1. Genetics and Genomics
  2. Microbiology and Infectious Disease
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A Genome-Phenome Association study in native microbiomes identifies a mechanism for cytosine modification in DNA and RNA

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Cite this article as: eLife 2021;10:e70021 doi: 10.7554/eLife.70021

Abstract

Shotgun metagenomic sequencing is a powerful approach to study microbiomes in an unbiased manner and of increasing relevance for identifying novel enzymatic functions. However, the potential of metagenomics to relate from microbiome composition to function has thus far been underutilized. Here, we introduce the Metagenomics Genome-Phenome Association (MetaGPA) study framework, which allows linking genetic information in metagenomes with a dedicated functional phenotype. We applied MetaGPA to identify enzymes associated with cytosine modifications in environmental samples. From the 2365 genes that met our significance criteria, we confirm known pathways for cytosine modifications and proposed novel cytosine-modifying mechanisms. Specifically, we characterized and identified a novel nucleic acid modifying enzyme, 5-hydroxymethylcytosine carbamoyltransferase, that catalyzes the formation of a previously unknown cytosine modification, 5-carbamoyloxymethylcytosine, in DNA and RNA. Our work introduces MetaGPA as a novel and versatile tool for advancing functional metagenomics.

Data availability

All raw and processed sequencing data generated in this study have been submitted to the NCBI Sequence Read Archive (SRA; https://www.ncbi.nlm.nih.gov/sra) under accession number PRJNA714147.

The following data sets were generated

Article and author information

Author details

  1. Weiwei Yang

    Research department, New England Biolabs Inc, Ipswich, United States
    Competing interests
    Weiwei Yang, The author is employee of New England Biolabs Inc. a manufacturer of restriction enzymes and molecular reagents..
  2. Yu-Cheng Lin

    Research department, New England Biolabs Inc, Ipswich, United States
    Competing interests
    Yu-Cheng Lin, The author was an employee of New England Biolabs Inc. a manufacturer of restriction enzymes and molecular reagents..
  3. William Johnson

    Research department, New England Biolabs Inc, Ipswich, United States
    Competing interests
    William Johnson, The author was an employee of New England Biolabs Inc. a manufacturer of restriction enzymes and molecular reagents..
  4. Nan Dai

    RNA Biology, New England Biolabs Inc, Ipswich, United States
    Competing interests
    Nan Dai, The author is an employee of New England Biolabs Inc. a manufacturer of restriction enzymes and molecular reagents..
  5. Romualdas Vaisvila

    Research department, New England Biolabs Inc, Ipswich, United States
    Competing interests
    Romualdas Vaisvila, The author is an employee of New England Biolabs Inc. a manufacturer of restriction enzymes and molecular reagents..
  6. Peter Weigele

    Research department, New England Biolabs Inc, Ipswich, United States
    Competing interests
    Peter Weigele, The author is an employee of New England Biolabs Inc. a manufacturer of restriction enzymes and molecular reagents..
  7. Yan-Jiun Lee

    Research department, New England Biolabs Inc, Ipswich, United States
    Competing interests
    Yan-Jiun Lee, The author is an employee of New England Biolabs Inc. a manufacturer of restriction enzymes and molecular reagents..
  8. Ivan R Corrêa Jr

    RNA Biology, New England Biolabs Inc, Ipswich, United States
    Competing interests
    Ivan R Corrêa, The author is an employee of New England Biolabs Inc. a manufacturer of restriction enzymes and molecular reagents..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3169-6878
  9. Ira Schildkraut

    Research department, New England Biolabs Inc, Ipswich, United States
    Competing interests
    Ira Schildkraut, The author is an employee of New England Biolabs Inc. a manufacturer of restriction enzymes and molecular reagents..
  10. Laurence Ettwiller

    Research department, New England Biolabs Inc, Ipswich, United States
    For correspondence
    laurence.ettwiller@gmail.com
    Competing interests
    Laurence Ettwiller, The author is employee of New England Biolabs Inc. a manufacturer of restriction enzymes and molecular reagents..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3957-6539

Funding

New England Biolabs (no data)

  • Weiwei Yang
  • Yu-Cheng Lin
  • William Johnson
  • Nan Dai
  • Romualdas Vaisvila
  • Peter Weigele
  • Yan-Jiun Lee
  • Ivan R Corrêa Jr
  • Ira Schildkraut
  • Laurence Ettwiller

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. María Mercedes Zambrano, CorpoGen, Colombia

Publication history

  1. Received: May 4, 2021
  2. Accepted: November 5, 2021
  3. Accepted Manuscript published: November 8, 2021 (version 1)

Copyright

© 2021, Yang et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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