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Deep metagenomic mining reveals bacteriophage sequence motifs driving host specificity

View ORCID ProfilePhil Huss, View ORCID ProfileKristopher Kieft, View ORCID ProfileAnthony Meger, View ORCID ProfileKyle Nishikawa, View ORCID ProfileKarthik Anantharaman, View ORCID ProfileSrivatsan Raman
doi: https://doi.org/10.1101/2023.02.07.527309
Phil Huss
1Department of Biochemistry, University of Wisconsin-Madison
2Department of Bacteriology, University of Wisconsin-Madison
3Microbiology Doctoral Training Program, University of Wisconsin-Madison
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Kristopher Kieft
2Department of Bacteriology, University of Wisconsin-Madison
3Microbiology Doctoral Training Program, University of Wisconsin-Madison
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Anthony Meger
1Department of Biochemistry, University of Wisconsin-Madison
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Kyle Nishikawa
1Department of Biochemistry, University of Wisconsin-Madison
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Karthik Anantharaman
2Department of Bacteriology, University of Wisconsin-Madison
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Srivatsan Raman
1Department of Biochemistry, University of Wisconsin-Madison
2Department of Bacteriology, University of Wisconsin-Madison
4Department of Chemical and Biological Engineering, University of Wisconsin-Madison
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  • For correspondence: sraman4@wisc.edu
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Abstract

Bacteriophages can adapt to new hosts by altering sequence motifs through recombination or convergent evolution. Where such motifs exist and what fitness advantage they confer remains largely unknown. We report a new method, Bacteriophage Library Informed Sequence Scoring (BLISS), to discover sequence motifs in metagenomic datasets governing phage activity. BLISS uses experimental deep mutational scanning data to create sequence profiles to enable deep mining of metagenomes for functional motifs which are otherwise invisible to searches. We experimentally tested 10,073 BLISS-derived sequence motifs for the receptor-binding protein of the T7 phage. The screen revealed hundreds of T7 variants with novel host specificity with functional motifs sourced from distant families besides other major phyla. Position, substitution and location preferences on T7 dictated different specificities. To demonstrate therapeutic utility, we engineered highly active T7 variants against urinary tract pathogens. BLISS is a powerful tool to unlock the functional potential encoded in phage metagenomes.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • The only change was changing 10,000 to 10,073 in the abstract to specify the exact number of sequence motifs tested.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted February 09, 2023.
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Deep metagenomic mining reveals bacteriophage sequence motifs driving host specificity
Phil Huss, Kristopher Kieft, Anthony Meger, Kyle Nishikawa, Karthik Anantharaman, Srivatsan Raman
bioRxiv 2023.02.07.527309; doi: https://doi.org/10.1101/2023.02.07.527309
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Deep metagenomic mining reveals bacteriophage sequence motifs driving host specificity
Phil Huss, Kristopher Kieft, Anthony Meger, Kyle Nishikawa, Karthik Anantharaman, Srivatsan Raman
bioRxiv 2023.02.07.527309; doi: https://doi.org/10.1101/2023.02.07.527309

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