{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T10:40:53Z","timestamp":1790419253282,"version":"4.1.0"},"reference-count":30,"publisher":"National Academy of Sciences","issue":"12","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2011,3,22]]},"abstract":"<jats:p>\n                    Many pathogens colonize different anatomical sites, but the selective pressures contributing to survival in the diverse niches are poorly understood. Group A\n                    <jats:italic>Streptococcus<\/jats:italic>\n                    (GAS) is a human-adapted bacterium that causes a range of infections. Much effort has been expended to dissect the molecular basis of invasive (sterile-site) infections, but little is known about the genomes of strains causing pharyngitis (streptococcal \u201csore throat\u201d). Additionally, there is essentially nothing known about the genetic relationships between populations of invasive and pharyngitis strains. In particular, it is unclear if invasive strains represent a distinct genetic subpopulation of strains that cause pharyngitis. We compared the genomes of 86 serotype M3 GAS pharyngitis strains with those of 215 invasive M3 strains from the same geographical location. The pharyngitis and invasive groups were highly related to each other and had virtually identical phylogenetic structures, indicating they belong to the same genetic pool. Despite the overall high degree of genetic similarity, we discovered that strains from different host environments (i.e., throat, normally sterile sites) have distinct patterns of diversifying selection at the nucleotide level. In particular, the pattern of polymorphisms in the hyaluronic acid capsule synthesis operon was especially different between the two strain populations. This finding was mirrored by data obtained from full-genome analysis of strains sequentially cultured from nonhuman primates. Our results answer the long-standing question of the genetic relationship between GAS pharyngitis and invasive strains. The data provide previously undescribed information about the evolutionary history of pathogenic microbes that cause disease in different anatomical sites.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1016282108","type":"journal-article","created":{"date-parts":[[2011,3,8]],"date-time":"2011-03-08T07:01:21Z","timestamp":1299567681000},"page":"5039-5044","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":90,"title":["Distinct signatures of diversifying selection revealed by genome analysis of respiratory tract and invasive bacterial populations"],"prefix":"10.1073","volume":"108","author":[{"given":"Patrick R.","family":"Shea","sequence":"first","affiliation":[{"name":"Center for Molecular and Translational Human Infectious Diseases Research, Department of Pathology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen B.","family":"Beres","sequence":"additional","affiliation":[{"name":"Center for Molecular and Translational Human Infectious Diseases Research, Department of Pathology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony R.","family":"Flores","sequence":"additional","affiliation":[{"name":"Center for Molecular and Translational Human Infectious Diseases Research, Department of Pathology, and"},{"name":"Section of Infectious Diseases, Department of Pediatrics, Texas Children's Hospital and Baylor College of Medicine, Houston, TX 77030; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy L.","family":"Ewbank","sequence":"additional","affiliation":[{"name":"Center for Molecular and Translational Human Infectious Diseases Research, Department of Pathology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Javier H.","family":"Gonzalez-Lugo","sequence":"additional","affiliation":[{"name":"Center for Molecular and Translational Human Infectious Diseases Research, Department of Pathology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandro J.","family":"Martagon-Rosado","sequence":"additional","affiliation":[{"name":"Center for Molecular and Translational Human Infectious Diseases Research, Department of Pathology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan C.","family":"Martinez-Gutierrez","sequence":"additional","affiliation":[{"name":"Center for Molecular and Translational Human Infectious Diseases Research, Department of Pathology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hina A.","family":"Rehman","sequence":"additional","affiliation":[{"name":"Center for Molecular and Translational Human Infectious Diseases Research, Department of Pathology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica","family":"Serrano-Gonzalez","sequence":"additional","affiliation":[{"name":"Center for Molecular and Translational Human Infectious Diseases Research, Department of Pathology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nahuel","family":"Fittipaldi","sequence":"additional","affiliation":[{"name":"Center for Molecular and Translational Human Infectious Diseases Research, Department of Pathology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen D.","family":"Ayers","sequence":"additional","affiliation":[{"name":"Section of Genomic Medicine, The Methodist Hospital Research Institute, Houston, TX 77030;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Webb","sequence":"additional","affiliation":[{"name":"Section of Genomic Medicine, The Methodist Hospital Research Institute, Houston, TX 77030;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara M.","family":"Willey","sequence":"additional","affiliation":[{"name":"Ontario Agency for Health Protection and Promotion and University of Toronto, Toronto, ON, Canada M5G 1X5"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donald E.","family":"Low","sequence":"additional","affiliation":[{"name":"Ontario Agency for Health Protection and Promotion and University of Toronto, Toronto, ON, Canada M5G 1X5"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James M.","family":"Musser","sequence":"additional","affiliation":[{"name":"Center for Molecular and Translational Human Infectious Diseases Research, Department of Pathology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2011,3,7]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1001\/jama.1997.03540250046030","article-title":"An outbreak of invasive group A streptococcal disease associated with high carriage rates of the invasive clone among school-aged children","volume":"277","author":"Cockerill FR","year":"1997","unstructured":"FR Cockerill, et al., An outbreak of invasive group A streptococcal disease associated with high carriage rates of the invasive clone among school-aged children. JAMA 277, 38\u201343 (1997).","journal-title":"JAMA"},{"key":"e_1_3_4_2_2","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1086\/318543","article-title":"Distribution of streptococcal inhibitor of complement variants in pharyngitis and invasive isolates in an epidemic of serotype M1 group A Streptococcus infection","volume":"183","author":"Hoe NP","year":"2001","unstructured":"NP Hoe, et al., Distribution of streptococcal inhibitor of complement variants in pharyngitis and invasive isolates in an epidemic of serotype M1 group A Streptococcus infection. J Infect Dis 183, 633\u2013639 (2001).","journal-title":"J Infect Dis"},{"key":"e_1_3_4_3_2","doi-asserted-by":"crossref","first-page":"4371","DOI":"10.1073\/pnas.0911295107","article-title":"Molecular complexity of successive bacterial epidemics deconvoluted by comparative pathogenomics","volume":"107","author":"Beres SB","year":"2010","unstructured":"SB Beres, et al., Molecular complexity of successive bacterial epidemics deconvoluted by comparative pathogenomics. Proc Natl Acad Sci USA 107, 4371\u20134376 (2010).","journal-title":"Proc Natl Acad Sci USA"},{"key":"e_1_3_4_4_2","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1038\/nmeth.1286","article-title":"Sensitive, specific polymorphism discovery in bacteria using massively parallel sequencing","volume":"6","author":"Nusbaum C","year":"2009","unstructured":"C Nusbaum, et al., Sensitive, specific polymorphism discovery in bacteria using massively parallel sequencing. Nat Methods 6, 67\u201369 (2009).","journal-title":"Nat Methods"},{"key":"e_1_3_4_5_2","doi-asserted-by":"crossref","first-page":"19181","DOI":"10.1016\/S0021-9258(19)36494-4","article-title":"Molecular cloning, identification, and sequence of the hyaluronan synthase gene from group A Streptococcus pyogenes","volume":"268","author":"DeAngelis PL","year":"1993","unstructured":"PL DeAngelis, J Papaconstantinou, PH Weigel, Molecular cloning, identification, and sequence of the hyaluronan synthase gene from group A Streptococcus pyogenes. J Biol Chem 268, 19181\u201319184 (1993).","journal-title":"J Biol Chem"},{"key":"e_1_3_4_6_2","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/S0021-9258(17)42330-1","article-title":"Molecular characterization of hasA from an operon required for hyaluronic acid synthesis in group A streptococci","volume":"269","author":"Dougherty BA","year":"1994","unstructured":"BA Dougherty, I van de Rijn, Molecular characterization of hasA from an operon required for hyaluronic acid synthesis in group A streptococci. J Biol Chem 269, 169\u2013175 (1994).","journal-title":"J Biol Chem"},{"key":"e_1_3_4_7_2","doi-asserted-by":"crossref","first-page":"7118","DOI":"10.1016\/S0021-9258(18)53153-7","article-title":"Molecular characterization of hasB from an operon required for hyaluronic acid synthesis in group A streptococci. Demonstration of UDP-glucose dehydrogenase activity","volume":"268","author":"Dougherty BA","year":"1993","unstructured":"BA Dougherty, I van de Rijn, Molecular characterization of hasB from an operon required for hyaluronic acid synthesis in group A streptococci. Demonstration of UDP-glucose dehydrogenase activity. J Biol Chem 268, 7118\u20137124 (1993).","journal-title":"J Biol Chem"},{"key":"e_1_3_4_8_2","doi-asserted-by":"crossref","first-page":"14568","DOI":"10.1016\/S0021-9258(18)82366-3","article-title":"Isolation of a Streptococcus pyogenes gene locus that directs hyaluronan biosynthesis in acapsular mutants and in heterologous bacteria","volume":"268","author":"DeAngelis PL","year":"1993","unstructured":"PL DeAngelis, J Papaconstantinou, PH Weigel, Isolation of a Streptococcus pyogenes gene locus that directs hyaluronan biosynthesis in acapsular mutants and in heterologous bacteria. J Biol Chem 268, 14568\u201314571 (1993).","journal-title":"J Biol Chem"},{"key":"e_1_3_4_9_2","doi-asserted-by":"crossref","first-page":"18452","DOI":"10.1074\/jbc.270.31.18452","article-title":"Hyaluronic acid synthesis operon (has) expression in group A streptococci","volume":"270","author":"Crater DL","year":"1995","unstructured":"DL Crater, I van de Rijn, Hyaluronic acid synthesis operon (has) expression in group A streptococci. J Biol Chem 270, 18452\u201318458 (1995).","journal-title":"J Biol Chem"},{"key":"e_1_3_4_10_2","doi-asserted-by":"crossref","first-page":"3649","DOI":"10.1128\/JB.181.12.3649-3657.1999","article-title":"A response regulator that represses transcription of several virulence operons in the group A streptococcus","volume":"181","author":"Federle MJ","year":"1999","unstructured":"MJ Federle, KS McIver, JR Scott, A response regulator that represses transcription of several virulence operons in the group A streptococcus. J Bacteriol 181, 3649\u20133657 (1999).","journal-title":"J Bacteriol"},{"key":"e_1_3_4_11_2","doi-asserted-by":"crossref","first-page":"e5","DOI":"10.1371\/journal.ppat.0020005","article-title":"Genome-wide analysis of group a streptococci reveals a mutation that modulates global phenotype and disease specificity","volume":"2","author":"Sumby P","year":"2006","unstructured":"P Sumby, AR Whitney, EA Graviss, FR DeLeo, JM Musser, Genome-wide analysis of group a streptococci reveals a mutation that modulates global phenotype and disease specificity. PLoS Pathog 2, e5 (2006).","journal-title":"PLoS Pathog"},{"key":"e_1_3_4_12_2","doi-asserted-by":"crossref","first-page":"1161","DOI":"10.1046\/j.1365-2958.2002.02810.x","article-title":"Identification of binding sites for the group A streptococcal global regulator CovR","volume":"43","author":"Federle MJ","year":"2002","unstructured":"MJ Federle, JR Scott, Identification of binding sites for the group A streptococcal global regulator CovR. Mol Microbiol 43, 1161\u20131172 (2002).","journal-title":"Mol Microbiol"},{"key":"e_1_3_4_13_2","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1046\/j.1365-2958.1998.00800.x","article-title":"Structure of the has operon promoter and regulation of hyaluronic acid capsule expression in group A Streptococcus","volume":"28","author":"Albert\u00ed S","year":"1998","unstructured":"S Albert\u00ed, CD Ashbaugh, MR Wessels, Structure of the has operon promoter and regulation of hyaluronic acid capsule expression in group A Streptococcus. Mol Microbiol 28, 343\u2013353 (1998).","journal-title":"Mol Microbiol"},{"key":"e_1_3_4_14_2","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1084\/jem.77.1.21","article-title":"The occurrence of mucoid polysaccharide in hemolytic streptococci of human origin","volume":"77","author":"Seastone CV","year":"1943","unstructured":"CV Seastone, The occurrence of mucoid polysaccharide in hemolytic streptococci of human origin. J Exp Med 77, 21\u201328 (1943).","journal-title":"J Exp Med"},{"key":"e_1_3_4_15_2","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1084\/jem.48.6.751","article-title":"Variants of hemolytic streptococci; their relation to type-specific substance, virulence, and toxin","volume":"48","author":"Todd EW","year":"1928","unstructured":"EW Todd, RC Lancefield, Variants of hemolytic streptococci; their relation to type-specific substance, virulence, and toxin. J Exp Med 48, 751\u2013767 (1928).","journal-title":"J Exp Med"},{"key":"e_1_3_4_16_2","doi-asserted-by":"crossref","first-page":"1038","DOI":"10.1086\/529194","article-title":"The importance of the group a streptococcus capsule in the pathogenesis of human infections: A historical perspective","volume":"46","author":"Stollerman GH","year":"2008","unstructured":"GH Stollerman, JB Dale, The importance of the group a streptococcus capsule in the pathogenesis of human infections: A historical perspective. Clin Infect Dis 46, 1038\u20131045 (2008).","journal-title":"Clin Infect Dis"},{"key":"e_1_3_4_17_2","doi-asserted-by":"crossref","first-page":"8317","DOI":"10.1073\/pnas.88.19.8317","article-title":"Hyaluronic acid capsule is a virulence factor for mucoid group A streptococci","volume":"88","author":"Wessels MR","year":"1991","unstructured":"MR Wessels, AE Moses, JB Goldberg, TJ DiCesare, Hyaluronic acid capsule is a virulence factor for mucoid group A streptococci. Proc Natl Acad Sci USA 88, 8317\u20138321 (1991).","journal-title":"Proc Natl Acad Sci USA"},{"key":"e_1_3_4_18_2","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1128\/iai.62.2.433-441.1994","article-title":"Effects on virulence of mutations in a locus essential for hyaluronic acid capsule expression in group A streptococci","volume":"62","author":"Wessels MR","year":"1994","unstructured":"MR Wessels, JB Goldberg, AE Moses, TJ DiCesare, Effects on virulence of mutations in a locus essential for hyaluronic acid capsule expression in group A streptococci. Infect Immun 62, 433\u2013441 (1994).","journal-title":"Infect Immun"},{"key":"e_1_3_4_19_2","doi-asserted-by":"crossref","first-page":"9014","DOI":"10.1073\/pnas.0503671102","article-title":"Longitudinal analysis of the group A Streptococcus transcriptome in experimental pharyngitis in cynomolgus macaques","volume":"102","author":"Virtaneva K","year":"2005","unstructured":"K Virtaneva, et al., Longitudinal analysis of the group A Streptococcus transcriptome in experimental pharyngitis in cynomolgus macaques. Proc Natl Acad Sci USA 102, 9014\u20139019 (2005).","journal-title":"Proc Natl Acad Sci USA"},{"key":"e_1_3_4_20_2","doi-asserted-by":"crossref","first-page":"10078","DOI":"10.1073\/pnas.152298499","article-title":"Genome sequence of a serotype M3 strain of group A Streptococcus: Phage-encoded toxins, the high-virulence phenotype, and clone emergence","volume":"99","author":"Beres SB","year":"2002","unstructured":"SB Beres, et al., Genome sequence of a serotype M3 strain of group A Streptococcus: Phage-encoded toxins, the high-virulence phenotype, and clone emergence. Proc Natl Acad Sci USA 99, 10078\u201310083 (2002).","journal-title":"Proc Natl Acad Sci USA"},{"key":"e_1_3_4_21_2","doi-asserted-by":"crossref","first-page":"1910","DOI":"10.1126\/science.272.5270.1910","article-title":"Lysogenic conversion by a filamentous phage encoding cholera toxin","volume":"272","author":"Waldor MK","year":"1996","unstructured":"MK Waldor, JJ Mekalanos, Lysogenic conversion by a filamentous phage encoding cholera toxin. Science 272, 1910\u20131914 (1996).","journal-title":"Science"},{"key":"e_1_3_4_22_2","doi-asserted-by":"crossref","first-page":"694","DOI":"10.1126\/science.6387911","article-title":"Shiga-like toxin-converting phages from Escherichia coli strains that cause hemorrhagic colitis or infantile diarrhea","volume":"226","author":"O'Brien AD","year":"1984","unstructured":"AD O'Brien, et al., Shiga-like toxin-converting phages from Escherichia coli strains that cause hemorrhagic colitis or infantile diarrhea. Science 226, 694\u2013696 (1984).","journal-title":"Science"},{"key":"e_1_3_4_23_2","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1101\/gr.074492.107","article-title":"Velvet: Algorithms for de novo short read assembly using de Bruijn graphs","volume":"18","author":"Zerbino DR","year":"2008","unstructured":"DR Zerbino, E Birney, Velvet: Algorithms for de novo short read assembly using de Bruijn graphs. Genome Res 18, 821\u2013829 (2008).","journal-title":"Genome Res"},{"key":"e_1_3_4_24_2","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1186\/1471-2334-10-233","article-title":"Spread of a highly mucoid Streptococcus pyogenes emm3\/ST15 clone","volume":"10","author":"Tamayo E","year":"2010","unstructured":"E Tamayo, M Montes, G Garc\u00eda-Medina, JM Garc\u00eda-Arenzana, E P\u00e9rez-Trallero, Spread of a highly mucoid Streptococcus pyogenes emm3\/ST15 clone. BMC Infect Dis 10, 233 (2010).","journal-title":"BMC Infect Dis"},{"key":"e_1_3_4_25_2","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1038\/nature09298","article-title":"Integrating common and rare genetic variation in diverse human populations","volume":"467","author":"Altshuler DM","year":"2010","unstructured":"DM Altshuler, et al., Integrating common and rare genetic variation in diverse human populations. Nature; International HapMap 3 Consortium 467, 52\u201358 (2010).","journal-title":"Nature"},{"key":"e_1_3_4_26_2","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1093\/molbev\/msj030","article-title":"Application of phylogenetic networks in evolutionary studies","volume":"23","author":"Huson DH","year":"2006","unstructured":"DH Huson, D Bryant, Application of phylogenetic networks in evolutionary studies. Mol Biol Evol 23, 254\u2013267 (2006).","journal-title":"Mol Biol Evol"},{"key":"e_1_3_4_27_2","doi-asserted-by":"crossref","first-page":"1596","DOI":"10.1093\/molbev\/msm092","article-title":"MEGA4: Molecular Evolutionary Genetics Analysis (MEGA) software version 4.0","volume":"24","author":"Tamura K","year":"2007","unstructured":"K Tamura, J Dudley, M Nei, S Kumar, MEGA4: Molecular Evolutionary Genetics Analysis (MEGA) software version 4.0. Mol Biol Evol 24, 1596\u20131599 (2007).","journal-title":"Mol Biol Evol"},{"key":"e_1_3_4_28_2","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1186\/1471-2105-8-460","article-title":"Dendroscope: An interactive viewer for large phylogenetic trees","volume":"8","author":"Huson DH","year":"2007","unstructured":"DH Huson, et al., Dendroscope: An interactive viewer for large phylogenetic trees. BMC Bioinformatics 8, 460 (2007).","journal-title":"BMC Bioinformatics"},{"key":"e_1_3_4_29_2","doi-asserted-by":"crossref","first-page":"1954","DOI":"10.1172\/JCI118998","article-title":"Hyaluronic acid capsule and the role of streptococcal entry into keratinocytes in invasive skin infection","volume":"98","author":"Schrager HM","year":"1996","unstructured":"HM Schrager, JG Rheinwald, MR Wessels, Hyaluronic acid capsule and the role of streptococcal entry into keratinocytes in invasive skin infection. J Clin Invest 98, 1954\u20131958 (1996).","journal-title":"J Clin Invest"},{"key":"e_1_3_4_30_2","doi-asserted-by":"crossref","first-page":"2199","DOI":"10.1128\/IAI.71.4.2199-2207.2003","article-title":"Group A Streptococcus gene expression in humans and cynomolgus macaques with acute pharyngitis","volume":"71","author":"Virtaneva K","year":"2003","unstructured":"K Virtaneva, et al., Group A Streptococcus gene expression in humans and cynomolgus macaques with acute pharyngitis. Infect Immun 71, 2199\u20132207 (2003).","journal-title":"Infect Immun"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.1016282108","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,6,7]],"date-time":"2022-06-07T03:38:54Z","timestamp":1654573134000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.1016282108"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2011,3,7]]},"references-count":30,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2011,3,22]]}},"alternative-id":["10.1073\/pnas.1016282108"],"URL":"https:\/\/doi.org\/10.1073\/pnas.1016282108","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.11170956.12157054","asserted-by":"object"}]},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2011,3,7]]},"assertion":[{"value":"2011-03-07","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}