The complex and intimate relationship between humans and their gut microbial communities is becoming less obscure, due in part to large-scale gut microbial genome-sequencing projects and culture-independent surveys of the composition and gene content of these communities. These studies build upon, and are complemented by, experimental efforts to define underlying mechanisms of host-microbe interactions in simplified model systems. This review highlights the intersection of these approaches. Experimental studies now leverage the advances in high-throughput DNA sequencing that have driven the explosion of microbial genome and community profiling projects, and the loss-of-function and gain-of-function strategies long employed in model organisms are now being extended to microbial genes, species, and communities from the human gut. These developments promise to deepen our understanding of human gut host–microbiota relationships and are readily applicable to other host-associated and free-living microbial communities.


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Literature Cited

  1. Allen HK, Donato J, Wang HH, Cloud-Hansen KA, Davies J, Handelsman J. 1.  2010. Call of the wild: antibiotic resistance genes in natural environments. Nat. Rev. Microbiol. 8:251–59 [Google Scholar]
  2. Antonopoulos DA, Huse SM, Morrison HG, Schmidt TM, Sogin ML, Young VB. 2.  2009. Reproducible community dynamics of the gastrointestinal microbiota following antibiotic perturbation. Infect. Immun. 77:2367–75 [Google Scholar]
  3. Arthur JC, Perez-Chanona E, Mühlbauer M, Tomkovich S, Uronis JM. 3.  et al. 2012. Intestinal inflammation targets cancer-inducing activity of the microbiota. Science 338:120–23Shows how effects of the microbiota can depend on host genotype. [Google Scholar]
  4. Arumugam M, Raes J, Pelletier E, Le Paslier D, Yamada T. 4.  et al. 2011. Enterotypes of the human gut microbiome. Nature 473:174–80 [Google Scholar]
  5. Backhed F, Ley RE, Sonnenburg JL, Peterson DA, Gordon JI. 5.  2005. Host-bacterial mutualism in the human intestine. Science 307:1915–20 [Google Scholar]
  6. Bjursell MK, Martens EC, Gordon JI. 6.  2006. Functional genomic and metabolic studies of the adaptations of a prominent adult human gut symbiont, Bacteroides thetaiotaomicron, to the suckling period. J. Biol. Chem. 281:36269–79 [Google Scholar]
  7. Blaser MJ, Falkow S. 7.  2009. What are the consequences of the disappearing human microbiota?. Nat. Rev. Microbiol. 7:887–94 [Google Scholar]
  8. Bloom SM, Bijanki VN, Nava GM, Sun L, Malvin NP. 8.  et al. 2011. Commensal Bacteroides species induce colitis in host-genotype-specific fashion in a mouse model of inflammatory bowel disease. Cell Host Microbe 9:390–403Demonstrates how gut microbes can impact disease independent of disease-associated changes in community composition. [Google Scholar]
  9. Brandl K, Plitas G, Mihu CN, Ubeda C, Jia T. 9.  et al. 2008. Vancomycin-resistant enterococci exploit antibiotic-induced innate immune deficits. Nature 455:804–7 [Google Scholar]
  10. Bravo JA, Forsythe P, Chew MV, Escaravage E, Savignac HM. 10.  et al. 2011. Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Proc. Natl. Acad. Sci. USA 108:16050–55 [Google Scholar]
  11. Caspi R, Altman T, Dreher K, Fulcher CA, Subhraveti P. 11.  et al. 2012. The MetaCyc database of metabolic pathways and enzymes and the BioCyc collection of pathway/genome databases. Nucleic Acids Res. 40:D742–53 [Google Scholar]
  12. Cheng G, Hu Y, Yin Y, Yang X, Xiang C. 12.  et al. 2012. Functional screening of antibiotic resistance genes from human gut microbiota reveals a novel gene fusion. FEMS Microbiol. Lett. 336:11–16 [Google Scholar]
  13. Chiang SL, Mekalanos JJ, Holden DW. 13.  1999. In vivo genetic analysis of bacterial virulence. Annu. Rev. Microbiol. 53:129–54 [Google Scholar]
  14. Cho I, Yamanishi S, Cox L, Methe BA, Zavadil J. 14.  et al. 2012. Antibiotics in early life alter the murine colonic microbiome and adiposity. Nature 488:621–26 [Google Scholar]
  15. Chung H, Pamp SJ, Hill JA, Surana NK, Edelman SM. 15.  et al. 2012. Gut immune maturation depends on colonization with a host-specific microbiota. Cell 149:1578–93 [Google Scholar]
  16. Cole JR, Chai B, Farris RJ, Wang Q, Kulam-Syed-Mohideen AS. 16.  et al. 2007. The ribosomal database project (RDP-II): introducing myRDP space and quality controlled public data. Nucleic Acids Res. 35:D169–72 [Google Scholar]
  17. Dantas G, Sommer MO. 17.  2012. Context matters—the complex interplay between resistome genotypes and resistance phenotypes. Curr. Opin. Microbiol. 15:577–82 [Google Scholar]
  18. de Lastours V, Cambau E, Guillard T, Marcade G, Chau F, Fantin B. 18.  2012. Diversity of individual dynamic patterns of emergence of resistance to quinolones in Escherichia coli from the fecal flora of healthy volunteers exposed to ciprofloxacin. J. Infect. Dis. 206:1399–406 [Google Scholar]
  19. de Vos WM, de Vos EA. 19.  2012. Role of the intestinal microbiome in health and disease: from correlation to causation. Nutr. Rev. 70:Suppl. 1S45–56 [Google Scholar]
  20. de Vries LE, Vallès Y, Agersø Y, Vaishampayan PA, García-Montaner A. 20.  et al. 2011. The gut as reservoir of antibiotic resistance: microbial diversity of tetracycline resistance in mother and infant. PLoS One 6:e21644 [Google Scholar]
  21. Dethlefsen L, Huse S, Sogin ML, Relman DA. 21.  2008. The pervasive effects of an antibiotic on the human gut microbiota, as revealed by deep 16S rRNA sequencing. PLoS Biol. 6:e280 [Google Scholar]
  22. Dethlefsen L, Relman DA. 22.  2011. Incomplete recovery and individualized responses of the human distal gut microbiota to repeated antibiotic perturbation. Proc. Natl. Acad. Sci. USA 108:Suppl. 14554–61 [Google Scholar]
  23. Dutton RJ, Turnbaugh PJ. 23.  2012. Taking a metagenomic view of human nutrition. Curr. Opin. Clin. Nutr. 15:448–54 [Google Scholar]
  24. Elinav E, Strowig T, Kau AL, Henao-Mejia J, Thaiss CA. 24.  et al. 2011. NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis. Cell 145:745–57 [Google Scholar]
  25. Flint HJ. 25.  2012. The impact of nutrition on the human microbiome. Nutr. Rev. 70:Suppl. 1S10–13 [Google Scholar]
  26. Friedberg I. 26.  2006. Automated protein function prediction—the genomic challenge. Brief Bioinform. 7:225–42 [Google Scholar]
  27. Gaboriau-Routhiau V, Rakotobe S, Lécuyer E, Mulder I, Lan A. 27.  et al. 2009. The key role of segmented filamentous bacteria in the coordinated maturation of gut helper T cell responses. Immunity 31:677–89 [Google Scholar]
  28. Gallagher LA, Shendure J, Manoil C. 28.  2011. Genome-scale identification of resistance functions in Pseudomonas aeruginosa using Tn-seq. mBio 2:e00315–10 [Google Scholar]
  29. Garner CD, Antonopoulos DA, Wagner B, Duhamel GE, Keresztes I. 29.  et al. 2009. Perturbation of the small intestine microbial ecology by streptomycin alters pathology in a Salmonella enterica serovar Typhimurium murine model of infection. Infect. Immun. 77:2691–702 [Google Scholar]
  30. Gawronski JD, Wong SM, Giannoukos G, Ward DV, Akerley BJ. 30.  2009. Tracking insertion mutants within libraries by deep sequencing and a genome-wide screen for Haemophilus genes required in the lung. Proc. Natl. Acad. Sci. USA 106:16422–27 [Google Scholar]
  31. Gill SR, Pop M, Deboy RT, Eckburg PB, Turnbaugh PJ. 31.  et al. 2006. Metagenomic analysis of the human distal gut microbiome. Science 312:1355–59 [Google Scholar]
  32. Goodman AL, Gordon JI. 32.  2010. Our unindicted coconspirators: human metabolism from a microbial perspective. Cell Metabol. 12:111–16 [Google Scholar]
  33. Goodman AL, Kallstrom G, Faith JJ, Reyes A, Moore A. 33.  et al. 2011. Extensive personal human gut microbiota culture collections characterized and manipulated in gnotobiotic mice. Proc. Natl. Acad. Sci. USA 108:6252–57 [Google Scholar]
  34. Goodman AL, McNulty NP, Zhao Y, Leip D, Mitra RD. 34.  et al. 2009. Identifying genetic determinants needed to establish a human gut symbiont in its habitat. Cell Host Microbe 6:279–89 [Google Scholar]
  35. Goodman AL, Wu M, Gordon JI. 35.  2011. Identifying microbial fitness determinants by insertion sequencing using genome-wide transposon mutant libraries. Nat. Protoc. 6:1969–80 [Google Scholar]
  36. Haiser HJ, Turnbaugh PJ. 36.  2012. Is it time for a metagenomic basis of therapeutics?. Science 336:1253–55 [Google Scholar]
  37. Handelsman J. 37.  2004. Metagenomics: application of genomics to uncultured microorganisms. Microbiol. Mol. Biol. Rev. 68:669–85 [Google Scholar]
  38. Hapfelmeier S, Lawson MA, Slack E, Kirundi JK, Stoel M. 38.  et al. 2010. Reversible microbial colonization of germ-free mice reveals the dynamics of IgA immune responses. Science 328:1705–9Uses microbial genetics to define the duration of host responses to the microbiota. [Google Scholar]
  39. Hehemann JH, Correc G, Barbeyron T, Helbert W, Czjzek M, Michel G. 39.  2010. Transfer of carbohydrate-active enzymes from marine bacteria to Japanese gut microbiota. Nature 464:908–12 [Google Scholar]
  40. Hooper LV, Wong MH, Thelin A, Hansson L, Falk PG, Gordon JI. 40.  2001. Molecular analysis of commensal host-microbial relationships in the intestine. Science 291:881–84 [Google Scholar]
  41. Huh D, Matthews BD, Mammoto A, Montoya-Zavala M, Hsin HY, Ingber DE. 41.  2010. Reconstituting organ-level lung functions on a chip. Science 328:1662–68 [Google Scholar]
  42. 42. Human Microbiome Project Consortium 2012. Structure, function and diversity of the healthy human microbiome. Nature 486:207–14 [Google Scholar]
  43. Ivanov II, Atarashi K, Manel N, Brodie EL, Shima T. 43.  et al. 2009. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 139:485–98Combines in situ analyses and experimental study to identify key microbes that induce immune response. [Google Scholar]
  44. Jobling MA, Hurles ME, Tyler-Smith C. 44.  2004. Human Evolutionary Genetics New York: Garland Sci.
  45. Karami N, Martner A, Enne VI, Swerkersson S, Adlerberth I, Wold AE. 45.  2007. Transfer of an ampicillin resistance gene between two Escherichia coli strains in the bowel microbiota of an infant treated with antibiotics. J. Antimicrobiol. Chemother. 60:1142–45 [Google Scholar]
  46. Keseler IM, Mackie A, Peralta-Gil M, Santos-Zavaleta A, Gama-Castro S. 46.  et al. 2012. EcoCyc: fusing model organism databases with systems biology. Nucleic Acids Res. 41:D605–D12 [Google Scholar]
  47. Kim HJ, Huh D, Hamilton G, Ingber DE. 47.  2012. Human gut-on-a-chip inhabited by microbial flora that experiences intestinal peristalsis-like motions and flow. Lab Chip 12:2165–74 [Google Scholar]
  48. Koenig JE, Spor A, Scalfone N, Fricker AD, Stombaugh J. 48.  et al. 2011. Succession of microbial consortia in the developing infant gut microbiome. Proc. Natl. Acad. Sci. USA 108:Suppl. 14578–85 [Google Scholar]
  49. Koren O, Goodrich JK, Cullender TC, Spor A, Laitinen K. 49.  et al. 2012. Host remodeling of the gut microbiome and metabolic changes during pregnancy. Cell 150:470–80Demonstrates transmission of a phenotype from humans to germ-free mice via their gut microbiota. [Google Scholar]
  50. Koropatkin NM, Cameron EA, Martens EC. 50.  2012. How glycan metabolism shapes the human gut microbiota. Nat. Rev. Microbiol. 10:323–35 [Google Scholar]
  51. Lampe DJ, Akerley BJ, Rubin EJ, Mekalanos JJ, Robertson HM. 51.  1999. Hyperactive transposase mutants of the Himar1 mariner transposon. Proc. Natl. Acad. Sci. USA 96:11428–33 [Google Scholar]
  52. Langridge GC, Phan MD, Turner DJ, Perkins TT, Parts L. 52.  et al. 2009. Simultaneous assay of every Salmonella Typhi gene using one million transposon mutants. Genome Res. 19:2308–16 [Google Scholar]
  53. Lester CH, Frimodt-Møller N, Sørensen TL, Monnet DL, Hammerum AM. 53.  2006. In vivo transfer of the vanA resistance gene from an Enterococcus faecium isolate of animal origin to an E. faecium isolate of human origin in the intestines of human volunteers. Antimicrob. Agents Chemother. 50:596–99 [Google Scholar]
  54. Lozupone CA, Hamady M, Cantarel BL, Coutinho PM, Henrissat B. 54.  et al. 2008. The convergence of carbohydrate active gene repertoires in human gut microbes. Proc. Natl. Acad. Sci. USA 105:15076–81 [Google Scholar]
  55. Lozupone C, Hamady M, Knight R. 55.  2006. UniFrac—an online tool for comparing microbial community diversity in a phylogenetic context. BMC Bioinforma. 7:371 [Google Scholar]
  56. Lozupone CA, Stombaugh JI, Gordon JI, Jansson JK, Knight R. 56.  2012. Diversity, stability and resilience of the human gut microbiota. Nature 489:220–30 [Google Scholar]
  57. Mahowald MA, Rey FE, Seedorf H, Turnbaugh PJ, Fulton RS. 57.  et al. 2009. Characterizing a model human gut microbiota composed of members of its two dominant bacterial phyla. Proc. Natl. Acad. Sci. USA 106:5859–64 [Google Scholar]
  58. Martens EC, Chiang HC, Gordon JI. 58.  2008. Mucosal glycan foraging enhances fitness and transmission of a saccharolytic human gut bacterial symbiont. Cell Host Microbe 4:447–57 [Google Scholar]
  59. Martin FP, Wang Y, Sprenger N, Yap IK, Lundstedt T. 59.  et al. 2008. Probiotic modulation of symbiotic gut microbial-host metabolic interactions in a humanized microbiome mouse model. Mol. Syst. Biol. 4:157 [Google Scholar]
  60. McNulty NP, Yatsunenko T, Hsiao A, Faith JJ, Muegge BD. 60.  et al. 2011. The impact of a consortium of fermented milk strains on the gut microbiome of gnotobiotic mice and monozygotic twins. Sci. Transl. Med. 3:106ra06 [Google Scholar]
  61. Moore AM, Munck C, Sommer MOA, Dantas G. 61.  2011. Functional metagenomic investigations of the human intestinal microbiota. Front. Microbiol. 2:188 [Google Scholar]
  62. Morgan RD, Bhatia TK, Lovasco L, Davis TB. 62.  2008. MmeI: a minimal Type II restriction-modification system that only modifies one DNA strand for host protection. Nucleic Acids Res. 36:6558–70 [Google Scholar]
  63. Muruganandan S, Sinal CJ. 63.  2008. Mice as clinically relevant models for the study of cytochrome P450-dependent metabolism. Clin. Pharmacol. Ther. 83:818–28 [Google Scholar]
  64. Neidhardt FC, Ingraham JL, Low KB, Magasanik B, Schaechter M, Umbarger HE. 64.  1987. Escherichia coli and Salmonella typhimurium: Cellular and Molecular Biology Washington, DC: ASM1,654, 1st ed..
  65. Nelson KE, Weinstock GM, Highlander SK, Worley KC, Creasy HH. 65.  et al. 2010. A catalog of reference genomes from the human microbiome. Science 328:994–99 [Google Scholar]
  66. Qin J, Li Y, Cai Z, Li S, Zhu J. 66.  et al. 2012. A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature 490:55–60 [Google Scholar]
  67. Qin J, Li R, Raes J, Arumugam M, Burgdorf KS. 67.  et al. 2010. A human gut microbial gene catalogue established by metagenomic sequencing. Nature 464:59–65 [Google Scholar]
  68. Rawls JF, Mahowald MA, Ley RE, Gordon JI. 68.  2006. Reciprocal gut microbiota transplants from zebrafish and mice to germ-free recipients reveal host habitat selection. Cell 127:423–33 [Google Scholar]
  69. Riesenfeld CS, Goodman RM, Handelsman J. 69.  2004. Uncultured soil bacteria are a reservoir of new antibiotic resistance genes. Environ. Microbiol. 6:981–89 [Google Scholar]
  70. Riesenfeld CS, Schloss PD, Handelsman J. 70.  2004. Metagenomics: genomic analysis of microbial communities. Annu. Rev. Genet. 38:525–52 [Google Scholar]
  71. Robinson CJ, Young VB. 71.  2010. Antibiotic administration alters the community structure of the gastrointestinal microbiota. Gut Microbes 1:279–84 [Google Scholar]
  72. Salyers AA, O'Brien M, Kotarski SF. 72.  1982. Utilization of chondroitin sulfate by Bacteroides thetaiotaomicron growing in carbohydrate-limited continuous culture. J. Bacteriol. 150:1008–15 [Google Scholar]
  73. Savage DC. 73.  1977. Microbial ecology of the gastrointestinal tract. Annu. Rev. Microbiol. 31:107–33 [Google Scholar]
  74. Sellon RK, Tonkonogy S, Schultz M, Dieleman LA, Grenther W. 74.  et al. 1998. Resident enteric bacteria are necessary for development of spontaneous colitis and immune system activation in interleukin-10-deficient mice. Infect. Immun. 66:5224–31 [Google Scholar]
  75. Shipman JA, Berleman JE, Salyers AA. 75.  2000. Characterization of four outer membrane proteins involved in binding starch to the cell surface of Bacteroides thetaiotaomicron. J. Bacteriol. 182:5365–72 [Google Scholar]
  76. Shipman JA, Cho KH, Siegel HA, Salyers AA. 76.  1999. Physiological characterization of SusG, an outer membrane protein essential for starch utilization by Bacteroides thetaiotaomicron. J. Bacteriol. 181:7206–11 [Google Scholar]
  77. Shultz LD, Brehm MA, Garcia-Martinez JV, Greiner DL. 77.  2012. Humanized mice for immune system investigation: progress, promise and challenges. Nat. Rev. Immunol. 12:786–98 [Google Scholar]
  78. Sjölund M, Tano E, Blaser MJ, Andersson DI, Engstrand L. 78.  2005. Persistence of resistant Staphylococcus epidermidis after single course of clarithromycin. Emerg. Infect. Dis. 11:1389–93 [Google Scholar]
  79. Sjölund M, Wreiber K, Andersson DI, Blaser MJ, Engstrand L. 79.  2003. Long-term persistence of resistant Enterococcus species after antibiotics to eradicate Helicobacter pylori. Ann. Intern. Med. 139:483–87 [Google Scholar]
  80. Skolimowski M, Nielsen MW, Emneus J, Molin S, Taboryski R. 80.  et al. 2010. Microfluidic dissolved oxygen gradient generator biochip as a useful tool in bacterial biofilm studies. Lab Chip 10:2162–69 [Google Scholar]
  81. Smith K, McCoy KD, MacPherson AJ. 81.  2007. Use of axenic animals in studying the adaptation of mammals to their commensal intestinal microbiota. Semin. Immunol. 19:59–69Lists a wide range of phenotypes observed in germ-free animals. [Google Scholar]
  82. Sommer MO, Church GM, Dantas G. 82.  2010. The human microbiome harbors a diverse reservoir of antibiotic resistance genes. Virulence 1:299–303 [Google Scholar]
  83. Sommer MO, Dantas G. 83.  2011. Antibiotics and the resistant microbiome. Curr. Opin. Microbiol. 14:556–63 [Google Scholar]
  84. Sommer MO, Dantas G, Church GM. 84.  2009. Functional characterization of the antibiotic resistance reservoir in the human microflora. Science 325:1128–31 [Google Scholar]
  85. Stappenbeck TS, Hooper LV, Gordon JI. 85.  2002. Developmental regulation of intestinal angiogenesis by indigenous microbes via Paneth cells. Proc. Natl. Acad. Sci. USA 99:15451–55 [Google Scholar]
  86. Tasse L, Bercovici J, Pizzut-Serin S, Robe P, Tap J. 86.  et al. 2010. Functional metagenomics to mine the human gut microbiome for dietary fiber catabolic enzymes. Genome Res. 20:1605–12 [Google Scholar]
  87. Temperton B, Giovannoni SJ. 87.  2012. Metagenomics: microbial diversity through a scratched lens. Curr. Opin. Microbiol. 15:605–12 [Google Scholar]
  88. Turnbaugh PJ, Hamady M, Yatsunenko T, Cantarel BL, Duncan A. 88.  et al. 2009. A core gut microbiome in obese and lean twins. Nature 457:480–84 [Google Scholar]
  89. Turnbaugh PJ, Ley RE, Hamady M, Fraser-Liggett CM, Knight R, Gordon JI. 89.  2007. The human microbiome project. Nature 449:804–10 [Google Scholar]
  90. Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI. 90.  2006. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 444:1027–31Combines metagenomics and gut microbiota transplantation experiments to define host and microbial contributions to obesity. [Google Scholar]
  91. Turnbaugh PJ, Ridaura VK, Faith JJ, Rey FE, Knight R, Gordon JI. 91.  2009. The effect of diet on the human gut microbiome: a metagenomic analysis in humanized gnotobiotic mice. Sci. Transl. Med. 1:6ra14 [Google Scholar]
  92. van Opijnen T, Bodi KL, Camilli A. 92.  2009. Tn-seq: high-throughput parallel sequencing for fitness and genetic interaction studies in microorganisms. Nat. Methods 6:767–72 [Google Scholar]
  93. Walter J, Ley R. 93.  2011. The human gut microbiome: ecology and recent evolutionary changes. Annu. Rev. Microbiol. 65:411–29 [Google Scholar]
  94. Werner G, Freitas AR, Coque TM, Sollid JE, Lester C. 94.  et al. 2011. Host range of enterococcal vanA plasmids among gram-positive intestinal bacteria. J. Antimicrobiol. Chemother. 66:273–82 [Google Scholar]
  95. Williamson LL, Borlee BR, Schloss PD, Guan C, Allen HK, Handelsman J. 95.  2005. Intracellular screen to identify metagenomic clones that induce or inhibit a quorum-sensing biosensor. Appl. Environ. Microbiol. 71:6335–44 [Google Scholar]
  96. Woese CR, Fox GE. 96.  1977. Phylogenetic structure of prokaryotic domain: the primary kingdoms. Proc. Natl. Acad. Sci. USA 74:5088–90 [Google Scholar]
  97. Xu J, Bjursell MK, Himrod J, Deng S, Carmichael LK. 97.  et al. 2003. A genomic view of the human-Bacteroides thetaiotaomicron symbiosis. Science 299:2074–76 [Google Scholar]
  98. Xu J, Gordon JI. 98.  2003. Honor thy symbionts. Proc. Natl. Acad. Sci. USA 100:10452–59 [Google Scholar]
  99. Yatsunenko T, Rey FE, Manary MJ, Trehan I, Dominguez-Bello MG. 99.  et al. 2012. Human gut microbiome viewed across age and geography. Nature 486:222–27 [Google Scholar]
  100. Yoshizato K, Tateno C, Utoh R. 100.  2012. Mice with liver composed of human hepatocytes as an animal model for drug testing. Curr. Drug Discov. Technol. 9:63–76 [Google Scholar]
  101. Young VB, Schmidt TM. 101.  2004. Antibiotic-associated diarrhea accompanied by large-scale alterations in the composition of the fecal microbiota. J. Clin. Microbiol. 42:1203–6 [Google Scholar]

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