Frequent seasonal reassortment between high and low path viruses drives the diversification of influenza A/H5N1

Since 2021, highly pathogenic (HPAI) H5N1 viruses have spread across the Americas, diversifying via reassortment into new genotypes that have spilled into humans and livestock, raising fears of a new influenza pandemic. Pandemic lineages are typically associated with reassortment, but we currently have limited understanding of where and when reassortment is expected to occur, which limits our ability to assess pandemic risks. Using a dataset of 9,052 full-genome sequences, we show that reassortment and novel genotype formation are associated with seasonal variation in low pathogenicity avian influenza (LPAI) cases and with the spatial and host distributions of viral transmission. We pinpoint ducks, geese, and the Central flyway as frequent sources of new genotypes, and show that reassortment rates vary seasonally, driven by mixing between high- and low-pathogenicity viruses. Cattle spillover genotypes (B3.13 and D1.1) evolved during periods of high reassortment, implicating reassortment as a common occurrence in lineages evolving during particular time periods. Together, these findings reframe reassortment as a predictable ecological process, with direct implications for how surveillance and pandemic risk assessment should be designed.