Global distribution and evolution of nine major non-polio enteroviruses revealed by genomic data mining

This study aimed to elucidate the global epidemic trends and evolutionary characteristics of nine major non-polio enterovirus serotypes (CVA2, CVA4, CVA6, CVA10, CVA16, CVB3, CVB5, EV-A71, and EV-D68) through genomic data mining, focusing on their spatiotemporal distribution and evolutionary dynamics. We employed a data mining framework integrating programming, phylogenetic analysis, Bayesian evolutionary modeling, and selection pressure assessment. Over 40,000 genomic sequences from GenBank were analyzed to reconstruct temporal phylogenies, estimate evolutionary rates, and characterize amino acid variability in the capsid protein VP1. Seasonal decomposition and spatial-temporal trend modeling were applied to evaluate epidemic patterns across the six WHO regions. Key findings include [1]: Distinct biennial or triennial epidemic cycles for EV-D68 and clear seasonal peaks for HFMD-associated serotypes [2]; A preliminary observation termed the “60% Transcendence” phenomenon, where once cumulative VP1 nucleotide mutations reach approximately 60%, the cumulative non-synonymous amino acid mutations begin to exceed this threshold [3]; Evidence of episodic positive selection at critical VP1 codons, suggesting immune-driven evolution [4]; Divergent trends in relative genetic diversity, with EV-A71, CVA16, and CVA6 showing sustained expansion, while the diversity of CVB5 and EV-D68 declined sharply during the COVID-19 pandemic. This study provides valuable insights into the changing landscape of global enterovirus infections and underscores the critical role of genomic epidemiology in tracking their spread. Sustained research in this field is essential for developing effective strategies to prevent and control enterovirus-related diseases worldwide. • Study shows spatiotemporal shifts of 9 enteroviruses across 6 WHO regions: EV-A71/CVA16/CVB5 in Asia/Europe, EV-D68 in Americas/Europe. • Analyzed >40k genomes of 9 non-polio enteroviruses for phylogenies, evolutionary rates & capsid protein variability. • New framework: 60% VP1 mutation rate triggers NSAM surge in antigenic loops (BC/DE/EF/GH/HI), revealing immune escape pressure. • Episodic diversifying selection in VP1 loops necessitates genomic surveillance to track evolution & guide enterovirus vaccine design.