Doctoral candidate William Thomas is a candidate no more after successfully defending his dissertation! Congratulations to Dr. Thomas!

High viral tolerance coupled with an extraordinary regulation of the immune response makes bats a great model to study host-pathogen evolution. Although many immune-related gene gains and losses have been previously reported in bats, important gene families such as antimicrobial peptides (AMPs) remain understudied. We built an exhaustive bioinformatic pipeline targeting the major gene families of defensins and cathelicidins to explore AMP diversity and analyze their evolution and distribution across six bat families. A combination of manual and automated procedures identified 29 AMP families across queried species, with α-, β-defensins, and cathelicidins representing around 10% of AMP diversity. Gene duplications were inferred in both α-defensins, which were absent in five species, and three β-defensin gene subfamilies, but cathelicidins did not show significant shifts in gene family size and were absent in Anoura caudifer and the pteropodids. Based on lineage-specific gains and losses, we propose diet and diet-related microbiome evolution may determine the evolution of α- and β-defensins gene families and subfamilies. These results highlight the importance of building species-specific libraries for genome annotation in non-model organisms and shed light on possible drivers responsible for the rapid evolution of AMPs. By focusing on these understudied defenses, we provide a robust framework for explaining bat responses to pathogens.

Evolvability is an emergent hallmark of cancer that depends on intra-tumor heterogeneity and, ultimately, genetic variation. Mutations generated by APOBEC3 cytidine deaminases can contribute to genetic variation and the consequences of APOBEC activation differ depending on the stage of cancer, with the most significant impact observed during the early stages. However, how APOBEC activity shapes evolutionary patterns of genes in the host genome and differential impacts on cancer-associated and non-cancer genes remain unclear. Analyzing over 40,000 human protein-coding transcripts, we identified distinct distribution patterns of APOBEC3A/B TC motifs between cancer-related genes and controls, suggesting unique associations with cancer. Studying a bat species with many more APOBEC3 genes, we found diverse motif patterns in orthologs of cancer genes compared to controls, similar to humans and suggesting APOBEC evolution to reduce impacts on the genome rather than the converse. Simulations confirmed that APOBEC-induced heterogeneity enhances cancer evolution, shaping clonal dynamics through bimodal introduction of mutations in certain classes of genes. Our results suggest that a major consequence of the bimodal distribution of APOBEC affects greater cancer heterogeneity.

APOBEC3, an enzyme subfamily that plays a role in virus restriction by generating mutations at particular DNA motifs or mutational ‘hotspots’, can drive viral mutagenesis with host-specific preferential hotspot mutations contributing to pathogen variation. While previous analysis of viral genomes from the 2022 Mpox (formerly Monkeypox) disease outbreak has shown a high frequency of C>T mutations at TC motifs, suggesting recent mutations are human APOBEC3-mediated, how emerging monkeypox virus (MPXV) strains will evolve as a consequence of APOBEC3-mediated mutations remains unknown. By measuring hotspot under-representation, depletion at synonymous sites, and a combination of the two, we analyzed APOBEC3-driven evolution in human poxvirus genomes, finding varying hotspot under-representation patterns. While the native poxvirus molluscum contagiosum exhibits a signature consistent with extensive coevolution with human APOBEC3, including depletion of TC hotspots, variola virus shows an intermediate effect consistent with ongoing evolution at the time of eradication. MPXV, likely the result of recent zoonosis, showed many genes with more TC hotspots than expected by chance (over-representation) and fewer GC hotspots than expected (under-representation). These results suggest the MPXV genome: (1) may have evolved in a host with a particular APOBEC GC hotspot preference, (2) has inverted terminal repeat (ITR) regions—which may be exposed to APOBEC3 for longer during viral replication—and longer genes likely to evolve faster, and therefore (3) has a heightened potential for future human APOBEC3-meditated evolution as the virus spreads in the human population. Our predictions of MPXV mutational potential can both help guide future vaccine development and identification of putative drug targets and add urgency to the task of containing human Mpox disease transmission and uncovering the ecology of the virus in its reservoir host.