A genome-phenome association study in native microbiomes identifies a mechanism for cytosine modification in DNA and RNA

Author:

Yang Weiwei1ORCID,Lin Yu-Cheng12ORCID,Johnson William1,Dai Nan1,Vaisvila Romualdas1,Weigele Peter1,Lee Yan-Jiun1,Corrêa Ivan R1ORCID,Schildkraut Ira1,Ettwiller Laurence1ORCID

Affiliation:

1. New England Biolabs

2. School of Dentistry, National Yang Ming Chiao Tung University

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.

Funder

New England Biolabs

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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