Ancient Evolution of Mammarenaviruses: Adaptation via Changes in the L Protein and No Evidence for Host-Virus Codivergence

Abstract

The Mammarenavirus genus includes several pathogenic species of rodent-borne viruses. Old World (OW) mammarenaviruses infect rodents in the Murinae subfamily and are mainly transmitted in Africa and Asia; New World (NW) mammarenaviruses are found in rodents of the Cricetidae subfamily in the Americas. We applied a selection-informed method to estimate that OW and NW mammarenaviruses diverged less than ∼45,000 years ago (ya). By incorporating phylogeographic inference, we show that NW mammarenaviruses emerged in the Latin America-Caribbean region ∼41,400-3,300 ya, whereas OW mammarenaviruses originated ∼23,100-1,880 ya, most likely in Southern Africa. Cophylogenetic analysis indicated that cospeciation did not contribute significantly to mammarenavirus-host associations. Finally, we show that extremely strong selective pressure on the viral polymerase accompanied the speciation of NW viruses. These data suggest that the evolutionary history of mammarenaviruses was not driven by codivergence with their hosts. The viral polymerase should be regarded as a major determinant of mammarenavirus adaptation.

Fig. 1.

—Mammarenavirus timescaled phylogenetic tree. The timescaled phylogenetic tree was estimated using the RdRp region. Branch lengths represent time (expressed in years ago) and the scale bar is shown at the tree base. The tMRCA of selected nodes is reported with 95% confidence intervals. Posterior probability of relevant nodes is also reported.

Fig. 2.

—Associations between mammarenaviruses and their known hosts. A total of 49 associations are drawn. When data for a natural host were not available (i.e., Argentine Akodont; Necromys benefactus and Long-tailed Field Mouse; Apodemus sylvaticus), the most closely related available rodent was used (Dark-furred Akodont; Necromys obscurus and Yellow-necked Field Mouse; Apodemus Flavicollis). In the case of Flexal virus, which was isolated from unidentified members of the oryzomyini tribe (Radoshitzky et al. 2015), association was drawn with Azara’s Broad-headed Oryzomys (Hylaeamys megacephalus, also known as Oryzomys capito).

Fig. 3.

—Phylogeographic analysis of the Mammarenavirus genus. Bayesian maximum clade credibility (MCC) tree for the RdRp region. Branches are colored according to inferred ancestral locations. Posterior probability support (pp) for relevant node locations are shown, as calculated with both the BEAST discrete model and BBM. Posterior probability of relevant nodes is also reported in black.

Fig. 4.

—Positive selection in NW mammarenaviruses. (A) Phylogenetic trees for L, Z, GPC, and NP. Asterisks denote tested branches, the yellow highlight indicates evidence of positive selection detected using two methods (BUSTED and the PAML branch-site models). (B) Positively selected sites are mapped onto a schematic representation of the NW mammarenavirus L protein (numbers refer to the MACV sequence, GenBank ID: AY624354). Circles indicate sites that are positively selected on more than one branch; color codes denote branches, as in panel (A). Regions where codons were filtered by GUIDANCE2 are shown in light gray. As a comparison, sites that were detected as positively selected in the OW mammarenavirus L protein are shown in dark gray below the cartoon structure. Sites that are positively selected in both NW and OW mammarenaviruses (based on the alignment between MACV and the LASV AV strain) are marked with numbers. As limited information is available for NW mammarenaviruses, the domain structure is based on the OW mammarenavirus L protein.