Nanopore sequencing-enabled evidence of non-canonical translation in the dengue genome | LC 25

Biography

Dr Rajesh Pandey, Principal Scientist and Group Leader at CSIR-IGIB, India, works on INtegrative GENomics of HOst-Pathogen (INGEN-HOPE). The laboratory is focused on finding answers to the hierarchical layers of genome regulation modulating differential disease severity and clinical outcome vis-a-vis pathogen/s interaction with the host. The interactome includes pathogen, host immune response, transcriptionally active microbes (TAMs), single-cell transcriptomics, and clinical partners. The focus is to identify the susceptible patient sub-groups towards future disease severity for focused medical care.

Abstract

RNA viruses are associated with a spectrum of human diseases, with dengue being a notable example of a vector-borne RNA virus responsible for severe hemorrhagic fever. It is a disease of long-term concern for tropical countries, especially India. Its compact genome necessitates reliance on the host’s translational machinery for replication. This study investigates the adaptive strategies employed by dengue serotypes for effective translation within hosts. By analyzing long viral reads from the nanopore-derived RNA sequencing dataset derived from hospital-admitted patients, we explored the impact of dinucleotide diversity on codon optimization, and compatibility of serotypes with the host. Our findings reveal only moderate congruency of serotypes with the host and identified genomic composition common to several RNA viruses. Notably, unique coverage patterns were observed within the genome of DENV2 serotypes. Using Ribo-seq data, we extended our analysis to assess the translatability of potential internal open reading frames (iORFs) identified in the RNA sequencing dataset. Nine common iORFs were identified across both datasets, underscoring non-canonical translational mechanisms that enhance genome optimization. The analysis of genome coverage and the identification of putative internal ORFs suggest that non-canonical translation events may play a role in viral survival, immune evasion, and protein synthesis regulation. In conclusion, it highlights the intricate evolutionary strategies employed by the dengue virus to adapt its genome for efficient replication and translation within the human host. These findings provide a foundation for future investigations into novel therapeutic targets and functional implications of non-canonical translation mechanisms in viral pathogenesis.