Schneor, L. | bioRxiv Science

bioRxiv2024

Evolutionary divergence of induced versus constitutive antiviral gene expression between primates and rodents

BackgroundHundreds of genes are upregulated in response to viral infection. These genes sequences often diverge across mammals, to counteract rapid virus evolution. However, the transcriptional divergence of these genes, their relative levels before and after infection in different host species, remains poorly understood. ResultsWe studied this divergence by comparing gene expression before and after viral stimulation in cells from primates and rodents. We developed a method to identify orthologs upregulated in one species that are unchanged in response to stimulus in another species. Using human and mouse data, we detected 578 transcriptionally divergent orthologous genes. While most divergent genes do not belong to the same cellular process, several pathways and protein complexes are enriched in this set, suggesting that divergence in immune responses between closely related mammals is limited to specific modules rather than involving entire pathways. Transcriptional divergence between human and mouse orthologs was also observed when ortholog expression from different primates and rodents were compared, when responses were studied in several cell types, and was recapitulated at the chromatin level, using histone mark patterns that denote active promoter regions. ConclusionsIn summary, we found genes whose orthologs diverge between primates and rodents in response to immune stimulation. Some of these genes are constitutively expressed in one species even before infection, potentially facilitating rapid antiviral activity, and suggesting clade-specific adaptation to confer greater resistance against viruses. Further comparative studies on diverse infections can point to additional species-specific responses and how they enable different species to overcome infection.

bioinformatics↗

bioRxiv2023

A comparative analysis of the antiviral response in two bat species reveals conserved and divergent innate immune pathways

Bats host a range of viruses that cause severe disease in humans without displaying clinical symptoms to these infections. The mechanisms of bat adaptation to these viruses are a continuous source of interest but remain largely unknown. To understand the landscape of bat antiviral response in a comprehensive and comparative manner, we studied this response in two bat species - the Egyptian fruit bat and the insectivore Kuhls pipistrelle, representing the two major bat subordinal clades. We profiled the transcriptional response to dsRNA - that triggers a rapid innate immune response - in skin fibroblasts from a large cohort of replicates from each bat species, using RNA-sequencing, and compared bat response with responses in primates and rodents. Both bat species upregulate a similar set of genes, many of which are known to be involved in the antiviral response across mammals. However, a subset of these genes is transcriptionally divergent in response between the two bat species. These transcriptionally divergent genes also evolve rapidly in coding sequence across the bat clade and have particular regulatory and functional characteristics, including specific promoter architectures and association with expression programs thought to underlie tolerance and resistance in response to viral infection. In addition, using single-cell transcriptomics, we show that transcriptionally divergent genes display high expression variability between individual cells. A focused analysis of dsRNA-sensing pathways further points to significant differences between bat and human in basal expression of genes important for triggering antiviral responses. Finally, a survey of genes recently lost or duplicated in bats points to a limited set of antiviral genes that have undergone rapid gene loss or gain in bats, with the latter group resulting in paralogs displaying divergence in both coding sequence and expression in bat tissues. Our study reveals a largely conserved regulatory program of genes upregulated in response to viral infection across bats and other mammals, and points to a set of genes that evolved rapidly in bats through multiple evolutionary mechanisms. This divergence can contribute to bat adaptation to viral infection and provides directions to understanding the mechanisms behind it.

evolutionary biology↗