Zika virus was previously considered to cause only a benign infection in humans. Studies of recent outbreaks of Zika virus in the Pacific, South America, Mexico and the Caribbean have associated the virus with severe neuropathology. As of August 2016, the virus has been reported to be transmitting autochthonously in Miami, Florida, USA. Serology indicates that Zika has a decades long history in Asia. Currently there is a re-emergent epidemic in Asia (e.g. Singapore, 2016). Most previous analyses, and some of ours, indicate a continuum of spread a Zika lineage from Africa, to Asia, across the Pacific, to the Americas. We call this the “Out of Africa” hypothesis. In contrast, in some of our analyses, we find support for the hypothesis that there is a deep common ancestor between African and Asian clade. We call this result the “Asia/Africa” hypothesis. The Asia/Africa hypothesis indicates that there may be understudied Zika virus reservoirs in Asia. The current outbreak in Singapore is consistent with the Asia/Africa hypothesis. Viral evolution may be one factor contributing to an apparent change in Zika disease as it spread from Africa to Asia, across the Pacific, to the Americas. To address this possibility, we have developed and leveraged existing computational tools to co-analyze the phylogeny, geography, immunology, and RNA structure of Zika virus isolates from Africa, Asia, the Pacific and the Americas. We identify and evaluate key mutations in viral envelope protein coding and untranslated terminal RNA regions. We find stepwise mutations that have altered immunologic motif sets and regulatory sequence elements. Both of these sets of changes distinguish viruses found in Africa (that cause benign disease) from the Asia-Pacific-Americas clade (that cause severe disease). These findings support the working hypothesis that recent mutations acquired by Zika virus in the Asia-Pacific-Americas clade contribute to changes in pathology. These results can inform experiments required to elucidate the role of viral genetic evolution in changes in neuropathology, including microcephaly and other neurological and skeletomuscular issues in infants and Guillain-Barré syndrome in adults.