Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 11.945
Filtrar
1.
Mem Inst Oswaldo Cruz ; 116: e200441, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34259736

RESUMO

BACKGROUND: A previous phylogeographic study revealed two Aedes aegypti African-related mitochondrial lineages distributed in Colombian's cities with different eco-epidemiologic characteristics with regard to dengue virus (DENV). It has been proposed these lineages might indicate independent invasion sources. OBJECTIVES: Assessing to Colombian population structure and to support evidence of its probable source origin. METHODS: We analysed a total of 267 individuals from cities of Bello, Riohacha and Villavicencio, which 241 were related to the West and East African mitochondrial lineages (termed here as WAL and EAL, respectively). Eight polymorphic microsatellite loci were analysed aiming population structure. FINDINGS: Results indicate substantial gene flow among distant and low-connected cities composing a panmictic population with incipient local differentiation of Ae. aegypti is placed in Colombia. Likewise, genetic evidence indicates no significant differences among individuals related to WAL and EAL is placed. MAIN CONCLUSIONS: Minimal genetic differentiation in low-connected Ae. aegypti populations of Colombia, and lack concordance between mitochondrial and nuclear genealogies suggest that Colombian Ae. aegypti shared a common demographic history. Under this scenario, we suggest current Ae. aegypti population structure reflects a single origin instead of contemporary migration, which founding populations have a single source from a mitochondrial polymorphic African ancient.


Assuntos
Aedes , Dengue , Aedes/genética , Animais , Colômbia , Variação Genética/genética , Humanos , Filogeografia
2.
Mem Inst Oswaldo Cruz ; 116: e200584, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34076074

RESUMO

In the present study, we investigated the genetic diversity of Plasmodium vivax metacaspase 1 (PvMCA1) catalytic domain in two municipalities of the main malaria hotspot in Brazil, i.e., the Juruá Valley, and observed complete sequence identity among all P. vivax field isolates and the Sal-1 reference strain. Analysis of PvMCA1 catalytic domain in different P. vivax genomic sequences publicly available also revealed a high degree of conservation worldwide, with very few amino acid substitutions that were not related to putative histidine and cysteine catalytic residues, whose involvement with the active site of protease was herein predicted by molecular modeling. The genetic conservation presented by PvMCA1 may contribute to its eligibility as a druggable target candidate in vivax malaria.


Assuntos
Malária Vivax , Plasmodium vivax , Brasil , Domínio Catalítico , Variação Genética/genética , Humanos , Plasmodium vivax/genética , Proteínas de Protozoários/genética
3.
Nat Commun ; 12(1): 3739, 2021 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-34145258

RESUMO

Serum amyloid P component (SAP, also known as Pentraxin 2; APCS gene) is a component of the humoral arm of innate immunity involved in resistance to bacterial infection and regulation of tissue remodeling. Here we investigate the role of SAP in antifungal resistance. Apcs-/- mice show enhanced susceptibility to A. fumigatus infection. Murine and human SAP bound conidia, activate the complement cascade and enhance phagocytosis by neutrophils. Apcs-/- mice are defective in vivo in terms of recruitment of neutrophils and phagocytosis in the lungs. Opsonic activity of SAP is dependent on the classical pathway of complement activation. In immunosuppressed mice, SAP administration protects hosts against A. fumigatus infection and death. In the context of a study of hematopoietic stem-cell transplantation, genetic variation in the human APCS gene is associated with susceptibility to invasive pulmonary aspergillosis. Thus, SAP is a fluid phase pattern recognition molecule essential for resistance against A. fumigatus.


Assuntos
Aspergillus fumigatus/imunologia , Aspergilose Pulmonar Invasiva/imunologia , Neutrófilos/imunologia , Componente Amiloide P Sérico/genética , Animais , Células Cultivadas , Variação Genética/genética , Humanos , Imunidade Inata/imunologia , Hospedeiro Imunocomprometido/imunologia , Aspergilose Pulmonar Invasiva/patologia , Pulmão/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fagocitose/imunologia
4.
Nat Commun ; 12(1): 3761, 2021 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-34145262

RESUMO

Pernicious anemia is a rare condition characterized by vitamin B12 deficiency anemia due to lack of intrinsic factor, often caused by autoimmune gastritis. Patients with pernicious anemia have a higher incidence of other autoimmune disorders, such as type 1 diabetes, vitiligo, and autoimmune thyroid issues. Therefore, the disease has a clear autoimmune basis, although the genetic susceptibility factors have thus far remained poorly studied. We conduct a genome-wide association study meta-analysis in 2166 cases and 659,516 European controls from population-based biobanks and identify genome-wide significant signals in or near the PTPN22 (rs6679677, p = 1.91 × 10-24, OR = 1.63), PNPT1 (rs12616502, p = 3.14 × 10-8, OR = 1.70), HLA-DQB1 (rs28414666, p = 1.40 × 10-16, OR = 1.38), IL2RA (rs2476491, p = 1.90 × 10-8, OR = 1.22) and AIRE (rs74203920, p = 2.33 × 10-9, OR = 1.83) genes, thus providing robust associations between pernicious anemia and genetic risk factors.


Assuntos
Anemia Perniciosa/genética , Doenças Autoimunes/genética , Predisposição Genética para Doença/genética , Adulto , Idoso , Exorribonucleases/genética , Feminino , Gastrite/patologia , Variação Genética/genética , Estudo de Associação Genômica Ampla , Cadeias beta de HLA-DQ/genética , Humanos , Subunidade alfa de Receptor de Interleucina-2/genética , Masculino , Pessoa de Meia-Idade , Proteína Tirosina Fosfatase não Receptora Tipo 22/genética , Fatores de Risco , Fatores de Transcrição/genética
5.
Nat Commun ; 12(1): 2493, 2021 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-33941778

RESUMO

The need for precision medicine approaches to monitor health and disease makes it important to develop sensitive and accurate assays for proteome profiles in blood. Here, we describe an approach for plasma profiling based on proximity extension assay combined with next generation sequencing. First, we analyze the variability of plasma profiles between and within healthy individuals in a longitudinal wellness study, including the influence of genetic variations on plasma levels. Second, we follow patients newly diagnosed with type 2 diabetes before and during therapeutic intervention using plasma proteome profiling. The studies show that healthy individuals have a unique and stable proteome profile and indicate that a panel of proteins could potentially be used for early diagnosis of diabetes, including stratification of patients with regards to response to metformin treatment. Although validation in larger cohorts is needed, the analysis demonstrates the usefulness of comprehensive plasma profiling for precision medicine efforts.


Assuntos
Proteínas Sanguíneas/análise , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Plasma/química , Proteoma/análise , Idoso , Diabetes Mellitus Tipo 2/genética , Diagnóstico Precoce , Feminino , Variação Genética/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Hipoglicemiantes/uso terapêutico , Estudos Longitudinais , Masculino , Metformina/uso terapêutico , Pessoa de Meia-Idade , Medicina de Precisão/métodos , Proteômica/métodos
6.
Nat Commun ; 12(1): 2491, 2021 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-33941780

RESUMO

Mycobacterium kansasii can cause serious pulmonary disease. It belongs to a group of closely-related species of non-tuberculous mycobacteria known as the M. kansasii complex (MKC). Here, we report a population genomics analysis of 358 MKC isolates from worldwide water and clinical sources. We find that recombination, likely mediated by distributive conjugative transfer, has contributed to speciation and on-going diversification of the MKC. Our analyses support municipal water as a main source of MKC infections. Furthermore, nearly 80% of the MKC infections are due to closely-related M. kansasii strains, forming a main cluster that apparently originated in the 1900s and subsequently expanded globally. Bioinformatic analyses indicate that several genes involved in metabolism (e.g., maintenance of the methylcitrate cycle), ESX-I secretion, metal ion homeostasis and cell surface remodelling may have contributed to M. kansasii's success and its ongoing adaptation to the human host.


Assuntos
Água Potável/microbiologia , Genoma Bacteriano/genética , Pneumopatias/epidemiologia , Infecções por Mycobacterium não Tuberculosas/epidemiologia , Mycobacterium kansasii/genética , Metabolismo Energético/genética , Variação Genética/genética , Genética Populacional/métodos , Genômica , Humanos , Pneumopatias/microbiologia , Infecções por Mycobacterium não Tuberculosas/microbiologia , Mycobacterium kansasii/isolamento & purificação , Virulência/genética , Microbiologia da Água
7.
Hum Biol ; 92(3): 135-152, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-34057327

RESUMO

Recent studies have produced a variety of advances in the investigation of genetic similarities and differences among human populations. In this reprinted article, originally published in Human Biology in 2011 (vol. 83, no. 6, pp. 659-684), I pose a series of questions about human population-genetic similarities and differences, and I then answer these questions by numerical computation with a single shared population-genetic data set. The collection of answers obtained provides an introductory perspective for understanding key results on the features of worldwide human genetic variation. A new foreword discusses the original article in light of the research that has followed.


Assuntos
Variação Genética , Repetições de Microssatélites , Alelos , Variação Genética/genética , Genética Populacional , Humanos
8.
Hum Biol ; 92(3): 153-166, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-34057328

RESUMO

Geneticists have argued that the linear decay in within-population genetic diversity with increasing geographic distance from East Africa is best explained by a phylogenetic process of repeated founder effects, growth, and isolation. However, this serial founder effect (SFE) process has not yet been adequately vetted against other evolutionary processes that may also affect geospatial patterns of diversity. Additionally, studies of the SFE process have been largely based on a limited 52-population sample. In this modestly updated article, originally published in Human Biology in 2016 (vol. 88, no. 3, pp. 219-231), we assess the effects of founder effect, admixture, and localized gene flow processes on patterns of global and regional diversity using a published data set of 645 autosomal microsatellite genotypes from 5,415 individuals in 248 widespread populations. We used a formal tree-fitting approach to explore the role of founder effects. The approach involved fitting global and regional population trees to extant patterns of gene diversity and then systematically examining the deviations in fit. We also informally tested the SFE process using linear models of gene diversity versus waypoint geographic distances from Africa. We tested the role of localized gene flow using partial Mantel correlograms of gene diversity versus geographic distance controlling for the confounding effects of treelike genetic structure. We corroborate previous findings that global patterns of diversity, both within and between populations, are the product of an out-of-Africa SFE process. Within regions, however, diversity within populations is uncorrelated with geographic distance from Africa. Here, patterns of diversity have been largely shaped by recent interregional admixture and secondary range expansions. Our detailed analyses of the pattern of diversity within and between populations reveal that the signatures of different evolutionary processes dominate at different geographic scales. These findings have important implications for recent publications on the biology of race. Our new foreword situates these findings in a long line of anthropological research that categorically rejects racial interpretations of analyses of human diversity.


Assuntos
Efeito Fundador , Fluxo Gênico , África , Variação Genética/genética , Genética Populacional , Humanos , Repetições de Microssatélites , Filogenia
10.
mSphere ; 6(3)2021 05 05.
Artigo em Inglês | MEDLINE | ID: covidwho-1218209

RESUMO

Genome-wide variation in SARS-CoV-2 reveals evolution and transmission dynamics which are critical considerations for disease control and prevention decisions. Here, we review estimates of the genome-wide viral mutation rates, summarize current COVID-19 case load in the province of Ontario, Canada (5 January 2021), and analyze published SARS-CoV-2 genomes from Ontario (collected prior to 24 November 2020) to test for more infectious genetic variants or lineages. The reported mutation rate (∼10-6 nucleotide [nt]-1 cycle-1) for SARS-CoV-2 is typical for coronaviruses. Analysis of published SARS-CoV-2 genomes revealed that the G614 spike protein mutation has dominated infections in Ontario and that SARS-CoV-2 lineages present in Ontario have not differed significantly in their rate of spread. These results suggest that the SARS-CoV-2 population circulating in Ontario has not changed significantly to date. However, ongoing genome monitoring is essential for identification of new variants and lineages that may contribute to increased viral transmission.


Assuntos
Variação Genética/genética , Genoma Viral/genética , Taxa de Mutação , SARS-CoV-2/genética , Glicoproteína da Espícula de Coronavírus/genética , Sequência de Bases , COVID-19/patologia , Humanos , Ontário , Filogenia , Análise de Sequência de RNA
11.
PLoS One ; 16(5): e0251585, 2021.
Artigo em Inglês | MEDLINE | ID: covidwho-1225814

RESUMO

Understanding how human ACE2 genetic variants differ in their recognition by SARS-CoV-2 can facilitate the leveraging of ACE2 as an axis for treating and preventing COVID-19. In this work, we experimentally interrogate thousands of ACE2 mutants to identify over one hundred human single-nucleotide variants (SNVs) that are likely to have altered recognition by the virus, and make the complementary discovery that ACE2 residues distant from the spike interface influence the ACE2-spike interaction. These findings illuminate new links between ACE2 sequence and spike recognition, and could find substantial utility in further fundamental research that augments epidemiological analyses and clinical trial design in the contexts of both existing strains of SARS-CoV-2 and novel variants that may arise in the future.


Assuntos
Enzima de Conversão de Angiotensina 2/genética , COVID-19/metabolismo , Glicoproteína da Espícula de Coronavírus/genética , Enzima de Conversão de Angiotensina 2/metabolismo , Sítios de Ligação/genética , COVID-19/genética , Variação Genética/genética , Humanos , Modelos Moleculares , Peptidil Dipeptidase A/metabolismo , Polimorfismo de Nucleotídeo Único/genética , Ligação Proteica/genética , Receptores Virais/genética , SARS-CoV-2/genética , SARS-CoV-2/metabolismo , SARS-CoV-2/patogenicidade , Glicoproteína da Espícula de Coronavírus/metabolismo , Replicação Viral/genética
12.
Cell Rep ; 35(6): 109109, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: covidwho-1201425

RESUMO

It is unclear whether individuals with enormous diversity in B cell receptor repertoires are consistently able to mount effective antibody responses against SARS-CoV-2. We analyzed antibody responses in a cohort of 55 convalescent patients and isolated 54 potent neutralizing monoclonal antibodies (mAbs). While most of the mAbs target the angiotensin-converting enzyme 2 (ACE2) binding surface on the receptor binding domain (RBD) of SARS-CoV-2 spike protein, mAb 47D1 binds only to one side of the receptor binding surface on the RBD. Neutralization by 47D1 is achieved independent of interfering RBD-ACE2 binding. A crystal structure of the mAb-RBD complex shows that the IF motif at the tip of 47D1 CDR H2 interacts with a hydrophobic pocket in the RBD. Diverse immunoglobulin gene usage and convergent epitope targeting characterize neutralizing antibody responses to SARS-CoV-2, suggesting that vaccines that effectively present the receptor binding site on the RBD will likely elicit neutralizing antibody responses in a large fraction of the population.


Assuntos
Anticorpos Neutralizantes/genética , COVID-19/genética , Imunoglobulinas/genética , Adulto , Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Sítios de Ligação/imunologia , COVID-19/imunologia , COVID-19/terapia , Epitopos/genética , Epitopos/imunologia , Feminino , Genes de Imunoglobulinas/genética , Variação Genética/genética , Humanos , Imunização Passiva/métodos , Imunoglobulinas/imunologia , Masculino , Pessoa de Meia-Idade , Peptidil Dipeptidase A/metabolismo , Ligação Proteica/imunologia , Domínios Proteicos/genética , Receptores Virais/imunologia , Receptores Virais/metabolismo , SARS-CoV-2/genética , SARS-CoV-2/imunologia , SARS-CoV-2/patogenicidade
13.
PLoS One ; 16(5): e0251585, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33979391

RESUMO

Understanding how human ACE2 genetic variants differ in their recognition by SARS-CoV-2 can facilitate the leveraging of ACE2 as an axis for treating and preventing COVID-19. In this work, we experimentally interrogate thousands of ACE2 mutants to identify over one hundred human single-nucleotide variants (SNVs) that are likely to have altered recognition by the virus, and make the complementary discovery that ACE2 residues distant from the spike interface influence the ACE2-spike interaction. These findings illuminate new links between ACE2 sequence and spike recognition, and could find substantial utility in further fundamental research that augments epidemiological analyses and clinical trial design in the contexts of both existing strains of SARS-CoV-2 and novel variants that may arise in the future.


Assuntos
Enzima de Conversão de Angiotensina 2/genética , COVID-19/metabolismo , Glicoproteína da Espícula de Coronavírus/genética , Enzima de Conversão de Angiotensina 2/metabolismo , Sítios de Ligação/genética , COVID-19/genética , Variação Genética/genética , Humanos , Modelos Moleculares , Peptidil Dipeptidase A/metabolismo , Polimorfismo de Nucleotídeo Único/genética , Ligação Proteica/genética , Receptores Virais/genética , SARS-CoV-2/genética , SARS-CoV-2/metabolismo , SARS-CoV-2/patogenicidade , Glicoproteína da Espícula de Coronavírus/metabolismo , Replicação Viral/genética
14.
Cell Rep ; 35(6): 109109, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33932326

RESUMO

It is unclear whether individuals with enormous diversity in B cell receptor repertoires are consistently able to mount effective antibody responses against SARS-CoV-2. We analyzed antibody responses in a cohort of 55 convalescent patients and isolated 54 potent neutralizing monoclonal antibodies (mAbs). While most of the mAbs target the angiotensin-converting enzyme 2 (ACE2) binding surface on the receptor binding domain (RBD) of SARS-CoV-2 spike protein, mAb 47D1 binds only to one side of the receptor binding surface on the RBD. Neutralization by 47D1 is achieved independent of interfering RBD-ACE2 binding. A crystal structure of the mAb-RBD complex shows that the IF motif at the tip of 47D1 CDR H2 interacts with a hydrophobic pocket in the RBD. Diverse immunoglobulin gene usage and convergent epitope targeting characterize neutralizing antibody responses to SARS-CoV-2, suggesting that vaccines that effectively present the receptor binding site on the RBD will likely elicit neutralizing antibody responses in a large fraction of the population.


Assuntos
Anticorpos Neutralizantes/genética , COVID-19/genética , Imunoglobulinas/genética , Adulto , Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Sítios de Ligação/imunologia , COVID-19/imunologia , COVID-19/terapia , Epitopos/genética , Epitopos/imunologia , Feminino , Genes de Imunoglobulinas/genética , Variação Genética/genética , Humanos , Imunização Passiva/métodos , Imunoglobulinas/imunologia , Masculino , Pessoa de Meia-Idade , Peptidil Dipeptidase A/metabolismo , Ligação Proteica/imunologia , Domínios Proteicos/genética , Receptores Virais/imunologia , Receptores Virais/metabolismo , SARS-CoV-2/genética , SARS-CoV-2/imunologia , SARS-CoV-2/patogenicidade
16.
Nat Commun ; 12(1): 3126, 2021 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-34035259

RESUMO

Hybridization and polyploidization are powerful mechanisms of speciation. Hybrid speciation often coincides with whole-genome duplication (WGD) in eukaryotes. This suggests that WGD may allow hybrids to thrive by increasing fitness, restoring fertility and/or increasing access to adaptive mutations. Alternatively, it has been suggested that hybridization itself may trigger WGD. Testing these models requires quantifying the rate of WGD in hybrids without the confounding effect of natural selection. Here we show, by measuring the spontaneous rate of WGD of more than 1300 yeast crosses evolved under relaxed selection, that some genotypes or combinations of genotypes are more prone to WGD, including some hybrids between closely related species. We also find that higher WGD rate correlates with higher genomic instability and that WGD increases fertility and genetic variability. These results provide evidence that hybridization itself can promote WGD, which in turn facilitates the evolution of hybrids.


Assuntos
Duplicação Gênica , Genoma Fúngico/genética , Hibridização Genética , Saccharomyces/genética , Adaptação Fisiológica/genética , Diploide , Evolução Molecular , Variação Genética/genética , Instabilidade Genômica/genética , Taxa de Mutação , Filogenia , Poliploidia , Saccharomyces/classificação , Saccharomyces cerevisiae/genética , Especificidade da Espécie
17.
Neurology ; 96(18): e2251-e2260, 2021 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-34038384

RESUMO

OBJECTIVE: To identify the causative gene in a large unsolved family with genetic epilepsy with febrile seizures plus (GEFS+), we sequenced the genomes of family members, and then determined the contribution of the identified gene to the pathogenicity of epilepsies by examining sequencing data from 2,772 additional patients. METHODS: We performed whole genome sequencing of 3 members of a GEFS+ family. Subsequently, whole exome sequencing data from 1,165 patients with epilepsy from the Epi4K dataset and 1,329 Australian patients with epilepsy from the Epi25 dataset were interrogated. Targeted resequencing was performed on 278 patients with febrile seizures or GEFS+ phenotypes. Variants were validated and familial segregation examined by Sanger sequencing. RESULTS: Eight previously unreported missense variants were identified in SLC32A1, coding for the vesicular inhibitory amino acid cotransporter VGAT. Two variants cosegregated with the phenotype in 2 large GEFS+ families containing 8 and 10 affected individuals, respectively. Six further variants were identified in smaller families with GEFS+ or idiopathic generalized epilepsy (IGE). CONCLUSION: Missense variants in SLC32A1 cause GEFS+ and IGE. These variants are predicted to alter γ-aminobutyric acid (GABA) transport into synaptic vesicles, leading to altered neuronal inhibition. Examination of further epilepsy cohorts will determine the full genotype-phenotype spectrum associated with SLC32A1 variants.


Assuntos
Epilepsia Generalizada/diagnóstico , Epilepsia Generalizada/genética , Variação Genética/genética , Mutação de Sentido Incorreto/genética , Convulsões Febris/diagnóstico , Convulsões Febris/genética , Proteínas Vesiculares de Transporte de Aminoácidos Inibidores/genética , Feminino , Estudos de Associação Genética/métodos , Humanos , Masculino , Linhagem
18.
Methods Mol Biol ; 2290: 157-169, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34009589

RESUMO

Sustainable biofuel sources require the new sources of biofuel crops that can be developed into scalable plantation to meet the growing energy demands. Diverse supply sources of bioenergy plantations (edible, nonedible, and perennial grasses) will enable de-risking impact on geography and climate change that humans are likely to face in future. Use of phenotypic descriptors alone does not provide a deep insight into plantation population dynamics and molecular diversity of a biofuel crop. We provide protocols and methods to rapidly assess population parameters for emerging biofuel crops using genomics. This article has an application focus on next-generation sequencing to assess biofuel crop diversity. Use of these methods can accelerate germplasm assessment to accelerate population development and creation of sustainable biofuel plantations.


Assuntos
Agricultura/métodos , Biocombustíveis/análise , Produtos Agrícolas/genética , Biomassa , Ecossistema , Variação Genética/genética , Solo
19.
mSphere ; 6(3)2021 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-33952657

RESUMO

Genome-wide variation in SARS-CoV-2 reveals evolution and transmission dynamics which are critical considerations for disease control and prevention decisions. Here, we review estimates of the genome-wide viral mutation rates, summarize current COVID-19 case load in the province of Ontario, Canada (5 January 2021), and analyze published SARS-CoV-2 genomes from Ontario (collected prior to 24 November 2020) to test for more infectious genetic variants or lineages. The reported mutation rate (∼10-6 nucleotide [nt]-1 cycle-1) for SARS-CoV-2 is typical for coronaviruses. Analysis of published SARS-CoV-2 genomes revealed that the G614 spike protein mutation has dominated infections in Ontario and that SARS-CoV-2 lineages present in Ontario have not differed significantly in their rate of spread. These results suggest that the SARS-CoV-2 population circulating in Ontario has not changed significantly to date. However, ongoing genome monitoring is essential for identification of new variants and lineages that may contribute to increased viral transmission.


Assuntos
Variação Genética/genética , Genoma Viral/genética , Taxa de Mutação , SARS-CoV-2/genética , Glicoproteína da Espícula de Coronavírus/genética , Sequência de Bases , COVID-19/patologia , Humanos , Ontário , Filogenia , Análise de Sequência de RNA
20.
Gene ; 791: 145709, 2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-33984442

RESUMO

Cervical cancer is the second most diagnosed cancer in Moroccan women. The main etiological factor for developing cervical cancer is the persistent infection with HPV16. Genetic studies have reported the occurrence of amino acid variations within the E6 oncoprotein that promotes host cell transformation by targeting p53 for degradation. To verify the biological effects of E6 polymorphisms towards p53 degradation, HPV16-E6 prototype and 7 variants isolated from cervical cancer biopsies of Moroccan women were evaluated for their activities by transient expression assays using pcDNA3.1-E6 constructs in C33A cell line. Expression of E6 genes in transfected cells was detected with reverse transcription PCR (RT-PCR), then, p53 levels were evaluated by western blot analysis. Significant dissimilarities in p53 degradation activities of HPV16-E6 prototype and intratypic variants were noticed. As compared to the prototype, the highest p53 degradation were exhibited by the African variants Af2-a/r, Af1-d/G295 and Af2-a/G285 (p < 0.001), followed by the European variants E- C442/G350 and E-G350/r (p < 0.01), then, the North American variant NA1-b/r (p < 0.05). The inter-variant differences were statistically significant between Af2-a/r variant and the North American variants NA1-b/r and NA1 (p < 0.05). Thus, the Af2-a/r variant was significantly more active in degrading p53 in our in vitro experiments (p < 0.0001). Our findings support the fact that HPV16-E6 variations have a biological impact on degrading p53, and so, represent a significant carcinogenic potential for developing cervical cancer.


Assuntos
Proteínas Oncogênicas Virais/genética , Proteínas Oncogênicas Virais/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Adulto , Idoso , Linhagem Celular , Feminino , Variação Genética/genética , Papillomavirus Humano 16/genética , Papillomavirus Humano 16/metabolismo , Humanos , Pessoa de Meia-Idade , Marrocos/epidemiologia , Mutação/genética , Infecções por Papillomavirus/genética , Polimorfismo Genético/genética , Proteína Supressora de Tumor p53/genética , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/virologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...