Whole-Genome Analysis of LSDV Isolates from the 2019 and 2023 Outbreaks in Israel Points to Undetected Circulation and Recombination Events

Lumpy skin disease virus (LSDV) is a large DNA capripoxvirus that causes LSD, a disease that has major economic impact. Since 1989, several sporadic outbreaks were reported in Israel, with the latest outbreaks in 2012, 2019 and 2023. Although considered genetically stable, LSDV shows a high degree of genetic recombination events and genetic variations. In particular, in-frame nonsense mutations were suggested to act as one of the main evolutionary drivers of outbreaks. Whole-genome sequencing of LSDV isolates from the 2019 and 2023 outbreaks was used for genomic analysis using various bioinformatics tools to characterize the genomic evolution, recombination events and micro-evolutionary forces shaping LSDV in Israel by comparing isolates. Comparative genomic analysis revealed substantial nucleotide substitutions in the 2019 and 2023 isolates relative to the 2012 isolate. Specifically, increased nucleotide mismatches, inter-genic deletion, enhanced APOBEC editing signatures and elevated codon usage. Additionally, numerous mutations were recognized, leading to structural disruptions in specific viral proteins and possible RNA instability. In conclusion, this analysis supports that nucleotide substitutions, codon selection pressure and APOBEC-associated editing had driven local microevolution of LSDV during the years between outbreaks despite the absence of clinical indications and major vaccination campaigns. Furthermore, genomic evidences of recombination events between the 2012 and 2019 isolates suggests that these processes may have contributed to the emergence of the variant identified during the 2023 outbreak.