RESUMEN
Monitoring the genetic variability of human respiratory syncytial virus (hRSV) is of paramount importance, especially for the potential implication of key antigenic mutations on the emergence of immune escape variants. Thus, to describe the genetic diversity and evolutionary dynamics of hRSV circulating in Sicily (Italy), a total of 153 hRSV whole-genome sequences collected from 770 hRSV-positive subjects between 2017 and 2023, before the introduction of expanded immunization programs into the population, were investigated. The phylogenetic analyses indicated that the genotypes GA.2.3.5 (ON1) for hRSV-A and GB.5.0.5a (BA9) for hRSV-B co-circulated in our region. Amino acid (AA) substitutions in the surface and internal proteins were evaluated, including the F protein antigenic sites, as the major targets of immunoprophylactic monoclonal antibodies and vaccines. Overall, the proportion of AA changes ranged between 1.5% and 22.6% among hRSV-A, whereas hRSV-B varied in the range 0.8-16.9%; the latter was more polymorphic than hRSV-A within the key antigenic sites. No AA substitutions were found at site III of both subgroups. Although several non-synonymous mutations were found, none of the polymorphisms known to potentially affect the efficacy of current preventive measures were documented. These findings provide new insights into the global hRSV molecular epidemiology and highlight the importance of defining a baseline genomic picture to monitor for future changes that might be induced by the selective pressures of immunological preventive measures, which will soon become widely available.
Asunto(s)
Variación Genética , Genotipo , Filogenia , Infecciones por Virus Sincitial Respiratorio , Virus Sincitial Respiratorio Humano , Secuenciación Completa del Genoma , Humanos , Virus Sincitial Respiratorio Humano/genética , Virus Sincitial Respiratorio Humano/clasificación , Virus Sincitial Respiratorio Humano/inmunología , Infecciones por Virus Sincitial Respiratorio/virología , Infecciones por Virus Sincitial Respiratorio/epidemiología , Sicilia/epidemiología , Preescolar , Lactante , Femenino , Masculino , Niño , Adulto , Adolescente , Genoma Viral , Persona de Mediana Edad , Adulto Joven , Anciano , Gripe Humana/virología , Gripe Humana/epidemiología , Sustitución de Aminoácidos , Recién NacidoRESUMEN
BACKGROUND: Temperament is an important production trait in cattle and multiple strategies had been developed to generate molecular markers to assist animal selection. As nonsynonymous single nucleotide polymorphisms are markers with the potential to affect gene functions, they could be useful to predict phenotypic effects. Genetic selection of less stress-responsive, temperamental animals is desirable from an economic and welfare point of view. METHODS AND RESULTS: Two nonsynonymous single nucleotide polymorphisms identified in HTR1B and SLC18A2 candidate genes for temperament were analyzed in silico to determine their effects on protein structure. Those nsSNPs allowing changes in proteins were selected for a temperament association analysis in a Brahman population. Transversion effects on protein structure were evaluated in silico for each amino acid change model, revealing structural changes in the proteins of the HTR1B and SLC18A2 genes. The selected nsSNPs were genotyped in a Brahman population (n = 138), and their genotypic effects on three temperament traits were analyzed: exit velocity, pen score, and temperament score. Only the SNP rs209984404-HTR1B (C/A) showed a significant association (P = 0.0144) with pen score. The heterozygous genotype showed a pen score value 1.17 points lower than that of the homozygous CC genotype. CONCLUSION: The results showed that in silico analysis could direct the selection of nsSNPs with the potential to change the protein. Non-synonymous single nucleotide polymorphisms causing structural changes and reduced protein stability were identified. Only rs209984404-HTR1B shows that the allele affecting protein stability was associated with the genotype linked to docility in cattle.
Asunto(s)
Polimorfismo de Nucleótido Simple , Temperamento , Bovinos , Animales , Genotipo , Alelos , FenotipoRESUMEN
BACKGROUND: The emergence and rapid spread of new severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) variants have challenged the control of the COVID-19 pandemic globally. Burundi was not spared by that pandemic, but the genetic diversity, evolution, and epidemiology of those variants in the country remained poorly understood. The present study sought to investigate the role of different SARS-COV-2 variants in the successive COVID-19 waves experienced in Burundi and the impact of their evolution on the course of that pandemic. We conducted a cross-sectional descriptive study using positive SARS-COV-2 samples for genomic sequencing. Subsequently, we performed statistical and bioinformatics analyses of the genome sequences in light of available metadata. RESULTS: In total, we documented 27 PANGO lineages of which BA.1, B.1.617.2, AY.46, AY.122, and BA.1.1, all VOCs, accounted for 83.15% of all the genomes isolated in Burundi from May 2021 to January 2022. Delta (B.1.617.2) and its descendants predominated the peak observed in July-October 2021. It replaced the previously predominant B.1.351 lineage. It was itself subsequently replaced by Omicron (B.1.1.529, BA.1, and BA.1.1). Furthermore, we identified amino acid mutations including E484K, D614G, and L452R known to increase infectivity and immune escape in the spike proteins of Delta and Omicron variants isolated in Burundi. The SARS-COV-2 genomes from imported and community-detected cases were genetically closely related. CONCLUSION: The global emergence of SARS-COV-2 VOCs and their subsequent introductions in Burundi was accompanied by new peaks (waves) of COVID-19. The relaxation of travel restrictions and the mutations occurring in the virus genome played an important role in the introduction and the spread of new SARS-COV-2 variants in the country. It is of utmost importance to strengthen the genomic surveillance of SARS-COV-2, enhance the protection by increasing the SARS-COV-2 vaccine coverage, and adjust the public health and social measures ahead of the emergence or introduction of new SARS-COV-2 VOCs in the country.
Asunto(s)
COVID-19 , SARS-CoV-2 , Humanos , SARS-CoV-2/genética , Vacunas contra la COVID-19 , Estudios Transversales , Pandemias , COVID-19/epidemiología , GenómicaRESUMEN
Since the beginning of the Coronavirus disease-2019 pandemic, there has been a growing interest in exploring SARS-CoV-2 genetic variation to understand the origin and spread of the pandemic, improve diagnostic methods and develop the appropriate vaccines. The objective of this study was to identify the SARS-CoV-2s lineages circulating in Tunisia and to explore their amino acid signature in order to follow their genome dynamics. Whole genome sequencing and genetic analyses of fifty-eight SARS-CoV-2 samples collected during one-year between March 2020 and March 2021 from the National Influenza Center were performed using three sampling strategies.. Multiple lineage introductions were noted during the initial phase of the pandemic, including B.4, B.1.1, B.1.428.2, B.1.540 and B.1.1.189. Subsequently, lineages B1.160 (24.2%) and B1.177 (22.4%) were dominant throughout the year. The Alpha variant (B.1.1.7 lineage) was identified in February 2021 and firstly observed in the center of our country. In addition, A clear diversity of lineages was observed in the North of the country. A total of 335 mutations including 10 deletions were found. The SARS-CoV-2 proteins ORF1ab, Spike, ORF3a, and Nucleocapsid were observed as mutation hotspots with a mutation frequency exceeding 20%. The 2 most frequent mutations, D614G in S protein and P314L in Nsp12 appeared simultaneously and are often associated with increased viral infectivity. Interestingly, deletions in coding regions causing consequent deletions of amino acids and frame shifts were identified in NSP3, NSP6, S, E, ORF7a, ORF8 and N proteins. These findings contribute to define the COVID-19 outbreak in Tunisia. Despite the country's limited resources, surveillance of SARS-CoV-2 genomic variation should be continued to control the occurrence of new variants.
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COVID-19 , SARS-CoV-2 , Aminoácidos/genética , COVID-19/epidemiología , Genoma Viral , Humanos , Mutación , Filogenia , SARS-CoV-2/genética , Glicoproteína de la Espiga del Coronavirus/química , Glicoproteína de la Espiga del Coronavirus/genética , Túnez/epidemiologíaRESUMEN
Acyclovir (ACV) and penciclovir and their prodrugs are recommended for therapy or prophylaxis of Herpes simplex virus 1 (HSV-1) infections. Their administration, however, can lead to the emergence of resistant strains with altered viral thymidine kinase (TK) function, especially in immunocompromised patients. Furthermore, amino acid (aa) changes of the viral deoxyribonucleic acid polymerase (POL) may contribute to resistance to the aforementioned nucleoside analogues. Given this, treatment with foscarnet (FOS) or cidofovir (CDV) may represent an important alternative. Both drugs directly affect POL activity. Several aa changes of POL, such as L49I, E70K, L359I, E421V, P829S, T1121M, and M1226I, have been observed in ACV-resistant clinical strains which also carried relevant aa changes in their TK. Their contribution to ACV, FOS, and CDV resistance is not fully understood. In this study, these seven aa changes with unknown significance for ACV, FOS and CDV resistance were introduced separately into the POL of a recombinant HSV-1 strain rHSV-1(17+)Lox, equipped with or without information for expression of green fluorescent protein (GFP). The GFP-expressing variants were tested for susceptibility to ACV, FOS and CDV. An rHSV-1(17+)Lox GFP strain with the S724N change conferring resistance to ACV and FOS was generated and included as a control. Only the S724N change was confirmed to induce ACV and FOS resistance, whereas the other changes did not contribute to resistance. The underlying nucleotide substitutions of the POL gene should be therefore considered as natural polymorphism. These data will improve sequence-based prediction of antiviral susceptibility.
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Antivirales/farmacología , ADN Polimerasa Dirigida por ADN/efectos de los fármacos , Herpes Simple/tratamiento farmacológico , Herpesvirus Humano 1/efectos de los fármacos , Herpesvirus Humano 1/genética , Aciclovir/farmacología , Animales , Chlorocebus aethiops , Cidofovir/farmacología , Farmacorresistencia Viral/efectos de los fármacos , Foscarnet/farmacología , Guanina/farmacología , Humanos , Huésped Inmunocomprometido , Pruebas de Sensibilidad Microbiana , Timidina Quinasa/efectos de los fármacos , Células VeroRESUMEN
Hepatitis-hydropericardium syndrome (HHS) is a severe disease that causes 20 to 80% mortality in chickens aged 3 to 6 wk. Fowl aviadenovirus serotype 4 (FAdV-4) plays an important role in the etiology of HHS. Since 2015, outbreaks of HHS have been reported in several provinces of China; however, details regarding the FAdV-4 genome properties are lacking. In the present study, the complete genomes of 9 isolates responsible for these outbreaks in Guangxi Province, China, were sequenced. To investigate the molecular characteristics of these FAdV-4 isolates, we compared their genomes with those of other reported pathogenic and nonpathogenic FAdV-4 isolates. A variable number of GA repeats were observed in the isolates of this study. Each of the isolates GX2017-01, GX2017-02, GX2018-08, and GX2019-09 had 11 GA repeats; GX2017-03, GX2017-04, and GX2017-05 each had 10 GA repeats, while GX2017-06 and GX2018-07 each had 8 GA repeats. We observed several deletions and distinct amino acid mutations in the major structural genes of these isolates when compared with non-Chinese isolates. We found 2 novel putative genetic markers in the hexon protein, one present in GX2017-02, in which aspartic acid (D) was changed to tyrosine (Y), and another present in each of isolates GX2018-08 and GX2019-09, in which serine (S) was changed to arginine (R), when compared with selected Chinese and some non-Chinese isolates. Moreover, the phylogenetic analysis revealed that all the isolates of this study were clustered within FAdV-C. We found that these isolates were closely related to other recently isolated Chinese strains. The data presented in this study will not only increase the understanding of the molecular epidemiology and genetic diversity of FAdV-4 isolates in China but also has an important reference value of the major factors that determine the virulence of FAdV-4 strains.
Asunto(s)
Aviadenovirus , Variación Genética , Genoma Viral , Animales , Aviadenovirus/genética , Pollos , China/epidemiología , Genoma Viral/genética , Mutación , FilogeniaRESUMEN
BACKGROUND & AIMS: Sofosbuvir is a frequently used pan-genotype inhibitor of hepatitis C virus (HCV) polymerase. This drug eliminates most chronic HCV infections, and resistance-associated substitutions in the polymerase are rare. However, HCV genotype 3 responds slightly less well to sofosbuvir-based therapies than other genotypes. We collected data from England's National Health Service Early Access Program to search for virus factors associated with sofosbuvir treatment failure. METHODS: We collected patient serum samples and used the capture-fusion assay to assess viral sensitivity to sofosbuvir in 14 HCV genotype 3 samples. We identified polymorphisms associated with reduced response and created modified forms of HCV and replicons containing the substitutions of interest and tested their sensitivity to sofosbuvir and ribavirin. We examined the effects of these polymorphisms by performing logistic regression multivariate analysis on their association with sustained virologic response in a separate cohort of 411 patients with chronic HCV genotype 3 infection who had been treated with sofosbuvir and ribavirin, with or without pegylated interferon. RESULTS: We identified a substitution in the HCV genotype 3a NS5b polymerase at amino acid 150 (alanine [A] to valine [V]), V at position 150 was observed in 42% of patients) with a reduced response to sofosbuvir in virus replication assays. In patients treated with sofosbuvir-containing regimens, the A150V variant was associated with a reduced response to treatment with sofosbuvir and ribavirin, with or without pegylated interferon. In 326 patients with V at position 150, 71% achieved an sustained virologic response compared to 88% with A at position 150. In cells, V at position 150 reduced the response to sofosbuvir 7-fold. We found that another rare substitution, glutamic acid (E) at position 206, significantly reduced the response to sofosbuvir (8.34-fold reduction); the combinations of V at position 150 and E at position 206 reduced the virus response to sofosbuvir 35.77-fold. Additionally, in a single patient, we identified 5 rare polymorphisms that reduced sensitivity to sofosbuvir our cell system. CONCLUSIONS: A common polymorphism, V at position 150 in the HCV genotype 3a NS5b polymerase, combined with other variants, reduces the virus response to sofosbuvir. Clinically, infection with HCV genotype 3 containing this variant reduces odds of sustained virologic response. In addition, we identified rare combinations of variants in HCV genotype 3 that reduce response to sofosbuvir.
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Antivirales/uso terapéutico , Farmacorresistencia Viral , Hepacivirus/efectos de los fármacos , Hepatitis C Crónica/tratamiento farmacológico , Mutación , Polimorfismo Genético , Sofosbuvir/uso terapéutico , Proteínas no Estructurales Virales/antagonistas & inhibidores , Sustitución de Aminoácidos , Antivirales/efectos adversos , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Farmacorresistencia Viral/genética , Quimioterapia Combinada , Genotipo , Hepacivirus/enzimología , Hepacivirus/genética , Hepatitis C Crónica/diagnóstico , Hepatitis C Crónica/virología , Humanos , Fenotipo , Sofosbuvir/efectos adversos , Respuesta Virológica Sostenida , Factores de Tiempo , Resultado del Tratamiento , Proteínas no Estructurales Virales/genética , Proteínas no Estructurales Virales/metabolismoRESUMEN
BACKGROUND & AIMS: We performed genetic analyses of a multiethnic cohort of patients with idiosyncratic drug-induced liver injury (DILI) to identify variants associated with susceptibility. METHODS: We performed a genome-wide association study of 2048 individuals with DILI (cases) and 12,429 individuals without (controls). Our analysis included subjects of European (1806 cases and 10,397 controls), African American (133 cases and 1,314 controls), and Hispanic (109 cases and 718 controls) ancestry. We analyzed DNA from 113 Icelandic cases and 239,304 controls to validate our findings. RESULTS: We associated idiosyncratic DILI with rs2476601, a nonsynonymous polymorphism that encodes a substitution of tryptophan with arginine in the protein tyrosine phosphatase, nonreceptor type 22 gene (PTPN22) (odds ratio [OR] 1.44; 95% confidence interval [CI] 1.28-1.62; P = 1.2 × 10-9 and replicated the finding in the validation set (OR 1.48; 95% CI 1.09-1.99; P = .01). The minor allele frequency showed the same effect size (OR > 1) among ethnic groups. The strongest association was with amoxicillin and clavulanate-associated DILI in persons of European ancestry (OR 1.62; 95% CI 1.32-1.98; P = 4.0 × 10-6; allele frequency = 13.3%), but the polymorphism was associated with DILI of other causes (OR 1.37; 95% CI 1.21-1.56; P = 1.5 × 10-6; allele frequency = 11.5%). Among amoxicillin- and clavulanate-associated cases of European ancestry, rs2476601 doubled the risk for DILI among those with the HLA risk alleles A*02:01 and DRB1*15:01. CONCLUSIONS: In a genome-wide association study, we identified rs2476601 in PTPN22 as a non-HLA variant that associates with risk of liver injury caused by multiple drugs and validated our finding in a separate cohort. This variant has been associated with increased risk of autoimmune diseases, providing support for the concept that alterations in immune regulation contribute to idiosyncratic DILI.
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Negro o Afroamericano/genética , Enfermedad Hepática Inducida por Sustancias y Drogas/genética , Hispánicos o Latinos/genética , Proteína Tirosina Fosfatasa no Receptora Tipo 22/genética , Población Blanca/genética , Adulto , Amoxicilina/efectos adversos , Antibacterianos/efectos adversos , Estudios de Casos y Controles , Ácido Clavulánico/efectos adversos , Femenino , Frecuencia de los Genes , Estudio de Asociación del Genoma Completo , Antígeno HLA-A2/genética , Cadenas HLA-DRB1/genética , Humanos , Masculino , Persona de Mediana Edad , Mutación Missense , Polimorfismo de Nucleótido Simple , Factores de RiesgoRESUMEN
BACKGROUND: The naked mole rat (NMR, Heterocephalus glaber) is a long-lived rodent model with multiple extraordinary traits. They live underground and have been known to live for up to thirty years, much longer than similar-sized mice. Moreover, congenital cancer or experimentally induced cancer genesis could not been observed in this rodent so far. Such unique biochemical and physiological characteristics lead them to become a popular model for cancer research. RESULTS: In this paper, a genome-wide comparative analysis was conducted based on the genomes of NMR and several other mammals. First, all the annotated proteins of NMR were searched against 11 selected mammalian genomes to verify their occurrence in these organisms. Among them, 66 NMR genes were not detected in other 11 mammals, almost all of which present alkalinity isoelectric points. In contrast, a total of 89 genes that are present in all of the 11 organisms could not be found in NMR genome. Among them, 3 genes are known to be related to cancer development. Finally, we identified NMR-specific single amino acid change (SAAC) events for the proteins that are present in both NMR and other mammals. KEGG pathway database was also used to investigate the metabolic processes in which these SAAC proteins may be involved. These genes were significantly enriched in two known cancer pathways, "Pathways in cancer" and "Pancreatic cancer". In the "Pancreatic cancer" pathway, 3 out of 6 paths leading to DNA duplication appeared to be affected by direct connection to the SAAC genes in NMR. In addition, a significant number of other SAAC genes enriched in several cancer-related pathways have been known to be associated with a variety of cancers, implying that many of them may be also related to tumor genesis in mammals. CONCLUSIONS: Overall, our results not only can be used to find possible genes involved in physiological mechanism of NMR but also provide new clues for the anti-cancer mechanism of NMR.
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Genes Supresores de Tumor , Ratas Topo/genética , Envejecimiento/genética , Secuencia de Aminoácidos , Animales , Carcinogénesis/genética , Gatos , Bovinos , Secuencia Conservada , Perros , Estudio de Asociación del Genoma Completo , Humanos , Sistema de Señalización de MAP Quinasas/genética , Mamíferos/genética , Ratones , Ratas Topo/metabolismo , Datos de Secuencia Molecular , Oncogenes , Neoplasias Pancreáticas/genética , Mapeo de Interacción de Proteínas , Proteínas/genética , Ratas , Homología de Secuencia de Aminoácido , Especificidad de la EspecieRESUMEN
MicroRNAs (miRNAs), a family of small nonprotein-coding RNAs, play a critical role in posttranscriptional gene regulation by acting as adaptors for the miRNA-induced silencing complex to inhibit gene expression by targeting mRNAs for translational repression and/or cleavage. miR-155-5p and miR-155-3p are processed from the B-cell Integration Cluster (BIC) gene (now designated, MIR155 host gene or MIR155HG). MiR-155-5p is highly expressed in both activated B- and T-cells and in monocytes/macrophages. MiR-155-5p is one of the best characterized miRNAs and recent data indicate that miR-155-5p plays a critical role in various physiological and pathological processes such as hematopoietic lineage differentiation, immunity, inflammation, viral infections, cancer, cardiovascular disease, and Down syndrome. In this review we summarize the mechanisms by which MIR155HG expression can be regulated. Given that the pathologies mediated by miR-155-5p result from the over-expression of this miRNA it may be possible to therapeutically attenuate miR-155-5p levels in the treatment of several pathological processes.