similar to modern-day Khoekhoe individuals from the Northern Cape Province (South Africa) and Namibia, but in the southern Cape, the Vaalkrans man's descendants have likely been assimilated into mixed-ancestry "Coloured" groups. The Vaalkrans man's genome reveals that Khoekhoe pastoralist groups/individuals lived in the southern Cape as late as 200 years ago, without mixing with non-African colonists or Bantu-speaking farmers. Our findings are also consistent with the model of a Holocene pastoralist migration, originating in Eastern Africa, shaping the genomic landscape of historic and current southern African populations.


Asunto(s)
Grupo de Ascendencia Continental Africana/genética , Grupos Étnicos/genética , Genética de Población/métodos , Cabello/química , Grupo de Ascendencia Continental Africana/historia , Antropología Física , Grupos Étnicos/historia , Genoma Humano/genética , Historia del Siglo XIX , Historia Antigua , Migración Humana/historia , Humanos , Polimorfismo de Nucleótido Simple/genética , Sudáfrica
5.
Am J Hum Genet ; 108(1): 202-208, 2021 01 07.
Artículo en Inglés | MEDLINE | ID: mdl-33321100

RESUMEN

The genetics of African North Americans are complex amalgamations of various West and Central African peoples with modest gene flow from specific European and Amerindian peoples. A comprehensive understanding of African North American biohistory is a prerequisite for accurate interpretations of the ancestral genetics of this population. Too often, genetic interpretations falter with ahistorical reconstructions. The recently reported overrepresentation of Nigerian lineages in African North Americans reflects pronounced limitations in the African genomic database, the artificiality of the colonial maps of Africa, the contributions of multiple African empires and kingdoms into the transatlantic trade in enslaved Africans, and the overrepresentation of Yoruba peoples in the existing limited representation of West Africans in public genomic databases. This Matters Arising paper is in response to Micheletti et al. (2020), published in The American Journal of Human Genetics. See also the response by Micheletti et al. (2020), published in this issue.


Asunto(s)
Personas Esclavizadas , Afroamericanos/genética , Grupo de Ascendencia Continental Africana/genética , Américas , Humanos , Nigeria , Estados Unidos
6.
mSphere ; 5(5)2020 09 30.
Artículo en Inglés | MEDLINE | ID: mdl-32999084

RESUMEN

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]).


Asunto(s)
Grupo de Ascendencia Continental Africana/genética , Determinismo Genético , Racismo/prevención & control , Betacoronavirus , Infecciones por Coronavirus/epidemiología , Humanos , Microbiología , Microbiota , Pandemias , Neumonía Viral/epidemiología
7.
Cell Transplant ; 29: 963689720968749, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33108902

RESUMEN

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.


Asunto(s)
Infecciones por Coronavirus/patología , Predisposición Genética a la Enfermedad , Neoplasias/patología , Peptidil-Dipeptidasa A/genética , Neumonía Viral/patología , Serina Endopeptidasas/genética , Adulto , Grupo de Ascendencia Continental Africana/genética , Betacoronavirus/aislamiento & purificación , Sitios de Unión , Estudios de Casos y Controles , Infecciones por Coronavirus/virología , Bases de Datos Genéticas , Femenino , Frecuencia de los Genes , Variación Genética , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Neoplasias/epidemiología , Neoplasias/genética , Pandemias , Peptidil-Dipeptidasa A/metabolismo , Neumonía Viral/virología , Serina Endopeptidasas/metabolismo , Glicoproteína de la Espiga del Coronavirus/química , Glicoproteína de la Espiga del Coronavirus/metabolismo , Adulto Joven
8.
Am J Hum Genet ; 107(3): 379-380, 2020 09 03.
Artículo en Inglés | MEDLINE | ID: mdl-32888506

RESUMEN

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.


Asunto(s)
Investigación Biomédica , Variación Genética/genética , Poblaciones Vulnerables , Grupo de Ascendencia Continental Africana/genética , Grupo de Ascendencia Continental Europea/genética , Genoma Humano , Genómica , Genética Humana , Humanos
9.
PLoS One ; 15(9): e0239300, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32956418

RESUMEN

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.


Asunto(s)
Síndrome Nefrótico/tratamiento farmacológico , Esteroides/efectos adversos , Adolescente , África Occidental/epidemiología , Grupo de Ascendencia Continental Africana/genética , Niño , Preescolar , Estudios Transversales , Femenino , Tasa de Filtración Glomerular/efectos de los fármacos , Humanos , Lactante , Recién Nacido , Masculino , Hombres , Síndrome Nefrótico/epidemiología , Síndrome Nefrótico/genética , Síndrome Nefrótico/patología , Nigeria/epidemiología , Esteroides/uso terapéutico
10.
Am J Hum Genet ; 107(3): 473-486, 2020 09 03.
Artículo en Inglés | MEDLINE | ID: mdl-32781046

RESUMEN

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.


Asunto(s)
Adaptación Fisiológica/genética , Variación Genética/genética , Selección Genética/genética , Pigmentación de la Piel/genética , Grupo de Ascendencia Continental Africana/genética , Antiportadores/genética , Manejo de Datos , Etiopía/epidemiología , Femenino , Genética de Población , Genoma Humano/genética , Haplotipos/genética , Humanos , Masculino , Glicoproteínas de Membrana/genética , Oxidorreductasas/genética , Polimorfismo de Nucleótido Simple/genética , Nexinas de Clasificación/genética , Proteínas Supresoras de Tumor/genética , Uganda/epidemiología
11.
PLoS One ; 15(8): e0237041, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32813691

RESUMEN

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.


Asunto(s)
Afroamericanos/genética , Melaninas/genética , Pigmentación de la Piel/genética , Adulto , Grupo de Ascendencia Continental Africana/genética , Ciudades , Estudios Transversales , District of Columbia , Grupo de Ascendencia Continental Europea/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , New York , Ohio , Oklahoma , Clase Social
12.
PLoS One ; 15(7): e0233808, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32673320

RESUMEN

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.


Asunto(s)
Grupo de Ascendencia Continental Africana/genética , Grupo de Ascendencia Continental Europea/genética , Genoma Humano , Indios Sudamericanos/genética , Matrimonio , Linaje , Grupo de Ascendencia Continental Africana/etnología , Argentina , Colonialismo , ADN/genética , Esclavización , Grupo de Ascendencia Continental Europea/etnología , Marcadores Genéticos , Variación Genética , Genética de Población , Genotipo , Migración Humana , Humanos , Indios Sudamericanos/etnología , Modelos Genéticos
13.
Am J Hum Genet ; 107(2): 265-277, 2020 08 06.
Artículo en Inglés | MEDLINE | ID: mdl-32707084

RESUMEN

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.


Asunto(s)
Grupo de Ascendencia Continental Africana/genética , Polimorfismo de Nucleótido Simple/genética , África , Américas , Personas Esclavizadas , Europa (Continente) , Femenino , Humanos , Masculino
14.
Hum Genet ; 139(11): 1471-1483, 2020 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-32583022

RESUMEN

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.


Asunto(s)
Grupo de Ascendencia Continental Africana/genética , Moléculas de Adhesión Celular/genética , Proteínas Ligadas a GPI/genética , Trastornos del Crecimiento/genética , Hialuronoglucosaminidasa/genética , Polimorfismo de Nucleótido Simple/genética , Adulto , Alelos , Estatura/genética , Exoma/genética , Femenino , Estudio de Asociación del Genoma Completo/métodos , Humanos , Masculino
15.
PLoS Genet ; 16(6): e1008867, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32555579

RESUMEN

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.


Asunto(s)
Introgresión Genética , Genética de Población/métodos , Genoma Humano/genética , Modelos Genéticos , Polimorfismo Genético , África del Sur del Sahara , Grupo de Ascendencia Continental Africana/genética , Alelos , Antígenos/genética , Simulación por Computador , Europa (Continente) , Grupo de Ascendencia Continental Europea/genética , Evolución Molecular , Haplotipos , Humanos , Proteínas de Filamentos Intermediarios/genética , Receptores de Tirotropina/genética , Proteínas S100/genética , Selección Genética , Programas Informáticos
16.
Immunogenetics ; 72(5): 305-314, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32556499

RESUMEN

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.


Asunto(s)
Complemento C1q/genética , Complemento C1q/metabolismo , Predisposición Genética a la Enfermedad/genética , Tuberculosis/genética , Adulto , Grupo de Ascendencia Continental Africana/genética , Alelos , Estudios de Casos y Controles , Femenino , Estudios de Asociación Genética , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Familia de Multigenes , Polimorfismo de Nucleótido Simple , Tuberculosis/inmunología , Adulto Joven
17.
J Biol Chem ; 295(33): 11742-11753, 2020 08 14.
Artículo en Inglés | MEDLINE | ID: mdl-32587094

RESUMEN

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.


Asunto(s)
Betacoronavirus/química , Betacoronavirus/genética , Infecciones por Coronavirus/metabolismo , Bases de Datos de Proteínas , Simulación de Dinámica Molecular , Neumonía Viral/metabolismo , Proteoma , Grupo de Ascendencia Continental Africana/genética , Sistemas de Transporte de Aminoácidos Neutros/química , Sistemas de Transporte de Aminoácidos Neutros/genética , Sistemas de Transporte de Aminoácidos Neutros/metabolismo , Infecciones por Coronavirus/virología , Predisposición Genética a la Enfermedad , Variación Genética , Interacciones Huésped-Patógeno , Humanos , Masculino , Proteínas de la Nucleocápside/química , Proteínas de la Nucleocápside/metabolismo , Pandemias , Peptidil-Dipeptidasa A/química , Peptidil-Dipeptidasa A/genética , Peptidil-Dipeptidasa A/metabolismo , Fosfoproteínas , Neumonía Viral/virología , Mapas de Interacción de Proteínas , Procesamiento Proteico-Postraduccional , Homología de Secuencia de Aminoácido , Serina Endopeptidasas/química , Serina Endopeptidasas/genética , Serina Endopeptidasas/metabolismo , Glicoproteína de la Espiga del Coronavirus/química , Glicoproteína de la Espiga del Coronavirus/metabolismo
18.
PLoS One ; 15(5): e0230815, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32379818

RESUMEN

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.


Asunto(s)
Glucemia/análisis , Fumar Cigarrillos/genética , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/genética , Ayuno/sangre , Genotipo , Adulto , Grupo de Ascendencia Continental Africana/genética , Anciano , Fumar Cigarrillos/etnología , Estudios de Cohortes , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/etnología , Grupo de Ascendencia Continental Europea/genética , Estudios de Factibilidad , Femenino , Sitios Genéticos , Estudio de Asociación del Genoma Completo , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Riesgo
19.
Mol Genet Genomics ; 295(5): 1079-1089, 2020 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-32440765

RESUMEN

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.


Asunto(s)
Grupo de Ascendencia Continental Africana/genética , Predisposición Genética a la Enfermedad/genética , Genética de Población/métodos , África Austral , Variación Genética , Genoma Humano , Humanos , Estudios Prospectivos
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