Evolutionary dynamics and molecular adaptation of Rift Valley fever virus across human and non-human outbreaks in Africa

Background Rift Valley fever virus (RVFV) is an emerging zoonotic virus of major public health and veterinary concern across Africa. Although past genomic studies focused on outbreak response and lineage classification, the molecular mechanisms driving viral persistence and adaptation remain poorly understood. This study aimed to identify RVFV protein-coding mutations and adaptive signatures across multiple epidemics and epizootics in Africa. Methods This retrospective genomic analysis examined 596 complete genomes of the three RVFV segments from the NCBI virus database, including L (n = 173), M (n = 196) and S (n = 227) from 13 African countries across both human and non-human hosts (1944–2022). Protein-coding mutations were identified using Genome Detective and custom scripts. Phylogenetic reconstruction was performed with IQ-TREE, host-state reconstruction was conducted to infer cross species transmission patterns and selection pressure analysis conducted using codon-based models implemented in the Datamonkey platform. All data analysis and visualizations were performed using R software. Results A total of 7,339 protein-coding mutations were identified, ranging from 2–20 per isolate. RVFV isolates collected in South Africa, Kenya and Madagascar exhibited the highest genomic diversity. Comparative analysis of the genome revealed higher mutation in L and S segments than in M and broader diversity among non-human hosts. Phylogenetic reconstruction showed human isolates formed sub clusters nested within livestock and vector lineages, consistent with transmission bottlenecks. We identified seven critical amino acid mutations across the genome: N277S, N277D and S278N in the polymerase (L); I442S, I442V, V659A in the glycoproteins (M) and N133S in the NSs protein (S). Positive selection at the corresponding codon sites, particularly within the polymerase and glycoprotein regions of human isolates, suggests adaptive evolution linked to replication efficiency and immune evasion. Conclusion RVFV evolution across Africa is shaped by both purifying and diversifying selection. Host-specific pressures drive adaptive substitutions that may fine tune polymerase function, alter glycoprotein antigenicity and enhance immune escape. These findings reveal molecular mechanisms of viral persistence and support the design of cross protective vaccines.