The Representativeness of Regional Influenza Virus Genomic Surveillance for National Trends in the United States

Genomic surveillance of influenza viruses informs vaccine strain selection and evolutionary forecasting. Sequencing efforts vary widely across U.S. states, which raises concerns about spatial sampling bias. We evaluated how well 10,958 influenza virus genomes sampled by our group in Michigan captured the genetic diversity in 34,743 genomes circulating nationally from the 2021/22 through 2024/25 seasons. We defined seasonal hemagglutinin haplotypes and tracked their detection across states. A small number of haplotypes dominated each season, and Michigan detected all major haplotypes, even under substantial downsampling. Detection delays were primarily driven by haplotype frequency rather than geographic factors. Comparisons across states showed that higher sequencing effort improved coverage and detection timeliness, with diminishing returns at higher volumes. Rarefaction analysis confirmed that relatively few sequences were needed to capture 95% of national haplotype diversity. These findings suggest that intensive sequencing in a single well-sampled location can be broadly representative of national influenza diversity. One sentence summaryDense influenza genomic sequencing from a single U.S. state captured nearly all nationally circulating haplotype diversity, with detection timeliness primarily driven by sequencing effort and haplotype frequency.