Large-Scale Analyses of Human Microbiomes Reveal Thousands of Small, Novel Genes

Cell. 2019 Aug 22;178(5):1245-1259.e14. doi: 10.1016/j.cell.2019.07.016. Epub 2019 Aug 8.


Small proteins are traditionally overlooked due to computational and experimental difficulties in detecting them. To systematically identify small proteins, we carried out a comparative genomics study on 1,773 human-associated metagenomes from four different body sites. We describe >4,000 conserved protein families, the majority of which are novel; ∼30% of these protein families are predicted to be secreted or transmembrane. Over 90% of the small protein families have no known domain and almost half are not represented in reference genomes. We identify putative housekeeping, mammalian-specific, defense-related, and protein families that are likely to be horizontally transferred. We provide evidence of transcription and translation for a subset of these families. Our study suggests that small proteins are highly abundant and those of the human microbiome, in particular, may perform diverse functions that have not been previously reported.

Keywords: annotation; bacteria; bioinformatics; domain; genome; microbe; microbiome; phage; prediction; small open reading frame; small proteins.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Cell Communication
  • Host-Pathogen Interactions
  • Humans
  • Metagenome
  • Microbiota*
  • Open Reading Frames / genetics
  • Proteins / chemistry
  • Proteins / metabolism*
  • Ribosomal Proteins / chemistry
  • Ribosomal Proteins / metabolism
  • Sequence Alignment


  • Proteins
  • Ribosomal Proteins