Study reveals how viruses acquire genes from hosts in evolution

Utilizing AlphaFold2, scientists employed structural prediction to unveil the makeup and origins of 214 orthopoxvirus proteins, shedding light on previously undisclosed insights into their evolutionary history. One revelation, according to a March/ April 2023 study, was the repurposing of host enzymes for non-enzymatic functions within viruses, resulting in distinctive protein structures found in approximately one-third of orthopoxvirus virion proteins.

According to a study in the American Society for Microbiology (ASM), viruses with large double-stranded DNA genomes have obtained most of their genes from their hosts during various stages of evolution. While many virus genes share significant sequence similarities with cellular homologs, especially enzymes like DNA and RNA polymerases, a substantial fraction of virus genes lack recognizable counterparts, leaving their origins a mystery.

In the study, researchers delved into the possible origins of proteins encoded in orthopoxviruses, a well-studied virus group that includes major human pathogens. Employing AlphaFold2, they predicted the structures of all 214 orthopoxvirus proteins. Among these, 14 previously unknown proteins' origins became apparent, validating earlier inferences drawn from sequence analysis.

The study found that the adaptation of enzymes from host organisms for non-enzymatic, structural roles in virus reproduction. This adaptation involves significant changes, such as disrupting catalytic sites and a drastic divergence that hinders the detection of homology at the sequence level. In a notable instance, 16 orthopoxvirus proteins were found to be inactivated enzyme derivatives, including A20, an inactivated NAD-dependent DNA ligase, A3, an inactivated deubiquitinase, and F11, an inactivated prolyl hydroxylase. Additionally, nearly one-third of orthopoxvirus virion proteins displayed unique structures, suggesting adaptation and substantial structural rearrangement.

"For nearly one-third of the orthopoxvirus virion proteins, no significantly similar structures were identified, suggesting exaptation with subsequent major structural rearrangement that yielded unique protein folds," researchers wrote in their study.

American Society for Microbiology: Pascal Mutz, et al. Exaptation of Inactivated Host Enzymes for Structural Roles in Orthopoxviruses and Novel Folds of Virus Proteins Revealed by Protein Structure Modeling. ASM Journals (March/April 2023). DOI: https://journals.asm.org/doi/10.1128/mbio.00408-23