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0.267 rg BT 15.000 700.036 Td /F3 9.8 Tf [(November 5, 2009)] TJ ET 0.267 0.267 0.267 rg BT 26.250 688.195 Td /F1 9.8 Tf [(Martha Nelson)] TJ ET 0.271 0.267 0.267 rg BT 89.644 688.195 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 95.066 688.195 Td /F1 9.8 Tf [(David Spiro)] TJ ET 0.271 0.267 0.267 rg BT 145.453 688.195 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 150.875 688.195 Td /F1 9.8 Tf [(David Wentworth)] TJ ET 0.271 0.267 0.267 rg BT 225.101 688.195 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 230.522 688.195 Td /F1 9.8 Tf [(Jiang Fan)] TJ ET 0.271 0.267 0.267 rg BT 273.334 688.195 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 278.755 688.195 Td /F1 9.8 Tf [(Eric Beck)] TJ ET 0.271 0.267 0.267 rg BT 319.930 688.195 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 325.351 688.195 Td /F1 9.8 Tf [(Kirsten St. George)] TJ ET 0.271 0.267 0.267 rg BT 405.554 688.195 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 410.975 688.195 Td /F1 9.8 Tf [(Elodie Ghedin)] TJ ET 0.271 0.267 0.267 rg BT 472.215 688.195 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 477.636 688.195 Td /F1 9.8 Tf [(Rebecca Halpin)] TJ ET 0.271 0.267 0.267 rg BT 546.452 688.195 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 551.873 688.195 Td /F1 9.8 Tf [(Jayati )] TJ ET BT 26.250 676.290 Td /F1 9.8 Tf [(Bera)] TJ ET 0.271 0.267 0.267 rg BT 46.842 676.290 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 52.263 676.290 Td /F1 9.8 Tf [(Erin Hine)] TJ ET 0.271 0.267 0.267 rg BT 92.355 676.290 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 97.776 676.290 Td /F1 9.8 Tf [(Katie Proudfoot)] TJ ET 0.271 0.267 0.267 rg BT 164.983 676.290 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 170.404 676.290 Td /F1 9.8 Tf [(Tim Stockwell)] TJ ET 0.271 0.267 0.267 rg BT 230.532 676.290 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 235.953 676.290 Td /F1 9.8 Tf [(Xudong Lin)] TJ ET 0.271 0.267 0.267 rg BT 285.278 676.290 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 290.699 676.290 Td /F1 9.8 Tf [(Sara Griesemer)] TJ ET 0.271 0.267 0.267 rg BT 359.505 676.290 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 364.926 676.290 Td /F1 9.8 Tf [(Michael Bose)] TJ ET 0.271 0.267 0.267 rg BT 423.445 676.290 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 428.866 676.290 Td /F1 9.8 Tf [(Lisa Jurgens)] TJ ET 0.271 0.267 0.267 rg BT 484.139 676.290 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 489.560 676.290 Td /F1 9.8 Tf [(Swati Kumar)] TJ ET 0.271 0.267 0.267 rg BT 544.823 676.290 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 550.244 676.290 Td /F1 9.8 Tf [(Cecile )] TJ ET BT 26.250 664.386 Td /F1 9.8 Tf [(Viboud)] TJ ET 0.271 0.267 0.267 rg BT 56.602 664.386 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 62.023 664.386 Td /F1 9.8 Tf [(Eddie Holmes)] TJ ET 0.271 0.267 0.267 rg BT 122.707 664.386 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 128.128 664.386 Td /F1 9.8 Tf [(Kelly Henrickson)] TJ ET 0.271 0.267 0.267 rg BT 26.250 652.481 Td /F1 9.8 Tf [(Nelson M, Spiro D, Wentworth D, Fan J, Beck E, St. George K, Ghedin E, Halpin R, Bera J, Hine E, Proudfoot K, Stockwell T, )] TJ ET BT 26.250 640.576 Td /F1 9.8 Tf [(Lin X, Griesemer S, Bose M, Jurgens L, Kumar S, Viboud C, Holmes E, Henrickson K. The early diversification of influenza )] TJ ET BT 26.250 628.671 Td /F1 9.8 Tf [(A/H1N1pdm. PLOS Currents Influenza. 2009 Nov 5 . Edition 1. doi: 10.1371/currents.RRN1126.)] TJ ET q 15.000 -95.618 577.500 721.908 re W n 0.271 0.267 0.267 rg BT 26.250 599.569 Td /F4 12.0 Tf [(Abstract)] TJ ET BT 26.250 579.615 Td /F1 9.8 Tf [(Background Since its initial detection in April 2009, the A/H1N1pdm influenza virus has spread rapidly in humans, with over )] TJ ET BT 26.250 567.710 Td /F1 9.8 Tf [(5,700 human deaths. However, little is known about the evolutionary dynamics of H1N1pdm and its geographic and temporal )] TJ ET BT 26.250 555.805 Td /F1 9.8 Tf [(diversification.)] TJ ET BT 26.250 536.400 Td /F1 9.8 Tf [(Methods Phylogenetic analysis was conducted upon the concatenated coding regions of whole-genome sequences from 290 )] TJ ET BT 26.250 524.496 Td /F1 9.8 Tf [(H1N1pdm isolates sampled globally between April 1 July 9, 2009, including relatively large samples from the US states of )] TJ ET BT 26.250 512.591 Td /F1 9.8 Tf [(Wisconsin and New York.)] TJ ET BT 26.250 493.186 Td /F1 9.8 Tf [(Results At least 7 phylogenetically distinct viral clades have disseminated globally and co-circulated in localities that )] TJ ET BT 26.250 481.281 Td /F1 9.8 Tf [(experienced multiple introductions of H1N1pdm. The epidemics in New York and Wisconsin were dominated by two different )] TJ ET BT 26.250 469.377 Td /F1 9.8 Tf [(clades, both phylogenetically distinct from the viruses first identified in California and Mexico, suggesting an important role for )] TJ ET BT 26.250 457.472 Td /F1 9.8 Tf [(founder effects in determining local viral population structures.)] TJ ET BT 26.250 438.067 Td /F1 9.8 Tf [(Conclusions Determining the global diversity of H1N1pdm is central to understanding the evolution and spatial spread of the )] TJ ET BT 26.250 426.162 Td /F1 9.8 Tf [(current pandemic, and to predict its future impact on human populations. Our results indicate that H1N1pdm has already )] TJ ET BT 26.250 414.258 Td /F1 9.8 Tf [(diversified into distinct viral lineages with defined spatial patterns.)] TJ ET BT 26.250 377.655 Td /F4 12.0 Tf [(Introduction)] TJ ET BT 26.250 357.701 Td /F1 9.8 Tf [(In April 2009 a novel influenza A virus H1N1pdm was identified in humans, initiating the first influenza pandemic of the 21st )] TJ ET BT 26.250 345.796 Td /F1 9.8 Tf [(century. As of November 2, 2009, there have been >440,000 laboratory confirmed cases of pandemic H1N1 \(H1N1pdm\) )] TJ ET BT 26.250 333.891 Td /F1 9.8 Tf [(influenza virus, resulting in > 5,700 deaths worldwide \( )] TJ ET 0.267 0.267 0.267 rg BT 263.331 333.891 Td /F1 9.8 Tf [(http://www.who.int/csr/don/2009_10_30/en/index.html)] TJ ET 0.271 0.267 0.267 rg BT 494.737 333.891 Td /F1 9.8 Tf [( , Accessed )] TJ ET BT 26.250 321.987 Td /F1 9.8 Tf [(November 2, 2009\) )] TJ ET 0.267 0.267 0.267 rg BT 112.411 321.987 Td /F1 9.8 Tf [([1])] TJ ET 0.271 0.267 0.267 rg BT 123.253 321.987 Td /F1 9.8 Tf [( . As most countries have discontinued the reporting of cases, this is thought to represent a minimum of 2-)] TJ ET BT 26.250 310.082 Td /F1 9.8 Tf [(5 million people infected. H1N1pdm is a novel reassortant between North American and Eurasian swine influenza viruses, )] TJ ET BT 26.250 298.177 Td /F1 9.8 Tf [(containing PB2, PB1, PA, HA, NP, and NS segments from North American triple-reassortant swine viruses and NA and M )] TJ ET BT 26.250 286.272 Td /F1 9.8 Tf [(segments derived from the Eurasian swine lineage )] TJ ET 0.267 0.267 0.267 rg BT 247.341 286.272 Td /F1 9.8 Tf [([2])] TJ ET 0.271 0.267 0.267 rg BT 258.183 286.272 Td /F1 9.8 Tf [( . The relatively large genetic distance between H1N1pdm and the most )] TJ ET BT 26.250 274.368 Td /F1 9.8 Tf [(closely related swine influenza viruses suggests that these segments have been circulating undetected for a decade or more, )] TJ ET BT 26.250 262.463 Td /F1 9.8 Tf [(with estimates of the Times to the Most Recent Common Ancestor \(TMRCA\) for individual genome segments ranging from 9 )] TJ ET BT 26.250 250.558 Td /F1 9.8 Tf [(17 years )] TJ ET 0.267 0.267 0.267 rg BT 66.352 250.558 Td /F1 9.8 Tf [([3])] TJ ET 0.271 0.267 0.267 rg BT 77.194 250.558 Td /F1 9.8 Tf [( . The relatively low genetic diversity of H1N1pdm suggests that the virus emerged in humans only recently, perhaps )] TJ ET BT 26.250 238.653 Td /F1 9.8 Tf [(in early 2009 )] TJ ET 0.267 0.267 0.267 rg BT 84.779 238.653 Td /F1 9.8 Tf [([3])] TJ ET 0.271 0.267 0.267 rg BT 95.621 238.653 Td /F1 9.8 Tf [( . Despite the large-scale surveillance of H1N1pdm at the molecular level, the evolutionary and spatial dynamics )] TJ ET BT 26.250 226.749 Td /F1 9.8 Tf [(of this virus in human populations have yet to be well characterized. Five early genome variants were identified on the basis of )] TJ ET BT 26.250 214.844 Td /F1 9.8 Tf [(amino acid differences within the United States and Mexico )] TJ ET 0.267 0.267 0.267 rg BT 284.196 214.844 Td /F1 9.8 Tf [([2])] TJ ET 0.271 0.267 0.267 rg BT 295.038 214.844 Td /F1 9.8 Tf [( , but it is not known whether genetically distinct viral lineages )] TJ ET BT 26.250 202.939 Td /F1 9.8 Tf [(have since proliferated globally, how patterns of genetic diversity vary spatially, or how outbreaks in different localities are )] TJ ET BT 26.250 191.034 Td /F1 9.8 Tf [(linked. To better understand the evolution, epidemiology, and spatial spread of H1N1pdm during its first months of )] TJ ET BT 26.250 179.130 Td /F1 9.8 Tf [(dissemination in humans, we conducted a large-scale phylogenetic analysis of 290 whole-genome sequences of H1N1pdm )] TJ ET BT 26.250 167.225 Td /F1 9.8 Tf [(sampled globally from April 1 July 9, 2009.)] TJ ET BT 26.250 130.622 Td /F4 12.0 Tf [(Results)] TJ ET BT 26.250 110.668 Td /F4 9.8 Tf [(Geographical patterns in viral density)] TJ ET BT 26.250 98.763 Td /F4 9.8 Tf [(Figure 1)] TJ ET 0.965 0.965 0.965 rg 26.250 -95.618 555.000 184.500 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 88.882 m 581.250 88.882 l 581.250 88.132 l 26.250 88.132 l f q 225.000 0 0 168.750 35.250 -89.618 cm /I4 Do Q q 35.250 -95.618 537.000 0.000 re W n Q Q q 15.000 709.302 577.500 28.698 re W n 0.267 0.267 0.267 rg BT 15.000 718.042 Td /F2 21.0 Tf [(The early diversification of influenza A/H1N1pdm)] TJ ET Q 0.271 0.267 0.267 rg BT 15.000 700.036 Td /F3 9.8 Tf [(November 5, 2009)] TJ ET 0.267 0.267 0.267 rg BT 26.250 688.195 Td /F1 9.8 Tf [(Martha Nelson)] TJ ET 0.271 0.267 0.267 rg BT 89.644 688.195 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 95.066 688.195 Td /F1 9.8 Tf [(David Spiro)] TJ ET 0.271 0.267 0.267 rg BT 145.453 688.195 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 150.875 688.195 Td /F1 9.8 Tf [(David Wentworth)] TJ ET 0.271 0.267 0.267 rg BT 225.101 688.195 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 230.522 688.195 Td /F1 9.8 Tf [(Jiang Fan)] TJ ET 0.271 0.267 0.267 rg BT 273.334 688.195 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 278.755 688.195 Td /F1 9.8 Tf [(Eric Beck)] TJ ET 0.271 0.267 0.267 rg BT 319.930 688.195 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 325.351 688.195 Td /F1 9.8 Tf [(Kirsten St. George)] TJ ET 0.271 0.267 0.267 rg BT 405.554 688.195 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 410.975 688.195 Td /F1 9.8 Tf [(Elodie Ghedin)] TJ ET 0.271 0.267 0.267 rg BT 472.215 688.195 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 477.636 688.195 Td /F1 9.8 Tf [(Rebecca Halpin)] TJ ET 0.271 0.267 0.267 rg BT 546.452 688.195 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 551.873 688.195 Td /F1 9.8 Tf [(Jayati )] TJ ET BT 26.250 676.290 Td /F1 9.8 Tf [(Bera)] TJ ET 0.271 0.267 0.267 rg BT 46.842 676.290 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 52.263 676.290 Td /F1 9.8 Tf [(Erin Hine)] TJ ET 0.271 0.267 0.267 rg BT 92.355 676.290 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 97.776 676.290 Td /F1 9.8 Tf [(Katie Proudfoot)] TJ ET 0.271 0.267 0.267 rg BT 164.983 676.290 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 170.404 676.290 Td /F1 9.8 Tf [(Tim Stockwell)] TJ ET 0.271 0.267 0.267 rg BT 230.532 676.290 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 235.953 676.290 Td /F1 9.8 Tf [(Xudong Lin)] TJ ET 0.271 0.267 0.267 rg BT 285.278 676.290 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 290.699 676.290 Td /F1 9.8 Tf [(Sara Griesemer)] TJ ET 0.271 0.267 0.267 rg BT 359.505 676.290 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 364.926 676.290 Td /F1 9.8 Tf [(Michael Bose)] TJ ET 0.271 0.267 0.267 rg BT 423.445 676.290 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 428.866 676.290 Td /F1 9.8 Tf [(Lisa Jurgens)] TJ ET 0.271 0.267 0.267 rg BT 484.139 676.290 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 489.560 676.290 Td /F1 9.8 Tf [(Swati Kumar)] TJ ET 0.271 0.267 0.267 rg BT 544.823 676.290 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 550.244 676.290 Td /F1 9.8 Tf [(Cecile )] TJ ET BT 26.250 664.386 Td /F1 9.8 Tf [(Viboud)] TJ ET 0.271 0.267 0.267 rg BT 56.602 664.386 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 62.023 664.386 Td /F1 9.8 Tf [(Eddie Holmes)] TJ ET 0.271 0.267 0.267 rg BT 122.707 664.386 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 128.128 664.386 Td /F1 9.8 Tf [(Kelly Henrickson)] TJ ET 0.271 0.267 0.267 rg BT 26.250 652.481 Td /F1 9.8 Tf [(Nelson M, Spiro D, Wentworth D, Fan J, Beck E, St. George K, Ghedin E, Halpin R, Bera J, Hine E, Proudfoot K, Stockwell T, )] TJ ET BT 26.250 640.576 Td /F1 9.8 Tf [(Lin X, Griesemer S, Bose M, Jurgens L, Kumar S, Viboud C, Holmes E, Henrickson K. The early diversification of influenza )] TJ ET BT 26.250 628.671 Td /F1 9.8 Tf [(A/H1N1pdm. PLOS Currents Influenza. 2009 Nov 5 . Edition 1. doi: 10.1371/currents.RRN1126.)] TJ ET q 15.000 -95.618 577.500 721.908 re W n 0.271 0.267 0.267 rg BT 26.250 599.569 Td /F4 12.0 Tf [(Abstract)] TJ ET BT 26.250 579.615 Td /F1 9.8 Tf [(Background Since its initial detection in April 2009, the A/H1N1pdm influenza virus has spread rapidly in humans, with over )] TJ ET BT 26.250 567.710 Td /F1 9.8 Tf [(5,700 human deaths. However, little is known about the evolutionary dynamics of H1N1pdm and its geographic and temporal )] TJ ET BT 26.250 555.805 Td /F1 9.8 Tf [(diversification.)] TJ ET BT 26.250 536.400 Td /F1 9.8 Tf [(Methods Phylogenetic analysis was conducted upon the concatenated coding regions of whole-genome sequences from 290 )] TJ ET BT 26.250 524.496 Td /F1 9.8 Tf [(H1N1pdm isolates sampled globally between April 1 July 9, 2009, including relatively large samples from the US states of )] TJ ET BT 26.250 512.591 Td /F1 9.8 Tf [(Wisconsin and New York.)] TJ ET BT 26.250 493.186 Td /F1 9.8 Tf [(Results At least 7 phylogenetically distinct viral clades have disseminated globally and co-circulated in localities that )] TJ ET BT 26.250 481.281 Td /F1 9.8 Tf [(experienced multiple introductions of H1N1pdm. The epidemics in New York and Wisconsin were dominated by two different )] TJ ET BT 26.250 469.377 Td /F1 9.8 Tf [(clades, both phylogenetically distinct from the viruses first identified in California and Mexico, suggesting an important role for )] TJ ET BT 26.250 457.472 Td /F1 9.8 Tf [(founder effects in determining local viral population structures.)] TJ ET BT 26.250 438.067 Td /F1 9.8 Tf [(Conclusions Determining the global diversity of H1N1pdm is central to understanding the evolution and spatial spread of the )] TJ ET BT 26.250 426.162 Td /F1 9.8 Tf [(current pandemic, and to predict its future impact on human populations. Our results indicate that H1N1pdm has already )] TJ ET BT 26.250 414.258 Td /F1 9.8 Tf [(diversified into distinct viral lineages with defined spatial patterns.)] TJ ET BT 26.250 377.655 Td /F4 12.0 Tf [(Introduction)] TJ ET BT 26.250 357.701 Td /F1 9.8 Tf [(In April 2009 a novel influenza A virus H1N1pdm was identified in humans, initiating the first influenza pandemic of the 21st )] TJ ET BT 26.250 345.796 Td /F1 9.8 Tf [(century. As of November 2, 2009, there have been >440,000 laboratory confirmed cases of pandemic H1N1 \(H1N1pdm\) )] TJ ET BT 26.250 333.891 Td /F1 9.8 Tf [(influenza virus, resulting in > 5,700 deaths worldwide \( )] TJ ET 0.267 0.267 0.267 rg BT 263.331 333.891 Td /F1 9.8 Tf [(http://www.who.int/csr/don/2009_10_30/en/index.html)] TJ ET 0.271 0.267 0.267 rg BT 494.737 333.891 Td /F1 9.8 Tf [( , Accessed )] TJ ET BT 26.250 321.987 Td /F1 9.8 Tf [(November 2, 2009\) )] TJ ET 0.267 0.267 0.267 rg BT 112.411 321.987 Td /F1 9.8 Tf [([1])] TJ ET 0.271 0.267 0.267 rg BT 123.253 321.987 Td /F1 9.8 Tf [( . As most countries have discontinued the reporting of cases, this is thought to represent a minimum of 2-)] TJ ET BT 26.250 310.082 Td /F1 9.8 Tf [(5 million people infected. H1N1pdm is a novel reassortant between North American and Eurasian swine influenza viruses, )] TJ ET BT 26.250 298.177 Td /F1 9.8 Tf [(containing PB2, PB1, PA, HA, NP, and NS segments from North American triple-reassortant swine viruses and NA and M )] TJ ET BT 26.250 286.272 Td /F1 9.8 Tf [(segments derived from the Eurasian swine lineage )] TJ ET 0.267 0.267 0.267 rg BT 247.341 286.272 Td /F1 9.8 Tf [([2])] TJ ET 0.271 0.267 0.267 rg BT 258.183 286.272 Td /F1 9.8 Tf [( . The relatively large genetic distance between H1N1pdm and the most )] TJ ET BT 26.250 274.368 Td /F1 9.8 Tf [(closely related swine influenza viruses suggests that these segments have been circulating undetected for a decade or more, )] TJ ET BT 26.250 262.463 Td /F1 9.8 Tf [(with estimates of the Times to the Most Recent Common Ancestor \(TMRCA\) for individual genome segments ranging from 9 )] TJ ET BT 26.250 250.558 Td /F1 9.8 Tf [(17 years )] TJ ET 0.267 0.267 0.267 rg BT 66.352 250.558 Td /F1 9.8 Tf [([3])] TJ ET 0.271 0.267 0.267 rg BT 77.194 250.558 Td /F1 9.8 Tf [( . The relatively low genetic diversity of H1N1pdm suggests that the virus emerged in humans only recently, perhaps )] TJ ET BT 26.250 238.653 Td /F1 9.8 Tf [(in early 2009 )] TJ ET 0.267 0.267 0.267 rg BT 84.779 238.653 Td /F1 9.8 Tf [([3])] TJ ET 0.271 0.267 0.267 rg BT 95.621 238.653 Td /F1 9.8 Tf [( . Despite the large-scale surveillance of H1N1pdm at the molecular level, the evolutionary and spatial dynamics )] TJ ET BT 26.250 226.749 Td /F1 9.8 Tf [(of this virus in human populations have yet to be well characterized. Five early genome variants were identified on the basis of )] TJ ET BT 26.250 214.844 Td /F1 9.8 Tf [(amino acid differences within the United States and Mexico )] TJ ET 0.267 0.267 0.267 rg BT 284.196 214.844 Td /F1 9.8 Tf [([2])] TJ ET 0.271 0.267 0.267 rg BT 295.038 214.844 Td /F1 9.8 Tf [( , but it is not known whether genetically distinct viral lineages )] TJ ET BT 26.250 202.939 Td /F1 9.8 Tf [(have since proliferated globally, how patterns of genetic diversity vary spatially, or how outbreaks in different localities are )] TJ ET BT 26.250 191.034 Td /F1 9.8 Tf [(linked. To better understand the evolution, epidemiology, and spatial spread of H1N1pdm during its first months of )] TJ ET BT 26.250 179.130 Td /F1 9.8 Tf [(dissemination in humans, we conducted a large-scale phylogenetic analysis of 290 whole-genome sequences of H1N1pdm )] TJ ET BT 26.250 167.225 Td /F1 9.8 Tf [(sampled globally from April 1 July 9, 2009.)] TJ ET BT 26.250 130.622 Td /F4 12.0 Tf [(Results)] TJ ET BT 26.250 110.668 Td /F4 9.8 Tf [(Geographical patterns in viral density)] TJ ET BT 26.250 98.763 Td /F4 9.8 Tf [(Figure 1)] TJ ET 0.965 0.965 0.965 rg 26.250 -95.618 555.000 184.500 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 88.882 m 581.250 88.882 l 581.250 88.132 l 26.250 88.132 l f q 225.000 0 0 168.750 35.250 -89.618 cm /I6 Do Q q 35.250 -95.618 537.000 0.000 re W n Q Q q 15.000 709.302 577.500 28.698 re W n 0.267 0.267 0.267 rg BT 15.000 718.042 Td /F2 21.0 Tf [(The early diversification of influenza A/H1N1pdm)] TJ ET Q 0.271 0.267 0.267 rg BT 15.000 700.036 Td /F3 9.8 Tf [(November 5, 2009)] TJ ET 0.267 0.267 0.267 rg BT 26.250 688.195 Td /F1 9.8 Tf [(Martha Nelson)] TJ ET 0.271 0.267 0.267 rg BT 89.644 688.195 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 95.066 688.195 Td /F1 9.8 Tf [(David Spiro)] TJ ET 0.271 0.267 0.267 rg BT 145.453 688.195 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 150.875 688.195 Td /F1 9.8 Tf [(David Wentworth)] TJ ET 0.271 0.267 0.267 rg BT 225.101 688.195 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 230.522 688.195 Td /F1 9.8 Tf [(Jiang Fan)] TJ ET 0.271 0.267 0.267 rg BT 273.334 688.195 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 278.755 688.195 Td /F1 9.8 Tf [(Eric Beck)] TJ ET 0.271 0.267 0.267 rg BT 319.930 688.195 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 325.351 688.195 Td /F1 9.8 Tf [(Kirsten St. George)] TJ ET 0.271 0.267 0.267 rg BT 405.554 688.195 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 410.975 688.195 Td /F1 9.8 Tf [(Elodie Ghedin)] TJ ET 0.271 0.267 0.267 rg BT 472.215 688.195 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 477.636 688.195 Td /F1 9.8 Tf [(Rebecca Halpin)] TJ ET 0.271 0.267 0.267 rg BT 546.452 688.195 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 551.873 688.195 Td /F1 9.8 Tf [(Jayati )] TJ ET BT 26.250 676.290 Td /F1 9.8 Tf [(Bera)] TJ ET 0.271 0.267 0.267 rg BT 46.842 676.290 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 52.263 676.290 Td /F1 9.8 Tf [(Erin Hine)] TJ ET 0.271 0.267 0.267 rg BT 92.355 676.290 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 97.776 676.290 Td /F1 9.8 Tf [(Katie Proudfoot)] TJ ET 0.271 0.267 0.267 rg BT 164.983 676.290 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 170.404 676.290 Td /F1 9.8 Tf [(Tim Stockwell)] TJ ET 0.271 0.267 0.267 rg BT 230.532 676.290 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 235.953 676.290 Td /F1 9.8 Tf [(Xudong Lin)] TJ ET 0.271 0.267 0.267 rg BT 285.278 676.290 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 290.699 676.290 Td /F1 9.8 Tf [(Sara Griesemer)] TJ ET 0.271 0.267 0.267 rg BT 359.505 676.290 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 364.926 676.290 Td /F1 9.8 Tf [(Michael Bose)] TJ ET 0.271 0.267 0.267 rg BT 423.445 676.290 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 428.866 676.290 Td /F1 9.8 Tf [(Lisa Jurgens)] TJ ET 0.271 0.267 0.267 rg BT 484.139 676.290 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 489.560 676.290 Td /F1 9.8 Tf [(Swati Kumar)] TJ ET 0.271 0.267 0.267 rg BT 544.823 676.290 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 550.244 676.290 Td /F1 9.8 Tf [(Cecile )] TJ ET BT 26.250 664.386 Td /F1 9.8 Tf [(Viboud)] TJ ET 0.271 0.267 0.267 rg BT 56.602 664.386 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 62.023 664.386 Td /F1 9.8 Tf [(Eddie Holmes)] TJ ET 0.271 0.267 0.267 rg BT 122.707 664.386 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 128.128 664.386 Td /F1 9.8 Tf [(Kelly Henrickson)] TJ ET 0.271 0.267 0.267 rg BT 26.250 652.481 Td /F1 9.8 Tf [(Nelson M, Spiro D, Wentworth D, Fan J, Beck E, St. George K, Ghedin E, Halpin R, Bera J, Hine E, Proudfoot K, Stockwell T, )] TJ ET BT 26.250 640.576 Td /F1 9.8 Tf [(Lin X, Griesemer S, Bose M, Jurgens L, Kumar S, Viboud C, Holmes E, Henrickson K. The early diversification of influenza )] TJ ET BT 26.250 628.671 Td /F1 9.8 Tf [(A/H1N1pdm. PLOS Currents Influenza. 2009 Nov 5 . Edition 1. doi: 10.1371/currents.RRN1126.)] TJ ET q 15.000 -95.618 577.500 721.908 re W n 0.271 0.267 0.267 rg BT 26.250 599.569 Td /F4 12.0 Tf [(Abstract)] TJ ET BT 26.250 579.615 Td /F1 9.8 Tf [(Background Since its initial detection in April 2009, the A/H1N1pdm influenza virus has spread rapidly in humans, with over )] TJ ET BT 26.250 567.710 Td /F1 9.8 Tf [(5,700 human deaths. However, little is known about the evolutionary dynamics of H1N1pdm and its geographic and temporal )] TJ ET BT 26.250 555.805 Td /F1 9.8 Tf [(diversification.)] TJ ET BT 26.250 536.400 Td /F1 9.8 Tf [(Methods Phylogenetic analysis was conducted upon the concatenated coding regions of whole-genome sequences from 290 )] TJ ET BT 26.250 524.496 Td /F1 9.8 Tf [(H1N1pdm isolates sampled globally between April 1 July 9, 2009, including relatively large samples from the US states of )] TJ ET BT 26.250 512.591 Td /F1 9.8 Tf [(Wisconsin and New York.)] TJ ET BT 26.250 493.186 Td /F1 9.8 Tf [(Results At least 7 phylogenetically distinct viral clades have disseminated globally and co-circulated in localities that )] TJ ET BT 26.250 481.281 Td /F1 9.8 Tf [(experienced multiple introductions of H1N1pdm. The epidemics in New York and Wisconsin were dominated by two different )] TJ ET BT 26.250 469.377 Td /F1 9.8 Tf [(clades, both phylogenetically distinct from the viruses first identified in California and Mexico, suggesting an important role for )] TJ ET BT 26.250 457.472 Td /F1 9.8 Tf [(founder effects in determining local viral population structures.)] TJ ET BT 26.250 438.067 Td /F1 9.8 Tf [(Conclusions Determining the global diversity of H1N1pdm is central to understanding the evolution and spatial spread of the )] TJ ET BT 26.250 426.162 Td /F1 9.8 Tf [(current pandemic, and to predict its future impact on human populations. Our results indicate that H1N1pdm has already )] TJ ET BT 26.250 414.258 Td /F1 9.8 Tf [(diversified into distinct viral lineages with defined spatial patterns.)] TJ ET BT 26.250 377.655 Td /F4 12.0 Tf [(Introduction)] TJ ET BT 26.250 357.701 Td /F1 9.8 Tf [(In April 2009 a novel influenza A virus H1N1pdm was identified in humans, initiating the first influenza pandemic of the 21st )] TJ ET BT 26.250 345.796 Td /F1 9.8 Tf [(century. As of November 2, 2009, there have been >440,000 laboratory confirmed cases of pandemic H1N1 \(H1N1pdm\) )] TJ ET BT 26.250 333.891 Td /F1 9.8 Tf [(influenza virus, resulting in > 5,700 deaths worldwide \( )] TJ ET 0.267 0.267 0.267 rg BT 263.331 333.891 Td /F1 9.8 Tf [(http://www.who.int/csr/don/2009_10_30/en/index.html)] TJ ET 0.271 0.267 0.267 rg BT 494.737 333.891 Td /F1 9.8 Tf [( , Accessed )] TJ ET BT 26.250 321.987 Td /F1 9.8 Tf [(November 2, 2009\) )] TJ ET 0.267 0.267 0.267 rg BT 112.411 321.987 Td /F1 9.8 Tf [([1])] TJ ET 0.271 0.267 0.267 rg BT 123.253 321.987 Td /F1 9.8 Tf [( . As most countries have discontinued the reporting of cases, this is thought to represent a minimum of 2-)] TJ ET BT 26.250 310.082 Td /F1 9.8 Tf [(5 million people infected. H1N1pdm is a novel reassortant between North American and Eurasian swine influenza viruses, )] TJ ET BT 26.250 298.177 Td /F1 9.8 Tf [(containing PB2, PB1, PA, HA, NP, and NS segments from North American triple-reassortant swine viruses and NA and M )] TJ ET BT 26.250 286.272 Td /F1 9.8 Tf [(segments derived from the Eurasian swine lineage )] TJ ET 0.267 0.267 0.267 rg BT 247.341 286.272 Td /F1 9.8 Tf [([2])] TJ ET 0.271 0.267 0.267 rg BT 258.183 286.272 Td /F1 9.8 Tf [( . The relatively large genetic distance between H1N1pdm and the most )] TJ ET BT 26.250 274.368 Td /F1 9.8 Tf [(closely related swine influenza viruses suggests that these segments have been circulating undetected for a decade or more, )] TJ ET BT 26.250 262.463 Td /F1 9.8 Tf [(with estimates of the Times to the Most Recent Common Ancestor \(TMRCA\) for individual genome segments ranging from 9 )] TJ ET BT 26.250 250.558 Td /F1 9.8 Tf [(17 years )] TJ ET 0.267 0.267 0.267 rg BT 66.352 250.558 Td /F1 9.8 Tf [([3])] TJ ET 0.271 0.267 0.267 rg BT 77.194 250.558 Td /F1 9.8 Tf [( . The relatively low genetic diversity of H1N1pdm suggests that the virus emerged in humans only recently, perhaps )] TJ ET BT 26.250 238.653 Td /F1 9.8 Tf [(in early 2009 )] TJ ET 0.267 0.267 0.267 rg BT 84.779 238.653 Td /F1 9.8 Tf [([3])] TJ ET 0.271 0.267 0.267 rg BT 95.621 238.653 Td /F1 9.8 Tf [( . Despite the large-scale surveillance of H1N1pdm at the molecular level, the evolutionary and spatial dynamics )] TJ ET BT 26.250 226.749 Td /F1 9.8 Tf [(of this virus in human populations have yet to be well characterized. Five early genome variants were identified on the basis of )] TJ ET BT 26.250 214.844 Td /F1 9.8 Tf [(amino acid differences within the United States and Mexico )] TJ ET 0.267 0.267 0.267 rg BT 284.196 214.844 Td /F1 9.8 Tf [([2])] TJ ET 0.271 0.267 0.267 rg BT 295.038 214.844 Td /F1 9.8 Tf [( , but it is not known whether genetically distinct viral lineages )] TJ ET BT 26.250 202.939 Td /F1 9.8 Tf [(have since proliferated globally, how patterns of genetic diversity vary spatially, or how outbreaks in different localities are )] TJ ET BT 26.250 191.034 Td /F1 9.8 Tf [(linked. To better understand the evolution, epidemiology, and spatial spread of H1N1pdm during its first months of )] TJ ET BT 26.250 179.130 Td /F1 9.8 Tf [(dissemination in humans, we conducted a large-scale phylogenetic analysis of 290 whole-genome sequences of H1N1pdm )] TJ ET BT 26.250 167.225 Td /F1 9.8 Tf [(sampled globally from April 1 July 9, 2009.)] TJ ET BT 26.250 130.622 Td /F4 12.0 Tf [(Results)] TJ ET BT 26.250 110.668 Td /F4 9.8 Tf [(Geographical patterns in viral density)] TJ ET BT 26.250 98.763 Td /F4 9.8 Tf [(Figure 1)] TJ ET 0.965 0.965 0.965 rg 26.250 -95.618 555.000 184.500 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 88.882 m 581.250 88.882 l 581.250 88.132 l 26.250 88.132 l f q 225.000 0 0 168.750 35.250 -89.618 cm /I8 Do Q q 35.250 -95.618 537.000 0.000 re W n Q Q q 225.000 0 0 168.750 35.250 -89.618 cm /I10 Do Q q 0.000 0.000 0.000 rg BT 291.710 19.825 Td /F1 11.0 Tf [(1)] TJ ET BT 25.000 19.825 Td /F1 11.0 Tf [(PLOS Currents Influenza)] TJ ET Q endstream endobj 8 0 obj << /Type /Font /Subtype /Type1 /Name /F1 /BaseFont /Helvetica /Encoding /WinAnsiEncoding >> endobj 9 0 obj << /Type /Font /Subtype /Type1 /Name /F2 /BaseFont /Times-Bold /Encoding /WinAnsiEncoding >> endobj 10 0 obj << /Type /Font /Subtype /Type1 /Name /F3 /BaseFont /Times-Italic /Encoding /WinAnsiEncoding >> endobj 11 0 obj << /Type /Font /Subtype /Type1 /Name /F4 /BaseFont /Helvetica-Bold /Encoding /WinAnsiEncoding >> endobj 12 0 obj << /Type /XObject /Subtype /Image /Width 500 /Height 52 /Filter /FlateDecode /DecodeParms << /Predictor 15 /Colors 1 /Columns 500 /BitsPerComponent 8>> /ColorSpace /DeviceGray /BitsPerComponent 8 /Length 144>> stream x1 0 'ݲ؎"e{dzAdzAdzAdzAdzAdzAdzAdzAdzAdzAdzAdzAtlM0\ endstream endobj 13 0 obj << /Type /XObject /Subtype /Image /Width 500 /Height 52 /SMask 12 0 R /Filter /FlateDecode /DecodeParms << /Predictor 15 /Colors 3 /Columns 500 /BitsPerComponent 8>> /ColorSpace /DeviceRGB /BitsPerComponent 8 /Length 3574>> stream x}ƕK*8+0T ֮ S L*0߇d" sl2FBiFwY0 00 0ŝa0 aqgR܋x||lu2 03UL۶BxI 0:UU0x;֝($z%șHڶ ÐVz ]IS> â(.* TQUuL5 $>BvpH0U:xkkGJT{OɗRNyGOΙyn)q7`(~_Ji2vgk]qVꔷ3N'ȴy4Ikm6!q:FJ)-0n܋v!^}_Z l61va_~Bxw8mv;EJY8}zzQ3]Pȹ,2_jfY4MQ[ '.uO O͋kշ9b6.#ߦUUzhf09+nKɿ4 f7Bu7ĨMfrF0`s8429j1}ZWDW;A4ҫ'TQ{7Cb[$ -"ΨMQgzN/2R7Tco*W:N݋6TUu8`RSi O>r;z^m(0w`:m=]գCE&t |ZYQ%{X[nR+zbEFΧ5pzq`ުం Ih{9G 4wMx' nmvEZ sg7?ZQ}&ҎKGuPu.j8UgNKꓙQC)s#$1䧈x[Z(|Xzc;t<~50Hh_T3Ur>a$]B8Fz[?K>Y/rQ=E4?EaLqzpX!(nNut]}e(/S\fz,<ZOEa]0 sCS_}I Y}n۶r(fg7#)h6ա}$ üvq]Aא$c0ddBDQ)ueypU-z~9Hk<$I©y'Tk`yY d}e{䨙ǐu>&w񚓶('GI\rm[G4 Sk7$B pEkYYC/ 9&Ʋ[V9MQ':X|C֨ʉ jt"ޡ+rttBռGdiM FuTEi(łv]fk"8Ldp' ^הMup2`M?dE!|KJ-\.MzکC=&¾HfR7$ev,La0+$OFuEQ"i,ːN?~E*t4qΚF:t`,{RkR]ޜ(Ԕѣ$IbN}5لS1(Ȱ$I$(eWp8Lٱ3߯ky۶&. 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The tree is automatically rooted through the )] TJ ET BT 35.250 722.465 Td /F1 9.8 Tf [(assumption of a strict molecular clock, such that tip times represent the time \(day\) of sampling. Clades of clearly related )] TJ ET BT 35.250 708.729 Td /F1 9.8 Tf [(isolates are represented by color-coded rectangles.)] TJ ET Q BT 26.250 670.208 Td /F1 9.8 Tf [(To identify discrete genetic lineages of H1N1pdm, we conducted a phylogenetic analysis on 290 concatenated whole-genome )] TJ ET BT 26.250 658.303 Td /F1 9.8 Tf [(sequences of H1N1pdm isolates collected between April 1, 2009 July 9, 2009, including 81 genomes collected from )] TJ ET BT 26.250 646.398 Td /F1 9.8 Tf [(Wisconsin between April 28, 2009 May 30, 2009. The exact collection date was available for each isolate. Our Bayesian )] TJ ET BT 26.250 634.494 Td /F1 9.8 Tf [(Markov chain Monte Carlo \(MCMC\) phylogenetic analysis, using the BEAST program )] TJ ET 0.267 0.267 0.267 rg BT 396.321 634.494 Td /F1 9.8 Tf [([4])] TJ ET 0.271 0.267 0.267 rg BT 407.163 634.494 Td /F1 9.8 Tf [( \(version 1.4.8\), revealed 7 discrete )] TJ ET BT 26.250 622.589 Td /F1 9.8 Tf [(clades of H1N1pdm circulating globally \(labeled clades 1-7, Fig. 1\). Each clade is defined by long branches and nodes )] TJ ET BT 26.250 610.684 Td /F1 9.8 Tf [(supported by high Bayesian posterior probability \(BPP\) values \(> 90%\). Each clade also is evident on phylogenies inferred )] TJ ET BT 26.250 598.779 Td /F1 9.8 Tf [(using the MrBayes )] TJ ET 0.267 0.267 0.267 rg BT 109.700 598.779 Td /F1 9.8 Tf [([5])] TJ ET 0.271 0.267 0.267 rg BT 120.542 598.779 Td /F1 9.8 Tf [( and PAUP* )] TJ ET 0.267 0.267 0.267 rg BT 175.279 598.779 Td /F1 9.8 Tf [([6])] TJ ET 0.271 0.267 0.267 rg BT 186.121 598.779 Td /F1 9.8 Tf [( programs \(data not shown\). Twenty-one isolates, which include two-thirds \(8/12\) of all )] TJ ET BT 26.250 586.875 Td /F1 9.8 Tf [(Mexican isolates available for this study, occupy a basal position on the tree with low phylogenetic resolution, and therefore are )] TJ ET BT 26.250 574.970 Td /F1 9.8 Tf [(not members of any of the clades defined here. Using these basal isolates as a reference point, amino acid changes became )] TJ ET BT 26.250 563.065 Td /F1 9.8 Tf [(fixed in every clade except for clade 3 and in every segment except in the matrix protein \(see below, Table 1\). However, none of )] TJ ET BT 26.250 551.160 Td /F1 9.8 Tf [(these amino acid changes are located in sites with known phenotypic effects, such as in antigenic sites on the H1 )] TJ ET 0.267 0.267 0.267 rg BT 517.240 551.160 Td /F1 9.8 Tf [([7])] TJ ET 0.271 0.267 0.267 rg BT 528.082 551.160 Td /F1 9.8 Tf [( or those in )] TJ ET BT 26.250 539.256 Td /F1 9.8 Tf [(the NA that are associated with resistance to the neuraminidase inhibitor \(NI\) antiviral drugs )] TJ ET 0.267 0.267 0.267 rg BT 423.991 539.256 Td /F1 9.8 Tf [([8])] TJ ET BT 434.833 539.256 Td /F1 9.8 Tf [([9])] TJ ET 0.271 0.267 0.267 rg BT 445.675 539.256 Td /F1 9.8 Tf [( .)] TJ ET BT 26.250 519.851 Td /F4 9.8 Tf [(Figure 2)] TJ ET 0.965 0.965 0.965 rg 26.250 254.870 555.000 255.100 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 509.970 m 581.250 509.970 l 581.250 509.220 l 26.250 509.220 l f 26.250 254.870 m 581.250 254.870 l 581.250 255.620 l 26.250 255.620 l f q 225.000 0 0 147.750 35.250 352.470 cm /I12 Do Q q 35.250 266.120 537.000 80.350 re W n 0.271 0.267 0.267 rg BT 35.250 336.946 Td /F4 9.8 Tf [(Fig. 2: Changing clade distributions through time and space.)] TJ ET BT 35.250 317.576 Td /F1 9.8 Tf [(The shading of each circle represents the proportion of isolates belonging to each of the clades identified in Fig. 1 from )] TJ ET BT 35.250 303.840 Td /F1 9.8 Tf [(each locality \(y-axis\) by epidemic week \(x-axis\). The shading of clades is identical to that of Fig. 1. Week 1 begins with the )] TJ ET BT 35.250 290.104 Td /F1 9.8 Tf [(first isolate collected in this study: April 1, 2009. Small circles denote weeks for which only a single isolate was available )] TJ ET BT 35.250 276.367 Td /F1 9.8 Tf [(from a locality.)] TJ ET Q BT 26.250 237.846 Td /F1 9.8 Tf [(The 7 clades vary considerably in size: clade 1 contains 9 isolates, clade 4 has 11 isolates, clade 6 has 13 isolates, clade 2 has )] TJ ET BT 26.250 225.942 Td /F1 9.8 Tf [(25 isolates, clade 3 has 32 isolates, clade 5 has 77 isolates, and clade 7 has 102 isolates. With the exception of clade 4, which )] TJ ET BT 26.250 214.037 Td /F1 9.8 Tf [(contains isolates collected only from Asia, all clades are geographically dispersed and appear to co-circulate over time and )] TJ ET BT 26.250 202.132 Td /F1 9.8 Tf [(space. As an extreme case in point, 5 different lineages \(clades 1, 2, 3, 6, and 7\) all co-circulated in New York during week 5 of )] TJ ET BT 26.250 190.227 Td /F1 9.8 Tf [(this study \(April 26 May 2, 2009, Fig. 2\). Five clades \(clades 2, 3, 4, 5, and 7\) co-circulated in Asia during week 8, and clades )] TJ ET BT 26.250 178.323 Td /F1 9.8 Tf [(2, 3, and 5 co-circulated in Wisconsin during week 6. Although the major epidemics in New York and Wisconsin both were )] TJ ET BT 26.250 166.418 Td /F1 9.8 Tf [(associated with multiple introductions of genetically distinct H1N1pdm, a single clade comprised >80% of virus specimens in )] TJ ET BT 26.250 154.513 Td /F1 9.8 Tf [(each locality: clade 5 in Wisconsin and clade 7 in New York \(Fig. 2\). Below we describe the evolutionary dynamics of individual )] TJ ET BT 26.250 142.608 Td /F1 9.8 Tf [(clades in further detail. Clade 1 includes first H1N1pdm isolates that was identified in our study: A/California/04/2009, collected )] TJ ET BT 26.250 130.704 Td /F1 9.8 Tf [(April 1, 2009. A Bayesian MCMC analysis estimates that the Time to the Most Recent Common Ancestor \(TMRCA\) of clade 1 )] TJ ET BT 26.250 118.799 Td /F1 9.8 Tf [(ranges from February 16 March 16, 2009 \(95% highest probability density \(HPD\)\), confirming that clade 1 was one of the )] TJ ET BT 26.250 106.894 Td /F1 9.8 Tf [(earliest to emerge and that it circulated for ~2 6 weeks before initial detection \(Fig. 3\). However, clade 1 is also the smallest )] TJ ET BT 26.250 94.989 Td /F1 9.8 Tf [(clade in our study \(9 isolates\) and exhibits only limited geographic dissemination \(Fig. 2\). Four unique amino acid changes were )] TJ ET BT 26.250 83.085 Td /F1 9.8 Tf [(observed among the majority \(7/9\) of clade 1 isolates: S224P in the PA and S91P, A200T, and V323I in the HA \(H3 numbering )] TJ ET BT 26.250 71.180 Td /F1 9.8 Tf [(system )] TJ ET 0.267 0.267 0.267 rg BT 59.839 71.180 Td /F1 9.8 Tf [([10])] TJ ET 0.271 0.267 0.267 rg BT 76.102 71.180 Td /F1 9.8 Tf [( \) \(Table 1\).)] TJ ET BT 26.250 51.775 Td /F4 9.8 Tf [(Figure 3)] TJ ET Q q 15.000 41.894 577.500 735.106 re W n 0.965 0.965 0.965 rg 26.250 687.232 555.000 89.768 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 687.232 m 581.250 687.232 l 581.250 687.982 l 26.250 687.982 l f q 35.250 698.482 537.000 78.518 re W n 0.271 0.267 0.267 rg BT 35.250 767.476 Td /F4 9.8 Tf [(Fig. 1: Maximum Clade Credibility \(MCC\) tree of the concatenated coding regions of 290 H1N1pdm isolates )] TJ ET BT 35.250 755.571 Td /F4 9.8 Tf [(sampled globally between April 1 July 9, 2009.)] TJ ET BT 35.250 736.201 Td /F1 9.8 Tf [(Bayesian posterior probability \(BPP\) values > 90% are included for key nodes. The tree is automatically rooted through the )] TJ ET BT 35.250 722.465 Td /F1 9.8 Tf [(assumption of a strict molecular clock, such that tip times represent the time \(day\) of sampling. Clades of clearly related )] TJ ET BT 35.250 708.729 Td /F1 9.8 Tf [(isolates are represented by color-coded rectangles.)] TJ ET Q BT 26.250 670.208 Td /F1 9.8 Tf [(To identify discrete genetic lineages of H1N1pdm, we conducted a phylogenetic analysis on 290 concatenated whole-genome )] TJ ET BT 26.250 658.303 Td /F1 9.8 Tf [(sequences of H1N1pdm isolates collected between April 1, 2009 July 9, 2009, including 81 genomes collected from )] TJ ET BT 26.250 646.398 Td /F1 9.8 Tf [(Wisconsin between April 28, 2009 May 30, 2009. The exact collection date was available for each isolate. Our Bayesian )] TJ ET BT 26.250 634.494 Td /F1 9.8 Tf [(Markov chain Monte Carlo \(MCMC\) phylogenetic analysis, using the BEAST program )] TJ ET 0.267 0.267 0.267 rg BT 396.321 634.494 Td /F1 9.8 Tf [([4])] TJ ET 0.271 0.267 0.267 rg BT 407.163 634.494 Td /F1 9.8 Tf [( \(version 1.4.8\), revealed 7 discrete )] TJ ET BT 26.250 622.589 Td /F1 9.8 Tf [(clades of H1N1pdm circulating globally \(labeled clades 1-7, Fig. 1\). Each clade is defined by long branches and nodes )] TJ ET BT 26.250 610.684 Td /F1 9.8 Tf [(supported by high Bayesian posterior probability \(BPP\) values \(> 90%\). Each clade also is evident on phylogenies inferred )] TJ ET BT 26.250 598.779 Td /F1 9.8 Tf [(using the MrBayes )] TJ ET 0.267 0.267 0.267 rg BT 109.700 598.779 Td /F1 9.8 Tf [([5])] TJ ET 0.271 0.267 0.267 rg BT 120.542 598.779 Td /F1 9.8 Tf [( and PAUP* )] TJ ET 0.267 0.267 0.267 rg BT 175.279 598.779 Td /F1 9.8 Tf [([6])] TJ ET 0.271 0.267 0.267 rg BT 186.121 598.779 Td /F1 9.8 Tf [( programs \(data not shown\). Twenty-one isolates, which include two-thirds \(8/12\) of all )] TJ ET BT 26.250 586.875 Td /F1 9.8 Tf [(Mexican isolates available for this study, occupy a basal position on the tree with low phylogenetic resolution, and therefore are )] TJ ET BT 26.250 574.970 Td /F1 9.8 Tf [(not members of any of the clades defined here. Using these basal isolates as a reference point, amino acid changes became )] TJ ET BT 26.250 563.065 Td /F1 9.8 Tf [(fixed in every clade except for clade 3 and in every segment except in the matrix protein \(see below, Table 1\). However, none of )] TJ ET BT 26.250 551.160 Td /F1 9.8 Tf [(these amino acid changes are located in sites with known phenotypic effects, such as in antigenic sites on the H1 )] TJ ET 0.267 0.267 0.267 rg BT 517.240 551.160 Td /F1 9.8 Tf [([7])] TJ ET 0.271 0.267 0.267 rg BT 528.082 551.160 Td /F1 9.8 Tf [( or those in )] TJ ET BT 26.250 539.256 Td /F1 9.8 Tf [(the NA that are associated with resistance to the neuraminidase inhibitor \(NI\) antiviral drugs )] TJ ET 0.267 0.267 0.267 rg BT 423.991 539.256 Td /F1 9.8 Tf [([8])] TJ ET BT 434.833 539.256 Td /F1 9.8 Tf [([9])] TJ ET 0.271 0.267 0.267 rg BT 445.675 539.256 Td /F1 9.8 Tf [( .)] TJ ET BT 26.250 519.851 Td /F4 9.8 Tf [(Figure 2)] TJ ET 0.965 0.965 0.965 rg 26.250 254.870 555.000 255.100 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 509.970 m 581.250 509.970 l 581.250 509.220 l 26.250 509.220 l f 26.250 254.870 m 581.250 254.870 l 581.250 255.620 l 26.250 255.620 l f q 225.000 0 0 147.750 35.250 352.470 cm /I14 Do Q q 35.250 266.120 537.000 80.350 re W n 0.271 0.267 0.267 rg BT 35.250 336.946 Td /F4 9.8 Tf [(Fig. 2: Changing clade distributions through time and space.)] TJ ET BT 35.250 317.576 Td /F1 9.8 Tf [(The shading of each circle represents the proportion of isolates belonging to each of the clades identified in Fig. 1 from )] TJ ET BT 35.250 303.840 Td /F1 9.8 Tf [(each locality \(y-axis\) by epidemic week \(x-axis\). The shading of clades is identical to that of Fig. 1. Week 1 begins with the )] TJ ET BT 35.250 290.104 Td /F1 9.8 Tf [(first isolate collected in this study: April 1, 2009. Small circles denote weeks for which only a single isolate was available )] TJ ET BT 35.250 276.367 Td /F1 9.8 Tf [(from a locality.)] TJ ET Q BT 26.250 237.846 Td /F1 9.8 Tf [(The 7 clades vary considerably in size: clade 1 contains 9 isolates, clade 4 has 11 isolates, clade 6 has 13 isolates, clade 2 has )] TJ ET BT 26.250 225.942 Td /F1 9.8 Tf [(25 isolates, clade 3 has 32 isolates, clade 5 has 77 isolates, and clade 7 has 102 isolates. With the exception of clade 4, which )] TJ ET BT 26.250 214.037 Td /F1 9.8 Tf [(contains isolates collected only from Asia, all clades are geographically dispersed and appear to co-circulate over time and )] TJ ET BT 26.250 202.132 Td /F1 9.8 Tf [(space. As an extreme case in point, 5 different lineages \(clades 1, 2, 3, 6, and 7\) all co-circulated in New York during week 5 of )] TJ ET BT 26.250 190.227 Td /F1 9.8 Tf [(this study \(April 26 May 2, 2009, Fig. 2\). Five clades \(clades 2, 3, 4, 5, and 7\) co-circulated in Asia during week 8, and clades )] TJ ET BT 26.250 178.323 Td /F1 9.8 Tf [(2, 3, and 5 co-circulated in Wisconsin during week 6. Although the major epidemics in New York and Wisconsin both were )] TJ ET BT 26.250 166.418 Td /F1 9.8 Tf [(associated with multiple introductions of genetically distinct H1N1pdm, a single clade comprised >80% of virus specimens in )] TJ ET BT 26.250 154.513 Td /F1 9.8 Tf [(each locality: clade 5 in Wisconsin and clade 7 in New York \(Fig. 2\). Below we describe the evolutionary dynamics of individual )] TJ ET BT 26.250 142.608 Td /F1 9.8 Tf [(clades in further detail. Clade 1 includes first H1N1pdm isolates that was identified in our study: A/California/04/2009, collected )] TJ ET BT 26.250 130.704 Td /F1 9.8 Tf [(April 1, 2009. A Bayesian MCMC analysis estimates that the Time to the Most Recent Common Ancestor \(TMRCA\) of clade 1 )] TJ ET BT 26.250 118.799 Td /F1 9.8 Tf [(ranges from February 16 March 16, 2009 \(95% highest probability density \(HPD\)\), confirming that clade 1 was one of the )] TJ ET BT 26.250 106.894 Td /F1 9.8 Tf [(earliest to emerge and that it circulated for ~2 6 weeks before initial detection \(Fig. 3\). However, clade 1 is also the smallest )] TJ ET BT 26.250 94.989 Td /F1 9.8 Tf [(clade in our study \(9 isolates\) and exhibits only limited geographic dissemination \(Fig. 2\). Four unique amino acid changes were )] TJ ET BT 26.250 83.085 Td /F1 9.8 Tf [(observed among the majority \(7/9\) of clade 1 isolates: S224P in the PA and S91P, A200T, and V323I in the HA \(H3 numbering )] TJ ET BT 26.250 71.180 Td /F1 9.8 Tf [(system )] TJ ET 0.267 0.267 0.267 rg BT 59.839 71.180 Td /F1 9.8 Tf [([10])] TJ ET 0.271 0.267 0.267 rg BT 76.102 71.180 Td /F1 9.8 Tf [( \) \(Table 1\).)] TJ ET BT 26.250 51.775 Td /F4 9.8 Tf [(Figure 3)] TJ ET Q q 15.000 41.894 577.500 735.106 re W n 0.965 0.965 0.965 rg 26.250 687.232 555.000 89.768 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 687.232 m 581.250 687.232 l 581.250 687.982 l 26.250 687.982 l f q 35.250 698.482 537.000 78.518 re W n 0.271 0.267 0.267 rg BT 35.250 767.476 Td /F4 9.8 Tf [(Fig. 1: Maximum Clade Credibility \(MCC\) tree of the concatenated coding regions of 290 H1N1pdm isolates )] TJ ET BT 35.250 755.571 Td /F4 9.8 Tf [(sampled globally between April 1 July 9, 2009.)] TJ ET BT 35.250 736.201 Td /F1 9.8 Tf [(Bayesian posterior probability \(BPP\) values > 90% are included for key nodes. The tree is automatically rooted through the )] TJ ET BT 35.250 722.465 Td /F1 9.8 Tf [(assumption of a strict molecular clock, such that tip times represent the time \(day\) of sampling. Clades of clearly related )] TJ ET BT 35.250 708.729 Td /F1 9.8 Tf [(isolates are represented by color-coded rectangles.)] TJ ET Q BT 26.250 670.208 Td /F1 9.8 Tf [(To identify discrete genetic lineages of H1N1pdm, we conducted a phylogenetic analysis on 290 concatenated whole-genome )] TJ ET BT 26.250 658.303 Td /F1 9.8 Tf [(sequences of H1N1pdm isolates collected between April 1, 2009 July 9, 2009, including 81 genomes collected from )] TJ ET BT 26.250 646.398 Td /F1 9.8 Tf [(Wisconsin between April 28, 2009 May 30, 2009. The exact collection date was available for each isolate. Our Bayesian )] TJ ET BT 26.250 634.494 Td /F1 9.8 Tf [(Markov chain Monte Carlo \(MCMC\) phylogenetic analysis, using the BEAST program )] TJ ET 0.267 0.267 0.267 rg BT 396.321 634.494 Td /F1 9.8 Tf [([4])] TJ ET 0.271 0.267 0.267 rg BT 407.163 634.494 Td /F1 9.8 Tf [( \(version 1.4.8\), revealed 7 discrete )] TJ ET BT 26.250 622.589 Td /F1 9.8 Tf [(clades of H1N1pdm circulating globally \(labeled clades 1-7, Fig. 1\). Each clade is defined by long branches and nodes )] TJ ET BT 26.250 610.684 Td /F1 9.8 Tf [(supported by high Bayesian posterior probability \(BPP\) values \(> 90%\). Each clade also is evident on phylogenies inferred )] TJ ET BT 26.250 598.779 Td /F1 9.8 Tf [(using the MrBayes )] TJ ET 0.267 0.267 0.267 rg BT 109.700 598.779 Td /F1 9.8 Tf [([5])] TJ ET 0.271 0.267 0.267 rg BT 120.542 598.779 Td /F1 9.8 Tf [( and PAUP* )] TJ ET 0.267 0.267 0.267 rg BT 175.279 598.779 Td /F1 9.8 Tf [([6])] TJ ET 0.271 0.267 0.267 rg BT 186.121 598.779 Td /F1 9.8 Tf [( programs \(data not shown\). Twenty-one isolates, which include two-thirds \(8/12\) of all )] TJ ET BT 26.250 586.875 Td /F1 9.8 Tf [(Mexican isolates available for this study, occupy a basal position on the tree with low phylogenetic resolution, and therefore are )] TJ ET BT 26.250 574.970 Td /F1 9.8 Tf [(not members of any of the clades defined here. Using these basal isolates as a reference point, amino acid changes became )] TJ ET BT 26.250 563.065 Td /F1 9.8 Tf [(fixed in every clade except for clade 3 and in every segment except in the matrix protein \(see below, Table 1\). However, none of )] TJ ET BT 26.250 551.160 Td /F1 9.8 Tf [(these amino acid changes are located in sites with known phenotypic effects, such as in antigenic sites on the H1 )] TJ ET 0.267 0.267 0.267 rg BT 517.240 551.160 Td /F1 9.8 Tf [([7])] TJ ET 0.271 0.267 0.267 rg BT 528.082 551.160 Td /F1 9.8 Tf [( or those in )] TJ ET BT 26.250 539.256 Td /F1 9.8 Tf [(the NA that are associated with resistance to the neuraminidase inhibitor \(NI\) antiviral drugs )] TJ ET 0.267 0.267 0.267 rg BT 423.991 539.256 Td /F1 9.8 Tf [([8])] TJ ET BT 434.833 539.256 Td /F1 9.8 Tf [([9])] TJ ET 0.271 0.267 0.267 rg BT 445.675 539.256 Td /F1 9.8 Tf [( .)] TJ ET BT 26.250 519.851 Td /F4 9.8 Tf [(Figure 2)] TJ ET 0.965 0.965 0.965 rg 26.250 254.870 555.000 255.100 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 509.970 m 581.250 509.970 l 581.250 509.220 l 26.250 509.220 l f 26.250 254.870 m 581.250 254.870 l 581.250 255.620 l 26.250 255.620 l f q 225.000 0 0 147.750 35.250 352.470 cm /I16 Do Q q 35.250 266.120 537.000 80.350 re W n 0.271 0.267 0.267 rg BT 35.250 336.946 Td /F4 9.8 Tf [(Fig. 2: Changing clade distributions through time and space.)] TJ ET BT 35.250 317.576 Td /F1 9.8 Tf [(The shading of each circle represents the proportion of isolates belonging to each of the clades identified in Fig. 1 from )] TJ ET BT 35.250 303.840 Td /F1 9.8 Tf [(each locality \(y-axis\) by epidemic week \(x-axis\). The shading of clades is identical to that of Fig. 1. Week 1 begins with the )] TJ ET BT 35.250 290.104 Td /F1 9.8 Tf [(first isolate collected in this study: April 1, 2009. Small circles denote weeks for which only a single isolate was available )] TJ ET BT 35.250 276.367 Td /F1 9.8 Tf [(from a locality.)] TJ ET Q BT 26.250 237.846 Td /F1 9.8 Tf [(The 7 clades vary considerably in size: clade 1 contains 9 isolates, clade 4 has 11 isolates, clade 6 has 13 isolates, clade 2 has )] TJ ET BT 26.250 225.942 Td /F1 9.8 Tf [(25 isolates, clade 3 has 32 isolates, clade 5 has 77 isolates, and clade 7 has 102 isolates. With the exception of clade 4, which )] TJ ET BT 26.250 214.037 Td /F1 9.8 Tf [(contains isolates collected only from Asia, all clades are geographically dispersed and appear to co-circulate over time and )] TJ ET BT 26.250 202.132 Td /F1 9.8 Tf [(space. As an extreme case in point, 5 different lineages \(clades 1, 2, 3, 6, and 7\) all co-circulated in New York during week 5 of )] TJ ET BT 26.250 190.227 Td /F1 9.8 Tf [(this study \(April 26 May 2, 2009, Fig. 2\). Five clades \(clades 2, 3, 4, 5, and 7\) co-circulated in Asia during week 8, and clades )] TJ ET BT 26.250 178.323 Td /F1 9.8 Tf [(2, 3, and 5 co-circulated in Wisconsin during week 6. Although the major epidemics in New York and Wisconsin both were )] TJ ET BT 26.250 166.418 Td /F1 9.8 Tf [(associated with multiple introductions of genetically distinct H1N1pdm, a single clade comprised >80% of virus specimens in )] TJ ET BT 26.250 154.513 Td /F1 9.8 Tf [(each locality: clade 5 in Wisconsin and clade 7 in New York \(Fig. 2\). Below we describe the evolutionary dynamics of individual )] TJ ET BT 26.250 142.608 Td /F1 9.8 Tf [(clades in further detail. Clade 1 includes first H1N1pdm isolates that was identified in our study: A/California/04/2009, collected )] TJ ET BT 26.250 130.704 Td /F1 9.8 Tf [(April 1, 2009. A Bayesian MCMC analysis estimates that the Time to the Most Recent Common Ancestor \(TMRCA\) of clade 1 )] TJ ET BT 26.250 118.799 Td /F1 9.8 Tf [(ranges from February 16 March 16, 2009 \(95% highest probability density \(HPD\)\), confirming that clade 1 was one of the )] TJ ET BT 26.250 106.894 Td /F1 9.8 Tf [(earliest to emerge and that it circulated for ~2 6 weeks before initial detection \(Fig. 3\). However, clade 1 is also the smallest )] TJ ET BT 26.250 94.989 Td /F1 9.8 Tf [(clade in our study \(9 isolates\) and exhibits only limited geographic dissemination \(Fig. 2\). Four unique amino acid changes were )] TJ ET BT 26.250 83.085 Td /F1 9.8 Tf [(observed among the majority \(7/9\) of clade 1 isolates: S224P in the PA and S91P, A200T, and V323I in the HA \(H3 numbering )] TJ ET BT 26.250 71.180 Td /F1 9.8 Tf [(system )] TJ ET 0.267 0.267 0.267 rg BT 59.839 71.180 Td /F1 9.8 Tf [([10])] TJ ET 0.271 0.267 0.267 rg BT 76.102 71.180 Td /F1 9.8 Tf [( \) \(Table 1\).)] TJ ET BT 26.250 51.775 Td /F4 9.8 Tf [(Figure 3)] TJ ET Q q 225.000 0 0 147.750 35.250 352.470 cm /I18 Do Q q 0.000 0.000 0.000 rg BT 291.710 19.825 Td /F1 11.0 Tf [(2)] TJ ET BT 25.000 19.825 Td /F1 11.0 Tf [(PLOS Currents Influenza)] TJ ET Q endstream endobj 204 0 obj << /Type /Annot /Subtype /Link /A 205 0 R /Border [0 0 0] /H /I /Rect [ 396.3210 633.5918 407.1630 643.5124 ] >> endobj 205 0 obj << /Type /Action >> endobj 206 0 obj << /Type /Annot /Subtype /Link /A 207 0 R /Border [0 0 0] /H /I /Rect [ 109.7002 597.8776 120.5422 607.7982 ] >> endobj 207 0 obj << /Type /Action >> endobj 208 0 obj << /Type /Annot /Subtype /Link /A 209 0 R /Border [0 0 0] /H /I /Rect [ 175.2788 597.8776 186.1208 607.7982 ] >> endobj 209 0 obj << /Type /Action >> endobj 210 0 obj << /Type /Annot /Subtype /Link /A 211 0 R /Border [0 0 0] /H /I /Rect [ 517.2405 550.2586 528.0825 560.1792 ] >> endobj 211 0 obj << /Type /Action >> endobj 212 0 obj << /Type /Annot /Subtype /Link /A 213 0 R /Border [0 0 0] /H /I /Rect [ 423.9915 538.3538 434.8335 548.2744 ] >> endobj 213 0 obj << /Type /Action >> endobj 214 0 obj << /Type /Annot /Subtype /Link /A 215 0 R /Border [0 0 0] /H /I /Rect [ 434.8335 538.3538 445.6755 548.2744 ] >> endobj 215 0 obj << /Type /Action >> endobj 216 0 obj << /Type /Annot /Subtype /Link /A 217 0 R /Border [0 0 0] /H /I /Rect [ 35.2500 352.4700 260.2500 500.2200 ] >> endobj 217 0 obj << /Type /Action /S /URI /URI (http://currents.plos.org/influenza/files/2009/11/fig2.png) >> endobj 218 0 obj << /Type /XObject /Subtype /Image /Width 300 /Height 197 /Filter /FlateDecode /DecodeParms << /Predictor 15 /Colors 1 /Columns 300 /BitsPerComponent 8>> /ColorSpace /DeviceGray /BitsPerComponent 8 /Length 423>> stream xA 0 =fy9뀟\ endstream endobj 219 0 obj << /Type /XObject /Subtype /Image /Width 300 /Height 197 /SMask 218 0 R /Filter /FlateDecode /DecodeParms << /Predictor 15 /Colors 3 /Columns 300 /BitsPerComponent 8>> /ColorSpace /DeviceRGB /BitsPerComponent 8 /Length 30834>> stream x}w|y;{{ @I콪*Vf'lUrl$qqbّDɖjQb  zw;{77;BZwf}鳳;;gcgyܞ̌ŋOLbҥc !1BHi^B7 dDq)#JT.^ZQ iv{FFf-).o]'.wnMcN{4';ԩ/vww\ W| ʼ\ݤGvIZC0+b.2CK%&L,ɢk׿‹'޳'77c^7';;?q⓷b2KrYɗK&Dodе ׌߅PBB0dkp.p6tY˖Y,’E LygΘY[{&5-- p;9qzYKN^te˖jd;J[&P#/65H#U\EQpIV,!n\\pl 3Fz㦣Ԍ`",&02p9b6⒍jb1\8#"0#c&-hu!f%^2n.̂\xuOw{p9ܨk4#3c2,lvdwiiH0ԇrrr&<±G\#ٓ!\Q;++k2{=ޒ nGSEQ1yaKq͈Ҝ:q)0󍌌(zNxB!EQ]4W%h ۧAIp WU###`^CjR/(c0ƚ劢~Q9p ], T]d:ʟX8^].;S}w~] z_z_7##q|޽{w%~g?9G2 ϿbGG.͖={`)9$W <Ν;|_EQOmۦ뫺^{_ÿzC;B?cmgz{{kϜk }˲|??n# _WG '0ƯFٳ,] ^L;݊5~/B ڸaúukSN36gggcs~uvu;{!g`E׭3+ &W9 \}0C,NJIIQo L ŋ_.!%##ᰋXQ^nTI4R+,,LX99"rX 747c8a`&Y&ewuu͝3Y_fMggaIpɓ5fX ;{vf,d36o̷*|ϗn .KQbH!uQQf3S[[[O:}ьpA6[ʊ;<>I31YoEyE(r: Psr5N uhoo9f"lVwޱhQuaa+$Eu˖`08{lM8\d6ZoV^mXF`"TWUL:loԩSwynz5p8ϛ7/fP9c $[ZZA3gn`0`С,<(/B7\}򲲩@gd~eeݿ5kH,kd3{M>!̼W]|;k=kԩSN.g̙3gLs*(:`]j6-FTܨ%+V$P Z7l˖] TV.)EEV4Ju8+HBgJhyJJ:f5Bb9#J`I/7%/sI9^f3`*h"33k4&떂.Ww `53makrRLTN6uc+ t,7)z5|Nxy޾/g\I ojjE$$2Y %\}}X&Cx0ljj!񔔔NL%K.]ܝ(`^w6i.=-}2z?1 V50UZWTQ\R8~nڊ 9 $җ.]f՛SQQnڬy7mܘf]n޴),8ppKKHKgee\FUizkD5h4Dq`].)\w5bqLH, M02uAJބmcsBpB3J/M)rI8LGp3zI'fTfkBMz! 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IO[o=p᣽HI.:v⢲NG0URn aoeE¹u`mc_DQ9"޽{[Z K\9? l!6_y~QD2{%ew:UGr!Ƶl I|Zipbo[;!;-?%_$D".]Ԍ帓iVNdl ܊ac5F}'(0 g,^mPѦk&̹DEt#."41v_fm#Ϳ}m q$-{`s ܶg߱KJ H"69sK~縏^ÉO>xl"b_#Gd⭶9sx;^~<_r‚Y^>ek# }vYJѼw(6 ]6 Zj}OH7CtyڦL;:hSr EyƏZƙc"@!s?~O|)(V.@ڹ{KNP~s|{c_zF#VgڟHNm;?Ŏ_6zUj4רIhG5kބ:u9>릚s*1 _B&elI*d - a} ΢i|ۖHh(ݽ B#$Oڣ0 Lȇ7Aa_{ǁwߏ2WΞ;ട޳~hFdEi8[ `?jK#q5%t^yK;}ҳy̼%;^~{#>~btU.tf nƌGq'|gζmR// ,'9! _QF'I9BV8s# mL0?cF2wO}?!{;> }>J«@m<~MJq4$!'GB>8끥\x|7"~-DTE GiDADLY!!`o |ɤ_nfvTt~oݶ#2"8xP;k1](Rj6vutOAiIv FZ:P#S  1TǓIXo`Q+p a ga^v^ih:uDgҔ.2/ tt?tx ̥!@#r1ŀ鋇(-C=$ D] pRgGA^\_@өӺ[FkHF`W "&<0w7<;ٹ}W_{ݢi\#ߌ0WPL@thz"C ?أc?gv "#ĵ`0>ja gԷ/( ΢[6_U ީ xxyywPo-nL [[D5S$ׇO rCC0b^W+ `swyt涵ae-nZjDL`žh[ҒtsI"Ĕ,BfLcq7ny:b CrTW2;GA1@̋@?|CC_( 4қjs6 L3()!r$!$$)TڨeVq z%tnAwwW3VZu⢁AE}b8^).:6*p\.Ĉ7@DEpn NKeva?0s.L)J2?ZwYAƝH@Q W @qFEjvF8o;W\̶P0L! @(S݅U*qn"Eea=3?O#"z,R)"29srWJ OX6en+XQj.WZsUz`-Tm]eRlF˗/GeRgiD7:!tW1I&y7QK+ɮ{߽{!Bm;karG#b0DfEZr.ON*J_uAiLCa{G[JCi32m WeC8Dq MrQ(mPApdO^06~tn0sFmIi@lo"[~Opvy*7Xvvx!S#@l0sNR>鹹w{=ayZ0eG-~U+M 6}]|\ f9j\Ԃu*Z⍸ZkrdTUM\٦B@֕VȲ17^1QR#7.z 9z`+AQ.27hg\qd|$"\p@ Vko+@ݗ hn\3ii5-g(d7(q&O=zSw?X\ _WX˰x-gyJ&L0xxsY/ΚFTEZjuUi5̹)n檼IvESSR':_;Yɭ $APNE`2TTe{::rU%H'7q1d-N;hQɑ;C,+]x-0֛˧J򾥊RXf퟾e%i5 &MUxDk( HH~{.{Rvc3XV]-Pn6T 8!UM|A3&Z a\mTĴ9WWWptF _]Q! шM9&U~CMĆ(Y|sNk֬EN㻏` KKKssw~Gd6J O7TN"юJX,*aMtZ/amPkQQi1mR&L:<8\ДUk`N|pJml_gekZwϚ.ol:qRz̈́;kg`aVkvO>qт_}0-#z(+5GlBJe/\陙t~3ڲGzO!Tn䢋.=ؿz~(_>.\{bRJI}65ks.1]Y䒗^~ⵔvG"+ )b&U~yl{:=nw.?=!@rR2to/YI9iY- 8 ]:Y?Iq:9A1L!*#HfQ(^OK qC.)--?'ሾ%•+eeeQ}<^BHz$+;z!*7.xJJJ,R 'TMޣtP;4w#×W;.'wjgPB-di.KWq+E[c՝pҩ8?ָY1ZƍkT6k+e K˥U/ WYGOy`3!I;J'ǹ܄1F:q5!+u\JLy4]KtpւDogL7rdؽ\ݢ/37.kWleFۃ̓J(wՍQT3_5g#cm`&/踌ugGU=S X$:RQ(eգzqRǹUmoJ<] Z+"0藗#[oD-׊,~\:\]*0>vQw aDjWK/{Z> endobj 261 0 obj << /Length 22650 >> stream 0.271 0.267 0.267 rg q 15.000 32.351 577.500 744.649 re W n 0.965 0.965 0.965 rg 26.250 504.136 555.000 272.864 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 777.000 m 581.250 777.000 l 581.250 776.250 l 26.250 776.250 l f 26.250 504.136 m 581.250 504.136 l 581.250 504.886 l 26.250 504.886 l f q 225.000 0 0 179.250 35.250 588.000 cm /I20 Do Q q 35.250 515.386 537.000 66.614 re W n 0.271 0.267 0.267 rg BT 35.250 572.476 Td /F4 9.8 Tf [(Fig. 3: Bayesian estimates of Times to the Most Recent Ancestor \(TMRCA\) for each clade identified in Fig. 1.)] TJ ET BT 35.250 553.106 Td /F1 9.8 Tf [(Points connected by a solid line on the left represent the 95% credible intervals for the TMRCA estimate of each clade, with )] TJ ET BT 35.250 539.370 Td /F1 9.8 Tf [(a dotted line connecting to the date when that clade was first identified in this study. The shading of points and lines )] TJ ET BT 35.250 525.634 Td /F1 9.8 Tf [(representing clades is identical to Figs. 1 and 2.)] TJ ET Q BT 26.250 487.113 Td /F1 9.8 Tf [(Clade 2 also contains isolates from among the earliest known cases of H1N1pdm in Mexico and California \(e.g., )] TJ ET BT 26.250 475.208 Td /F1 9.8 Tf [(A/Mexico/4108/2009, collected April 2, 2009\). The TMRCA of clade 2 suggests it emerged around the same time as clade 1 )] TJ ET BT 26.250 463.303 Td /F1 9.8 Tf [(\(February 14 March 12, 2009, 95% HPD\) and circulated for ~3 6 weeks prior to detection \(Fig. 3\). In contrast to clade 1, )] TJ ET BT 26.250 451.398 Td /F1 9.8 Tf [(clade 2 disseminated widely to Canada, France, Germany, China, and to multiple US states: Indiana, Kansas, Maryland, New )] TJ ET BT 26.250 439.494 Td /F1 9.8 Tf [(York, Washington, and Wisconsin \(Fig. 2\). Clade 2 is characterized by two amino acid substitutions: M581L \(PA\) and T373I )] TJ ET BT 26.250 427.589 Td /F1 9.8 Tf [(\(NP\) \(Table 1\). Following week 8, no isolates collected globally were members of clade 2 \(Fig. 2\), but further surveillance is )] TJ ET BT 26.250 415.684 Td /F1 9.8 Tf [(needed to determine whether this clade may still be circulating at low levels. Clade 3 was detected by surveillance several )] TJ ET BT 26.250 403.779 Td /F1 9.8 Tf [(weeks after clades 1 and 2 \(A/Arizona/01/2009, collected April 22, 2009\). However, the TMRCA \(February 21 March 19, 2009, )] TJ ET BT 26.250 391.875 Td /F1 9.8 Tf [(95% HPD\) suggests that clade 3 emerged at a similar time as clades 1 and 2, and only was detected later. Clade 3 is the most )] TJ ET BT 26.250 379.970 Td /F1 9.8 Tf [(geographically diverse, containing isolates from Norway, France, England, Germany, Puerto Rico, China, Japan, Canada, )] TJ ET BT 26.250 368.065 Td /F1 9.8 Tf [(Mexico, and the US states of New York, Wisconsin, and Arizona \(Fig. 2\). Although no amino acid changes have been fixed )] TJ ET BT 26.250 356.160 Td /F1 9.8 Tf [(among all clade 3 isolates, at least 13 different amino acid changes were observed among clusters of isolates contained within )] TJ ET BT 26.250 344.256 Td /F1 9.8 Tf [(this clade \(data not shown\). Clade 4 is the only clade in this study that contains isolates from only one region: all 11 isolates are )] TJ ET BT 26.250 332.351 Td /F1 9.8 Tf [(from East Asia. Clade 4 is characterized by fixed amino acid changes in the PB2 \(V649I\), PB1 \(I667T\), NP \(V100I\), and NA )] TJ ET BT 26.250 320.446 Td /F1 9.8 Tf [(\(V106I\), and NS2 \(E63K\) \(Table 1\). Clade 4 was the last to be detected in this study, as the first isolate \(A/Korea/01/2009\) was )] TJ ET BT 26.250 308.541 Td /F1 9.8 Tf [(not identified until May 2, 2009. However, the TMRCA of clade 4 \(March 5 April 18, 2009, 95% HPD\) suggests that clade 4 )] TJ ET BT 26.250 296.637 Td /F1 9.8 Tf [(circulated for ~2 7 weeks prior to detection, and likely in non-Asian countries as well \(Fig. 3\). Clade 5 is the second largest )] TJ ET BT 26.250 284.732 Td /F1 9.8 Tf [(clade identified here, due primarily to the fact that nearly 88% \(71/81\) of isolates collected from Wisconsin belong to this clade )] TJ ET BT 26.250 272.827 Td /F1 9.8 Tf [(\(Fig. 2\). More than 90% \(71/77\) of isolates in clade 5 were collected from Wisconsin, where the clade was first detected \(April )] TJ ET BT 26.250 260.922 Td /F1 9.8 Tf [(28, 2009\) and appears to have proliferated rapidly \(Table S1\). Clade 5 also was identified several weeks later in Canada, China, )] TJ ET BT 26.250 249.018 Td /F1 9.8 Tf [(and Japan \(Fig. 2\). Although clade 5 was detected <1 week after clade 3, the TMRCA of clade 5 ranges from March 28 April )] TJ ET BT 26.250 237.113 Td /F1 9.8 Tf [(18, 2009 \(95% HPD\), more than one month later than clades 1, 2, and 3 \(Fig. 3\). Clade 5 is characterized by amino acid )] TJ ET BT 26.250 225.208 Td /F1 9.8 Tf [(changes in the NP \(V100I\) and NA \(V106I and N248D\), relative to basal isolates, but these changes are also observed among )] TJ ET BT 26.250 213.303 Td /F1 9.8 Tf [(clades 6 and 7 \(Table 1\). Clade 6 is geographically diverse, given its size in this study \(13 isolates\) and relatively late TMRCA, )] TJ ET BT 26.250 201.399 Td /F1 9.8 Tf [(ranging from April 4 April 20, 2009 \(95% HPD\), which is ~1 3 weeks prior to detection \(Fig. 3\). Following the collection of the )] TJ ET BT 26.250 189.494 Td /F1 9.8 Tf [(first clade 6 isolates on April 28, 2009 in the US, isolates were collected from Canada, China, Italy, and Japan \(Fig. 2\). In )] TJ ET BT 26.250 177.589 Td /F1 9.8 Tf [(addition to the amino acid changes in the NP and NA that also are observed in clade 5, two unique amino acid substitutions in )] TJ ET BT 26.250 165.684 Td /F1 9.8 Tf [(the HA are present among clade 6 isolates: K\(-6\)E and Q295H, but neither are epitopes \(Table 1\). Clade 7 is the largest )] TJ ET BT 26.250 153.780 Td /F1 9.8 Tf [(identified in this study, representing more than one-third of all isolates \(35.2%, 102/290\) \(Table S1\). Almost 83% \(67/81\) of )] TJ ET BT 26.250 141.875 Td /F1 9.8 Tf [(isolates from New York are members of clade 7. Clade 7 also contains isolates from Canada, China, Japan, Germany, Italy, )] TJ ET BT 26.250 129.970 Td /F1 9.8 Tf [(Luxembourg, Russia, and the US states of California, Maryland, Massachusetts, Ohio, and Wisconsin \(Fig. 2\). Approximately )] TJ ET BT 26.250 118.065 Td /F1 9.8 Tf [(40% of the isolates collected from Europe and Asia are members of clade 7 \(Fig. 2\). Clade 7 is characterized by fixed amino )] TJ ET BT 26.250 106.161 Td /F1 9.8 Tf [(acid changes in the NP \(V100I\) and NA \(V106I and N248D\) that are also found in clades 5 and 6, as well as by unique amino )] TJ ET BT 26.250 94.256 Td /F1 9.8 Tf [(acid changes in the HA \(S206T\) and NS1 \(I123V\) \(Table 1\). Clade 7 was first detected April 24, 2009, and the TMRCA of clade )] TJ ET BT 26.250 82.351 Td /F1 9.8 Tf [(7 ranges from March 28 April 16, 2009 \(95% HPD\), suggesting that clade 7 emerged approximately ~1 4 weeks prior to the )] TJ ET BT 26.250 70.446 Td /F1 9.8 Tf [(date of first detection in this study and at a similar time as clade 5 \(Fig. 3\). Although none of the 12 HA amino acid substitutions )] TJ ET BT 26.250 58.542 Td /F1 9.8 Tf [(that define clades were located in any of the four antigenic subsites of the H1 \(13\) \(Table 1\), amino acid changes of potential )] TJ ET BT 26.250 46.637 Td /F1 9.8 Tf [(antigenic importance were observed among 4/290 isolates in this study. In the Cb subsite, S79Y and S79F substitutions were )] TJ ET Q q 15.000 32.351 577.500 744.649 re W n 0.965 0.965 0.965 rg 26.250 504.136 555.000 272.864 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 777.000 m 581.250 777.000 l 581.250 776.250 l 26.250 776.250 l f 26.250 504.136 m 581.250 504.136 l 581.250 504.886 l 26.250 504.886 l f q 225.000 0 0 179.250 35.250 588.000 cm /I22 Do Q q 35.250 515.386 537.000 66.614 re W n 0.271 0.267 0.267 rg BT 35.250 572.476 Td /F4 9.8 Tf [(Fig. 3: Bayesian estimates of Times to the Most Recent Ancestor \(TMRCA\) for each clade identified in Fig. 1.)] TJ ET BT 35.250 553.106 Td /F1 9.8 Tf [(Points connected by a solid line on the left represent the 95% credible intervals for the TMRCA estimate of each clade, with )] TJ ET BT 35.250 539.370 Td /F1 9.8 Tf [(a dotted line connecting to the date when that clade was first identified in this study. The shading of points and lines )] TJ ET BT 35.250 525.634 Td /F1 9.8 Tf [(representing clades is identical to Figs. 1 and 2.)] TJ ET Q BT 26.250 487.113 Td /F1 9.8 Tf [(Clade 2 also contains isolates from among the earliest known cases of H1N1pdm in Mexico and California \(e.g., )] TJ ET BT 26.250 475.208 Td /F1 9.8 Tf [(A/Mexico/4108/2009, collected April 2, 2009\). The TMRCA of clade 2 suggests it emerged around the same time as clade 1 )] TJ ET BT 26.250 463.303 Td /F1 9.8 Tf [(\(February 14 March 12, 2009, 95% HPD\) and circulated for ~3 6 weeks prior to detection \(Fig. 3\). In contrast to clade 1, )] TJ ET BT 26.250 451.398 Td /F1 9.8 Tf [(clade 2 disseminated widely to Canada, France, Germany, China, and to multiple US states: Indiana, Kansas, Maryland, New )] TJ ET BT 26.250 439.494 Td /F1 9.8 Tf [(York, Washington, and Wisconsin \(Fig. 2\). Clade 2 is characterized by two amino acid substitutions: M581L \(PA\) and T373I )] TJ ET BT 26.250 427.589 Td /F1 9.8 Tf [(\(NP\) \(Table 1\). Following week 8, no isolates collected globally were members of clade 2 \(Fig. 2\), but further surveillance is )] TJ ET BT 26.250 415.684 Td /F1 9.8 Tf [(needed to determine whether this clade may still be circulating at low levels. Clade 3 was detected by surveillance several )] TJ ET BT 26.250 403.779 Td /F1 9.8 Tf [(weeks after clades 1 and 2 \(A/Arizona/01/2009, collected April 22, 2009\). However, the TMRCA \(February 21 March 19, 2009, )] TJ ET BT 26.250 391.875 Td /F1 9.8 Tf [(95% HPD\) suggests that clade 3 emerged at a similar time as clades 1 and 2, and only was detected later. Clade 3 is the most )] TJ ET BT 26.250 379.970 Td /F1 9.8 Tf [(geographically diverse, containing isolates from Norway, France, England, Germany, Puerto Rico, China, Japan, Canada, )] TJ ET BT 26.250 368.065 Td /F1 9.8 Tf [(Mexico, and the US states of New York, Wisconsin, and Arizona \(Fig. 2\). Although no amino acid changes have been fixed )] TJ ET BT 26.250 356.160 Td /F1 9.8 Tf [(among all clade 3 isolates, at least 13 different amino acid changes were observed among clusters of isolates contained within )] TJ ET BT 26.250 344.256 Td /F1 9.8 Tf [(this clade \(data not shown\). Clade 4 is the only clade in this study that contains isolates from only one region: all 11 isolates are )] TJ ET BT 26.250 332.351 Td /F1 9.8 Tf [(from East Asia. Clade 4 is characterized by fixed amino acid changes in the PB2 \(V649I\), PB1 \(I667T\), NP \(V100I\), and NA )] TJ ET BT 26.250 320.446 Td /F1 9.8 Tf [(\(V106I\), and NS2 \(E63K\) \(Table 1\). Clade 4 was the last to be detected in this study, as the first isolate \(A/Korea/01/2009\) was )] TJ ET BT 26.250 308.541 Td /F1 9.8 Tf [(not identified until May 2, 2009. However, the TMRCA of clade 4 \(March 5 April 18, 2009, 95% HPD\) suggests that clade 4 )] TJ ET BT 26.250 296.637 Td /F1 9.8 Tf [(circulated for ~2 7 weeks prior to detection, and likely in non-Asian countries as well \(Fig. 3\). Clade 5 is the second largest )] TJ ET BT 26.250 284.732 Td /F1 9.8 Tf [(clade identified here, due primarily to the fact that nearly 88% \(71/81\) of isolates collected from Wisconsin belong to this clade )] TJ ET BT 26.250 272.827 Td /F1 9.8 Tf [(\(Fig. 2\). More than 90% \(71/77\) of isolates in clade 5 were collected from Wisconsin, where the clade was first detected \(April )] TJ ET BT 26.250 260.922 Td /F1 9.8 Tf [(28, 2009\) and appears to have proliferated rapidly \(Table S1\). Clade 5 also was identified several weeks later in Canada, China, )] TJ ET BT 26.250 249.018 Td /F1 9.8 Tf [(and Japan \(Fig. 2\). Although clade 5 was detected <1 week after clade 3, the TMRCA of clade 5 ranges from March 28 April )] TJ ET BT 26.250 237.113 Td /F1 9.8 Tf [(18, 2009 \(95% HPD\), more than one month later than clades 1, 2, and 3 \(Fig. 3\). Clade 5 is characterized by amino acid )] TJ ET BT 26.250 225.208 Td /F1 9.8 Tf [(changes in the NP \(V100I\) and NA \(V106I and N248D\), relative to basal isolates, but these changes are also observed among )] TJ ET BT 26.250 213.303 Td /F1 9.8 Tf [(clades 6 and 7 \(Table 1\). Clade 6 is geographically diverse, given its size in this study \(13 isolates\) and relatively late TMRCA, )] TJ ET BT 26.250 201.399 Td /F1 9.8 Tf [(ranging from April 4 April 20, 2009 \(95% HPD\), which is ~1 3 weeks prior to detection \(Fig. 3\). Following the collection of the )] TJ ET BT 26.250 189.494 Td /F1 9.8 Tf [(first clade 6 isolates on April 28, 2009 in the US, isolates were collected from Canada, China, Italy, and Japan \(Fig. 2\). In )] TJ ET BT 26.250 177.589 Td /F1 9.8 Tf [(addition to the amino acid changes in the NP and NA that also are observed in clade 5, two unique amino acid substitutions in )] TJ ET BT 26.250 165.684 Td /F1 9.8 Tf [(the HA are present among clade 6 isolates: K\(-6\)E and Q295H, but neither are epitopes \(Table 1\). Clade 7 is the largest )] TJ ET BT 26.250 153.780 Td /F1 9.8 Tf [(identified in this study, representing more than one-third of all isolates \(35.2%, 102/290\) \(Table S1\). Almost 83% \(67/81\) of )] TJ ET BT 26.250 141.875 Td /F1 9.8 Tf [(isolates from New York are members of clade 7. Clade 7 also contains isolates from Canada, China, Japan, Germany, Italy, )] TJ ET BT 26.250 129.970 Td /F1 9.8 Tf [(Luxembourg, Russia, and the US states of California, Maryland, Massachusetts, Ohio, and Wisconsin \(Fig. 2\). Approximately )] TJ ET BT 26.250 118.065 Td /F1 9.8 Tf [(40% of the isolates collected from Europe and Asia are members of clade 7 \(Fig. 2\). Clade 7 is characterized by fixed amino )] TJ ET BT 26.250 106.161 Td /F1 9.8 Tf [(acid changes in the NP \(V100I\) and NA \(V106I and N248D\) that are also found in clades 5 and 6, as well as by unique amino )] TJ ET BT 26.250 94.256 Td /F1 9.8 Tf [(acid changes in the HA \(S206T\) and NS1 \(I123V\) \(Table 1\). Clade 7 was first detected April 24, 2009, and the TMRCA of clade )] TJ ET BT 26.250 82.351 Td /F1 9.8 Tf [(7 ranges from March 28 April 16, 2009 \(95% HPD\), suggesting that clade 7 emerged approximately ~1 4 weeks prior to the )] TJ ET BT 26.250 70.446 Td /F1 9.8 Tf [(date of first detection in this study and at a similar time as clade 5 \(Fig. 3\). Although none of the 12 HA amino acid substitutions )] TJ ET BT 26.250 58.542 Td /F1 9.8 Tf [(that define clades were located in any of the four antigenic subsites of the H1 \(13\) \(Table 1\), amino acid changes of potential )] TJ ET BT 26.250 46.637 Td /F1 9.8 Tf [(antigenic importance were observed among 4/290 isolates in this study. In the Cb subsite, S79Y and S79F substitutions were )] TJ ET Q q 15.000 32.351 577.500 744.649 re W n 0.965 0.965 0.965 rg 26.250 504.136 555.000 272.864 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 777.000 m 581.250 777.000 l 581.250 776.250 l 26.250 776.250 l f 26.250 504.136 m 581.250 504.136 l 581.250 504.886 l 26.250 504.886 l f q 225.000 0 0 179.250 35.250 588.000 cm /I24 Do Q q 35.250 515.386 537.000 66.614 re W n 0.271 0.267 0.267 rg BT 35.250 572.476 Td /F4 9.8 Tf [(Fig. 3: Bayesian estimates of Times to the Most Recent Ancestor \(TMRCA\) for each clade identified in Fig. 1.)] TJ ET BT 35.250 553.106 Td /F1 9.8 Tf [(Points connected by a solid line on the left represent the 95% credible intervals for the TMRCA estimate of each clade, with )] TJ ET BT 35.250 539.370 Td /F1 9.8 Tf [(a dotted line connecting to the date when that clade was first identified in this study. The shading of points and lines )] TJ ET BT 35.250 525.634 Td /F1 9.8 Tf [(representing clades is identical to Figs. 1 and 2.)] TJ ET Q BT 26.250 487.113 Td /F1 9.8 Tf [(Clade 2 also contains isolates from among the earliest known cases of H1N1pdm in Mexico and California \(e.g., )] TJ ET BT 26.250 475.208 Td /F1 9.8 Tf [(A/Mexico/4108/2009, collected April 2, 2009\). The TMRCA of clade 2 suggests it emerged around the same time as clade 1 )] TJ ET BT 26.250 463.303 Td /F1 9.8 Tf [(\(February 14 March 12, 2009, 95% HPD\) and circulated for ~3 6 weeks prior to detection \(Fig. 3\). In contrast to clade 1, )] TJ ET BT 26.250 451.398 Td /F1 9.8 Tf [(clade 2 disseminated widely to Canada, France, Germany, China, and to multiple US states: Indiana, Kansas, Maryland, New )] TJ ET BT 26.250 439.494 Td /F1 9.8 Tf [(York, Washington, and Wisconsin \(Fig. 2\). Clade 2 is characterized by two amino acid substitutions: M581L \(PA\) and T373I )] TJ ET BT 26.250 427.589 Td /F1 9.8 Tf [(\(NP\) \(Table 1\). Following week 8, no isolates collected globally were members of clade 2 \(Fig. 2\), but further surveillance is )] TJ ET BT 26.250 415.684 Td /F1 9.8 Tf [(needed to determine whether this clade may still be circulating at low levels. Clade 3 was detected by surveillance several )] TJ ET BT 26.250 403.779 Td /F1 9.8 Tf [(weeks after clades 1 and 2 \(A/Arizona/01/2009, collected April 22, 2009\). However, the TMRCA \(February 21 March 19, 2009, )] TJ ET BT 26.250 391.875 Td /F1 9.8 Tf [(95% HPD\) suggests that clade 3 emerged at a similar time as clades 1 and 2, and only was detected later. Clade 3 is the most )] TJ ET BT 26.250 379.970 Td /F1 9.8 Tf [(geographically diverse, containing isolates from Norway, France, England, Germany, Puerto Rico, China, Japan, Canada, )] TJ ET BT 26.250 368.065 Td /F1 9.8 Tf [(Mexico, and the US states of New York, Wisconsin, and Arizona \(Fig. 2\). Although no amino acid changes have been fixed )] TJ ET BT 26.250 356.160 Td /F1 9.8 Tf [(among all clade 3 isolates, at least 13 different amino acid changes were observed among clusters of isolates contained within )] TJ ET BT 26.250 344.256 Td /F1 9.8 Tf [(this clade \(data not shown\). Clade 4 is the only clade in this study that contains isolates from only one region: all 11 isolates are )] TJ ET BT 26.250 332.351 Td /F1 9.8 Tf [(from East Asia. Clade 4 is characterized by fixed amino acid changes in the PB2 \(V649I\), PB1 \(I667T\), NP \(V100I\), and NA )] TJ ET BT 26.250 320.446 Td /F1 9.8 Tf [(\(V106I\), and NS2 \(E63K\) \(Table 1\). Clade 4 was the last to be detected in this study, as the first isolate \(A/Korea/01/2009\) was )] TJ ET BT 26.250 308.541 Td /F1 9.8 Tf [(not identified until May 2, 2009. However, the TMRCA of clade 4 \(March 5 April 18, 2009, 95% HPD\) suggests that clade 4 )] TJ ET BT 26.250 296.637 Td /F1 9.8 Tf [(circulated for ~2 7 weeks prior to detection, and likely in non-Asian countries as well \(Fig. 3\). Clade 5 is the second largest )] TJ ET BT 26.250 284.732 Td /F1 9.8 Tf [(clade identified here, due primarily to the fact that nearly 88% \(71/81\) of isolates collected from Wisconsin belong to this clade )] TJ ET BT 26.250 272.827 Td /F1 9.8 Tf [(\(Fig. 2\). More than 90% \(71/77\) of isolates in clade 5 were collected from Wisconsin, where the clade was first detected \(April )] TJ ET BT 26.250 260.922 Td /F1 9.8 Tf [(28, 2009\) and appears to have proliferated rapidly \(Table S1\). Clade 5 also was identified several weeks later in Canada, China, )] TJ ET BT 26.250 249.018 Td /F1 9.8 Tf [(and Japan \(Fig. 2\). Although clade 5 was detected <1 week after clade 3, the TMRCA of clade 5 ranges from March 28 April )] TJ ET BT 26.250 237.113 Td /F1 9.8 Tf [(18, 2009 \(95% HPD\), more than one month later than clades 1, 2, and 3 \(Fig. 3\). Clade 5 is characterized by amino acid )] TJ ET BT 26.250 225.208 Td /F1 9.8 Tf [(changes in the NP \(V100I\) and NA \(V106I and N248D\), relative to basal isolates, but these changes are also observed among )] TJ ET BT 26.250 213.303 Td /F1 9.8 Tf [(clades 6 and 7 \(Table 1\). Clade 6 is geographically diverse, given its size in this study \(13 isolates\) and relatively late TMRCA, )] TJ ET BT 26.250 201.399 Td /F1 9.8 Tf [(ranging from April 4 April 20, 2009 \(95% HPD\), which is ~1 3 weeks prior to detection \(Fig. 3\). Following the collection of the )] TJ ET BT 26.250 189.494 Td /F1 9.8 Tf [(first clade 6 isolates on April 28, 2009 in the US, isolates were collected from Canada, China, Italy, and Japan \(Fig. 2\). In )] TJ ET BT 26.250 177.589 Td /F1 9.8 Tf [(addition to the amino acid changes in the NP and NA that also are observed in clade 5, two unique amino acid substitutions in )] TJ ET BT 26.250 165.684 Td /F1 9.8 Tf [(the HA are present among clade 6 isolates: K\(-6\)E and Q295H, but neither are epitopes \(Table 1\). Clade 7 is the largest )] TJ ET BT 26.250 153.780 Td /F1 9.8 Tf [(identified in this study, representing more than one-third of all isolates \(35.2%, 102/290\) \(Table S1\). Almost 83% \(67/81\) of )] TJ ET BT 26.250 141.875 Td /F1 9.8 Tf [(isolates from New York are members of clade 7. Clade 7 also contains isolates from Canada, China, Japan, Germany, Italy, )] TJ ET BT 26.250 129.970 Td /F1 9.8 Tf [(Luxembourg, Russia, and the US states of California, Maryland, Massachusetts, Ohio, and Wisconsin \(Fig. 2\). Approximately )] TJ ET BT 26.250 118.065 Td /F1 9.8 Tf [(40% of the isolates collected from Europe and Asia are members of clade 7 \(Fig. 2\). Clade 7 is characterized by fixed amino )] TJ ET BT 26.250 106.161 Td /F1 9.8 Tf [(acid changes in the NP \(V100I\) and NA \(V106I and N248D\) that are also found in clades 5 and 6, as well as by unique amino )] TJ ET BT 26.250 94.256 Td /F1 9.8 Tf [(acid changes in the HA \(S206T\) and NS1 \(I123V\) \(Table 1\). Clade 7 was first detected April 24, 2009, and the TMRCA of clade )] TJ ET BT 26.250 82.351 Td /F1 9.8 Tf [(7 ranges from March 28 April 16, 2009 \(95% HPD\), suggesting that clade 7 emerged approximately ~1 4 weeks prior to the )] TJ ET BT 26.250 70.446 Td /F1 9.8 Tf [(date of first detection in this study and at a similar time as clade 5 \(Fig. 3\). Although none of the 12 HA amino acid substitutions )] TJ ET BT 26.250 58.542 Td /F1 9.8 Tf [(that define clades were located in any of the four antigenic subsites of the H1 \(13\) \(Table 1\), amino acid changes of potential )] TJ ET BT 26.250 46.637 Td /F1 9.8 Tf [(antigenic importance were observed among 4/290 isolates in this study. In the Cb subsite, S79Y and S79F substitutions were )] TJ ET Q q 225.000 0 0 179.250 35.250 588.000 cm /I26 Do Q q 0.000 0.000 0.000 rg BT 291.710 19.825 Td /F1 11.0 Tf [(3)] TJ ET BT 25.000 19.825 Td /F1 11.0 Tf [(PLOS Currents Influenza)] TJ ET Q endstream endobj 262 0 obj << /Type /Annot /Subtype /Link /A 263 0 R /Border [0 0 0] /H /I /Rect [ 35.2500 588.0000 260.2500 767.2500 ] >> endobj 263 0 obj << /Type /Action /S /URI /URI (http://currents.plos.org/influenza/files/2009/11/fig3.pnas_.png) >> endobj 264 0 obj << /Type /XObject /Subtype /Image /Width 300 /Height 239 /Filter /FlateDecode /DecodeParms << /Predictor 15 /Colors 1 /Columns 300 /BitsPerComponent 8>> /ColorSpace /DeviceGray /BitsPerComponent 8 /Length 507>> stream xA 0 =fy9뀟\N endstream endobj 265 0 obj << /Type /XObject /Subtype /Image /Width 300 /Height 239 /SMask 264 0 R /Filter /FlateDecode /DecodeParms << /Predictor 15 /Colors 3 /Columns 300 /BitsPerComponent 8>> /ColorSpace /DeviceRGB /BitsPerComponent 8 /Length 35836>> stream xi\u&x#ʪBjCa- { (\EPdjd[#=Z7G==:gl9^cc(,RX}),V^Yn܈2$rqp7{#,!GK!ԉ [$i wV1 2a8NƬ͠f9ʆ1-J!좀78-xi;X#J>E61;Y}G1BY*Ƒ.uرGaGRI֯__]].qF=YhDo̫ L&r `Cw3u {2T$܊ͬ qX2{sb] [<Ҭ2fTޥZ hTW1 *,i-֪y.I3HjI)12_uBɨb~PlfE, L#]iD$9K a$-Rt\\YTU%U! )i!4$BH ,4iELCnA͙EՖZ+ jě5# ;YzEB(y [!ZsJ!@'S2 9Cs(ر*avlh'WؚѦ!ay.L0E07Ãpi@I2V V٨'FS ݬ!͠*%"}LAyB;: x, \rn~ Y0v n3OHE/N~w駛SҎձ . 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The G159E )] TJ ET BT 26.250 755.571 Td /F1 9.8 Tf [(replacement, located within the Sa subsite, was observed in A/Bayern/62/2009. And A/Wisconsin/629-D0223/2009 experienced )] TJ ET BT 26.250 743.667 Td /F1 9.8 Tf [(the N160T replacement, located within the Sb subsite.)] TJ ET BT 26.250 724.262 Td /F4 9.8 Tf [(Table 1)] TJ ET q 225.000 0 0 93.000 26.250 621.381 cm /I28 Do Q BT 26.250 604.357 Td /F4 9.8 Tf [(Table 1.)] TJ ET BT 62.559 604.357 Td /F1 9.8 Tf [( Amino acid changes defining clades 1-7, identified using the MacClade program \(30\). The asterisk \(*\) denotes changes )] TJ ET BT 26.250 592.452 Td /F1 9.8 Tf [(that are present in a majority, but not all of the isolates from a clade.)] TJ ET BT 26.250 555.850 Td /F4 12.0 Tf [(Discussion)] TJ ET BT 26.250 535.896 Td /F1 9.8 Tf [(Our whole-genome phylogenetic analysis of 290 H1N1pdm isolates collected globally, including the intensively sampled )] TJ ET BT 26.250 523.991 Td /F1 9.8 Tf [(populations in Wisconsin and New York, reveals at least 7 major clades of the H1N1pdm influenza virus that have co-circulated )] TJ ET BT 26.250 512.086 Td /F1 9.8 Tf [(over time and space since April 2009. Clearly, the evolution and spatial-temporal dynamics of the H1N1pdm virus are more )] TJ ET BT 26.250 500.181 Td /F1 9.8 Tf [(complex than the global dissemination of a single viral lineage. The TMRCA estimates suggest that the 7 major clades emerged )] TJ ET BT 26.250 488.277 Td /F1 9.8 Tf [(between mid-February and late April of 2009, with clades 1, 2, and 3 appearing between mid-February and mid-March, and )] TJ ET BT 26.250 476.372 Td /F1 9.8 Tf [(clades 5, 6, and 7 emerging between mid-March and mid-April. The global origins of clade 4 from Asia remain unclear. Our )] TJ ET BT 26.250 464.467 Td /F1 9.8 Tf [(estimate for the TMRCA of the entire H1N1pdm viral population ranges from late January early March, and is consistent with )] TJ ET BT 26.250 452.562 Td /F1 9.8 Tf [(previous estimates )] TJ ET 0.267 0.267 0.267 rg BT 110.237 452.562 Td /F1 9.8 Tf [([11])] TJ ET 0.271 0.267 0.267 rg BT 126.500 452.562 Td /F1 9.8 Tf [( . All of these clades circulated for at least two weeks prior to detection in this study, most likely in )] TJ ET BT 26.250 440.658 Td /F1 9.8 Tf [(Mexico and perhaps elsewhere as well. Due to the co-circulation of these lineages, epidemics in discrete localities involve )] TJ ET BT 26.250 428.753 Td /F1 9.8 Tf [(multiple introductions of genetically distinct H1N1pdm viruses. However, in locations that are more extensively sampled, such )] TJ ET BT 26.250 416.848 Td /F1 9.8 Tf [(as Wisconsin and New York, a single clade dominated. It was unexpected that different clades would predominate in Wisconsin )] TJ ET BT 26.250 404.943 Td /F1 9.8 Tf [(and New York, given the similar timing of their outbreaks and presumed population movements, and suggests that founder )] TJ ET BT 26.250 393.039 Td /F1 9.8 Tf [(effects are strong. Such clear spatial patterns have not been observed previously with seasonal influenza, although sampling )] TJ ET BT 26.250 381.134 Td /F1 9.8 Tf [(has not been as intensive )] TJ ET 0.267 0.267 0.267 rg BT 139.525 381.134 Td /F1 9.8 Tf [([12])] TJ ET 0.271 0.267 0.267 rg BT 155.788 381.134 Td /F1 9.8 Tf [( . As viral sequence data becomes available from additional localities, it will be possible to )] TJ ET BT 26.250 369.229 Td /F1 9.8 Tf [(compare the dominant H1N1pdm lineages in other localities and to better understand the spatial movements of the H1N1pdm )] TJ ET BT 26.250 357.324 Td /F1 9.8 Tf [(virus. It is unclear whether differences in fitness or clinical severity exist among these co-circulating lineages, particularly for )] TJ ET BT 26.250 345.420 Td /F1 9.8 Tf [(clade 7, which was the most commonly detected clade here. We did not observe any significant differences in age distribution )] TJ ET BT 26.250 333.515 Td /F1 9.8 Tf [(among these clades or any fixed amino acid changes likely to impact fitness )] TJ ET 0.267 0.267 0.267 rg BT 356.268 333.515 Td /F1 9.8 Tf [([7])] TJ ET BT 367.110 333.515 Td /F1 9.8 Tf [([8])] TJ ET BT 377.952 333.515 Td /F1 9.8 Tf [([9])] TJ ET 0.271 0.267 0.267 rg BT 388.794 333.515 Td /F1 9.8 Tf [( . All of these clades appear to transmit )] TJ ET BT 26.250 321.610 Td /F1 9.8 Tf [(successfully in humans, as even the smaller clades were isolated from multiple weeks and in more than one country. Although )] TJ ET BT 26.250 309.705 Td /F1 9.8 Tf [(fewer cases of H1N1pdm virus have been reported in Asia )] TJ ET 0.267 0.267 0.267 rg BT 280.940 309.705 Td /F1 9.8 Tf [([1])] TJ ET 0.271 0.267 0.267 rg BT 291.781 309.705 Td /F1 9.8 Tf [( , all 7 clades were detected in at least one Asian country, )] TJ ET BT 26.250 297.801 Td /F1 9.8 Tf [(reflecting the speed and extent of the global dissemination of the H1N1pdm virus.)] TJ ET BT 26.250 261.198 Td /F4 12.0 Tf [(Materials and Methods)] TJ ET BT 26.250 241.244 Td /F1 9.8 Tf [(Sample collection and viral isolation in Wisconsin. Patient specimens were collected at Childrens Hospital of Wisconsin \(CHW\), )] TJ ET BT 26.250 229.339 Td /F1 9.8 Tf [(Dynacare Laboratories \(DL\), and their associated clinics in Milwaukee, Wisconsin. Nasopharyngeal were transported in M4 or )] TJ ET BT 26.250 217.434 Td /F1 9.8 Tf [(M6 viral transport medium \(Remel, Lenexa, KS\) to CHW or DL microbiology laboratories to test for the presence of influenza A, )] TJ ET BT 26.250 205.530 Td /F1 9.8 Tf [(influenza B, or respiratory syncytial virus \(RSV\) using two multiplex real-time RT-PCR assays. The CHW test )] TJ ET 0.267 0.267 0.267 rg BT 497.604 205.530 Td /F1 9.8 Tf [([13])] TJ ET 0.271 0.267 0.267 rg BT 513.867 205.530 Td /F1 9.8 Tf [( utilized an in-)] TJ ET BT 26.250 193.625 Td /F1 9.8 Tf [(house assay with automated extraction and real-time PCR amplification and detection. Influenza A samples were sent to the )] TJ ET BT 26.250 181.720 Td /F1 9.8 Tf [(Midwest Respiratory Virus Program \(MRVP\) laboratory to distinguish between H1N1pdm and seasonal H1N1 and H3N2 )] TJ ET BT 26.250 169.815 Td /F1 9.8 Tf [(influenza A viruses with real-time RT-PCR or an RT-PCR enzyme hybridization assay )] TJ ET 0.267 0.267 0.267 rg BT 397.920 169.815 Td /F1 9.8 Tf [([14])] TJ ET BT 414.183 169.815 Td /F1 9.8 Tf [([15])] TJ ET 0.271 0.267 0.267 rg BT 430.446 169.815 Td /F1 9.8 Tf [( . All clinical specimens were de-)] TJ ET BT 26.250 157.911 Td /F1 9.8 Tf [(identified. H1N1pdm viruses were isolated from clinical specimens by inoculating samples onto Madin-Darby canine kidney )] TJ ET BT 26.250 146.006 Td /F1 9.8 Tf [(\(MDCK\) cells, grown until 95% confluent, and stored at -80C. From a total of ~700 H1N1pdm positive samples collected in )] TJ ET BT 26.250 134.101 Td /F1 9.8 Tf [(Milwaukee beginning April 28, 2009, 90 samples were selected for RNA extraction and genome sequencing: 50 samples were )] TJ ET BT 26.250 122.196 Td /F1 9.8 Tf [(selected from the first week of the outbreak and 10 samples from each of the next four weeks. The samples were distributed )] TJ ET BT 26.250 110.292 Td /F1 9.8 Tf [(relatively evenly by sex and among three age groups: 0 5 years, 5 18 years, and 18+ years.)] TJ ET BT 26.250 90.887 Td /F1 9.8 Tf [(RNA extraction and sequencing of Wisconsin and New York isolates. The extraction of the entire viral RNA genome from )] TJ ET BT 26.250 78.982 Td /F1 9.8 Tf [(isolates from Wisconsin and from clinical samples from New York State was performed at the Wadsworth Center, New York )] TJ ET BT 26.250 67.077 Td /F1 9.8 Tf [(State Department of Health, in Albany, NY, using the NucliSENS easyMAG robot \(bioMrieux, Durham, NC\), RNeasy Kit )] TJ ET BT 26.250 55.173 Td /F1 9.8 Tf [(\(Qiagen, Valencia, CA\) or QIAamp Viral RNA Kit with the QIAcube automated extractor \(Qiagen\). The influenza A genomic RNA )] TJ ET BT 26.250 43.268 Td /F1 9.8 Tf [(segments were simultaneously amplified from 5 uls of purified RNA using a multisegment RT-PCR strategy )] TJ ET 0.267 0.267 0.267 rg BT 490.058 43.268 Td /F1 9.8 Tf [([16])] TJ ET 0.271 0.267 0.267 rg BT 506.320 43.268 Td /F1 9.8 Tf [( . Whole-)] TJ ET Q q 15.000 28.982 577.500 748.018 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F1 9.8 Tf [(identified in the isolates A/Wisconsin/629-D01521/2009 and A/Wisconsin/629-D01705/2009, respectively. The G159E )] TJ ET BT 26.250 755.571 Td /F1 9.8 Tf [(replacement, located within the Sa subsite, was observed in A/Bayern/62/2009. And A/Wisconsin/629-D0223/2009 experienced )] TJ ET BT 26.250 743.667 Td /F1 9.8 Tf [(the N160T replacement, located within the Sb subsite.)] TJ ET BT 26.250 724.262 Td /F4 9.8 Tf [(Table 1)] TJ ET q 225.000 0 0 93.000 26.250 621.381 cm /I30 Do Q BT 26.250 604.357 Td /F4 9.8 Tf [(Table 1.)] TJ ET BT 62.559 604.357 Td /F1 9.8 Tf [( Amino acid changes defining clades 1-7, identified using the MacClade program \(30\). The asterisk \(*\) denotes changes )] TJ ET BT 26.250 592.452 Td /F1 9.8 Tf [(that are present in a majority, but not all of the isolates from a clade.)] TJ ET BT 26.250 555.850 Td /F4 12.0 Tf [(Discussion)] TJ ET BT 26.250 535.896 Td /F1 9.8 Tf [(Our whole-genome phylogenetic analysis of 290 H1N1pdm isolates collected globally, including the intensively sampled )] TJ ET BT 26.250 523.991 Td /F1 9.8 Tf [(populations in Wisconsin and New York, reveals at least 7 major clades of the H1N1pdm influenza virus that have co-circulated )] TJ ET BT 26.250 512.086 Td /F1 9.8 Tf [(over time and space since April 2009. Clearly, the evolution and spatial-temporal dynamics of the H1N1pdm virus are more )] TJ ET BT 26.250 500.181 Td /F1 9.8 Tf [(complex than the global dissemination of a single viral lineage. The TMRCA estimates suggest that the 7 major clades emerged )] TJ ET BT 26.250 488.277 Td /F1 9.8 Tf [(between mid-February and late April of 2009, with clades 1, 2, and 3 appearing between mid-February and mid-March, and )] TJ ET BT 26.250 476.372 Td /F1 9.8 Tf [(clades 5, 6, and 7 emerging between mid-March and mid-April. The global origins of clade 4 from Asia remain unclear. Our )] TJ ET BT 26.250 464.467 Td /F1 9.8 Tf [(estimate for the TMRCA of the entire H1N1pdm viral population ranges from late January early March, and is consistent with )] TJ ET BT 26.250 452.562 Td /F1 9.8 Tf [(previous estimates )] TJ ET 0.267 0.267 0.267 rg BT 110.237 452.562 Td /F1 9.8 Tf [([11])] TJ ET 0.271 0.267 0.267 rg BT 126.500 452.562 Td /F1 9.8 Tf [( . All of these clades circulated for at least two weeks prior to detection in this study, most likely in )] TJ ET BT 26.250 440.658 Td /F1 9.8 Tf [(Mexico and perhaps elsewhere as well. Due to the co-circulation of these lineages, epidemics in discrete localities involve )] TJ ET BT 26.250 428.753 Td /F1 9.8 Tf [(multiple introductions of genetically distinct H1N1pdm viruses. However, in locations that are more extensively sampled, such )] TJ ET BT 26.250 416.848 Td /F1 9.8 Tf [(as Wisconsin and New York, a single clade dominated. It was unexpected that different clades would predominate in Wisconsin )] TJ ET BT 26.250 404.943 Td /F1 9.8 Tf [(and New York, given the similar timing of their outbreaks and presumed population movements, and suggests that founder )] TJ ET BT 26.250 393.039 Td /F1 9.8 Tf [(effects are strong. Such clear spatial patterns have not been observed previously with seasonal influenza, although sampling )] TJ ET BT 26.250 381.134 Td /F1 9.8 Tf [(has not been as intensive )] TJ ET 0.267 0.267 0.267 rg BT 139.525 381.134 Td /F1 9.8 Tf [([12])] TJ ET 0.271 0.267 0.267 rg BT 155.788 381.134 Td /F1 9.8 Tf [( . As viral sequence data becomes available from additional localities, it will be possible to )] TJ ET BT 26.250 369.229 Td /F1 9.8 Tf [(compare the dominant H1N1pdm lineages in other localities and to better understand the spatial movements of the H1N1pdm )] TJ ET BT 26.250 357.324 Td /F1 9.8 Tf [(virus. It is unclear whether differences in fitness or clinical severity exist among these co-circulating lineages, particularly for )] TJ ET BT 26.250 345.420 Td /F1 9.8 Tf [(clade 7, which was the most commonly detected clade here. We did not observe any significant differences in age distribution )] TJ ET BT 26.250 333.515 Td /F1 9.8 Tf [(among these clades or any fixed amino acid changes likely to impact fitness )] TJ ET 0.267 0.267 0.267 rg BT 356.268 333.515 Td /F1 9.8 Tf [([7])] TJ ET BT 367.110 333.515 Td /F1 9.8 Tf [([8])] TJ ET BT 377.952 333.515 Td /F1 9.8 Tf [([9])] TJ ET 0.271 0.267 0.267 rg BT 388.794 333.515 Td /F1 9.8 Tf [( . All of these clades appear to transmit )] TJ ET BT 26.250 321.610 Td /F1 9.8 Tf [(successfully in humans, as even the smaller clades were isolated from multiple weeks and in more than one country. Although )] TJ ET BT 26.250 309.705 Td /F1 9.8 Tf [(fewer cases of H1N1pdm virus have been reported in Asia )] TJ ET 0.267 0.267 0.267 rg BT 280.940 309.705 Td /F1 9.8 Tf [([1])] TJ ET 0.271 0.267 0.267 rg BT 291.781 309.705 Td /F1 9.8 Tf [( , all 7 clades were detected in at least one Asian country, )] TJ ET BT 26.250 297.801 Td /F1 9.8 Tf [(reflecting the speed and extent of the global dissemination of the H1N1pdm virus.)] TJ ET BT 26.250 261.198 Td /F4 12.0 Tf [(Materials and Methods)] TJ ET BT 26.250 241.244 Td /F1 9.8 Tf [(Sample collection and viral isolation in Wisconsin. Patient specimens were collected at Childrens Hospital of Wisconsin \(CHW\), )] TJ ET BT 26.250 229.339 Td /F1 9.8 Tf [(Dynacare Laboratories \(DL\), and their associated clinics in Milwaukee, Wisconsin. Nasopharyngeal were transported in M4 or )] TJ ET BT 26.250 217.434 Td /F1 9.8 Tf [(M6 viral transport medium \(Remel, Lenexa, KS\) to CHW or DL microbiology laboratories to test for the presence of influenza A, )] TJ ET BT 26.250 205.530 Td /F1 9.8 Tf [(influenza B, or respiratory syncytial virus \(RSV\) using two multiplex real-time RT-PCR assays. The CHW test )] TJ ET 0.267 0.267 0.267 rg BT 497.604 205.530 Td /F1 9.8 Tf [([13])] TJ ET 0.271 0.267 0.267 rg BT 513.867 205.530 Td /F1 9.8 Tf [( utilized an in-)] TJ ET BT 26.250 193.625 Td /F1 9.8 Tf [(house assay with automated extraction and real-time PCR amplification and detection. Influenza A samples were sent to the )] TJ ET BT 26.250 181.720 Td /F1 9.8 Tf [(Midwest Respiratory Virus Program \(MRVP\) laboratory to distinguish between H1N1pdm and seasonal H1N1 and H3N2 )] TJ ET BT 26.250 169.815 Td /F1 9.8 Tf [(influenza A viruses with real-time RT-PCR or an RT-PCR enzyme hybridization assay )] TJ ET 0.267 0.267 0.267 rg BT 397.920 169.815 Td /F1 9.8 Tf [([14])] TJ ET BT 414.183 169.815 Td /F1 9.8 Tf [([15])] TJ ET 0.271 0.267 0.267 rg BT 430.446 169.815 Td /F1 9.8 Tf [( . All clinical specimens were de-)] TJ ET BT 26.250 157.911 Td /F1 9.8 Tf [(identified. H1N1pdm viruses were isolated from clinical specimens by inoculating samples onto Madin-Darby canine kidney )] TJ ET BT 26.250 146.006 Td /F1 9.8 Tf [(\(MDCK\) cells, grown until 95% confluent, and stored at -80C. From a total of ~700 H1N1pdm positive samples collected in )] TJ ET BT 26.250 134.101 Td /F1 9.8 Tf [(Milwaukee beginning April 28, 2009, 90 samples were selected for RNA extraction and genome sequencing: 50 samples were )] TJ ET BT 26.250 122.196 Td /F1 9.8 Tf [(selected from the first week of the outbreak and 10 samples from each of the next four weeks. The samples were distributed )] TJ ET BT 26.250 110.292 Td /F1 9.8 Tf [(relatively evenly by sex and among three age groups: 0 5 years, 5 18 years, and 18+ years.)] TJ ET BT 26.250 90.887 Td /F1 9.8 Tf [(RNA extraction and sequencing of Wisconsin and New York isolates. The extraction of the entire viral RNA genome from )] TJ ET BT 26.250 78.982 Td /F1 9.8 Tf [(isolates from Wisconsin and from clinical samples from New York State was performed at the Wadsworth Center, New York )] TJ ET BT 26.250 67.077 Td /F1 9.8 Tf [(State Department of Health, in Albany, NY, using the NucliSENS easyMAG robot \(bioMrieux, Durham, NC\), RNeasy Kit )] TJ ET BT 26.250 55.173 Td /F1 9.8 Tf [(\(Qiagen, Valencia, CA\) or QIAamp Viral RNA Kit with the QIAcube automated extractor \(Qiagen\). The influenza A genomic RNA )] TJ ET BT 26.250 43.268 Td /F1 9.8 Tf [(segments were simultaneously amplified from 5 uls of purified RNA using a multisegment RT-PCR strategy )] TJ ET 0.267 0.267 0.267 rg BT 490.058 43.268 Td /F1 9.8 Tf [([16])] TJ ET 0.271 0.267 0.267 rg BT 506.320 43.268 Td /F1 9.8 Tf [( . Whole-)] TJ ET Q q 15.000 28.982 577.500 748.018 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F1 9.8 Tf [(identified in the isolates A/Wisconsin/629-D01521/2009 and A/Wisconsin/629-D01705/2009, respectively. The G159E )] TJ ET BT 26.250 755.571 Td /F1 9.8 Tf [(replacement, located within the Sa subsite, was observed in A/Bayern/62/2009. And A/Wisconsin/629-D0223/2009 experienced )] TJ ET BT 26.250 743.667 Td /F1 9.8 Tf [(the N160T replacement, located within the Sb subsite.)] TJ ET BT 26.250 724.262 Td /F4 9.8 Tf [(Table 1)] TJ ET q 225.000 0 0 93.000 26.250 621.381 cm /I32 Do Q BT 26.250 604.357 Td /F4 9.8 Tf [(Table 1.)] TJ ET BT 62.559 604.357 Td /F1 9.8 Tf [( Amino acid changes defining clades 1-7, identified using the MacClade program \(30\). The asterisk \(*\) denotes changes )] TJ ET BT 26.250 592.452 Td /F1 9.8 Tf [(that are present in a majority, but not all of the isolates from a clade.)] TJ ET BT 26.250 555.850 Td /F4 12.0 Tf [(Discussion)] TJ ET BT 26.250 535.896 Td /F1 9.8 Tf [(Our whole-genome phylogenetic analysis of 290 H1N1pdm isolates collected globally, including the intensively sampled )] TJ ET BT 26.250 523.991 Td /F1 9.8 Tf [(populations in Wisconsin and New York, reveals at least 7 major clades of the H1N1pdm influenza virus that have co-circulated )] TJ ET BT 26.250 512.086 Td /F1 9.8 Tf [(over time and space since April 2009. Clearly, the evolution and spatial-temporal dynamics of the H1N1pdm virus are more )] TJ ET BT 26.250 500.181 Td /F1 9.8 Tf [(complex than the global dissemination of a single viral lineage. The TMRCA estimates suggest that the 7 major clades emerged )] TJ ET BT 26.250 488.277 Td /F1 9.8 Tf [(between mid-February and late April of 2009, with clades 1, 2, and 3 appearing between mid-February and mid-March, and )] TJ ET BT 26.250 476.372 Td /F1 9.8 Tf [(clades 5, 6, and 7 emerging between mid-March and mid-April. The global origins of clade 4 from Asia remain unclear. Our )] TJ ET BT 26.250 464.467 Td /F1 9.8 Tf [(estimate for the TMRCA of the entire H1N1pdm viral population ranges from late January early March, and is consistent with )] TJ ET BT 26.250 452.562 Td /F1 9.8 Tf [(previous estimates )] TJ ET 0.267 0.267 0.267 rg BT 110.237 452.562 Td /F1 9.8 Tf [([11])] TJ ET 0.271 0.267 0.267 rg BT 126.500 452.562 Td /F1 9.8 Tf [( . All of these clades circulated for at least two weeks prior to detection in this study, most likely in )] TJ ET BT 26.250 440.658 Td /F1 9.8 Tf [(Mexico and perhaps elsewhere as well. Due to the co-circulation of these lineages, epidemics in discrete localities involve )] TJ ET BT 26.250 428.753 Td /F1 9.8 Tf [(multiple introductions of genetically distinct H1N1pdm viruses. However, in locations that are more extensively sampled, such )] TJ ET BT 26.250 416.848 Td /F1 9.8 Tf [(as Wisconsin and New York, a single clade dominated. It was unexpected that different clades would predominate in Wisconsin )] TJ ET BT 26.250 404.943 Td /F1 9.8 Tf [(and New York, given the similar timing of their outbreaks and presumed population movements, and suggests that founder )] TJ ET BT 26.250 393.039 Td /F1 9.8 Tf [(effects are strong. Such clear spatial patterns have not been observed previously with seasonal influenza, although sampling )] TJ ET BT 26.250 381.134 Td /F1 9.8 Tf [(has not been as intensive )] TJ ET 0.267 0.267 0.267 rg BT 139.525 381.134 Td /F1 9.8 Tf [([12])] TJ ET 0.271 0.267 0.267 rg BT 155.788 381.134 Td /F1 9.8 Tf [( . As viral sequence data becomes available from additional localities, it will be possible to )] TJ ET BT 26.250 369.229 Td /F1 9.8 Tf [(compare the dominant H1N1pdm lineages in other localities and to better understand the spatial movements of the H1N1pdm )] TJ ET BT 26.250 357.324 Td /F1 9.8 Tf [(virus. It is unclear whether differences in fitness or clinical severity exist among these co-circulating lineages, particularly for )] TJ ET BT 26.250 345.420 Td /F1 9.8 Tf [(clade 7, which was the most commonly detected clade here. We did not observe any significant differences in age distribution )] TJ ET BT 26.250 333.515 Td /F1 9.8 Tf [(among these clades or any fixed amino acid changes likely to impact fitness )] TJ ET 0.267 0.267 0.267 rg BT 356.268 333.515 Td /F1 9.8 Tf [([7])] TJ ET BT 367.110 333.515 Td /F1 9.8 Tf [([8])] TJ ET BT 377.952 333.515 Td /F1 9.8 Tf [([9])] TJ ET 0.271 0.267 0.267 rg BT 388.794 333.515 Td /F1 9.8 Tf [( . All of these clades appear to transmit )] TJ ET BT 26.250 321.610 Td /F1 9.8 Tf [(successfully in humans, as even the smaller clades were isolated from multiple weeks and in more than one country. Although )] TJ ET BT 26.250 309.705 Td /F1 9.8 Tf [(fewer cases of H1N1pdm virus have been reported in Asia )] TJ ET 0.267 0.267 0.267 rg BT 280.940 309.705 Td /F1 9.8 Tf [([1])] TJ ET 0.271 0.267 0.267 rg BT 291.781 309.705 Td /F1 9.8 Tf [( , all 7 clades were detected in at least one Asian country, )] TJ ET BT 26.250 297.801 Td /F1 9.8 Tf [(reflecting the speed and extent of the global dissemination of the H1N1pdm virus.)] TJ ET BT 26.250 261.198 Td /F4 12.0 Tf [(Materials and Methods)] TJ ET BT 26.250 241.244 Td /F1 9.8 Tf [(Sample collection and viral isolation in Wisconsin. Patient specimens were collected at Childrens Hospital of Wisconsin \(CHW\), )] TJ ET BT 26.250 229.339 Td /F1 9.8 Tf [(Dynacare Laboratories \(DL\), and their associated clinics in Milwaukee, Wisconsin. Nasopharyngeal were transported in M4 or )] TJ ET BT 26.250 217.434 Td /F1 9.8 Tf [(M6 viral transport medium \(Remel, Lenexa, KS\) to CHW or DL microbiology laboratories to test for the presence of influenza A, )] TJ ET BT 26.250 205.530 Td /F1 9.8 Tf [(influenza B, or respiratory syncytial virus \(RSV\) using two multiplex real-time RT-PCR assays. The CHW test )] TJ ET 0.267 0.267 0.267 rg BT 497.604 205.530 Td /F1 9.8 Tf [([13])] TJ ET 0.271 0.267 0.267 rg BT 513.867 205.530 Td /F1 9.8 Tf [( utilized an in-)] TJ ET BT 26.250 193.625 Td /F1 9.8 Tf [(house assay with automated extraction and real-time PCR amplification and detection. Influenza A samples were sent to the )] TJ ET BT 26.250 181.720 Td /F1 9.8 Tf [(Midwest Respiratory Virus Program \(MRVP\) laboratory to distinguish between H1N1pdm and seasonal H1N1 and H3N2 )] TJ ET BT 26.250 169.815 Td /F1 9.8 Tf [(influenza A viruses with real-time RT-PCR or an RT-PCR enzyme hybridization assay )] TJ ET 0.267 0.267 0.267 rg BT 397.920 169.815 Td /F1 9.8 Tf [([14])] TJ ET BT 414.183 169.815 Td /F1 9.8 Tf [([15])] TJ ET 0.271 0.267 0.267 rg BT 430.446 169.815 Td /F1 9.8 Tf [( . All clinical specimens were de-)] TJ ET BT 26.250 157.911 Td /F1 9.8 Tf [(identified. H1N1pdm viruses were isolated from clinical specimens by inoculating samples onto Madin-Darby canine kidney )] TJ ET BT 26.250 146.006 Td /F1 9.8 Tf [(\(MDCK\) cells, grown until 95% confluent, and stored at -80C. From a total of ~700 H1N1pdm positive samples collected in )] TJ ET BT 26.250 134.101 Td /F1 9.8 Tf [(Milwaukee beginning April 28, 2009, 90 samples were selected for RNA extraction and genome sequencing: 50 samples were )] TJ ET BT 26.250 122.196 Td /F1 9.8 Tf [(selected from the first week of the outbreak and 10 samples from each of the next four weeks. The samples were distributed )] TJ ET BT 26.250 110.292 Td /F1 9.8 Tf [(relatively evenly by sex and among three age groups: 0 5 years, 5 18 years, and 18+ years.)] TJ ET BT 26.250 90.887 Td /F1 9.8 Tf [(RNA extraction and sequencing of Wisconsin and New York isolates. The extraction of the entire viral RNA genome from )] TJ ET BT 26.250 78.982 Td /F1 9.8 Tf [(isolates from Wisconsin and from clinical samples from New York State was performed at the Wadsworth Center, New York )] TJ ET BT 26.250 67.077 Td /F1 9.8 Tf [(State Department of Health, in Albany, NY, using the NucliSENS easyMAG robot \(bioMrieux, Durham, NC\), RNeasy Kit )] TJ ET BT 26.250 55.173 Td /F1 9.8 Tf [(\(Qiagen, Valencia, CA\) or QIAamp Viral RNA Kit with the QIAcube automated extractor \(Qiagen\). The influenza A genomic RNA )] TJ ET BT 26.250 43.268 Td /F1 9.8 Tf [(segments were simultaneously amplified from 5 uls of purified RNA using a multisegment RT-PCR strategy )] TJ ET 0.267 0.267 0.267 rg BT 490.058 43.268 Td /F1 9.8 Tf [([16])] TJ ET 0.271 0.267 0.267 rg BT 506.320 43.268 Td /F1 9.8 Tf [( . 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J׬^+0+ߟM_a;vzڴn-[nݺuK/NGCT$(}ZpM9K_| >DGG[[[B7ceIPPJ287\K^)˕&2\R'B%ԩQ(F&}>:E/FJBA_nnД"wuMp "]8T*o!‚@hXpe%L-24,PDr~i^Ǐ{-@rO 2SU%,%1FBAes/uŋ,:'zn= < 㓙y ~Fyy90%%%aJPƍW(G=w<˲+..NMM]LW^:wnnQ(AAA ð,{…ߏ)---,,=!!~Q={(++ ѝwsss-YrަM>>G^z^^۷o߹aUW+%?̝0+''V͚9m-ZdffF|* ʃ/<(//_jվ3::eee~~~n#Fl޼ ݡ⛨ o^̛;M6SLn֬f.x#˄/P]b,D!PICQԫ[sdΝ;̞5gE+WnղRw6ݻ7o޼ظJNNN6$B_#n޺Ų_*J7{yd2eCBB\ڥKzzzttt~F:8`"4a9s 5`Ҥ,˾xGVV6m߼y6bD_Z5k=mSbL0KԪYeٵWlѢ^*ؾUVH$ݺu}*&&fX$/ZsQv>g 5 o \Z,=+ yau!춹t^!efVց}}/,(߿'MʲlPPЩ3g~۹30q%S,ͅIq[_.eUJDbt֍OcjrsBCC5sH$vEŜDRqMd&xqswfڔĄozSˍaJe6gF7mܰ~FܲuO&t,Z+UVFȡ*h}%DAqP@' JZdи8̌_/OJN 077p/(Ubcc###o4֭[]v۷OaA;f9sǍYvٳ/]]V˖-N:u߻u늂CYuOr׮]9r[4lݻ|hڤ QFzGDիcǎ62jժFFu&%&tUTV)vaNNNuءo\JU:88TT@Q0iV-[կ_w^T^YG(o!Z_֩Snݺ͚5㐥Ri*UԮ 061=jTΝ#?Gh޼k.ժU^7vv666؞Mj,.T*^zN|Jll +;99::i&""b̙[5lضm,Tccي}+e^(䤫ZQT~\u B3Ԙo;@ `Q8/AS5g7*;Y^B\*Dӑ!oCB>Zk΁TfFH3GXQD"X$D蜱SxQdD;lo n 5} ΀nlT܈*)/Xc]TFFjd_™hXtَB<~dR;@Oi'jco^t@\z'ӧI'.qwW؁5pI[[A.ZDT:tmۣd2L&۲ݻG̚9^/(mzHc1 @c7ȐPX_tdaKĺӔ3]IqIeyyaaQVV9s~?|а0|EFFe˞ԫ#71[%("ދrRkVCKEllL& N_D199zDO' =?! vKQ3)Cdz̙>p 5 r6ol8p.Zp=/UD"Sj  B!{G򿁳vB9 9i?$R1wI[E3 K1Z)4HN5BK67zPcS9CPw(s( ~Kߍ?Fh+,a,&B(x%:fpH] r毢)Τ> endobj 325 0 obj << /Type /Action >> endobj 326 0 obj << /Type /Annot /Subtype /Link /A 327 0 R /Border [0 0 0] /H /I /Rect [ 139.5255 380.2321 155.7885 390.1527 ] >> endobj 327 0 obj << /Type /Action >> endobj 328 0 obj << /Type /Annot /Subtype /Link /A 329 0 R /Border [0 0 0] /H /I /Rect [ 356.2680 332.6131 367.1100 342.5337 ] >> endobj 329 0 obj << /Type /Action >> endobj 330 0 obj << /Type /Annot /Subtype /Link /A 331 0 R /Border [0 0 0] /H /I /Rect [ 367.1100 332.6131 377.9520 342.5337 ] >> endobj 331 0 obj << /Type /Action >> endobj 332 0 obj << /Type /Annot /Subtype /Link /A 333 0 R /Border [0 0 0] /H /I /Rect [ 377.9520 332.6131 388.7940 342.5337 ] >> endobj 333 0 obj << /Type /Action >> endobj 334 0 obj << /Type /Annot /Subtype /Link /A 335 0 R /Border [0 0 0] /H /I /Rect [ 280.9395 308.8036 291.7815 318.7242 ] >> endobj 335 0 obj << /Type /Action >> endobj 336 0 obj << /Type /Annot /Subtype /Link /A 337 0 R /Border [0 0 0] /H /I /Rect [ 497.6040 204.6278 513.8670 214.5485 ] >> endobj 337 0 obj << /Type /Action >> endobj 338 0 obj << /Type /Annot /Subtype /Link /A 339 0 R /Border [0 0 0] /H /I /Rect [ 397.9200 168.9136 414.1830 178.8342 ] >> endobj 339 0 obj << /Type /Action >> endobj 340 0 obj << /Type /Annot /Subtype /Link /A 341 0 R /Border [0 0 0] /H /I /Rect [ 414.1830 168.9136 430.4460 178.8342 ] >> endobj 341 0 obj << /Type /Action >> endobj 342 0 obj << /Type /Annot /Subtype /Link /A 343 0 R /Border [0 0 0] /H /I /Rect [ 490.0575 42.3661 506.3205 52.2867 ] >> endobj 343 0 obj << /Type /Action >> endobj 344 0 obj << /Type /Page /Parent 3 0 R /Annots [ 346 0 R 348 0 R 350 0 R 352 0 R 354 0 R 356 0 R 358 0 R 360 0 R 362 0 R 364 0 R 366 0 R 368 0 R 370 0 R 372 0 R 374 0 R 376 0 R 378 0 R 380 0 R 382 0 R 384 0 R 386 0 R 388 0 R 390 0 R 392 0 R 394 0 R 396 0 R 398 0 R 400 0 R 402 0 R 404 0 R 406 0 R 408 0 R 410 0 R 412 0 R 414 0 R 416 0 R 418 0 R 420 0 R 422 0 R ] /Contents 345 0 R >> endobj 345 0 obj << /Length 27808 >> stream 0.271 0.267 0.267 rg q 15.000 55.178 577.500 721.822 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F1 9.8 Tf [(genome sequencing was performed at the J. Craig Venter Institute \(JCVI\) in Rockville, MD. Oligonucleotide primers were )] TJ ET BT 26.250 755.571 Td /F1 9.8 Tf [(designed using a computational PCR primer design pipeline developed at JCVI )] TJ ET 0.267 0.267 0.267 rg BT 369.820 755.571 Td /F1 9.8 Tf [([17])] TJ ET 0.271 0.267 0.267 rg BT 386.083 755.571 Td /F1 9.8 Tf [( . Tiled amplicons were designed to have an )] TJ ET BT 26.250 743.667 Td /F1 9.8 Tf [(optimal size of 550 bp with 100 bp overlap in order to provide six fold sequence coverage of the influenza genome. Influenza )] TJ ET BT 26.250 731.762 Td /F1 9.8 Tf [(segment DNA was amplified using Accuprime Taq at 35 cycles \(denaturation: 0.5 min., 94C; annealing: 0.5 min., 55C; )] TJ ET BT 26.250 719.857 Td /F1 9.8 Tf [(extension: 2 min., 68C\) and amplicons were treated with Shrimp Alkaline Phosphatase and Exonuclease I. Sequencing, )] TJ ET BT 26.250 707.952 Td /F1 9.8 Tf [(genome assembly, and closure reactions were performed as described previously )] TJ ET 0.267 0.267 0.267 rg BT 381.716 707.952 Td /F1 9.8 Tf [([18])] TJ ET 0.271 0.267 0.267 rg BT 397.978 707.952 Td /F1 9.8 Tf [( . All genome sequences were submitted )] TJ ET BT 26.250 696.048 Td /F1 9.8 Tf [(to GenBank.)] TJ ET BT 26.250 676.643 Td /F1 9.8 Tf [(Phylogenetic analysis. The sequence data used in this study came from 81 H1N1pdm isolates collected from Wisconsin )] TJ ET BT 26.250 664.738 Td /F1 9.8 Tf [(between April 28, 2009 May 30, 2009 and 209 H1N1pdm isolates that were collected globally between April 1, 2009 July 9, )] TJ ET BT 26.250 652.833 Td /F1 9.8 Tf [(2009, which were downloaded from the National Center for Biotechnology \(NCBI\) Influenza Virus Resource \( )] TJ ET 0.267 0.267 0.267 rg BT 26.250 640.929 Td /F1 9.8 Tf [(http://www.ncbi.nlm.nih.gov/genomes/FLU/FLU.html)] TJ ET 0.271 0.267 0.267 rg BT 251.114 640.929 Td /F1 9.8 Tf [( \) available on GenBank )] TJ ET 0.267 0.267 0.267 rg BT 357.877 640.929 Td /F1 9.8 Tf [([19])] TJ ET 0.271 0.267 0.267 rg BT 374.140 640.929 Td /F1 9.8 Tf [( . Only isolates for which whole-genome )] TJ ET BT 26.250 629.024 Td /F1 9.8 Tf [(sequences and exact date of collection were available were used \(Table S1\). Nucleotide alignments were manually constructed )] TJ ET BT 26.250 617.119 Td /F1 9.8 Tf [(for the coding regions of the eight genome segments of each isolate using the Se-Al program )] TJ ET 0.267 0.267 0.267 rg BT 429.998 617.119 Td /F1 9.8 Tf [([20])] TJ ET 0.271 0.267 0.267 rg BT 446.260 617.119 Td /F1 9.8 Tf [( . To maximize phylogenetic )] TJ ET BT 26.250 605.214 Td /F1 9.8 Tf [(resolution, and given no evidence of genomic reassortment, the eight segments were concatenated. To infer the evolutionary )] TJ ET BT 26.250 593.310 Td /F1 9.8 Tf [(relationships and timescale for the complete H1N1pdm data set analyzed here, we employed a Bayesian Markov chain Monte )] TJ ET BT 26.250 581.405 Td /F1 9.8 Tf [(Carlo \(MCMC\) method using a strict molecular clock, as implemented in the BEAST program \(version 1.4.8\) )] TJ ET 0.267 0.267 0.267 rg BT 493.841 581.405 Td /F1 9.8 Tf [([4])] TJ ET 0.271 0.267 0.267 rg BT 504.683 581.405 Td /F1 9.8 Tf [( . Use of a strict )] TJ ET BT 26.250 569.500 Td /F1 9.8 Tf [(molecular clock facilitates computational tractability and is justified here given the strong clock-like evolution of the influenza A )] TJ ET BT 26.250 557.595 Td /F1 9.8 Tf [(virus. This analysis incorporated a GTR+?4 model of nucleotide substitution, with a different substitution rate estimated for each )] TJ ET BT 26.250 545.691 Td /F1 9.8 Tf [(codon position, and a Bayesian skyline coalescent prior, with the latter clearly the best descriptor of the complex population )] TJ ET BT 26.250 533.786 Td /F1 9.8 Tf [(dynamics of influenza virus. Due to the large size of this data set, we used a UPGMA starting tree and ran a chain length of 500 )] TJ ET BT 26.250 521.881 Td /F1 9.8 Tf [(million \(sampling trees every 50,000 generations\), until convergence was reached. The Maximum Clade Credibility \(MCC\) tree )] TJ ET BT 26.250 509.976 Td /F1 9.8 Tf [(generated by BEAST was analyzed using TreeAnnotator \(v1.4.8, available at http://beast.bio.ed.ac.uk\) after a 10% burn-in. )] TJ ET BT 26.250 498.072 Td /F1 9.8 Tf [(Statistical uncertainly is reflected in values of the 95% Highest Probability Density \(HPD\). The tree was visualized using FigTree )] TJ ET BT 26.250 486.167 Td /F1 9.8 Tf [(\(v1.2.3, available at )] TJ ET 0.267 0.267 0.267 rg BT 113.503 486.167 Td /F1 9.8 Tf [(http://beast.bio.ed.ac.uk)] TJ ET 0.271 0.267 0.267 rg BT 217.028 486.167 Td /F1 9.8 Tf [( \), where individual clades supported by high Bayesian posterior probabilities \(BPP )] TJ ET BT 26.250 474.262 Td /F1 9.8 Tf [(> 90%\) and long branch lengths were identified. To further assess the reliability of our phylogenetic inferences, two additional )] TJ ET BT 26.250 462.357 Td /F1 9.8 Tf [(trees were estimated \(Figs. S2 and S3\). First, a consensus phylogenetic tree was inferred using the Bayesian approach )] TJ ET BT 26.250 450.453 Td /F1 9.8 Tf [(available in MrBayes program )] TJ ET 0.267 0.267 0.267 rg BT 157.914 450.453 Td /F1 9.8 Tf [([5])] TJ ET 0.271 0.267 0.267 rg BT 168.756 450.453 Td /F1 9.8 Tf [( , employing the GTR+I+?4 model of nucleotide substitution, as determined by MODELTEST )] TJ ET 0.267 0.267 0.267 rg BT 26.250 438.548 Td /F1 9.8 Tf [([21])] TJ ET 0.271 0.267 0.267 rg BT 42.513 438.548 Td /F1 9.8 Tf [( and run for a total of 5.5 x 106 generations, sampling every 1000. In contrast to the MCC tree generated by BEAST, this )] TJ ET BT 26.250 426.643 Td /F1 9.8 Tf [(analysis did not assume a strict molecular clock. Second, we employed the maximum likelihood \(ML\) method available in the )] TJ ET BT 26.250 414.738 Td /F1 9.8 Tf [(PAUP* package )] TJ ET 0.267 0.267 0.267 rg BT 98.868 414.738 Td /F1 9.8 Tf [([6])] TJ ET 0.271 0.267 0.267 rg BT 109.710 414.738 Td /F1 9.8 Tf [( . Because of the very large size of the data set available, this analysis was restricted to Nearest Neighbor-)] TJ ET BT 26.250 402.834 Td /F1 9.8 Tf [(Interchange \(NNI\) branch-swapping. In this case a bootstrap resampling process \(1,000 replications\) using the neighbor-joining )] TJ ET BT 26.250 390.929 Td /F1 9.8 Tf [(\(NJ\) method was also undertaken, incorporating the ML substitution model. Both the MrBayes and PAUP* analyses produced )] TJ ET BT 26.250 379.024 Td /F1 9.8 Tf [(phylogenies similar, although less well supported, tree topologies to that obtained using BEAST. Amino acid changes were )] TJ ET BT 26.250 367.119 Td /F1 9.8 Tf [(identified using the MacClade program )] TJ ET 0.267 0.267 0.267 rg BT 195.861 367.119 Td /F1 9.8 Tf [([22])] TJ ET 0.271 0.267 0.267 rg BT 212.124 367.119 Td /F1 9.8 Tf [( , with the four antigenic sites \(designated Sa, Sb, Ca1/Ca2, and Cb\) those identified )] TJ ET BT 26.250 355.215 Td /F1 9.8 Tf [(on the A/PR/8/34\(H1N1\) virus )] TJ ET 0.267 0.267 0.267 rg BT 157.924 355.215 Td /F1 9.8 Tf [([7])] TJ ET 0.271 0.267 0.267 rg BT 168.766 355.215 Td /F1 9.8 Tf [( and converted into H3 numbering )] TJ ET 0.267 0.267 0.267 rg BT 318.341 355.215 Td /F1 9.8 Tf [([10])] TJ ET 0.271 0.267 0.267 rg BT 334.603 355.215 Td /F1 9.8 Tf [( . The isolates with the most basal position on the )] TJ ET BT 26.250 343.310 Td /F1 9.8 Tf [(phylogenetic tree \(e.g., A/Mexico/4603/2009\(H1N1\)\), not located within any clade, were used as a basis for comparison.)] TJ ET BT 26.250 306.707 Td /F4 12.0 Tf [(Acknowledgements)] TJ ET BT 26.250 286.753 Td /F1 9.8 Tf [(We would like to thank Drs. Sue Kehl, Nate Ledeboer, Ruoyan Chen, Jessica Trost, Teresa Patitucci, Lorraine Witt, Meredith )] TJ ET BT 26.250 274.848 Td /F1 9.8 Tf [(VanDyke, Elizabeth Davis, and Kate Gaffney from the MRVP and Medical College of Wisconsin, and Gerardo Chowell from )] TJ ET BT 26.250 262.944 Td /F1 9.8 Tf [(Arizona State University for their help in this study. We are also greatly indebted to all those who submitted H1N1pdm )] TJ ET BT 26.250 251.039 Td /F1 9.8 Tf [(sequences to GenBanks Influenza Virus Resource. The Madin-Darby canine kidney \(MDCK\) cells used for viral isolation were )] TJ ET BT 26.250 239.134 Td /F1 9.8 Tf [(kindly provided by Dr. Xiyang Xu at the Centers for Disease Control and Prevention \(Atlanta, GA\).)] TJ ET BT 26.250 202.532 Td /F4 12.0 Tf [(Funding Information)] TJ ET BT 26.250 182.577 Td /F1 9.8 Tf [(This project has been funded in part with federal funds from the National Institute of Allergy and Infectious Diseases \(NIAID\), )] TJ ET BT 26.250 170.673 Td /F1 9.8 Tf [(National Institutes of Health, Department of Health and Human Services under contract number HHSN272200900007C and by )] TJ ET BT 26.250 158.768 Td /F1 9.8 Tf [(NIAID grants UO1-AI070428, U01-387 AI077988, and U01-AI066584.)] TJ ET BT 26.250 122.165 Td /F4 12.0 Tf [(Competing Interests)] TJ ET BT 26.250 102.211 Td /F1 9.8 Tf [(The authors have declared that no competing interests exist.)] TJ ET BT 26.250 65.609 Td /F4 12.0 Tf [(References)] TJ ET Q q 15.000 55.178 577.500 721.822 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F1 9.8 Tf [(genome sequencing was performed at the J. Craig Venter Institute \(JCVI\) in Rockville, MD. Oligonucleotide primers were )] TJ ET BT 26.250 755.571 Td /F1 9.8 Tf [(designed using a computational PCR primer design pipeline developed at JCVI )] TJ ET 0.267 0.267 0.267 rg BT 369.820 755.571 Td /F1 9.8 Tf [([17])] TJ ET 0.271 0.267 0.267 rg BT 386.083 755.571 Td /F1 9.8 Tf [( . Tiled amplicons were designed to have an )] TJ ET BT 26.250 743.667 Td /F1 9.8 Tf [(optimal size of 550 bp with 100 bp overlap in order to provide six fold sequence coverage of the influenza genome. Influenza )] TJ ET BT 26.250 731.762 Td /F1 9.8 Tf [(segment DNA was amplified using Accuprime Taq at 35 cycles \(denaturation: 0.5 min., 94C; annealing: 0.5 min., 55C; )] TJ ET BT 26.250 719.857 Td /F1 9.8 Tf [(extension: 2 min., 68C\) and amplicons were treated with Shrimp Alkaline Phosphatase and Exonuclease I. Sequencing, )] TJ ET BT 26.250 707.952 Td /F1 9.8 Tf [(genome assembly, and closure reactions were performed as described previously )] TJ ET 0.267 0.267 0.267 rg BT 381.716 707.952 Td /F1 9.8 Tf [([18])] TJ ET 0.271 0.267 0.267 rg BT 397.978 707.952 Td /F1 9.8 Tf [( . All genome sequences were submitted )] TJ ET BT 26.250 696.048 Td /F1 9.8 Tf [(to GenBank.)] TJ ET BT 26.250 676.643 Td /F1 9.8 Tf [(Phylogenetic analysis. The sequence data used in this study came from 81 H1N1pdm isolates collected from Wisconsin )] TJ ET BT 26.250 664.738 Td /F1 9.8 Tf [(between April 28, 2009 May 30, 2009 and 209 H1N1pdm isolates that were collected globally between April 1, 2009 July 9, )] TJ ET BT 26.250 652.833 Td /F1 9.8 Tf [(2009, which were downloaded from the National Center for Biotechnology \(NCBI\) Influenza Virus Resource \( )] TJ ET 0.267 0.267 0.267 rg BT 26.250 640.929 Td /F1 9.8 Tf [(http://www.ncbi.nlm.nih.gov/genomes/FLU/FLU.html)] TJ ET 0.271 0.267 0.267 rg BT 251.114 640.929 Td /F1 9.8 Tf [( \) available on GenBank )] TJ ET 0.267 0.267 0.267 rg BT 357.877 640.929 Td /F1 9.8 Tf [([19])] TJ ET 0.271 0.267 0.267 rg BT 374.140 640.929 Td /F1 9.8 Tf [( . Only isolates for which whole-genome )] TJ ET BT 26.250 629.024 Td /F1 9.8 Tf [(sequences and exact date of collection were available were used \(Table S1\). Nucleotide alignments were manually constructed )] TJ ET BT 26.250 617.119 Td /F1 9.8 Tf [(for the coding regions of the eight genome segments of each isolate using the Se-Al program )] TJ ET 0.267 0.267 0.267 rg BT 429.998 617.119 Td /F1 9.8 Tf [([20])] TJ ET 0.271 0.267 0.267 rg BT 446.260 617.119 Td /F1 9.8 Tf [( . To maximize phylogenetic )] TJ ET BT 26.250 605.214 Td /F1 9.8 Tf [(resolution, and given no evidence of genomic reassortment, the eight segments were concatenated. To infer the evolutionary )] TJ ET BT 26.250 593.310 Td /F1 9.8 Tf [(relationships and timescale for the complete H1N1pdm data set analyzed here, we employed a Bayesian Markov chain Monte )] TJ ET BT 26.250 581.405 Td /F1 9.8 Tf [(Carlo \(MCMC\) method using a strict molecular clock, as implemented in the BEAST program \(version 1.4.8\) )] TJ ET 0.267 0.267 0.267 rg BT 493.841 581.405 Td /F1 9.8 Tf [([4])] TJ ET 0.271 0.267 0.267 rg BT 504.683 581.405 Td /F1 9.8 Tf [( . Use of a strict )] TJ ET BT 26.250 569.500 Td /F1 9.8 Tf [(molecular clock facilitates computational tractability and is justified here given the strong clock-like evolution of the influenza A )] TJ ET BT 26.250 557.595 Td /F1 9.8 Tf [(virus. This analysis incorporated a GTR+?4 model of nucleotide substitution, with a different substitution rate estimated for each )] TJ ET BT 26.250 545.691 Td /F1 9.8 Tf [(codon position, and a Bayesian skyline coalescent prior, with the latter clearly the best descriptor of the complex population )] TJ ET BT 26.250 533.786 Td /F1 9.8 Tf [(dynamics of influenza virus. Due to the large size of this data set, we used a UPGMA starting tree and ran a chain length of 500 )] TJ ET BT 26.250 521.881 Td /F1 9.8 Tf [(million \(sampling trees every 50,000 generations\), until convergence was reached. The Maximum Clade Credibility \(MCC\) tree )] TJ ET BT 26.250 509.976 Td /F1 9.8 Tf [(generated by BEAST was analyzed using TreeAnnotator \(v1.4.8, available at http://beast.bio.ed.ac.uk\) after a 10% burn-in. )] TJ ET BT 26.250 498.072 Td /F1 9.8 Tf [(Statistical uncertainly is reflected in values of the 95% Highest Probability Density \(HPD\). The tree was visualized using FigTree )] TJ ET BT 26.250 486.167 Td /F1 9.8 Tf [(\(v1.2.3, available at )] TJ ET 0.267 0.267 0.267 rg BT 113.503 486.167 Td /F1 9.8 Tf [(http://beast.bio.ed.ac.uk)] TJ ET 0.271 0.267 0.267 rg BT 217.028 486.167 Td /F1 9.8 Tf [( \), where individual clades supported by high Bayesian posterior probabilities \(BPP )] TJ ET BT 26.250 474.262 Td /F1 9.8 Tf [(> 90%\) and long branch lengths were identified. To further assess the reliability of our phylogenetic inferences, two additional )] TJ ET BT 26.250 462.357 Td /F1 9.8 Tf [(trees were estimated \(Figs. S2 and S3\). First, a consensus phylogenetic tree was inferred using the Bayesian approach )] TJ ET BT 26.250 450.453 Td /F1 9.8 Tf [(available in MrBayes program )] TJ ET 0.267 0.267 0.267 rg BT 157.914 450.453 Td /F1 9.8 Tf [([5])] TJ ET 0.271 0.267 0.267 rg BT 168.756 450.453 Td /F1 9.8 Tf [( , employing the GTR+I+?4 model of nucleotide substitution, as determined by MODELTEST )] TJ ET 0.267 0.267 0.267 rg BT 26.250 438.548 Td /F1 9.8 Tf [([21])] TJ ET 0.271 0.267 0.267 rg BT 42.513 438.548 Td /F1 9.8 Tf [( and run for a total of 5.5 x 106 generations, sampling every 1000. In contrast to the MCC tree generated by BEAST, this )] TJ ET BT 26.250 426.643 Td /F1 9.8 Tf [(analysis did not assume a strict molecular clock. Second, we employed the maximum likelihood \(ML\) method available in the )] TJ ET BT 26.250 414.738 Td /F1 9.8 Tf [(PAUP* package )] TJ ET 0.267 0.267 0.267 rg BT 98.868 414.738 Td /F1 9.8 Tf [([6])] TJ ET 0.271 0.267 0.267 rg BT 109.710 414.738 Td /F1 9.8 Tf [( . Because of the very large size of the data set available, this analysis was restricted to Nearest Neighbor-)] TJ ET BT 26.250 402.834 Td /F1 9.8 Tf [(Interchange \(NNI\) branch-swapping. In this case a bootstrap resampling process \(1,000 replications\) using the neighbor-joining )] TJ ET BT 26.250 390.929 Td /F1 9.8 Tf [(\(NJ\) method was also undertaken, incorporating the ML substitution model. Both the MrBayes and PAUP* analyses produced )] TJ ET BT 26.250 379.024 Td /F1 9.8 Tf [(phylogenies similar, although less well supported, tree topologies to that obtained using BEAST. Amino acid changes were )] TJ ET BT 26.250 367.119 Td /F1 9.8 Tf [(identified using the MacClade program )] TJ ET 0.267 0.267 0.267 rg BT 195.861 367.119 Td /F1 9.8 Tf [([22])] TJ ET 0.271 0.267 0.267 rg BT 212.124 367.119 Td /F1 9.8 Tf [( , with the four antigenic sites \(designated Sa, Sb, Ca1/Ca2, and Cb\) those identified )] TJ ET BT 26.250 355.215 Td /F1 9.8 Tf [(on the A/PR/8/34\(H1N1\) virus )] TJ ET 0.267 0.267 0.267 rg BT 157.924 355.215 Td /F1 9.8 Tf [([7])] TJ ET 0.271 0.267 0.267 rg BT 168.766 355.215 Td /F1 9.8 Tf [( and converted into H3 numbering )] TJ ET 0.267 0.267 0.267 rg BT 318.341 355.215 Td /F1 9.8 Tf [([10])] TJ ET 0.271 0.267 0.267 rg BT 334.603 355.215 Td /F1 9.8 Tf [( . The isolates with the most basal position on the )] TJ ET BT 26.250 343.310 Td /F1 9.8 Tf [(phylogenetic tree \(e.g., A/Mexico/4603/2009\(H1N1\)\), not located within any clade, were used as a basis for comparison.)] TJ ET BT 26.250 306.707 Td /F4 12.0 Tf [(Acknowledgements)] TJ ET BT 26.250 286.753 Td /F1 9.8 Tf [(We would like to thank Drs. Sue Kehl, Nate Ledeboer, Ruoyan Chen, Jessica Trost, Teresa Patitucci, Lorraine Witt, Meredith )] TJ ET BT 26.250 274.848 Td /F1 9.8 Tf [(VanDyke, Elizabeth Davis, and Kate Gaffney from the MRVP and Medical College of Wisconsin, and Gerardo Chowell from )] TJ ET BT 26.250 262.944 Td /F1 9.8 Tf [(Arizona State University for their help in this study. We are also greatly indebted to all those who submitted H1N1pdm )] TJ ET BT 26.250 251.039 Td /F1 9.8 Tf [(sequences to GenBanks Influenza Virus Resource. The Madin-Darby canine kidney \(MDCK\) cells used for viral isolation were )] TJ ET BT 26.250 239.134 Td /F1 9.8 Tf [(kindly provided by Dr. Xiyang Xu at the Centers for Disease Control and Prevention \(Atlanta, GA\).)] TJ ET BT 26.250 202.532 Td /F4 12.0 Tf [(Funding Information)] TJ ET BT 26.250 182.577 Td /F1 9.8 Tf [(This project has been funded in part with federal funds from the National Institute of Allergy and Infectious Diseases \(NIAID\), )] TJ ET BT 26.250 170.673 Td /F1 9.8 Tf [(National Institutes of Health, Department of Health and Human Services under contract number HHSN272200900007C and by )] TJ ET BT 26.250 158.768 Td /F1 9.8 Tf [(NIAID grants UO1-AI070428, U01-387 AI077988, and U01-AI066584.)] TJ ET BT 26.250 122.165 Td /F4 12.0 Tf [(Competing Interests)] TJ ET BT 26.250 102.211 Td /F1 9.8 Tf [(The authors have declared that no competing interests exist.)] TJ ET BT 26.250 65.609 Td /F4 12.0 Tf [(References)] TJ ET Q q 15.000 55.178 577.500 721.822 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F1 9.8 Tf [(genome sequencing was performed at the J. Craig Venter Institute \(JCVI\) in Rockville, MD. Oligonucleotide primers were )] TJ ET BT 26.250 755.571 Td /F1 9.8 Tf [(designed using a computational PCR primer design pipeline developed at JCVI )] TJ ET 0.267 0.267 0.267 rg BT 369.820 755.571 Td /F1 9.8 Tf [([17])] TJ ET 0.271 0.267 0.267 rg BT 386.083 755.571 Td /F1 9.8 Tf [( . Tiled amplicons were designed to have an )] TJ ET BT 26.250 743.667 Td /F1 9.8 Tf [(optimal size of 550 bp with 100 bp overlap in order to provide six fold sequence coverage of the influenza genome. Influenza )] TJ ET BT 26.250 731.762 Td /F1 9.8 Tf [(segment DNA was amplified using Accuprime Taq at 35 cycles \(denaturation: 0.5 min., 94C; annealing: 0.5 min., 55C; )] TJ ET BT 26.250 719.857 Td /F1 9.8 Tf [(extension: 2 min., 68C\) and amplicons were treated with Shrimp Alkaline Phosphatase and Exonuclease I. Sequencing, )] TJ ET BT 26.250 707.952 Td /F1 9.8 Tf [(genome assembly, and closure reactions were performed as described previously )] TJ ET 0.267 0.267 0.267 rg BT 381.716 707.952 Td /F1 9.8 Tf [([18])] TJ ET 0.271 0.267 0.267 rg BT 397.978 707.952 Td /F1 9.8 Tf [( . All genome sequences were submitted )] TJ ET BT 26.250 696.048 Td /F1 9.8 Tf [(to GenBank.)] TJ ET BT 26.250 676.643 Td /F1 9.8 Tf [(Phylogenetic analysis. The sequence data used in this study came from 81 H1N1pdm isolates collected from Wisconsin )] TJ ET BT 26.250 664.738 Td /F1 9.8 Tf [(between April 28, 2009 May 30, 2009 and 209 H1N1pdm isolates that were collected globally between April 1, 2009 July 9, )] TJ ET BT 26.250 652.833 Td /F1 9.8 Tf [(2009, which were downloaded from the National Center for Biotechnology \(NCBI\) Influenza Virus Resource \( )] TJ ET 0.267 0.267 0.267 rg BT 26.250 640.929 Td /F1 9.8 Tf [(http://www.ncbi.nlm.nih.gov/genomes/FLU/FLU.html)] TJ ET 0.271 0.267 0.267 rg BT 251.114 640.929 Td /F1 9.8 Tf [( \) available on GenBank )] TJ ET 0.267 0.267 0.267 rg BT 357.877 640.929 Td /F1 9.8 Tf [([19])] TJ ET 0.271 0.267 0.267 rg BT 374.140 640.929 Td /F1 9.8 Tf [( . Only isolates for which whole-genome )] TJ ET BT 26.250 629.024 Td /F1 9.8 Tf [(sequences and exact date of collection were available were used \(Table S1\). Nucleotide alignments were manually constructed )] TJ ET BT 26.250 617.119 Td /F1 9.8 Tf [(for the coding regions of the eight genome segments of each isolate using the Se-Al program )] TJ ET 0.267 0.267 0.267 rg BT 429.998 617.119 Td /F1 9.8 Tf [([20])] TJ ET 0.271 0.267 0.267 rg BT 446.260 617.119 Td /F1 9.8 Tf [( . To maximize phylogenetic )] TJ ET BT 26.250 605.214 Td /F1 9.8 Tf [(resolution, and given no evidence of genomic reassortment, the eight segments were concatenated. To infer the evolutionary )] TJ ET BT 26.250 593.310 Td /F1 9.8 Tf [(relationships and timescale for the complete H1N1pdm data set analyzed here, we employed a Bayesian Markov chain Monte )] TJ ET BT 26.250 581.405 Td /F1 9.8 Tf [(Carlo \(MCMC\) method using a strict molecular clock, as implemented in the BEAST program \(version 1.4.8\) )] TJ ET 0.267 0.267 0.267 rg BT 493.841 581.405 Td /F1 9.8 Tf [([4])] TJ ET 0.271 0.267 0.267 rg BT 504.683 581.405 Td /F1 9.8 Tf [( . Use of a strict )] TJ ET BT 26.250 569.500 Td /F1 9.8 Tf [(molecular clock facilitates computational tractability and is justified here given the strong clock-like evolution of the influenza A )] TJ ET BT 26.250 557.595 Td /F1 9.8 Tf [(virus. This analysis incorporated a GTR+?4 model of nucleotide substitution, with a different substitution rate estimated for each )] TJ ET BT 26.250 545.691 Td /F1 9.8 Tf [(codon position, and a Bayesian skyline coalescent prior, with the latter clearly the best descriptor of the complex population )] TJ ET BT 26.250 533.786 Td /F1 9.8 Tf [(dynamics of influenza virus. Due to the large size of this data set, we used a UPGMA starting tree and ran a chain length of 500 )] TJ ET BT 26.250 521.881 Td /F1 9.8 Tf [(million \(sampling trees every 50,000 generations\), until convergence was reached. The Maximum Clade Credibility \(MCC\) tree )] TJ ET BT 26.250 509.976 Td /F1 9.8 Tf [(generated by BEAST was analyzed using TreeAnnotator \(v1.4.8, available at http://beast.bio.ed.ac.uk\) after a 10% burn-in. )] TJ ET BT 26.250 498.072 Td /F1 9.8 Tf [(Statistical uncertainly is reflected in values of the 95% Highest Probability Density \(HPD\). The tree was visualized using FigTree )] TJ ET BT 26.250 486.167 Td /F1 9.8 Tf [(\(v1.2.3, available at )] TJ ET 0.267 0.267 0.267 rg BT 113.503 486.167 Td /F1 9.8 Tf [(http://beast.bio.ed.ac.uk)] TJ ET 0.271 0.267 0.267 rg BT 217.028 486.167 Td /F1 9.8 Tf [( \), where individual clades supported by high Bayesian posterior probabilities \(BPP )] TJ ET BT 26.250 474.262 Td /F1 9.8 Tf [(> 90%\) and long branch lengths were identified. To further assess the reliability of our phylogenetic inferences, two additional )] TJ ET BT 26.250 462.357 Td /F1 9.8 Tf [(trees were estimated \(Figs. S2 and S3\). First, a consensus phylogenetic tree was inferred using the Bayesian approach )] TJ ET BT 26.250 450.453 Td /F1 9.8 Tf [(available in MrBayes program )] TJ ET 0.267 0.267 0.267 rg BT 157.914 450.453 Td /F1 9.8 Tf [([5])] TJ ET 0.271 0.267 0.267 rg BT 168.756 450.453 Td /F1 9.8 Tf [( , employing the GTR+I+?4 model of nucleotide substitution, as determined by MODELTEST )] TJ ET 0.267 0.267 0.267 rg BT 26.250 438.548 Td /F1 9.8 Tf [([21])] TJ ET 0.271 0.267 0.267 rg BT 42.513 438.548 Td /F1 9.8 Tf [( and run for a total of 5.5 x 106 generations, sampling every 1000. In contrast to the MCC tree generated by BEAST, this )] TJ ET BT 26.250 426.643 Td /F1 9.8 Tf [(analysis did not assume a strict molecular clock. Second, we employed the maximum likelihood \(ML\) method available in the )] TJ ET BT 26.250 414.738 Td /F1 9.8 Tf [(PAUP* package )] TJ ET 0.267 0.267 0.267 rg BT 98.868 414.738 Td /F1 9.8 Tf [([6])] TJ ET 0.271 0.267 0.267 rg BT 109.710 414.738 Td /F1 9.8 Tf [( . Because of the very large size of the data set available, this analysis was restricted to Nearest Neighbor-)] TJ ET BT 26.250 402.834 Td /F1 9.8 Tf [(Interchange \(NNI\) branch-swapping. In this case a bootstrap resampling process \(1,000 replications\) using the neighbor-joining )] TJ ET BT 26.250 390.929 Td /F1 9.8 Tf [(\(NJ\) method was also undertaken, incorporating the ML substitution model. Both the MrBayes and PAUP* analyses produced )] TJ ET BT 26.250 379.024 Td /F1 9.8 Tf [(phylogenies similar, although less well supported, tree topologies to that obtained using BEAST. Amino acid changes were )] TJ ET BT 26.250 367.119 Td /F1 9.8 Tf [(identified using the MacClade program )] TJ ET 0.267 0.267 0.267 rg BT 195.861 367.119 Td /F1 9.8 Tf [([22])] TJ ET 0.271 0.267 0.267 rg BT 212.124 367.119 Td /F1 9.8 Tf [( , with the four antigenic sites \(designated Sa, Sb, Ca1/Ca2, and Cb\) those identified )] TJ ET BT 26.250 355.215 Td /F1 9.8 Tf [(on the A/PR/8/34\(H1N1\) virus )] TJ ET 0.267 0.267 0.267 rg BT 157.924 355.215 Td /F1 9.8 Tf [([7])] TJ ET 0.271 0.267 0.267 rg BT 168.766 355.215 Td /F1 9.8 Tf [( and converted into H3 numbering )] TJ ET 0.267 0.267 0.267 rg BT 318.341 355.215 Td /F1 9.8 Tf [([10])] TJ ET 0.271 0.267 0.267 rg BT 334.603 355.215 Td /F1 9.8 Tf [( . The isolates with the most basal position on the )] TJ ET BT 26.250 343.310 Td /F1 9.8 Tf [(phylogenetic tree \(e.g., A/Mexico/4603/2009\(H1N1\)\), not located within any clade, were used as a basis for comparison.)] TJ ET BT 26.250 306.707 Td /F4 12.0 Tf [(Acknowledgements)] TJ ET BT 26.250 286.753 Td /F1 9.8 Tf [(We would like to thank Drs. Sue Kehl, Nate Ledeboer, Ruoyan Chen, Jessica Trost, Teresa Patitucci, Lorraine Witt, Meredith )] TJ ET BT 26.250 274.848 Td /F1 9.8 Tf [(VanDyke, Elizabeth Davis, and Kate Gaffney from the MRVP and Medical College of Wisconsin, and Gerardo Chowell from )] TJ ET BT 26.250 262.944 Td /F1 9.8 Tf [(Arizona State University for their help in this study. We are also greatly indebted to all those who submitted H1N1pdm )] TJ ET BT 26.250 251.039 Td /F1 9.8 Tf [(sequences to GenBanks Influenza Virus Resource. The Madin-Darby canine kidney \(MDCK\) cells used for viral isolation were )] TJ ET BT 26.250 239.134 Td /F1 9.8 Tf [(kindly provided by Dr. Xiyang Xu at the Centers for Disease Control and Prevention \(Atlanta, GA\).)] TJ ET BT 26.250 202.532 Td /F4 12.0 Tf [(Funding Information)] TJ ET BT 26.250 182.577 Td /F1 9.8 Tf [(This project has been funded in part with federal funds from the National Institute of Allergy and Infectious Diseases \(NIAID\), )] TJ ET BT 26.250 170.673 Td /F1 9.8 Tf [(National Institutes of Health, Department of Health and Human Services under contract number HHSN272200900007C and by )] TJ ET BT 26.250 158.768 Td /F1 9.8 Tf [(NIAID grants UO1-AI070428, U01-387 AI077988, and U01-AI066584.)] TJ ET BT 26.250 122.165 Td /F4 12.0 Tf [(Competing Interests)] TJ ET BT 26.250 102.211 Td /F1 9.8 Tf [(The authors have declared that no competing interests exist.)] TJ ET BT 26.250 65.609 Td /F4 12.0 Tf [(References)] TJ ET Q q 0.000 0.000 0.000 rg BT 291.710 19.825 Td /F1 11.0 Tf [(5)] TJ ET BT 25.000 19.825 Td /F1 11.0 Tf [(PLOS Currents Influenza)] TJ ET Q endstream endobj 346 0 obj << /Type /Annot /Subtype /Link /A 347 0 R /Border [0 0 0] /H /I /Rect [ 369.8205 754.6696 386.0835 764.5902 ] >> endobj 347 0 obj << /Type /Action >> endobj 348 0 obj << /Type /Annot /Subtype /Link /A 349 0 R /Border [0 0 0] /H /I /Rect [ 381.7155 707.0506 397.9785 716.9712 ] >> endobj 349 0 obj << /Type /Action >> endobj 350 0 obj << /Type /Annot /Subtype /Link /A 351 0 R /Border [0 0 0] /H /I /Rect [ 26.2500 640.0268 251.1142 649.9474 ] >> endobj 351 0 obj << /Type /Action /S /URI /URI (http://www.ncbi.nlm.nih.gov/genomes/FLU/FLU.html) >> endobj 352 0 obj << /Type /Annot /Subtype /Link /A 353 0 R /Border [0 0 0] /H /I /Rect [ 357.8768 640.0268 374.1397 649.9474 ] >> endobj 353 0 obj << /Type /Action >> endobj 354 0 obj << /Type /Annot /Subtype /Link /A 355 0 R /Border [0 0 0] /H /I /Rect [ 429.9975 616.2173 446.2605 626.1379 ] >> endobj 355 0 obj << /Type /Action >> 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Accessed November 2, 2009. )] TJ ET BT 26.250 748.071 Td /F1 9.8 Tf [(http://www.who.int/csr/don/2009_10_30/en/index.html)] TJ ET BT 26.250 728.667 Td /F1 9.8 Tf [(2.)] TJ ET BT 38.132 728.667 Td /F1 9.8 Tf [(Garten RJ, et al. \(2009\) Antigenic and genetic characteristics of swine-origin 2009 A\(H1N1\) influenza viruses circulating in )] TJ ET BT 26.250 716.762 Td /F1 9.8 Tf [(humans. Science 325:197-201.)] TJ ET BT 26.250 697.357 Td /F1 9.8 Tf [(3.)] TJ ET BT 38.132 697.357 Td /F1 9.8 Tf [(Smith GJD, et al. \(2009\) Origins and evolutionary genomics of the 2009 swine-origin H1N1 influenza A epidemic. Nature )] TJ ET BT 26.250 685.452 Td /F1 9.8 Tf [(459:1122-1125.)] TJ ET BT 26.250 666.048 Td /F1 9.8 Tf [(4.)] TJ ET BT 38.132 666.048 Td /F1 9.8 Tf [(Drummond AJ, Rambaut A \(2007\) BEAST: Bayesian evolutionary analysis by sampling trees. 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Nature 292:72-5.)] TJ ET BT 26.250 470.691 Td /F1 9.8 Tf [(11.)] TJ ET BT 43.553 470.691 Td /F1 9.8 Tf [(Rambaut A, Holmes EC \(2009\) The early molecular epidemiology of the swine-origin A/H1N1 human influenza pandemic. )] TJ ET BT 26.250 458.786 Td /F1 9.8 Tf [(PLoS Currents: Influenza \(Available at http://knol.google.com/k/plos/plos-currents-influenza/28qm4w0q65e4w/1#\).)] TJ ET BT 26.250 439.381 Td /F1 9.8 Tf [(12.)] TJ ET BT 43.553 439.381 Td /F1 9.8 Tf [(Nelson MI, et al. \(2008\) Molecular epidemiology of A/H3N2 and A/H1N1 influenza virus during a single epidemic season in )] TJ ET BT 26.250 427.476 Td /F1 9.8 Tf [(the United States. PLoS Pathog 4:e1000133.)] TJ ET BT 26.250 408.072 Td /F1 9.8 Tf [(13.)] TJ ET BT 43.553 408.072 Td /F1 9.8 Tf [(Kumar S, et al. \(2009\) Introduction of a novel swine-origin influenza A \(H1N1\) virus into Milwaukee, Wisconsin in 2009. )] TJ ET BT 26.250 396.167 Td /F1 9.8 Tf [(Viruses 1:72-83.)] TJ ET BT 26.250 376.762 Td /F1 9.8 Tf [(14.)] TJ ET BT 43.553 376.762 Td /F1 9.8 Tf [(Bose ME, et al. \(2009\) Rapid semi-automated subtyping of influenza during the 2009 swine-origin influenza A H1N1 virus )] TJ ET BT 26.250 364.857 Td /F1 9.8 Tf [(epidemic in Milwaukee, Wisconsin. J Clin Microbiol 47:2779-86.)] TJ ET BT 26.250 345.453 Td /F1 9.8 Tf [(15.)] TJ ET BT 43.553 345.453 Td /F1 9.8 Tf [(He J, et al. \(2009\) Rapid multiplex RT-PCR typing of influenza A and B and subtyping of influenza A into H1, 2, 3, 5, 7, 9, )] TJ ET BT 26.250 333.548 Td /F1 9.8 Tf [(N1 \(human\), N1 \(animal\), N2 and N7 including typing of novel swine-origin influenza A \(H1N1\) virus during the current 2009 )] TJ ET BT 26.250 321.643 Td /F1 9.8 Tf [(outbreak in Milwaukee, WI. J Clin Microbiol 47:2772-78.)] TJ ET BT 26.250 302.238 Td /F1 9.8 Tf [(16.)] TJ ET BT 43.553 302.238 Td /F1 9.8 Tf [(Zhou B, et al. \(2009\) Single-Reaction Genomic Amplification Accelerates Sequencing and Vaccine Production for Classical )] TJ ET BT 26.250 290.334 Td /F1 9.8 Tf [(and Swine Origin Human Influenza A Viruses. J Virol 83:10309-10313.)] TJ ET BT 26.250 270.929 Td /F1 9.8 Tf [(17.)] TJ ET BT 43.553 270.929 Td /F1 9.8 Tf [(Li K, et al. \(2008\) Novel computational methods for increasing PCR primer design effectiveness in directed sequencing. )] TJ ET BT 26.250 259.024 Td /F1 9.8 Tf [(BMC Bioinformatics 9:191.)] TJ ET BT 26.250 239.619 Td /F1 9.8 Tf [(18.)] TJ ET BT 43.553 239.619 Td /F1 9.8 Tf [(Ghedin E, et al. \(2005\) Large-scale sequencing of human influenza reveals the dynamic nature of viral genome evolution. )] TJ ET BT 26.250 227.715 Td /F1 9.8 Tf [(Nature 437:1162-6.)] TJ ET BT 26.250 208.310 Td /F1 9.8 Tf [(19.)] TJ ET BT 43.553 208.310 Td /F1 9.8 Tf [(Bao Y, et al. \(2008\) The Influenza Virus Resource at the National Center for Biotechnology Information. J Virol 82:596-601.)] TJ ET BT 26.250 188.905 Td /F1 9.8 Tf [(20.)] TJ ET BT 43.553 188.905 Td /F1 9.8 Tf [(Rambaut, A \(2002\) Sequence alignment editor. \(Computer program downloaded from http://tree.bio.ed.ac.uk/software/seal/\).)] TJ ET BT 26.250 169.500 Td /F1 9.8 Tf [(21.)] TJ ET BT 43.553 169.500 Td /F1 9.8 Tf [(Posada D, Crandall, KA \(1998\) MODELTEST: testing the model of DNA substitution. Bioinformatics 14:817-818.)] TJ ET BT 26.250 150.096 Td /F1 9.8 Tf [(22.)] TJ ET BT 43.553 150.096 Td /F1 9.8 Tf [(Maddison DR, Maddison WP \(2000\) MacClade. Analysis of Phylogeny and Character Evolution, version 4.0 [computer )] TJ ET BT 26.250 138.191 Td /F1 9.8 Tf [(program]. Sunderland, Massachusetts: Sinauer Associates.)] TJ ET Q q 15.000 120.810 577.500 656.190 re W n 0.271 0.267 0.267 rg BT 26.250 759.976 Td /F1 9.8 Tf [(1.)] TJ ET BT 38.132 759.976 Td /F1 9.8 Tf [(WHO \(2009\) Pandemic \(H1N1\) 2009 update 72. Accessed November 2, 2009. )] TJ ET BT 26.250 748.071 Td /F1 9.8 Tf [(http://www.who.int/csr/don/2009_10_30/en/index.html)] TJ ET BT 26.250 728.667 Td /F1 9.8 Tf [(2.)] TJ ET BT 38.132 728.667 Td /F1 9.8 Tf [(Garten RJ, et al. \(2009\) Antigenic and genetic characteristics of swine-origin 2009 A\(H1N1\) influenza viruses circulating in )] TJ ET BT 26.250 716.762 Td /F1 9.8 Tf [(humans. Science 325:197-201.)] TJ ET BT 26.250 697.357 Td /F1 9.8 Tf [(3.)] TJ ET BT 38.132 697.357 Td /F1 9.8 Tf [(Smith GJD, et al. \(2009\) Origins and evolutionary genomics of the 2009 swine-origin H1N1 influenza A epidemic. Nature )] TJ ET BT 26.250 685.452 Td /F1 9.8 Tf [(459:1122-1125.)] TJ ET BT 26.250 666.048 Td /F1 9.8 Tf [(4.)] TJ ET BT 38.132 666.048 Td /F1 9.8 Tf [(Drummond AJ, Rambaut A \(2007\) BEAST: Bayesian evolutionary analysis by sampling trees. 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Cell 31:417-427.)] TJ ET BT 26.250 564.619 Td /F1 9.8 Tf [(8.)] TJ ET BT 38.132 564.619 Td /F1 9.8 Tf [(Gubareva LV, Webster RG, Hayden FG \(2002\) Detection of influenza virus resistance to neuraminidase inhibitors by an )] TJ ET BT 26.250 552.714 Td /F1 9.8 Tf [(enzyme inhibition assay. Antiviral Res 53:47-61.)] TJ ET BT 26.250 533.310 Td /F1 9.8 Tf [(9.)] TJ ET BT 38.132 533.310 Td /F1 9.8 Tf [(Hurt AC, Holien JK, Parker M, Kelso A, Barr IG \(2009\) Zanamivir-resistant influenza viruses with a novel neuraminidase )] TJ ET BT 26.250 521.405 Td /F1 9.8 Tf [(mutation. J Virol \(Epub ahead of print\).)] TJ ET BT 26.250 502.000 Td /F1 9.8 Tf [(10.)] TJ ET BT 43.553 502.000 Td /F1 9.8 Tf [(Winter G, Fields S, Brownlee GG \(1981\) Nucleotide sequence of a haemagglutinin gene of a human influenza virus H1 )] TJ ET BT 26.250 490.095 Td /F1 9.8 Tf [(subtype. Nature 292:72-5.)] TJ ET BT 26.250 470.691 Td /F1 9.8 Tf [(11.)] TJ ET BT 43.553 470.691 Td /F1 9.8 Tf [(Rambaut A, Holmes EC \(2009\) The early molecular epidemiology of the swine-origin A/H1N1 human influenza pandemic. )] TJ ET BT 26.250 458.786 Td /F1 9.8 Tf [(PLoS Currents: Influenza \(Available at http://knol.google.com/k/plos/plos-currents-influenza/28qm4w0q65e4w/1#\).)] TJ ET BT 26.250 439.381 Td /F1 9.8 Tf [(12.)] TJ ET BT 43.553 439.381 Td /F1 9.8 Tf [(Nelson MI, et al. \(2008\) Molecular epidemiology of A/H3N2 and A/H1N1 influenza virus during a single epidemic season in )] TJ ET BT 26.250 427.476 Td /F1 9.8 Tf [(the United States. PLoS Pathog 4:e1000133.)] TJ ET BT 26.250 408.072 Td /F1 9.8 Tf [(13.)] TJ ET BT 43.553 408.072 Td /F1 9.8 Tf [(Kumar S, et al. \(2009\) Introduction of a novel swine-origin influenza A \(H1N1\) virus into Milwaukee, Wisconsin in 2009. )] TJ ET BT 26.250 396.167 Td /F1 9.8 Tf [(Viruses 1:72-83.)] TJ ET BT 26.250 376.762 Td /F1 9.8 Tf [(14.)] TJ ET BT 43.553 376.762 Td /F1 9.8 Tf [(Bose ME, et al. \(2009\) Rapid semi-automated subtyping of influenza during the 2009 swine-origin influenza A H1N1 virus )] TJ ET BT 26.250 364.857 Td /F1 9.8 Tf [(epidemic in Milwaukee, Wisconsin. J Clin Microbiol 47:2779-86.)] TJ ET BT 26.250 345.453 Td /F1 9.8 Tf [(15.)] TJ ET BT 43.553 345.453 Td /F1 9.8 Tf [(He J, et al. \(2009\) Rapid multiplex RT-PCR typing of influenza A and B and subtyping of influenza A into H1, 2, 3, 5, 7, 9, )] TJ ET BT 26.250 333.548 Td /F1 9.8 Tf [(N1 \(human\), N1 \(animal\), N2 and N7 including typing of novel swine-origin influenza A \(H1N1\) virus during the current 2009 )] TJ ET BT 26.250 321.643 Td /F1 9.8 Tf [(outbreak in Milwaukee, WI. J Clin Microbiol 47:2772-78.)] TJ ET BT 26.250 302.238 Td /F1 9.8 Tf [(16.)] TJ ET BT 43.553 302.238 Td /F1 9.8 Tf [(Zhou B, et al. \(2009\) Single-Reaction Genomic Amplification Accelerates Sequencing and Vaccine Production for Classical )] TJ ET BT 26.250 290.334 Td /F1 9.8 Tf [(and Swine Origin Human Influenza A Viruses. J Virol 83:10309-10313.)] TJ ET BT 26.250 270.929 Td /F1 9.8 Tf [(17.)] TJ ET BT 43.553 270.929 Td /F1 9.8 Tf [(Li K, et al. \(2008\) Novel computational methods for increasing PCR primer design effectiveness in directed sequencing. )] TJ ET BT 26.250 259.024 Td /F1 9.8 Tf [(BMC Bioinformatics 9:191.)] TJ ET BT 26.250 239.619 Td /F1 9.8 Tf [(18.)] TJ ET BT 43.553 239.619 Td /F1 9.8 Tf [(Ghedin E, et al. \(2005\) Large-scale sequencing of human influenza reveals the dynamic nature of viral genome evolution. )] TJ ET BT 26.250 227.715 Td /F1 9.8 Tf [(Nature 437:1162-6.)] TJ ET BT 26.250 208.310 Td /F1 9.8 Tf [(19.)] TJ ET BT 43.553 208.310 Td /F1 9.8 Tf [(Bao Y, et al. \(2008\) The Influenza Virus Resource at the National Center for Biotechnology Information. J Virol 82:596-601.)] TJ ET BT 26.250 188.905 Td /F1 9.8 Tf [(20.)] TJ ET BT 43.553 188.905 Td /F1 9.8 Tf [(Rambaut, A \(2002\) Sequence alignment editor. \(Computer program downloaded from http://tree.bio.ed.ac.uk/software/seal/\).)] TJ ET BT 26.250 169.500 Td /F1 9.8 Tf [(21.)] TJ ET BT 43.553 169.500 Td /F1 9.8 Tf [(Posada D, Crandall, KA \(1998\) MODELTEST: testing the model of DNA substitution. Bioinformatics 14:817-818.)] TJ ET BT 26.250 150.096 Td /F1 9.8 Tf [(22.)] TJ ET BT 43.553 150.096 Td /F1 9.8 Tf [(Maddison DR, Maddison WP \(2000\) MacClade. Analysis of Phylogeny and Character Evolution, version 4.0 [computer )] TJ ET BT 26.250 138.191 Td /F1 9.8 Tf [(program]. Sunderland, Massachusetts: Sinauer Associates.)] TJ ET Q q 15.000 120.810 577.500 656.190 re W n 0.271 0.267 0.267 rg BT 26.250 759.976 Td /F1 9.8 Tf [(1.)] TJ ET BT 38.132 759.976 Td /F1 9.8 Tf [(WHO \(2009\) Pandemic \(H1N1\) 2009 update 72. Accessed November 2, 2009. )] TJ ET BT 26.250 748.071 Td /F1 9.8 Tf [(http://www.who.int/csr/don/2009_10_30/en/index.html)] TJ ET BT 26.250 728.667 Td /F1 9.8 Tf [(2.)] TJ ET BT 38.132 728.667 Td /F1 9.8 Tf [(Garten RJ, et al. \(2009\) Antigenic and genetic characteristics of swine-origin 2009 A\(H1N1\) influenza viruses circulating in )] TJ ET BT 26.250 716.762 Td /F1 9.8 Tf [(humans. Science 325:197-201.)] TJ ET BT 26.250 697.357 Td /F1 9.8 Tf [(3.)] TJ ET BT 38.132 697.357 Td /F1 9.8 Tf [(Smith GJD, et al. \(2009\) Origins and evolutionary genomics of the 2009 swine-origin H1N1 influenza A epidemic. Nature )] TJ ET BT 26.250 685.452 Td /F1 9.8 Tf [(459:1122-1125.)] TJ ET BT 26.250 666.048 Td /F1 9.8 Tf [(4.)] TJ ET BT 38.132 666.048 Td /F1 9.8 Tf [(Drummond AJ, Rambaut A \(2007\) BEAST: Bayesian evolutionary analysis by sampling trees. MBC Evol Biol 7:214.)] TJ ET BT 26.250 646.643 Td /F1 9.8 Tf [(5.)] TJ ET BT 38.132 646.643 Td /F1 9.8 Tf [(Huelsenback HP, Ronquist F \(2001\) MRBAYES: Bayesian inference of phylogeny. Bioinformatics 17:754-755.)] TJ ET BT 26.250 627.238 Td /F1 9.8 Tf [(6.)] TJ ET BT 38.132 627.238 Td /F1 9.8 Tf [(Swofford DL \(2003\) PAUP*: Phylogenetic analysis using parsimony \(*and other methods\) version 4.0 [computer program]. )] TJ ET BT 26.250 615.333 Td /F1 9.8 Tf [(Sunderland, Massachusetts: Sinauer Associates.)] TJ ET BT 26.250 595.929 Td /F1 9.8 Tf [(7.)] TJ ET BT 38.132 595.929 Td /F1 9.8 Tf [(Caton AJ, Brownlee GG, Yewdell JW, Gerhard W \(1982\) The antigenic structure of the influenza virus A/PR/8/34 )] TJ ET BT 26.250 584.024 Td /F1 9.8 Tf [(hemagglutinin \(H1 subtype\). Cell 31:417-427.)] TJ ET BT 26.250 564.619 Td /F1 9.8 Tf [(8.)] TJ ET BT 38.132 564.619 Td /F1 9.8 Tf [(Gubareva LV, Webster RG, Hayden FG \(2002\) Detection of influenza virus resistance to neuraminidase inhibitors by an )] TJ ET BT 26.250 552.714 Td /F1 9.8 Tf [(enzyme inhibition assay. Antiviral Res 53:47-61.)] TJ ET BT 26.250 533.310 Td /F1 9.8 Tf [(9.)] TJ ET BT 38.132 533.310 Td /F1 9.8 Tf [(Hurt AC, Holien JK, Parker M, Kelso A, Barr IG \(2009\) Zanamivir-resistant influenza viruses with a novel neuraminidase )] TJ ET BT 26.250 521.405 Td /F1 9.8 Tf [(mutation. J Virol \(Epub ahead of print\).)] TJ ET BT 26.250 502.000 Td /F1 9.8 Tf [(10.)] TJ ET BT 43.553 502.000 Td /F1 9.8 Tf [(Winter G, Fields S, Brownlee GG \(1981\) Nucleotide sequence of a haemagglutinin gene of a human influenza virus H1 )] TJ ET BT 26.250 490.095 Td /F1 9.8 Tf [(subtype. Nature 292:72-5.)] TJ ET BT 26.250 470.691 Td /F1 9.8 Tf [(11.)] TJ ET BT 43.553 470.691 Td /F1 9.8 Tf [(Rambaut A, Holmes EC \(2009\) The early molecular epidemiology of the swine-origin A/H1N1 human influenza pandemic. )] TJ ET BT 26.250 458.786 Td /F1 9.8 Tf [(PLoS Currents: Influenza \(Available at http://knol.google.com/k/plos/plos-currents-influenza/28qm4w0q65e4w/1#\).)] TJ ET BT 26.250 439.381 Td /F1 9.8 Tf [(12.)] TJ ET BT 43.553 439.381 Td /F1 9.8 Tf [(Nelson MI, et al. \(2008\) Molecular epidemiology of A/H3N2 and A/H1N1 influenza virus during a single epidemic season in )] TJ ET BT 26.250 427.476 Td /F1 9.8 Tf [(the United States. PLoS Pathog 4:e1000133.)] TJ ET BT 26.250 408.072 Td /F1 9.8 Tf [(13.)] TJ ET BT 43.553 408.072 Td /F1 9.8 Tf [(Kumar S, et al. \(2009\) Introduction of a novel swine-origin influenza A \(H1N1\) virus into Milwaukee, Wisconsin in 2009. )] TJ ET BT 26.250 396.167 Td /F1 9.8 Tf [(Viruses 1:72-83.)] TJ ET BT 26.250 376.762 Td /F1 9.8 Tf [(14.)] TJ ET BT 43.553 376.762 Td /F1 9.8 Tf [(Bose ME, et al. \(2009\) Rapid semi-automated subtyping of influenza during the 2009 swine-origin influenza A H1N1 virus )] TJ ET BT 26.250 364.857 Td /F1 9.8 Tf [(epidemic in Milwaukee, Wisconsin. J Clin Microbiol 47:2779-86.)] TJ ET BT 26.250 345.453 Td /F1 9.8 Tf [(15.)] TJ ET BT 43.553 345.453 Td /F1 9.8 Tf [(He J, et al. \(2009\) Rapid multiplex RT-PCR typing of influenza A and B and subtyping of influenza A into H1, 2, 3, 5, 7, 9, )] TJ ET BT 26.250 333.548 Td /F1 9.8 Tf [(N1 \(human\), N1 \(animal\), N2 and N7 including typing of novel swine-origin influenza A \(H1N1\) virus during the current 2009 )] TJ ET BT 26.250 321.643 Td /F1 9.8 Tf [(outbreak in Milwaukee, WI. J Clin Microbiol 47:2772-78.)] TJ ET BT 26.250 302.238 Td /F1 9.8 Tf [(16.)] TJ ET BT 43.553 302.238 Td /F1 9.8 Tf [(Zhou B, et al. \(2009\) Single-Reaction Genomic Amplification Accelerates Sequencing and Vaccine Production for Classical )] TJ ET BT 26.250 290.334 Td /F1 9.8 Tf [(and Swine Origin Human Influenza A Viruses. J Virol 83:10309-10313.)] TJ ET BT 26.250 270.929 Td /F1 9.8 Tf [(17.)] TJ ET BT 43.553 270.929 Td /F1 9.8 Tf [(Li K, et al. \(2008\) Novel computational methods for increasing PCR primer design effectiveness in directed sequencing. )] TJ ET BT 26.250 259.024 Td /F1 9.8 Tf [(BMC Bioinformatics 9:191.)] TJ ET BT 26.250 239.619 Td /F1 9.8 Tf [(18.)] TJ ET BT 43.553 239.619 Td /F1 9.8 Tf [(Ghedin E, et al. \(2005\) Large-scale sequencing of human influenza reveals the dynamic nature of viral genome evolution. )] TJ ET BT 26.250 227.715 Td /F1 9.8 Tf [(Nature 437:1162-6.)] TJ ET BT 26.250 208.310 Td /F1 9.8 Tf [(19.)] TJ ET BT 43.553 208.310 Td /F1 9.8 Tf [(Bao Y, et al. \(2008\) The Influenza Virus Resource at the National Center for Biotechnology Information. J Virol 82:596-601.)] TJ ET BT 26.250 188.905 Td /F1 9.8 Tf [(20.)] TJ ET BT 43.553 188.905 Td /F1 9.8 Tf [(Rambaut, A \(2002\) Sequence alignment editor. \(Computer program downloaded from http://tree.bio.ed.ac.uk/software/seal/\).)] TJ ET BT 26.250 169.500 Td /F1 9.8 Tf [(21.)] TJ ET BT 43.553 169.500 Td /F1 9.8 Tf [(Posada D, Crandall, KA \(1998\) MODELTEST: testing the model of DNA substitution. Bioinformatics 14:817-818.)] TJ ET BT 26.250 150.096 Td /F1 9.8 Tf [(22.)] TJ ET BT 43.553 150.096 Td /F1 9.8 Tf [(Maddison DR, Maddison WP \(2000\) MacClade. Analysis of Phylogeny and Character Evolution, version 4.0 [computer )] TJ ET BT 26.250 138.191 Td /F1 9.8 Tf [(program]. 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