Sequence amplification via cell passaging creates spurious signals of positive adaptation in influenza H3N2 hemagglutinin

Author:

McWhite Claire D.ORCID,Meyer Austin G.ORCID,Wilke Claus O.ORCID

Abstract

AbstractClinical influenza A isolates are frequently not sequenced directly. Instead, a majority of these isolates (~70% in 2015) are first subjected to passaging for amplification, most commonly in non-human cell culture. Here, we find that this passaging leaves distinct signals of adaptation in the viral sequences, which can confound evolutionary analyses of the viral sequences. We find distinct patterns of adaptation to Madin-Darby (MDCK) and monkey cell culture absent from unpassaged hemagglutinin sequences. These patterns also dominate pooled datasets not separated by passaging type, and they increase in proportion to the number of passages performed. By contrast, MDCK-SIAT1 passaged sequences seem mostly (but not entirely) free of passaging adaptations. Contrary to previous studies, we find that using only internal branches of the influenza phylogenetic trees is insufficient to correct for passaging artifacts. These artifacts can only be safely avoided by excluding passaged sequences entirely from subsequent analysis. We conclude that future influenza evolutionary analyses should appropriately control for potentially confounding effects of passaging adaptations.

Publisher

Cold Spring Harbor Laboratory

Cited by 1 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

1. Complexities in Ferret Influenza Virus Pathogenesis and Transmission Models;Microbiology and Molecular Biology Reviews;2016-09

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