RESUMO
BACKGROUND: The absence of melanocytes poses a challenge for long-term tissue homeostasis in vitiligo. Surprisingly, while individuals with Fitzpatrick phototypes I-II (low melanin content) have a higher incidence of melanoma and nonmelanoma skin cancer, people with vitiligo are at a decreased risk for the same. OBJECTIVES: To understand the molecular mechanisms that protect vitiligo skin from ultraviolet (UV)-induced DNA damage by (i) characterizing differentially expressed microRNAs in lesional vs. nonlesional epidermis and (ii) identifying their upstream regulators and downstream gene targets. METHODS: Genome-wide microRNA profiling of nonlesional and lesional epidermis was performed on five individuals with stable nonsegmental vitiligo using next-generation RNA sequencing. The relevance of the upstream regulator and downstream target gene of the most differentially expressed microRNA was studied. RESULTS: Our study found sirtuin1 (SIRT1), an NAD-dependent deacetylase, to be a direct target of miR-211 - the most significantly downregulated microRNA in lesional epidermis. Inhibition of SIRT1 with EX-527 downregulated keratin 10 and involucrin, suggesting that SIRT1 promotes keratinocyte differentiation. Overexpression of miR-211 mimic led to a significant increase in γ-H2AX positivity and cyclobutane pyrimidine dimer (CPD) formation, hallmarks of UVB-mediated DNA damage. These effects could be ameliorated by the addition of resveratrol, a SIRT1 activator. Furthermore, a long noncoding RNA, MALAT1, was identified as a negative upstream regulator of miR-211. Overexpression of MALAT1 resulted in increased expression of SIRT1 and a concomitant removal of UVB-induced CPDs in primary keratinocytes. CONCLUSIONS: These findings establish a novel MALAT1-miR-211-SIRT1 signalling axis that potentially confers protection to the 'amelanotic' keratinocytes in vitiligo.
Assuntos
Dano ao DNA , MicroRNAs , RNA Longo não Codificante , Sirtuína 1 , Raios Ultravioleta/efeitos adversos , Vitiligo , Epiderme , Humanos , MicroRNAs/genética , RNA Longo não Codificante/genética , Sirtuína 1/genética , Vitiligo/genéticaRESUMO
Familial Mediterranean fever (FMF), an autosomal recessive and rare autoinflammatory disease is caused by genetic mutations in the MEFV gene and is highly prevalent in the Mediterranean basin. Although the carrier frequency of specific disease variants in the MEFV gene has been reported from isolated studies, a comprehensive view of variants in the Mediterranean region has not been possible due to paucity of data. The recent availability of whole-genome and whole-exome datasets prompted us to study the genetic epidemiology of MEFV variants in the region. We assembled data from 5 datasets encompassing whole-genome and whole-exome datasets for 2115 individuals from multiple subpopulations in the region and also created a compendium for MEFV genetic variants, which were further systematically annotated as per the American College of Medical Genetics and Genomics (ACMG) guidelines. Our analysis points to significant differences in allele frequencies in the subpopulations, and the carrier frequency for MEFV genetic variants in the population to be about 8%. The MEFV gene appears to be under natural selection from our analysis. To the best of our knowledge, this is the most comprehensive study and analysis of population epidemiology of MEFV gene variants in the Middle East and North African populations.
Assuntos
Sequenciamento do Exoma/métodos , Febre Familiar do Mediterrâneo/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , África do Norte/epidemiologia , Febre Familiar do Mediterrâneo/epidemiologia , Frequência do Gene , Genômica/métodos , Humanos , Oriente Médio/epidemiologia , Mutação , Pirina/genéticaRESUMO
White spot syndrome virus (WSSV)-infected shrimp samples collected from grow-out ponds located at Nellore, Andhra Pradesh, India, showed WSSV negative and positive by PCR using primer sets specific to ORF119 and VP28 gene of WSSV, respectively. This indicated the deletion of genetic fragments in the genome of WSSV. The WSSV isolate along with lab strain of WSSV was subjected to next-generation sequencing. The sequence analysis revealed a deletion of 13,170 bp at five positions in the genome of WSSV-NS (new strain) relative to WSSV-TH and WSSV-LS (lab strain). The PCR analysis using the ORF's specific primer sets revealed the complete deletion of 10 ORFs in the genome of WSSV-NS strain. The primer set was designed based on sequence covering ORF161/162/163 to amplify a product of 2,748 bp for WSSV-LS and 402 bp for WSSV-NS. Our surveillance programme carried out since 2002 revealed the replacement of WSSV-LS by WSSV-NS in Indian shrimp culture system.
Assuntos
DNA Viral/análise , Genoma Viral , Penaeidae/virologia , Vírus da Síndrome da Mancha Branca 1/fisiologia , Animais , Deleção de Genes , Sequenciamento de Nucleotídeos em Larga Escala , Índia , Vírus da Síndrome da Mancha Branca 1/genéticaRESUMO
Expanding the scope of pharmacogenomic research by including multiple global populations is integral to building robust evidence for its clinical translation. Deep whole-genome sequencing of diverse ethnic populations provides a unique opportunity to study rare and common pharmacogenomic markers that often vary in frequency across populations. In this study, we aim to build a diverse map of pharmacogenetic variants in South East Asian (SEA) Malay population using deep whole-genome sequences of 100 healthy SEA Malay individuals. We investigated the allelic diversity of potentially deleterious pharmacogenomic variants in SEA Malay population. Our analysis revealed 227 common and 466 rare potentially functional single nucleotide variants (SNVs) in 437 pharmacogenomic genes involved in drug metabolism, transport and target genes, including 74 novel variants. This study has created one of the most comprehensive maps of pharmacogenetic markers in any population from whole genomes and will hugely benefit pharmacogenomic investigations and drug dosage recommendations in SEA Malays.