Zika virus (ZIKV) infections were more common in the zoonotic cycle until the end of the 20 th century with few human cases in Africa and Southeastern Asia. Recently, the Asian lineage of ZIKV is spreading along human-to-human chains of transmission in the Pacific Islands and in South America. To better understand its recent urban expansion, we compared genetic differences among the lineages. Herein we show that the recent Asian lineage spread is associated with significant NS1 codon usage adaptation to human housekeeping genes, which could facilitate viral replication and increase viral titers. These findings were supported by a significant correlation with growth in Malthusian fitness. Furthermore, we predicted several epitopes in the NS1 protein that are shared between ZIKV and Dengue. Our results imply in a significant dependence of the recent human ZIKV spread on NS1 translational selection.
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