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Is There a Twelfth Protein-Coding Gene in the Genome of Influenza A? A Selection-Based Approach to the Detection of Overlapping Genes in Closely Related Sequences

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Abstract

Protein-coding genes often contain long overlapping open-reading frames (ORFs), which may or may not be functional. Current methods that utilize the signature of purifying selection to detect functional overlapping genes are limited to the analysis of sequences from divergent species, thus rendering them inapplicable to genes found only in closely related sequences. Here, we present a method for the detection of selection signatures on overlapping reading frames by using closely related sequences, and apply the method to several known overlapping genes, and to an overlapping ORF on the negative strand of segment 8 of influenza A virus (NEG8), for which the suggestion has been made that it is functional. We find no evidence that NEG8 is under selection, suggesting that the intact reading frame might be non-functional, although we cannot fully exclude the possibility that the method is not sensitive enough to detect the signature of selection acting on this gene. We present the limitations of the method using known overlapping genes and suggest several approaches to improve it in future studies. Finally, we examine alternative explanations for the sequence conservation of NEG8 in the absence of selection. We show that overlap type and genomic context affect the conservation of intact overlapping ORFs and should therefore be considered in any attempt of estimating the signature of selection in overlapping genes.

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Acknowledgments

We thank Dr. Chris Upton for suggesting this problem and providing valuable information. DG and NS were supported by a Small Grant Award from the University of Houston and by the US National Library of Medicine grant LM010009-01 to DG and Giddy Landan.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Institute of Evolutionary Biology and Environmental Studies, University of Zurich, 8057, Zurich, Switzerland

    Niv Sabath

  2. The Swiss Institute of Bioinformatics, Basel, Switzerland

    Niv Sabath

  3. Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, TX, 77230, USA

    Jeffrey S. Morris

  4. Department of Biology and Biochemistry, University of Houston, Houston, TX, 77204, USA

    Dan Graur

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  1. Niv Sabath
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  2. Jeffrey S. Morris
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Correspondence to Niv Sabath.

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Sabath, N., Morris, J.S. & Graur, D. Is There a Twelfth Protein-Coding Gene in the Genome of Influenza A? A Selection-Based Approach to the Detection of Overlapping Genes in Closely Related Sequences. J Mol Evol 73, 305–315 (2011). https://doi.org/10.1007/s00239-011-9477-9

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