Molecular evolution of Andes virus lineages leading to recent human outbreaks

Andes virus (ANDV) is exceptional among hantaviruses in its capacity for person-to-person transmission, but whether outbreaks reflect recent viral adaptation or emergence of pre-existing reservoir lineages remains unclear. We generated paired blood- and nasal-derived genomes from the MV Hondius outbreak and integrated them with a segment-linked collection of human- and rodent-derived ANDV sequences, including incomplete genomes. We developed a linkage-informed missing-segment framework that preserves isolate identity, sampling time, and cross-segment placement without imputing nucleotide states, enabling sensitivity analyses of patchy segment coverage. Across five human outbreaks, dated phylogenies placed outbreak lineages independently within geographically structured reservoir diversity, with closest sampled ancestry predating detection. Time-dependent-rate analyses indicated a deeper reservoir-associated history, while mutation reconstruction, selection tests, branch-rate comparisons, and structural mapping found no recurrent adaptive transition preceding human transmission. MV Hondius samples showed minimal consensus-level diversification. These results shift attention from repeated recent adaptation toward deeper lineage properties and ecological opportunity.