Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Genomic variation landscape of the human gut microbiome

Abstract

Whereas large-scale efforts have rapidly advanced the understanding and practical impact of human genomic variation, the practical impact of variation is largely unexplored in the human microbiome. We therefore developed a framework for metagenomic variation analysis and applied it to 252 faecal metagenomes of 207 individuals from Europe and North America. Using 7.4 billion reads aligned to 101 reference species, we detected 10.3 million single nucleotide polymorphisms (SNPs), 107,991 short insertions/deletions, and 1,051 structural variants. The average ratio of non-synonymous to synonymous polymorphism rates of 0.11 was more variable between gut microbial species than across human hosts. Subjects sampled at varying time intervals exhibited individuality and temporal stability of SNP variation patterns, despite considerable composition changes of their gut microbiota. This indicates that individual-specific strains are not easily replaced and that an individual might have a unique metagenomic genotype, which may be exploitable for personalized diet or drug intake.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Genomic variation statistics for 101 gut microbial species prevalent in 252 samples from 207 individuals.
Figure 2: pN/pS ratios of 66 dominant species reveal more variation between species than between individuals.
Figure 3: Individuality and temporal stability of genomic variation patterns.
Figure 4: Inter-continental comparison of gut microbial species.

Accession codes

Data deposits

Single nucleotide polymorphism data have been submitted to dbSNP under accession numbers ss539238913–ss549853572.

References

  1. 1

    International HapMap Consortium. A second generation human haplotype map of over 3.1 million SNPs. Nature 449, 851–861 (2007)

    Article  Google Scholar 

  2. 2

    The 1000 Genomes Project Consortium. A map of human genome variation from population-scale sequencing. Nature 467, 1061–1073 (2010)

    Article  Google Scholar 

  3. 3

    Backhed, F., Ley, R. E., Sonnenburg, J. L., Peterson, D. A. & Gordon, J. I. Host-bacterial mutualism in the human intestine. Science 307, 1915–1920 (2005)

    ADS  Article  Google Scholar 

  4. 4

    Hooper, L. V., Midtvedt, T. & Gordon, J. I. How host-microbial interactions shape the nutrient environment of the mammalian intestine. Annu. Rev. Nutr. 22, 283–307 (2002)

    CAS  Article  Google Scholar 

  5. 5

    Bagel, S., Hüllen, V., Wiedemann, B. & Heisig, P. Impact of gyrA and parC mutations on quinolone resistance, doubling time, and supercoiling degree of Escherichia coli . Antimicrob. Agents Chemother. 43, 868–875 (1999)

    CAS  Article  Google Scholar 

  6. 6

    Eckburg, P. B. et al. Diversity of the human intestinal microbial flora. Science 308, 1635–1638 (2005)

    ADS  Article  Google Scholar 

  7. 7

    Morowitz, M. J. et al. Strain-resolved community genomic analysis of gut microbial colonization in a premature infant. Proc. Natl Acad. Sci. USA 108, 1128–1133 (2011)

    ADS  CAS  Article  Google Scholar 

  8. 8

    Sokurenko, E. V. et al. Pathogenic adaptation of Escherichia coli by natural variation of the FimH adhesin. Proc. Natl Acad. Sci. USA 95, 8922–8926 (1998)

    ADS  CAS  Article  Google Scholar 

  9. 9

    The Human Microbiome Project Consortium. A framework for human microbiome research. Nature 486, 215–221 (2012)

  10. 10

    Lay, C. et al. Colonic microbiota signatures across five northern European countries. Appl. Environ. Microbiol. 71, 4153–4155 (2005)

    CAS  Article  Google Scholar 

  11. 11

    Qin, J. et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature 464, 59–65 (2010)

    CAS  Article  Google Scholar 

  12. 12

    Turnbaugh, P. J. et al. A core gut microbiome in obese and lean twins. Nature 457, 480–484 (2009)

    ADS  CAS  Article  Google Scholar 

  13. 13

    Arumugam, M. et al. Enterotypes of the human gut microbiome. Nature 473, 174–180 (2011)

    CAS  Article  Google Scholar 

  14. 14

    Tyson, G. W. et al. Community structure and metabolism through reconstruction of microbial genomes from the environment. Nature 428, 37–43 (2004)

    ADS  CAS  Article  Google Scholar 

  15. 15

    Allen, E. E. et al. Genome dynamics in a natural archaeal population. Proc. Natl Acad. Sci. USA 104, 1883–1888 (2007)

    ADS  CAS  Article  Google Scholar 

  16. 16

    Harris, S. R. et al. Evolution of MRSA during hospital transmission and intercontinental spread. Science 327, 469–474 (2010)

    ADS  CAS  Article  Google Scholar 

  17. 17

    Peterson, J. et al. The NIH Human Microbiome Project. Genome Res. 19, 2317–2323 (2009)

    Article  Google Scholar 

  18. 18

    Ciccarelli, F. D. et al. Toward automatic reconstruction of a highly resolved tree of life. Science 311, 1283–1287 (2006)

    ADS  CAS  Article  Google Scholar 

  19. 19

    Sorek, R. et al. Genome-wide experimental determination of barriers to horizontal gene transfer. Science 318, 1449–1452 (2007)

    ADS  CAS  Article  Google Scholar 

  20. 20

    Konstantinidis, K. T. & Tiedje, J. M. Prokaryotic taxonomy and phylogeny in the genomic era: advancements and challenges ahead. Curr. Opin. Microbiol. 10, 504–509 (2007)

    CAS  Article  Google Scholar 

  21. 21

    Touchon, M. et al. Organised genome dynamics in the Escherichia coli species results in highly diverse adaptive paths. PLoS Genet. 5, e1000344 (2009)

    Article  Google Scholar 

  22. 22

    DePristo, M. A. et al. A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nature Genet. 43, 491–498 (2011)

    CAS  Article  Google Scholar 

  23. 23

    Muller, J. et al. eggNOG v2.0: extending the evolutionary genealogy of genes with enhanced non-supervised orthologous groups, species and functional annotations. Nucleic Acids Res. 38, D190–D195 (2010)

    ADS  CAS  Article  Google Scholar 

  24. 24

    Kunz, B. A. & Glickman, B. W. The infidelity of conjugal DNA transfer in Escherichia coli . Genetics 105, 489–500 (1983)

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25

    Simmons, S. L. et al. Population genomic analysis of strain variation in Leptospirillum group II bacteria involved in acid mine drainage formation. PLoS Biol. 6, e177 (2008)

    Article  Google Scholar 

  26. 26

    McDonald, J. H. & Kreitman, M. Adaptive protein evolution at the Adh locus in Drosophila . Nature 351, 652–654 (1991)

    ADS  CAS  Article  Google Scholar 

  27. 27

    Friedman, R., Drake, J. W. & Hughes, A. L. Genome-wide patterns of nucleotide substitution reveal stringent functional constraints on the protein sequences of thermophiles. Genetics 167, 1507–1512 (2004)

    CAS  Article  Google Scholar 

  28. 28

    Novichkov, P. S., Wolf, Y. I., Dubchak, I. & Koonin, E. V. Trends in prokaryotic evolution revealed by comparison of closely related bacterial and archaeal genomes. J. Bacteriol. 191, 65–73 (2009)

    CAS  Article  Google Scholar 

  29. 29

    Frey, P. A. The Leloir pathway: a mechanistic imperative for three enzymes to change the stereochemical configuration of a single carbon in galactose. FASEB J. 10, 461–470 (1996)

    CAS  Article  Google Scholar 

  30. 30

    Kuhner, S. et al. Proteome organization in a genome-reduced bacterium. Science 326, 1235–1240 (2009)

    ADS  Article  Google Scholar 

  31. 31

    Holdeman, L. V. & Moore, W. E. C. New genus, Coprococcus, twelve new species, and emended descriptions of four previously described species of bacteria from human feces. Int. J. Syst. Bacteriol. 24, 260–277 (1974)

    Article  Google Scholar 

  32. 32

    Duncan, S. H., Hold, G. L., Barcenilla, A., Stewart, C. S. & Flint, H. J. Roseburia intestinalis sp. nov., a novel saccharolytic, butyrate-producing bacterium from human faeces. Int. J. Syst. Evol. Microbiol. 52, 1615–1620 (2002)

    CAS  Google Scholar 

  33. 33

    Alvarez-Martinez, C. E. & Christie, P. J. Biological diversity of prokaryotic type IV secretion systems. Microbiol. Mol. Biol. Rev. 73, 775–808 (2009)

    CAS  Article  Google Scholar 

  34. 34

    Nagai, H. & Roy, C. R. Show me the substrates: modulation of host cell function by type IV secretion systems. Cell Microbiol. 5, 373–383 (2003)

    CAS  Article  Google Scholar 

  35. 35

    Kelly, D., Conway, S. & Aminov, R. Commensal gut bacteria: mechanisms of immune modulation. Trends Immunol. 26, 326–333 (2005)

    CAS  Article  Google Scholar 

  36. 36

    Jones, B. V., Begley, M., Hill, C., Gahan, C. G. M. & Marchesi, J. R. Functional and comparative metagenomic analysis of bile salt hydrolase activity in the human gut microbiome. Proc. Natl Acad. Sci. USA 105, 13580–13585 (2008)

    ADS  CAS  Article  Google Scholar 

  37. 37

    Begley, M., Hill, C. & Gahan, C. G. M. Bile salt hydrolase activity in probiotics. Appl. Environ. Microbiol. 72, 1729–1738 (2006)

    CAS  Article  Google Scholar 

  38. 38

    Caporaso, J. G. et al. Moving pictures of the human microbiome. Genome Biol. 12, R50 (2011)

    Article  Google Scholar 

  39. 39

    Dethlefsen, L. & Relman, D. A. Incomplete recovery and individualized responses of the human distal gut microbiota to repeated antibiotic perturbation. Proc. Natl Acad. Sci. USA 108, 4554–4561 (2011)

    ADS  CAS  Article  Google Scholar 

  40. 40

    Zoetendal, E. G., Akkermans, A. D. & De Vos, W. M. Temperature gradient gel electrophoresis analysis of 16S rRNA from human fecal samples reveals stable and host-specific communities of active bacteria. Appl. Environ. Microbiol. 64, 3854–3859 (1998)

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41

    Fierer, N. et al. Forensic identification using skin bacterial communities. Proc. Natl Acad. Sci. USA 107, 6477–6481 (2010)

    ADS  CAS  Article  Google Scholar 

  42. 42

    Tenaillon, O., Skurnik, D., Picard, B. & Denamur, E. The population genetics of commensal Escherichia coli . Nature Rev. Microbiol. 8, 207–217 (2010)

    CAS  Article  Google Scholar 

  43. 43

    Jernberg, C., Lofmark, S., Edlund, C. & Jansson, J. K. Long-term ecological impacts of antibiotic administration on the human intestinal microbiota. ISME J. 1, 56–66 (2007)

    CAS  Article  Google Scholar 

  44. 44

    Suzuki, R., Shiota, S. & Yamaoka, Y. Molecular epidemiology, population genetics, and pathogenic role of Helicobacter pylori . Infect. Genet. Evol. 12, 203–213 (2012)

    Article  Google Scholar 

  45. 45

    Yamaoka, Y. Helicobacter pylori typing as a tool for tracking human migration. Clin. Microbiol. Infect. 15, 829–834 (2009)

    CAS  Article  Google Scholar 

  46. 46

    Achtman, M. & Wagner, M. Microbial diversity and the genetic nature of microbial species. Nature Rev. Microbiol. 6, 431–440 (2008)

    CAS  Article  Google Scholar 

  47. 47

    Morelli, G. et al. Yersinia pestis genome sequencing identifies patterns of global phylogenetic diversity. Nature Genet. 42, 1140–1143 (2010)

    CAS  Article  Google Scholar 

  48. 48

    Ye, K., Schulz, M. H., Long, Q., Apweiler, R. & Ning, Z. Pindel: a pattern growth approach to detect break points of large deletions and medium sized insertions from paired-end short reads. Bioinformatics 25, 2865–2871 (2009)

    CAS  Article  Google Scholar 

Download references

Acknowledgements

The authors are grateful to J. Korbel and the members of the Bork group at EMBL for discussions and assistance, especially S. Powell for performing some of the computations. We thank the EMBL IT core facility and Y. Yuan for managing the high-performance computing resources. We would like to thank J. I. Gordon for providing three of the samples used. We are also grateful to the European MetaHIT consortium and the NIH Common Fund Human Microbiome Project Consortium for generating and making available the data sets used in this study. The research leading to these results has received funding from EMBL, the European Community’s Seventh Framework Programme via the MetaHIT (HEALTH-F4-2007-201052) and IHMS (HEALTH-F4-2010-261376) grants as well as from the National Institutes of Health grants U54HG003079 and U54HG004968.

Author information

Affiliations

Authors

Contributions

P.B. and G.M.W. conceived the study. P.B., M.A., G.M.W. and S.R.S. designed the analyses. Si.S., Sh.S., M.A., M.M., J.T., A.Z., A.W., D.R.M., J.R.K., J.M. and K.K. performed the analyses. M.A., Sh.S., Si.S. and P.B. wrote the manuscript. All authors read and approved the manuscript.

Corresponding authors

Correspondence to George M. Weinstock or Peer Bork.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Methods and Notes, additional references, Supplementary Figures 1-8 and legends for Supplementary Tables 1-15. (PDF 1947 kb)

Supplementary Tables

This file contains Supplementary Tables 1-15 (see Supplementary Information file for Supplementary Table legends). (XLS 5425 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Schloissnig, S., Arumugam, M., Sunagawa, S. et al. Genomic variation landscape of the human gut microbiome. Nature 493, 45–50 (2013). https://doi.org/10.1038/nature11711

Download citation

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links