Comparative analysis of protein evolution and RNA structural changes in the genome of pre-epidemic and epidemic Zika virus

ABSTRACT Zika virus (ZIKV) infection is associated with microcephaly, neurological disorders and poor pregnancy outcome 1-3 and no vaccine is available. Although ZIKV was first discovered in 1947, the exact mechanism of virus replication and pathogenesis still remains unknown. Recent outbreaks of Zika virus in the Americas clearly suggest a better adaptation of viral strains to human host. Understanding the conserved and adaptive features in the evolution of ZIKV genome will reveal the molecular mechanism of virus replication and host adaptation. Here, we show comprehensive analysis of protein evolution and changes in RNA secondary structures of ZIKV strains including the current 2015-16 outbreak. To identify the constraints on ZIKV evolution, selection pressure at individual codons, immune epitopes, co-evolving sites, and RNA structures were analyzed. The proteome of current 2015/16 epidemic ZIKV strains of Asian genotype is found to be genetically conserved due to genome-wide negative selection on codons, with limited positive selection. Predicted RNA structures at the 5’ and 3’ ends of ZIKV strains reveal substantial changes such as an additional stem loop which makes it similar to that of Yellow Fever Virus. Concisely, the targeted changes at both the amino acid and the RNA levels contribute to the better adaptation of ZIKV strains to human host with an enhanced neurotropism.