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In early 2024, an unprecedented outbreak of H5N1 high pathogenicity avian 23 influenza was detected in dairy cattle in the USA. The epidemic remains uncontrolled, 24 with spillbacks into poultry, wild birds and other mammals including humans. Here, we 25 present molecular and virological evidence that the cattle B3.13 genotype H5N1 viruses 26 rapidly accumulated adaptations in polymerase genes that enabled better replication in 27 bovine cells, as well as cells of other mammalian species including humans and pigs. 28 We find evidence of several mammalian adaptations gained early in the evolution of 29 these viruses in cattle including PB2 M631L, which is found in all cattle sequences, and 30 PA K497R, which is found in the majority. Structurally, PB2 M631L maps to the 31 polymerase-ANP32 interface, an essential host factor for viral genome replication. We 32 show this mutation adapts the virus to co-opt bovine ANP32 proteins and thereby 33 enhances virus replication in bovine and primary human airway cells. Importantly, we 34 show that ongoing evolution during 2024 in the PB2 gene, including a convergently 35 arising D740N substitution, further increases polymerase activity in a range of 36 . CC-BY 4.0 International license available under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made The copyright holder for this preprint this version posted January 6, 2025. ; https://doi.org/10.1101/2025.01.06.631435 doi: bioRxiv preprint 37 The copyright holder for this preprint bioRxiv preprint doi: https://doi.org/10.1101/2025.01.06.631435 ; this version posted January 6, 2025. (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license 38 . mammalian cells. Thus, the continued circulation of H5N1 in dairy cattle allows virus adaption improving replicative ability in cattle and increasing zoonotic spillover risk.