Large-Scale Analyses of Human Microbiomes Reveal Thousands of Small, Novel Genes
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Abstract
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.
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Growing experimental evidence in mycobacteria and other prokaryotes has shown that many sproteins are functional, requiring a rethinking of gene definitions.
“However, growing experimental evidence in mycobacteria and other prokaryotes has shown that many sproteins are functional, requiring a rethinking of gene definitions (71–75).”
From Mycobacterium smegmatis: The Vanguard of Mycobacterial Research (2023) · cites this paper as [73]
The Introduction says recent studies have found functions for small proteins in prokaryotes, and the Discussion says accumulating evidence suggests roles in bacterial physiology. But this paper does not specifically discuss experimental evidence in mycobacteria or conclude that many small proteins are functionally established; it says mechanistic studies are still needed. Its account of overlooked small genes supports reconsidering annotation practices, but not an explicit call to rethink gene definitions. Page numbers are unavailable in our copy. (LLM, conf=0.85)
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- Authors
- Sberro, H., Fremin, B. J., Zlitni, S., Edfors, F., Greenfield, N., Snyder, M. P., Pavlopoulos, G. A., Kyrpides, N. C., & Bhatt, A. S.
- Affiliations
- Stanford Medicine (US)
- Stanford University (US)
- Joint Genome Institute (US)
- Lawrence Berkeley National Laboratory (US)
- Corresponding author
- Bhatt, Ami S.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2019-08
- Volume
- 178
- Issue
- 5
- Pages
- 1245-1259.e14
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC6764417
- OpenAlex
- W2968334948
- Cited by
- 237
- References
- 102
- Citations by year
- 2026: 22 · 2025: 30 · 2024: 30 · 2023: 29 · 2022: 31 · 2021: 42 · 2020: 44 · 2019: 9
- FWCI
- 10.43
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
- Funders
- National Human Genome Research Institute (T32 HG000044)
- National Institutes of Health (S100D023452, P30 CA124435)
- U.S. Department of Energy (P30 CA124435)
- National Cancer Institute (1R01AT01023201, K08 CA184420)
- Stanford Cancer Institute
- Damon Runyon Cancer Research Foundation
- Office of Science (DE-AC02-05CH11231)
- Stanford University
- Stiftelsen Blanceflor Boncompagni Ludovisi, född Bildt
- Pharmaceutical Research and Manufacturers of America Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Phylogenetic Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Physical Sciences › Environmental Science › Ecology › Microbial Community Ecology and Physiology
- Keywords
- small proteins, human microbiome, metagenome, novel protein families, conserved protein families, secreted proteins, transmembrane proteins, horizontal gene transfer, host defense proteins
- MeSH terms
- Amino Acid Sequence, Cell Communication, Humans, Proteins, Ribosomal Proteins, Open Reading Frames, Sequence Alignment, Host-Pathogen Interactions, Metagenome, Microbiota
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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