Viruses have an extraordinary ability to diversify and evolve. For segmented viruses, reassortment can introduce drastic genomic and phenotypic changes by allowing a direct exchange of genetic material between coinfecting strains. For instance, multiple influenza pandemics were caused by reassortments of viruses typically found in separate hosts. What is unclear, however, are the underlying mechanisms driving these events and the level of intrinsic bias in the diversity of strains that emerge from coinfection. To address this problem, previous experiments looked for correlations between segments of strains that coinfect cells in vitro. Here, we present an information theory approach as the natural mathematical framework for this question. We study, for influenza and other segmented viruses, the extent to which a virus's segments can communicate strain information across an infection and among one another. Our approach goes beyond previous association studies and quantifies how much the diversity of emerging strains is altered by patterns in reassortment, whether biases are consistent across multiple strains and cell types, and if significant information is shared among more than two segments. We apply our approach to a new experiment that examines reassortment patterns between the 2009 H1N1 pandemic and seasonal H1N1 strains, contextualizing its segmental information sharing by comparison with previously reported strain reassortments. We find evolutionary patterns across classes of experiments and previously unobserved higher-level structures. Finally, we show how this approach can be combined with virulence potentials to assess pandemic threats. viral evolution | systems biology | emerging infectious disease R eassortment of segmented viruses is a key mechanism for rapid novel virus creation. At least two human influenza pandemics in the last century were linked to lineages where some number of genomic segments reassorted with a genome of nonhuman origin (1, 2). This fact was reinforced by the emergence of the 2009 H1N1 pandemic (2009 pdm) virus (3-5). Novel reassortant strains can evade adaptive immunity by introducing antigens to a naïve host population or overly stimulate innate immunity by presenting a new host with abundant nonself molecular signals (6-10). Moreover, both sequence database studies and in vitro experiments have shown that genome reassortment between strains happens nonrandomly: If two strains coinfect the same cell, their progeny may not sample all possible strain/segment combinations uniformly (11)(12)(13)(14). These analyses focused on whether it is more likely that pairs of segments from the same strain appear together in reassortments, typically using chi-square tests to establish significance.Because influenza has eight segments, there are 256 possible reassortant viruses when a cell is coinfected by two strains. Each strain type and host cellular environment can influence reassortment differently, so it would seem impossible to predict whether a new pandemic strain can form. However, ...