RESUMO
Nasopharyngeal Carcinoma (NPC) found to be dependent on geographical and racial variation and is more prevalent in Northeast (NE) India. WES-based study was conducted in three states (tribes); Nagaland (Naga), Mizoram (Mizo) and Manipur (Manipuri), which provided an overview of germline variants involved inthemajor signaling pathways. Validation and recurrence assessment of WES data confirmed the risk effect of STEAP3_rs138941861 and JAG1_rs2273059, and the protective role of PARP4_rs17080653 and TGFBR1_rs11568778 variants, where STEAP3_rs138941861conferring Arg290His substitution was the only exonic non-synonymous variant and to be located in proximity to the linking region between the transmembrane and oxidoreductasedomainsof STEAP3 protein, andaffectedits structural and functional dynamics by altering the Electrostatic Potential around this connecting region. Moreover, these significantly associated variants having deleterious effect were observed to have interactions in p53 signaling pathway which emphasizes the importance of this pathway in the causation of NPC.
Assuntos
Proteínas de Ciclo Celular/genética , Sequenciamento do Exoma/métodos , Proteína Jagged-1/genética , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/genética , Proteínas Nucleares/genética , Oxirredutases/genética , Receptor do Fator de Crescimento Transformador beta Tipo I/genética , Adulto , Substituição de Aminoácidos , Estudos de Casos e Controles , Proteínas de Ciclo Celular/química , Feminino , Predisposição Genética para Doença , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Índia , Masculino , Pessoa de Meia-Idade , Modelos Moleculares , Oxirredutases/química , Polimorfismo de Nucleotídeo Único , Conformação Proteica , Domínios ProteicosRESUMO
Epidemiological mapping shows Staphylococcus aureus to be the leading mastitis causing pathogen in India with diverse genetic lineages circulating in the dairy cattle population. We previously reported that endemic clonal strains of S. aureus isolated from subclinical mastitis lead to specific alteration of epigenetic modulators resulting in deviating immune response in intramammary infection mouse model. However, the extent of transcriptome modulation and associated alternative splicing in S. aureus mastitis is poorly understood. Hence, to gain a deeper insight of the extent of modulation of transcriptome landscape, we expanded the study here using high throughput, paired-end RNA sequencing analysis of the mouse mammary gland inoculated with three strains of S. aureus (SA1, SA2, and SA3) possessing specific genotype, virulence and enterotoxin traits. Overall, we detected 35,878 transcripts in S. aureus inoculated mammary gland, 23% more than those annotated in the reference genome. Expression of 20,756 transcripts was > 1 fragment per kilobase of transcript per million mapped fragments and 25.95% of multi-exonic genes were alternatively spliced. We noted Alternative Splicing (AS) events for > 100 immune-related genes. S. aureus infection quantitatively altered AS events in mice mammary gland. Collectively, the majority of differentially expressed significant genes clustered into immune-associated, cell adhesion and metabolic process categories. We observed AS events for 379 transcripts of genes putatively encoding several splicing associated proteins and transcription factors besides inflammatory mediators. The present analysis provides new insights into global transcriptome landscape and AS events in host-defense related genes in response to S. aureus intramammary infection, suggesting the need for studies focusing on multi-target and/or network therapeutics approach to combat mastitis.
