Evolutionary analysis of the Musashi family: What can it tell us about Zika?

Abstract

Despite worldwide research efforts since 2015, Zika virus infection and its consequences are not fully understood yet. Nowadays, it is known that microcephaly is only one of the possible outcomes of being infected by ZIKV during the early stages of life. Musashi 1 (MSI1) is an RNA-binding protein that is involved in neurodevelopmental processes. Also, ZIKV genome (a single-stranded positive-sense RNA) uses MSI1 for its replication. Here we perform an evolutionary analysis of MSI1 coding sequence and their orthologs in vertebrate species. We added original sequencing data from selected regions of interest (RNA-binding domains-RBDs of MSI1) of sixteen Platyrrhini (or New World monkeys), known to have high evolutionary rates. The Musashi family (MF) includes MSI2, TARDBP, DAZAP1, HNRNPD, HNRNPDL, and HNRNPAB, which do not interact with the virus but are critical RNA-binding proteins that act on many regulatory processes ubiquitously. We found that all sixteen primate species have the RBD1 of MSI1 conserved. While the general code sequences of MF genes are under purifying selection, the evolution of regulatory mechanisms, especially alternative splicing, seems to be a frequent phenomenon in these genes. Different isoforms differ in the N-terminal region and it affects protein size. Existing MSI1 isoforms probably diverge in their binding affinity, the kinetics of interaction, and other aspects when in the MSI1-ZIKV complex. It is a signal that some RBD-containing MSI1 isoforms can be incompatible to ZIKV binding and replication. Consequently, the chance of ZIKV successfully infecting host cells could also be associated with alternative splicing and expression of ZIKV-compatible MSI1 isoforms in both inter and intraspecific levels.