%PDF-1.3 1 0 obj << /Type /Catalog /Outlines 2 0 R /Pages 3 0 R >> endobj 2 0 obj << /Type /Outlines /Count 0 >> endobj 3 0 obj << /Type /Pages /Kids [6 0 R 86 0 R 139 0 R ] /Count 3 /Resources << /ProcSet 4 0 R /Font << /F1 8 0 R /F2 9 0 R /F3 10 0 R /F4 11 0 R /F5 88 0 R >> /XObject << /I1 12 0 R /I2 13 0 R /I3 32 0 R /I4 33 0 R /I5 56 0 R /I6 57 0 R /I7 80 0 R /I8 81 0 R /I9 93 0 R /I10 94 0 R /I11 109 0 R /I12 110 0 R /I13 125 0 R /I14 126 0 R /I15 137 0 R /I16 138 0 R >> >> /MediaBox [0.000 0.000 612.000 792.000] >> endobj 4 0 obj [/PDF /Text /ImageC ] endobj 5 0 obj << /Creator (DOMPDF) /CreationDate (D:20180721120834+00'00') /ModDate (D:20180721120834+00'00') /Title (The early molecular epidemiology of the swine-origin A/H1N1 human influenza pandemic PLOS Currents Influenza) >> endobj 6 0 obj << /Type /Page /Parent 3 0 R /Annots [ 14 0 R 16 0 R 18 0 R 20 0 R 22 0 R 24 0 R 26 0 R 28 0 R 30 0 R 34 0 R 36 0 R 38 0 R 40 0 R 42 0 R 44 0 R 46 0 R 48 0 R 50 0 R 52 0 R 54 0 R 58 0 R 60 0 R 62 0 R 64 0 R 66 0 R 68 0 R 70 0 R 72 0 R 74 0 R 76 0 R 78 0 R 82 0 R 84 0 R ] /Contents 7 0 R >> endobj 7 0 obj << /Length 23489 >> stream q 375.000 0 0 39.000 222.000 738.000 cm /I2 Do Q q 15.000 684.354 577.500 53.646 re W n 0.267 0.267 0.267 rg BT 15.000 718.042 Td /F2 21.0 Tf [(The early molecular epidemiology of the swine-origin A/H1N1 )] TJ ET BT 15.000 693.094 Td /F2 21.0 Tf [(human influenza pandemic)] TJ ET Q 0.271 0.267 0.267 rg BT 15.000 675.088 Td /F3 9.8 Tf [(August 18, 2009)] TJ ET 0.267 0.267 0.267 rg BT 26.250 663.247 Td /F1 9.8 Tf [(Andrew Rambaut)] TJ ET 0.271 0.267 0.267 rg BT 101.569 663.247 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 106.990 663.247 Td /F1 9.8 Tf [(Eddie Holmes)] TJ ET 0.271 0.267 0.267 rg BT 26.250 651.342 Td /F1 9.8 Tf [(Rambaut A, Holmes E. The early molecular epidemiology of the swine-origin A/H1N1 human influenza pandemic. PLOS )] TJ ET BT 26.250 639.438 Td /F1 9.8 Tf [(Currents Influenza. 2009 Aug 18 . Edition 1. doi: 10.1371/currents.RRN1003.)] TJ ET q 15.000 29.878 577.500 607.179 re W n 0.271 0.267 0.267 rg BT 26.250 610.335 Td /F4 12.0 Tf [(Abstract)] TJ ET BT 26.250 590.381 Td /F1 9.8 Tf [(Swine-origin pandemic human influenza A virus \(H1N1pdm\) has spread rapidly around the world since its initial documentation )] TJ ET BT 26.250 578.476 Td /F1 9.8 Tf [(in April 2009. Here we have updated initial estimates of the rate of molecular evolution and estimates of the time of origin of this )] TJ ET BT 26.250 566.571 Td /F1 9.8 Tf [(virus in the human population using the large number of viral sequences made available as part of the public health response to )] TJ ET BT 26.250 554.667 Td /F1 9.8 Tf [(this global pandemic. Currently sampled H1N1pdm sequences share a most recent common ancestor in the first 7 weeks of )] TJ ET BT 26.250 542.762 Td /F1 9.8 Tf [(2009 with the implication that the virus was transmitting cryptically for up to 3 months prior to recognition. A phylogenetic )] TJ ET BT 26.250 530.857 Td /F1 9.8 Tf [(reconstruction of the data shows that the virus has been circling the globe extensively with multiple introductions into most )] TJ ET BT 26.250 518.952 Td /F1 9.8 Tf [(geographical areas.)] TJ ET BT 26.250 482.350 Td /F4 12.0 Tf [(Introduction)] TJ ET BT 26.250 462.396 Td /F1 9.8 Tf [(H1N1pdm \(also referred to as S-OIV\) is a newly emergent human influenza A virus that is closely related to a number of )] TJ ET BT 26.250 450.491 Td /F1 9.8 Tf [(currently circulating pig viruses in the classic North American and Eurasian swine influenza virus lineages )] TJ ET 0.267 0.267 0.267 rg BT 491.686 450.491 Td /F1 9.8 Tf [([1])] TJ ET BT 502.528 450.491 Td /F1 9.8 Tf [([2])] TJ ET 0.271 0.267 0.267 rg BT 513.370 450.491 Td /F1 9.8 Tf [(. Since the first )] TJ ET BT 26.250 438.586 Td /F1 9.8 Tf [(reports of the virus in humans in April 2009, H1N1pdm has spread to 168 countries and overseas territories, with >177,000 )] TJ ET BT 26.250 426.681 Td /F1 9.8 Tf [(reported cases )] TJ ET 0.267 0.267 0.267 rg BT 93.447 426.681 Td /F1 9.8 Tf [([3])] TJ ET 0.271 0.267 0.267 rg BT 104.289 426.681 Td /F1 9.8 Tf [(. To reveal the early molecular epidemiology of the H1N1pdm, particularly its spatial patterning and )] TJ ET BT 26.250 414.777 Td /F1 9.8 Tf [(evolutionary dynamics, we performed an evolutionary analysis on available genome sequence data sampled globally. The aim )] TJ ET BT 26.250 402.872 Td /F1 9.8 Tf [(of our study was to provide updated information on estimates of the rate of evolutionary change in H1N1pdm, its date of origin, )] TJ ET BT 26.250 390.967 Td /F1 9.8 Tf [(and its growth rate in human populations.)] TJ ET BT 26.250 354.365 Td /F4 12.0 Tf [(Methods)] TJ ET BT 26.250 334.410 Td /F1 9.8 Tf [(H1N1pdm sequences were collated from the NCBI Influenza Database on 6th August 2009. These sequences were then filtered )] TJ ET BT 26.250 322.506 Td /F1 9.8 Tf [(to produce a data set that met the following criteria; that the exact date \(day\) of collection was given, that both of the )] TJ ET BT 26.250 310.601 Td /F1 9.8 Tf [(hemagglutinin \(HA\) and neuraminidase \(NA\) gene sequences were available \(any other sequenced genes were also included\), )] TJ ET BT 26.250 298.696 Td /F1 9.8 Tf [(and that they had been isolated from humans. This resulted in a data set of 377 isolates. In a previous application of these )] TJ ET BT 26.250 286.791 Td /F1 9.8 Tf [(approaches to sequences collected early in the outbreak )] TJ ET 0.267 0.267 0.267 rg BT 272.837 286.791 Td /F1 9.8 Tf [([4])] TJ ET 0.271 0.267 0.267 rg BT 283.679 286.791 Td /F1 9.8 Tf [(, it was possible to trace epidemiologically-linked clusters and )] TJ ET BT 26.250 274.887 Td /F1 9.8 Tf [(correct for this sampling bias explicitly by picking one isolate from each cluster. Given the large number of cases globally, this is )] TJ ET BT 26.250 262.982 Td /F1 9.8 Tf [(no longer possible. Therefore, to reduce any effect of over-sampling of epidemiologically-linked isolates \(such as those from )] TJ ET BT 26.250 251.077 Td /F1 9.8 Tf [(New York State, USA\), a further filtering was applied where, for each day of isolation, only one virus from a given location )] TJ ET BT 26.250 239.172 Td /F1 9.8 Tf [(\(country and state\) was retained; this resulted in a total of 242 isolates. This final set included isolates from 23 different )] TJ ET BT 26.250 227.268 Td /F1 9.8 Tf [(countries with the majority \(118\) coming from the USA.)] TJ ET BT 26.250 207.863 Td /F1 9.8 Tf [(These sequences were then analysed using BEAST v1.5.0 )] TJ ET 0.267 0.267 0.267 rg BT 283.133 207.863 Td /F1 9.8 Tf [([5])] TJ ET 0.271 0.267 0.267 rg BT 293.975 207.863 Td /F1 9.8 Tf [(, an analysis package that uses a Bayesian Markov chain Monte )] TJ ET BT 26.250 195.958 Td /F1 9.8 Tf [(Carlo \(MCMC\) approach to sample time-structured evolutionary trees from their joint posterior probability distribution derived )] TJ ET BT 26.250 184.053 Td /F1 9.8 Tf [(from a combination of molecular evolutionary and population genetic models. The data were analysed under an exponential-)] TJ ET BT 26.250 172.149 Td /F1 9.8 Tf [(growth coalescent model as a prior on the tree, the HKY+)] TJ ET q 8.250 0 0 10.500 274.183 171.172 cm /I4 Do Q BT 282.433 172.149 Td /F1 9.8 Tf [( model of nucleotide substitution and a relaxed molecular clock )] TJ ET 0.267 0.267 0.267 rg BT 556.096 172.149 Td /F1 9.8 Tf [([6])] TJ ET 0.271 0.267 0.267 rg BT 566.938 172.149 Td /F1 9.8 Tf [(. 4 )] TJ ET BT 26.250 160.244 Td /F1 9.8 Tf [(independent runs of 10 million steps were peformed, compared for convergence and combined less a 10% burnin from each.)] TJ ET BT 26.250 123.641 Td /F4 12.0 Tf [(Results & Discussion)] TJ ET BT 26.250 103.687 Td /F1 9.8 Tf [(The results of the Bayesian MCMC analysis are summarized in )] TJ ET BT 300.956 103.687 Td /F4 9.8 Tf [(Table 1)] TJ ET BT 334.555 103.687 Td /F1 9.8 Tf [( . The analysis of this much larger sample of H1N1pdm )] TJ ET BT 26.250 91.782 Td /F1 9.8 Tf [(virus confirms that the date of the most recent common ancestor \(MRCA\) of circulating human lineages pre-dates the first )] TJ ET BT 26.250 79.878 Td /F1 9.8 Tf [(sampled case by approximately 2 months. Assuming that a single cross-species transfer from pigs to humans gave rise to all )] TJ ET BT 26.250 67.973 Td /F1 9.8 Tf [(the sampled H1N1pdm diversity, the date of the MRCA is a lower limit of how recently this event occurred. The estimate )] TJ ET BT 26.250 56.068 Td /F1 9.8 Tf [(presented here represents a considerable increase in precision over that published previously )] TJ ET 0.267 0.267 0.267 rg BT 432.679 56.068 Td /F1 9.8 Tf [([2])] TJ ET 0.271 0.267 0.267 rg BT 443.521 56.068 Td /F1 9.8 Tf [( concomitant with the )] TJ ET BT 26.250 44.163 Td /F1 9.8 Tf [(increased period of sampling and greater number of viruses in this study \(we estimate a credible interval spanning )] TJ ET Q q 15.000 684.354 577.500 53.646 re W n 0.267 0.267 0.267 rg BT 15.000 718.042 Td /F2 21.0 Tf [(The early molecular epidemiology of the swine-origin A/H1N1 )] TJ ET BT 15.000 693.094 Td /F2 21.0 Tf [(human influenza pandemic)] TJ ET Q 0.271 0.267 0.267 rg BT 15.000 675.088 Td /F3 9.8 Tf [(August 18, 2009)] TJ ET 0.267 0.267 0.267 rg BT 26.250 663.247 Td /F1 9.8 Tf [(Andrew Rambaut)] TJ ET 0.271 0.267 0.267 rg BT 101.569 663.247 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 106.990 663.247 Td /F1 9.8 Tf [(Eddie Holmes)] TJ ET 0.271 0.267 0.267 rg BT 26.250 651.342 Td /F1 9.8 Tf [(Rambaut A, Holmes E. The early molecular epidemiology of the swine-origin A/H1N1 human influenza pandemic. PLOS )] TJ ET BT 26.250 639.438 Td /F1 9.8 Tf [(Currents Influenza. 2009 Aug 18 . Edition 1. doi: 10.1371/currents.RRN1003.)] TJ ET q 15.000 29.878 577.500 607.179 re W n 0.271 0.267 0.267 rg BT 26.250 610.335 Td /F4 12.0 Tf [(Abstract)] TJ ET BT 26.250 590.381 Td /F1 9.8 Tf [(Swine-origin pandemic human influenza A virus \(H1N1pdm\) has spread rapidly around the world since its initial documentation )] TJ ET BT 26.250 578.476 Td /F1 9.8 Tf [(in April 2009. Here we have updated initial estimates of the rate of molecular evolution and estimates of the time of origin of this )] TJ ET BT 26.250 566.571 Td /F1 9.8 Tf [(virus in the human population using the large number of viral sequences made available as part of the public health response to )] TJ ET BT 26.250 554.667 Td /F1 9.8 Tf [(this global pandemic. Currently sampled H1N1pdm sequences share a most recent common ancestor in the first 7 weeks of )] TJ ET BT 26.250 542.762 Td /F1 9.8 Tf [(2009 with the implication that the virus was transmitting cryptically for up to 3 months prior to recognition. A phylogenetic )] TJ ET BT 26.250 530.857 Td /F1 9.8 Tf [(reconstruction of the data shows that the virus has been circling the globe extensively with multiple introductions into most )] TJ ET BT 26.250 518.952 Td /F1 9.8 Tf [(geographical areas.)] TJ ET BT 26.250 482.350 Td /F4 12.0 Tf [(Introduction)] TJ ET BT 26.250 462.396 Td /F1 9.8 Tf [(H1N1pdm \(also referred to as S-OIV\) is a newly emergent human influenza A virus that is closely related to a number of )] TJ ET BT 26.250 450.491 Td /F1 9.8 Tf [(currently circulating pig viruses in the classic North American and Eurasian swine influenza virus lineages )] TJ ET 0.267 0.267 0.267 rg BT 491.686 450.491 Td /F1 9.8 Tf [([1])] TJ ET BT 502.528 450.491 Td /F1 9.8 Tf [([2])] TJ ET 0.271 0.267 0.267 rg BT 513.370 450.491 Td /F1 9.8 Tf [(. Since the first )] TJ ET BT 26.250 438.586 Td /F1 9.8 Tf [(reports of the virus in humans in April 2009, H1N1pdm has spread to 168 countries and overseas territories, with >177,000 )] TJ ET BT 26.250 426.681 Td /F1 9.8 Tf [(reported cases )] TJ ET 0.267 0.267 0.267 rg BT 93.447 426.681 Td /F1 9.8 Tf [([3])] TJ ET 0.271 0.267 0.267 rg BT 104.289 426.681 Td /F1 9.8 Tf [(. To reveal the early molecular epidemiology of the H1N1pdm, particularly its spatial patterning and )] TJ ET BT 26.250 414.777 Td /F1 9.8 Tf [(evolutionary dynamics, we performed an evolutionary analysis on available genome sequence data sampled globally. The aim )] TJ ET BT 26.250 402.872 Td /F1 9.8 Tf [(of our study was to provide updated information on estimates of the rate of evolutionary change in H1N1pdm, its date of origin, )] TJ ET BT 26.250 390.967 Td /F1 9.8 Tf [(and its growth rate in human populations.)] TJ ET BT 26.250 354.365 Td /F4 12.0 Tf [(Methods)] TJ ET BT 26.250 334.410 Td /F1 9.8 Tf [(H1N1pdm sequences were collated from the NCBI Influenza Database on 6th August 2009. These sequences were then filtered )] TJ ET BT 26.250 322.506 Td /F1 9.8 Tf [(to produce a data set that met the following criteria; that the exact date \(day\) of collection was given, that both of the )] TJ ET BT 26.250 310.601 Td /F1 9.8 Tf [(hemagglutinin \(HA\) and neuraminidase \(NA\) gene sequences were available \(any other sequenced genes were also included\), )] TJ ET BT 26.250 298.696 Td /F1 9.8 Tf [(and that they had been isolated from humans. This resulted in a data set of 377 isolates. In a previous application of these )] TJ ET BT 26.250 286.791 Td /F1 9.8 Tf [(approaches to sequences collected early in the outbreak )] TJ ET 0.267 0.267 0.267 rg BT 272.837 286.791 Td /F1 9.8 Tf [([4])] TJ ET 0.271 0.267 0.267 rg BT 283.679 286.791 Td /F1 9.8 Tf [(, it was possible to trace epidemiologically-linked clusters and )] TJ ET BT 26.250 274.887 Td /F1 9.8 Tf [(correct for this sampling bias explicitly by picking one isolate from each cluster. Given the large number of cases globally, this is )] TJ ET BT 26.250 262.982 Td /F1 9.8 Tf [(no longer possible. Therefore, to reduce any effect of over-sampling of epidemiologically-linked isolates \(such as those from )] TJ ET BT 26.250 251.077 Td /F1 9.8 Tf [(New York State, USA\), a further filtering was applied where, for each day of isolation, only one virus from a given location )] TJ ET BT 26.250 239.172 Td /F1 9.8 Tf [(\(country and state\) was retained; this resulted in a total of 242 isolates. This final set included isolates from 23 different )] TJ ET BT 26.250 227.268 Td /F1 9.8 Tf [(countries with the majority \(118\) coming from the USA.)] TJ ET BT 26.250 207.863 Td /F1 9.8 Tf [(These sequences were then analysed using BEAST v1.5.0 )] TJ ET 0.267 0.267 0.267 rg BT 283.133 207.863 Td /F1 9.8 Tf [([5])] TJ ET 0.271 0.267 0.267 rg BT 293.975 207.863 Td /F1 9.8 Tf [(, an analysis package that uses a Bayesian Markov chain Monte )] TJ ET BT 26.250 195.958 Td /F1 9.8 Tf [(Carlo \(MCMC\) approach to sample time-structured evolutionary trees from their joint posterior probability distribution derived )] TJ ET BT 26.250 184.053 Td /F1 9.8 Tf [(from a combination of molecular evolutionary and population genetic models. The data were analysed under an exponential-)] TJ ET BT 26.250 172.149 Td /F1 9.8 Tf [(growth coalescent model as a prior on the tree, the HKY+)] TJ ET q 8.250 0 0 10.500 274.183 171.172 cm /I6 Do Q BT 282.433 172.149 Td /F1 9.8 Tf [( model of nucleotide substitution and a relaxed molecular clock )] TJ ET 0.267 0.267 0.267 rg BT 556.096 172.149 Td /F1 9.8 Tf [([6])] TJ ET 0.271 0.267 0.267 rg BT 566.938 172.149 Td /F1 9.8 Tf [(. 4 )] TJ ET BT 26.250 160.244 Td /F1 9.8 Tf [(independent runs of 10 million steps were peformed, compared for convergence and combined less a 10% burnin from each.)] TJ ET BT 26.250 123.641 Td /F4 12.0 Tf [(Results & Discussion)] TJ ET BT 26.250 103.687 Td /F1 9.8 Tf [(The results of the Bayesian MCMC analysis are summarized in )] TJ ET BT 300.956 103.687 Td /F4 9.8 Tf [(Table 1)] TJ ET BT 334.555 103.687 Td /F1 9.8 Tf [( . The analysis of this much larger sample of H1N1pdm )] TJ ET BT 26.250 91.782 Td /F1 9.8 Tf [(virus confirms that the date of the most recent common ancestor \(MRCA\) of circulating human lineages pre-dates the first )] TJ ET BT 26.250 79.878 Td /F1 9.8 Tf [(sampled case by approximately 2 months. Assuming that a single cross-species transfer from pigs to humans gave rise to all )] TJ ET BT 26.250 67.973 Td /F1 9.8 Tf [(the sampled H1N1pdm diversity, the date of the MRCA is a lower limit of how recently this event occurred. The estimate )] TJ ET BT 26.250 56.068 Td /F1 9.8 Tf [(presented here represents a considerable increase in precision over that published previously )] TJ ET 0.267 0.267 0.267 rg BT 432.679 56.068 Td /F1 9.8 Tf [([2])] TJ ET 0.271 0.267 0.267 rg BT 443.521 56.068 Td /F1 9.8 Tf [( concomitant with the )] TJ ET BT 26.250 44.163 Td /F1 9.8 Tf [(increased period of sampling and greater number of viruses in this study \(we estimate a credible interval spanning )] TJ ET Q q 15.000 684.354 577.500 53.646 re W n 0.267 0.267 0.267 rg BT 15.000 718.042 Td /F2 21.0 Tf [(The early molecular epidemiology of the swine-origin A/H1N1 )] TJ ET BT 15.000 693.094 Td /F2 21.0 Tf [(human influenza pandemic)] TJ ET Q 0.271 0.267 0.267 rg BT 15.000 675.088 Td /F3 9.8 Tf [(August 18, 2009)] TJ ET 0.267 0.267 0.267 rg BT 26.250 663.247 Td /F1 9.8 Tf [(Andrew Rambaut)] TJ ET 0.271 0.267 0.267 rg BT 101.569 663.247 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 106.990 663.247 Td /F1 9.8 Tf [(Eddie Holmes)] TJ ET 0.271 0.267 0.267 rg BT 26.250 651.342 Td /F1 9.8 Tf [(Rambaut A, Holmes E. The early molecular epidemiology of the swine-origin A/H1N1 human influenza pandemic. PLOS )] TJ ET BT 26.250 639.438 Td /F1 9.8 Tf [(Currents Influenza. 2009 Aug 18 . Edition 1. doi: 10.1371/currents.RRN1003.)] TJ ET q 15.000 29.878 577.500 607.179 re W n 0.271 0.267 0.267 rg BT 26.250 610.335 Td /F4 12.0 Tf [(Abstract)] TJ ET BT 26.250 590.381 Td /F1 9.8 Tf [(Swine-origin pandemic human influenza A virus \(H1N1pdm\) has spread rapidly around the world since its initial documentation )] TJ ET BT 26.250 578.476 Td /F1 9.8 Tf [(in April 2009. Here we have updated initial estimates of the rate of molecular evolution and estimates of the time of origin of this )] TJ ET BT 26.250 566.571 Td /F1 9.8 Tf [(virus in the human population using the large number of viral sequences made available as part of the public health response to )] TJ ET BT 26.250 554.667 Td /F1 9.8 Tf [(this global pandemic. Currently sampled H1N1pdm sequences share a most recent common ancestor in the first 7 weeks of )] TJ ET BT 26.250 542.762 Td /F1 9.8 Tf [(2009 with the implication that the virus was transmitting cryptically for up to 3 months prior to recognition. A phylogenetic )] TJ ET BT 26.250 530.857 Td /F1 9.8 Tf [(reconstruction of the data shows that the virus has been circling the globe extensively with multiple introductions into most )] TJ ET BT 26.250 518.952 Td /F1 9.8 Tf [(geographical areas.)] TJ ET BT 26.250 482.350 Td /F4 12.0 Tf [(Introduction)] TJ ET BT 26.250 462.396 Td /F1 9.8 Tf [(H1N1pdm \(also referred to as S-OIV\) is a newly emergent human influenza A virus that is closely related to a number of )] TJ ET BT 26.250 450.491 Td /F1 9.8 Tf [(currently circulating pig viruses in the classic North American and Eurasian swine influenza virus lineages )] TJ ET 0.267 0.267 0.267 rg BT 491.686 450.491 Td /F1 9.8 Tf [([1])] TJ ET BT 502.528 450.491 Td /F1 9.8 Tf [([2])] TJ ET 0.271 0.267 0.267 rg BT 513.370 450.491 Td /F1 9.8 Tf [(. Since the first )] TJ ET BT 26.250 438.586 Td /F1 9.8 Tf [(reports of the virus in humans in April 2009, H1N1pdm has spread to 168 countries and overseas territories, with >177,000 )] TJ ET BT 26.250 426.681 Td /F1 9.8 Tf [(reported cases )] TJ ET 0.267 0.267 0.267 rg BT 93.447 426.681 Td /F1 9.8 Tf [([3])] TJ ET 0.271 0.267 0.267 rg BT 104.289 426.681 Td /F1 9.8 Tf [(. To reveal the early molecular epidemiology of the H1N1pdm, particularly its spatial patterning and )] TJ ET BT 26.250 414.777 Td /F1 9.8 Tf [(evolutionary dynamics, we performed an evolutionary analysis on available genome sequence data sampled globally. The aim )] TJ ET BT 26.250 402.872 Td /F1 9.8 Tf [(of our study was to provide updated information on estimates of the rate of evolutionary change in H1N1pdm, its date of origin, )] TJ ET BT 26.250 390.967 Td /F1 9.8 Tf [(and its growth rate in human populations.)] TJ ET BT 26.250 354.365 Td /F4 12.0 Tf [(Methods)] TJ ET BT 26.250 334.410 Td /F1 9.8 Tf [(H1N1pdm sequences were collated from the NCBI Influenza Database on 6th August 2009. These sequences were then filtered )] TJ ET BT 26.250 322.506 Td /F1 9.8 Tf [(to produce a data set that met the following criteria; that the exact date \(day\) of collection was given, that both of the )] TJ ET BT 26.250 310.601 Td /F1 9.8 Tf [(hemagglutinin \(HA\) and neuraminidase \(NA\) gene sequences were available \(any other sequenced genes were also included\), )] TJ ET BT 26.250 298.696 Td /F1 9.8 Tf [(and that they had been isolated from humans. This resulted in a data set of 377 isolates. In a previous application of these )] TJ ET BT 26.250 286.791 Td /F1 9.8 Tf [(approaches to sequences collected early in the outbreak )] TJ ET 0.267 0.267 0.267 rg BT 272.837 286.791 Td /F1 9.8 Tf [([4])] TJ ET 0.271 0.267 0.267 rg BT 283.679 286.791 Td /F1 9.8 Tf [(, it was possible to trace epidemiologically-linked clusters and )] TJ ET BT 26.250 274.887 Td /F1 9.8 Tf [(correct for this sampling bias explicitly by picking one isolate from each cluster. Given the large number of cases globally, this is )] TJ ET BT 26.250 262.982 Td /F1 9.8 Tf [(no longer possible. Therefore, to reduce any effect of over-sampling of epidemiologically-linked isolates \(such as those from )] TJ ET BT 26.250 251.077 Td /F1 9.8 Tf [(New York State, USA\), a further filtering was applied where, for each day of isolation, only one virus from a given location )] TJ ET BT 26.250 239.172 Td /F1 9.8 Tf [(\(country and state\) was retained; this resulted in a total of 242 isolates. This final set included isolates from 23 different )] TJ ET BT 26.250 227.268 Td /F1 9.8 Tf [(countries with the majority \(118\) coming from the USA.)] TJ ET BT 26.250 207.863 Td /F1 9.8 Tf [(These sequences were then analysed using BEAST v1.5.0 )] TJ ET 0.267 0.267 0.267 rg BT 283.133 207.863 Td /F1 9.8 Tf [([5])] TJ ET 0.271 0.267 0.267 rg BT 293.975 207.863 Td /F1 9.8 Tf [(, an analysis package that uses a Bayesian Markov chain Monte )] TJ ET BT 26.250 195.958 Td /F1 9.8 Tf [(Carlo \(MCMC\) approach to sample time-structured evolutionary trees from their joint posterior probability distribution derived )] TJ ET BT 26.250 184.053 Td /F1 9.8 Tf [(from a combination of molecular evolutionary and population genetic models. The data were analysed under an exponential-)] TJ ET BT 26.250 172.149 Td /F1 9.8 Tf [(growth coalescent model as a prior on the tree, the HKY+)] TJ ET q 8.250 0 0 10.500 274.183 171.172 cm /I8 Do Q BT 282.433 172.149 Td /F1 9.8 Tf [( model of nucleotide substitution and a relaxed molecular clock )] TJ ET 0.267 0.267 0.267 rg BT 556.096 172.149 Td /F1 9.8 Tf [([6])] TJ ET 0.271 0.267 0.267 rg BT 566.938 172.149 Td /F1 9.8 Tf [(. 4 )] TJ ET BT 26.250 160.244 Td /F1 9.8 Tf [(independent runs of 10 million steps were peformed, compared for convergence and combined less a 10% burnin from each.)] TJ ET BT 26.250 123.641 Td /F4 12.0 Tf [(Results & Discussion)] TJ ET BT 26.250 103.687 Td /F1 9.8 Tf [(The results of the Bayesian MCMC analysis are summarized in )] TJ ET BT 300.956 103.687 Td /F4 9.8 Tf [(Table 1)] TJ ET BT 334.555 103.687 Td /F1 9.8 Tf [( . The analysis of this much larger sample of H1N1pdm )] TJ ET BT 26.250 91.782 Td /F1 9.8 Tf [(virus confirms that the date of the most recent common ancestor \(MRCA\) of circulating human lineages pre-dates the first )] TJ ET BT 26.250 79.878 Td /F1 9.8 Tf [(sampled case by approximately 2 months. Assuming that a single cross-species transfer from pigs to humans gave rise to all )] TJ ET BT 26.250 67.973 Td /F1 9.8 Tf [(the sampled H1N1pdm diversity, the date of the MRCA is a lower limit of how recently this event occurred. The estimate )] TJ ET BT 26.250 56.068 Td /F1 9.8 Tf [(presented here represents a considerable increase in precision over that published previously )] TJ ET 0.267 0.267 0.267 rg BT 432.679 56.068 Td /F1 9.8 Tf [([2])] TJ ET 0.271 0.267 0.267 rg BT 443.521 56.068 Td /F1 9.8 Tf [( concomitant with the )] TJ ET BT 26.250 44.163 Td /F1 9.8 Tf [(increased period of sampling and greater number of viruses in this study \(we estimate a credible interval spanning )] TJ ET Q q 0.000 0.000 0.000 rg BT 291.710 19.825 Td /F1 11.0 Tf [(1)] TJ ET BT 25.000 19.825 Td /F1 11.0 Tf [(PLOS Currents Influenza)] TJ ET Q endstream endobj 8 0 obj << /Type /Font /Subtype /Type1 /Name /F1 /BaseFont /Helvetica /Encoding /WinAnsiEncoding >> endobj 9 0 obj << /Type /Font /Subtype /Type1 /Name /F2 /BaseFont /Times-Bold /Encoding /WinAnsiEncoding >> endobj 10 0 obj << /Type /Font /Subtype /Type1 /Name /F3 /BaseFont /Times-Italic /Encoding /WinAnsiEncoding >> endobj 11 0 obj << /Type /Font /Subtype /Type1 /Name /F4 /BaseFont /Helvetica-Bold /Encoding /WinAnsiEncoding >> endobj 12 0 obj << /Type /XObject /Subtype /Image /Width 500 /Height 52 /Filter /FlateDecode /DecodeParms << /Predictor 15 /Colors 1 /Columns 500 /BitsPerComponent 8>> /ColorSpace /DeviceGray /BitsPerComponent 8 /Length 144>> stream x1 0 'ݲ؎"e{dzAdzAdzAdzAdzAdzAdzAdzAdzAdzAdzAdzAtlM0\ endstream endobj 13 0 obj << /Type /XObject /Subtype /Image /Width 500 /Height 52 /SMask 12 0 R /Filter /FlateDecode /DecodeParms << /Predictor 15 /Colors 3 /Columns 500 /BitsPerComponent 8>> /ColorSpace /DeviceRGB /BitsPerComponent 8 /Length 3574>> stream x}ƕK*8+0T ֮ S L*0߇d" sl2FBiFwY0 00 0ŝa0 aqgR܋x||lu2 03UL۶BxI 0:UU0x;֝($z%șHڶ ÐVz ]IS> â(.* TQUuL5 $>BvpH0U:xkkGJT{OɗRNyGOΙyn)q7`(~_Ji2vgk]qVꔷ3N'ȴy4Ikm6!q:FJ)-0n܋v!^}_Z l61va_~Bxw8mv;EJY8}zzQ3]Pȹ,2_jfY4MQ[ '.uO O͋kշ9b6.#ߦUUzhf09+nKɿ4 f7Bu7ĨMfrF0`s8429j1}ZWDW;A4ҫ'TQ{7Cb[$ -"ΨMQgzN/2R7Tco*W:N݋6TUu8`RSi O>r;z^m(0w`:m=]գCE&t |ZYQ%{X[nR+zbEFΧ5pzq`ުం Ih{9G 4wMx' nmvEZ sg7?ZQ}&ҎKGuPu.j8UgNKꓙQC)s#$1䧈x[Z(|Xzc;t<~50Hh_T3Ur>a$]B8Fz[?K>Y/rQ=E4?EaLqzpX!(nNut]}e(/S\fz,<ZOEa]0 sCS_}I Y}n۶r(fg7#)h6ա}$ üvq]Aא$c0ddBDQ)ueypU-z~9Hk<$I©y'Tk`yY d}e{䨙ǐu>&w񚓶('GI\rm[G4 Sk7$B pEkYYC/ 9&Ʋ[V9MQ':X|C֨ʉ jt"ޡ+rttBռGdiM FuTEi(łv]fk"8Ldp' ^הMup2`M?dE!|KJ-\.MzکC=&¾HfR7$ev,La0+$OFuEQ"i,ːN?~E*t4qΚF:t`,{RkR]ޜ(Ԕѣ$IbN}5لS1(Ȱ$I$(eWp8Lٱ3߯ky۶&. 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[(approximately the first 7 weeks of 2009\). In sum, this means that there was a period of up to about 3 months where the virus )] TJ ET BT 26.250 755.571 Td /F1 9.8 Tf [(was circulating in humans prior to initial characterization \(cryptic transmission\).)] TJ ET BT 26.250 736.167 Td /F1 9.8 Tf [(The substitution rate for H1N1pdm is significantly higher than that estimated by Smith )] TJ ET BT 396.906 736.167 Td /F5 9.8 Tf [(et al.)] TJ ET 0.267 0.267 0.267 rg BT 418.044 736.167 Td /F1 9.8 Tf [( [2])] TJ ET 0.271 0.267 0.267 rg BT 431.596 736.167 Td /F1 9.8 Tf [( for each of the genomic )] TJ ET BT 26.250 724.262 Td /F1 9.8 Tf [(segments for a panel of related swine viruses \(at ~3 x 10 )] TJ ET BT 273.637 728.150 Td /F1 8.7 Tf [(-3)] TJ ET BT 281.341 724.262 Td /F1 9.8 Tf [( substitutions/site/year\). This higher rate in H1N1pdm was noted by )] TJ ET BT 26.250 712.357 Td /F1 9.8 Tf [(Smith )] TJ ET BT 53.882 712.357 Td /F5 9.8 Tf [(et al.)] TJ ET BT 75.019 712.357 Td /F1 9.8 Tf [( , and as an explanation it was suggested that the rapid epidemic spread and short timescale had resulted in a )] TJ ET BT 26.250 700.452 Td /F1 9.8 Tf [(proportion of mildly-deleterious mutations being maintained in the population. It will be possible to test this hypothesis when )] TJ ET BT 26.250 688.548 Td /F1 9.8 Tf [(H1N1pdm sequences are sampled over a longer time-period.)] TJ ET BT 26.250 669.143 Td /F4 9.8 Tf [(Table 1)] TJ ET BT 59.849 669.143 Td /F4 9.8 Tf [(. )] TJ ET BT 65.269 669.143 Td /F1 9.8 Tf [( Marginal posterior estimates of model parameters.)] TJ ET 1.000 1.000 1.000 rg 26.250 592.524 555.000 66.738 re f 0.267 0.267 0.267 rg 26.625 658.137 128.929 0.750 re f 26.625 624.043 0.750 34.844 re f 154.804 658.137 123.439 0.750 re f 154.804 624.043 0.750 34.844 re f 0.271 0.267 0.267 rg BT 176.967 648.282 Td /F1 9.8 Tf [(Rate of molecular )] TJ ET BT 195.658 640.651 Td /F1 9.8 Tf [(evolution )] TJ ET BT 168.781 630.659 Td /F1 9.8 Tf [(\(x10 )] TJ ET BT 190.455 633.224 Td /F1 8.7 Tf [(-3)] TJ ET BT 198.160 630.659 Td /F1 9.8 Tf [( subs/site/year\))] TJ ET 0.267 0.267 0.267 rg 277.493 658.137 114.292 0.750 re f 277.493 624.043 0.750 34.844 re f 0.271 0.267 0.267 rg BT 290.744 648.282 Td /F1 9.8 Tf [(Date of most recent )] TJ ET BT 295.897 640.651 Td /F1 9.8 Tf [(common ancestor)] TJ ET 0.267 0.267 0.267 rg 391.035 658.137 104.001 0.750 re f 391.035 624.043 0.750 34.844 re f 0.271 0.267 0.267 rg BT 400.223 648.282 Td /F1 9.8 Tf [(Exponential growth )] TJ ET BT 434.636 640.651 Td /F1 9.8 Tf [(rate)] TJ ET 0.267 0.267 0.267 rg 494.286 658.137 86.589 0.750 re f 494.286 624.043 0.750 34.844 re f 580.125 624.043 0.750 34.844 re f 0.271 0.267 0.267 rg BT 506.424 648.282 Td /F1 9.8 Tf [(Doubling time )] TJ ET BT 524.038 640.651 Td /F1 9.8 Tf [(\(days\))] TJ ET 0.267 0.267 0.267 rg 26.625 624.043 128.929 0.750 re f 26.625 592.899 128.929 0.750 re f 26.625 592.899 0.750 31.894 re f 0.271 0.267 0.267 rg BT 48.277 614.188 Td /F1 9.8 Tf [(mean estimate and )] TJ ET BT 35.548 606.556 Td /F1 9.8 Tf [(Bayesian credible interval)] TJ ET 0.267 0.267 0.267 rg 154.804 624.043 123.439 0.750 re f 154.804 592.899 123.439 0.750 re f 154.804 592.899 0.750 31.894 re f 0.271 0.267 0.267 rg BT 205.681 614.188 Td /F1 9.8 Tf [(5.02 )] TJ ET BT 191.592 606.556 Td /F1 9.8 Tf [(\(4.17, 5.95\))] TJ ET 0.267 0.267 0.267 rg 277.493 624.043 114.292 0.750 re f 277.493 592.899 114.292 0.750 re f 277.493 592.899 0.750 31.894 re f 0.271 0.267 0.267 rg BT 305.915 614.188 Td /F1 9.8 Tf [(27-Jan-2009 )] TJ ET BT 285.060 606.556 Td /F1 9.8 Tf [(\(30-Dec-2008, 22-Feb-)] TJ ET BT 322.174 598.925 Td /F1 9.8 Tf [(2009\))] TJ ET 0.267 0.267 0.267 rg 391.035 624.043 104.001 0.750 re f 391.035 592.899 104.001 0.750 re f 391.035 592.899 0.750 31.894 re f 0.271 0.267 0.267 rg BT 429.483 614.188 Td /F1 9.8 Tf [(14.92 )] TJ ET BT 412.684 606.556 Td /F1 9.8 Tf [(\(10.44, 19.61\))] TJ ET 0.267 0.267 0.267 rg 494.286 624.043 86.589 0.750 re f 494.286 592.899 86.589 0.750 re f 494.286 592.899 0.750 31.894 re f 580.125 592.899 0.750 31.894 re f 0.271 0.267 0.267 rg BT 526.739 614.188 Td /F1 9.8 Tf [(17.0 )] TJ ET BT 512.650 606.556 Td /F1 9.8 Tf [(\(12.9, 24.2\))] TJ ET BT 26.250 545.500 Td /F1 9.8 Tf [(Figure 1 shows the maximum clade credibility tree \(the tree sampled from the MCMC with the highest product of individual clade )] TJ ET BT 26.250 533.595 Td /F1 9.8 Tf [(probabilities\). This tree is intended as a representative tree from the posterior sample; however, the ages of each node in the )] TJ ET BT 26.250 521.690 Td /F1 9.8 Tf [(tree are set to the mean across the entire sample.)] TJ ET 0.965 0.965 0.965 rg 26.250 193.196 555.000 318.614 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 511.810 m 581.250 511.810 l 581.250 511.060 l 26.250 511.060 l f 26.250 193.196 m 581.250 193.196 l 581.250 193.946 l 26.250 193.946 l f q 155.250 0 0 225.000 35.250 277.060 cm /I10 Do Q q 35.250 204.446 537.000 66.614 re W n 0.271 0.267 0.267 rg BT 35.250 261.536 Td /F4 9.8 Tf [(Fig. 1: The maximum clade credibility \(MCC\) tree of H1N1pdm.)] TJ ET BT 35.250 242.166 Td /F1 9.8 Tf [(In blue is the marginal posterior probability density of the time of the most recent common ancestors of the sampled )] TJ ET BT 35.250 228.429 Td /F1 9.8 Tf [(lineages \(95% credible interval shown by darker blue\). Clades are labelled with their posterior probability where greater )] TJ ET BT 35.250 214.693 Td /F1 9.8 Tf [(than 0.5. Lineages are coloured using a parsimonious reconstruction based on the locations of the sampled viruses.)] TJ ET Q 0.267 0.267 0.267 rg BT 26.250 176.172 Td /F1 9.8 Tf [(PDF version with isolate names)] TJ ET 0.271 0.267 0.267 rg BT 26.250 156.767 Td /F1 9.8 Tf [(The color-coded branches highlight the rapid spatial diffusion of H1N1pdm, which multiple entries into countries from Asia and )] TJ ET BT 26.250 144.863 Td /F1 9.8 Tf [(Europe. Such a spatial mixing is typical for influenza A virus )] TJ ET 0.267 0.267 0.267 rg BT 286.351 144.863 Td /F1 9.8 Tf [([7])] TJ ET 0.271 0.267 0.267 rg BT 297.193 144.863 Td /F1 9.8 Tf [( and suggests that H1N1pdm exhibits similar spatial dynamics to )] TJ ET BT 26.250 132.958 Td /F1 9.8 Tf [(those of seasonal influenza. It is also notable that multiple lineages of H1N1pdm are circulating in a single geographical region )] TJ ET BT 26.250 121.053 Td /F1 9.8 Tf [(\(with the United States a notable example\), providing the raw material for intra-subtype reassortment.)] TJ ET BT 26.250 101.648 Td /F1 9.8 Tf [(The population growth rates and epidemic doubling times inferred here are similar to those estimated previously for H1N1pdm )] TJ ET 0.267 0.267 0.267 rg BT 26.250 89.744 Td /F1 9.8 Tf [([4])] TJ ET 0.271 0.267 0.267 rg BT 37.092 89.744 Td /F1 9.8 Tf [( and suggest that the virus will continue to spread globally. However, it is difficult to compare these coalescent-based )] TJ ET BT 26.250 77.839 Td /F1 9.8 Tf [(estimates of epidemiological dynamics with those of seasonal influenza viruses, as multiple introductions into any locality in any )] TJ ET BT 26.250 65.934 Td /F1 9.8 Tf [(season )] TJ ET 0.267 0.267 0.267 rg BT 60.395 65.934 Td /F1 9.8 Tf [([8])] TJ ET BT 71.237 65.934 Td /F1 9.8 Tf [([9])] TJ ET 0.271 0.267 0.267 rg BT 82.078 65.934 Td /F1 9.8 Tf [( mean that equivalent point-source outbreaks are rarely observed.)] TJ ET Q q 15.000 18.901 577.500 758.099 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F1 9.8 Tf [(approximately the first 7 weeks of 2009\). In sum, this means that there was a period of up to about 3 months where the virus )] TJ ET BT 26.250 755.571 Td /F1 9.8 Tf [(was circulating in humans prior to initial characterization \(cryptic transmission\).)] TJ ET BT 26.250 736.167 Td /F1 9.8 Tf [(The substitution rate for H1N1pdm is significantly higher than that estimated by Smith )] TJ ET BT 396.906 736.167 Td /F5 9.8 Tf [(et al.)] TJ ET 0.267 0.267 0.267 rg BT 418.044 736.167 Td /F1 9.8 Tf [( [2])] TJ ET 0.271 0.267 0.267 rg BT 431.596 736.167 Td /F1 9.8 Tf [( for each of the genomic )] TJ ET BT 26.250 724.262 Td /F1 9.8 Tf [(segments for a panel of related swine viruses \(at ~3 x 10 )] TJ ET BT 273.637 728.150 Td /F1 8.7 Tf [(-3)] TJ ET BT 281.341 724.262 Td /F1 9.8 Tf [( substitutions/site/year\). This higher rate in H1N1pdm was noted by )] TJ ET BT 26.250 712.357 Td /F1 9.8 Tf [(Smith )] TJ ET BT 53.882 712.357 Td /F5 9.8 Tf [(et al.)] TJ ET BT 75.019 712.357 Td /F1 9.8 Tf [( , and as an explanation it was suggested that the rapid epidemic spread and short timescale had resulted in a )] TJ ET BT 26.250 700.452 Td /F1 9.8 Tf [(proportion of mildly-deleterious mutations being maintained in the population. It will be possible to test this hypothesis when )] TJ ET BT 26.250 688.548 Td /F1 9.8 Tf [(H1N1pdm sequences are sampled over a longer time-period.)] TJ ET BT 26.250 669.143 Td /F4 9.8 Tf [(Table 1)] TJ ET BT 59.849 669.143 Td /F4 9.8 Tf [(. )] TJ ET BT 65.269 669.143 Td /F1 9.8 Tf [( Marginal posterior estimates of model parameters.)] TJ ET 1.000 1.000 1.000 rg 26.250 592.524 555.000 66.738 re f 0.267 0.267 0.267 rg 26.625 658.137 128.929 0.750 re f 26.625 624.043 0.750 34.844 re f 154.804 658.137 123.439 0.750 re f 154.804 624.043 0.750 34.844 re f 0.271 0.267 0.267 rg BT 176.967 648.282 Td /F1 9.8 Tf [(Rate of molecular )] TJ ET BT 195.658 640.651 Td /F1 9.8 Tf [(evolution )] TJ ET BT 168.781 630.659 Td /F1 9.8 Tf [(\(x10 )] TJ ET BT 190.455 633.224 Td /F1 8.7 Tf [(-3)] TJ ET BT 198.160 630.659 Td /F1 9.8 Tf [( subs/site/year\))] TJ ET 0.267 0.267 0.267 rg 277.493 658.137 114.292 0.750 re f 277.493 624.043 0.750 34.844 re f 0.271 0.267 0.267 rg BT 290.744 648.282 Td /F1 9.8 Tf [(Date of most recent )] TJ ET BT 295.897 640.651 Td /F1 9.8 Tf [(common ancestor)] TJ ET 0.267 0.267 0.267 rg 391.035 658.137 104.001 0.750 re f 391.035 624.043 0.750 34.844 re f 0.271 0.267 0.267 rg BT 400.223 648.282 Td /F1 9.8 Tf [(Exponential growth )] TJ ET BT 434.636 640.651 Td /F1 9.8 Tf [(rate)] TJ ET 0.267 0.267 0.267 rg 494.286 658.137 86.589 0.750 re f 494.286 624.043 0.750 34.844 re f 580.125 624.043 0.750 34.844 re f 0.271 0.267 0.267 rg BT 506.424 648.282 Td /F1 9.8 Tf [(Doubling time )] TJ ET BT 524.038 640.651 Td /F1 9.8 Tf [(\(days\))] TJ ET 0.267 0.267 0.267 rg 26.625 624.043 128.929 0.750 re f 26.625 592.899 128.929 0.750 re f 26.625 592.899 0.750 31.894 re f 0.271 0.267 0.267 rg BT 48.277 614.188 Td /F1 9.8 Tf [(mean estimate and )] TJ ET BT 35.548 606.556 Td /F1 9.8 Tf [(Bayesian credible interval)] TJ ET 0.267 0.267 0.267 rg 154.804 624.043 123.439 0.750 re f 154.804 592.899 123.439 0.750 re f 154.804 592.899 0.750 31.894 re f 0.271 0.267 0.267 rg BT 205.681 614.188 Td /F1 9.8 Tf [(5.02 )] TJ ET BT 191.592 606.556 Td /F1 9.8 Tf [(\(4.17, 5.95\))] TJ ET 0.267 0.267 0.267 rg 277.493 624.043 114.292 0.750 re f 277.493 592.899 114.292 0.750 re f 277.493 592.899 0.750 31.894 re f 0.271 0.267 0.267 rg BT 305.915 614.188 Td /F1 9.8 Tf [(27-Jan-2009 )] TJ ET BT 285.060 606.556 Td /F1 9.8 Tf [(\(30-Dec-2008, 22-Feb-)] TJ ET BT 322.174 598.925 Td /F1 9.8 Tf [(2009\))] TJ ET 0.267 0.267 0.267 rg 391.035 624.043 104.001 0.750 re f 391.035 592.899 104.001 0.750 re f 391.035 592.899 0.750 31.894 re f 0.271 0.267 0.267 rg BT 429.483 614.188 Td /F1 9.8 Tf [(14.92 )] TJ ET BT 412.684 606.556 Td /F1 9.8 Tf [(\(10.44, 19.61\))] TJ ET 0.267 0.267 0.267 rg 494.286 624.043 86.589 0.750 re f 494.286 592.899 86.589 0.750 re f 494.286 592.899 0.750 31.894 re f 580.125 592.899 0.750 31.894 re f 0.271 0.267 0.267 rg BT 526.739 614.188 Td /F1 9.8 Tf [(17.0 )] TJ ET BT 512.650 606.556 Td /F1 9.8 Tf [(\(12.9, 24.2\))] TJ ET BT 26.250 545.500 Td /F1 9.8 Tf [(Figure 1 shows the maximum clade credibility tree \(the tree sampled from the MCMC with the highest product of individual clade )] TJ ET BT 26.250 533.595 Td /F1 9.8 Tf [(probabilities\). This tree is intended as a representative tree from the posterior sample; however, the ages of each node in the )] TJ ET BT 26.250 521.690 Td /F1 9.8 Tf [(tree are set to the mean across the entire sample.)] TJ ET 0.965 0.965 0.965 rg 26.250 193.196 555.000 318.614 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 511.810 m 581.250 511.810 l 581.250 511.060 l 26.250 511.060 l f 26.250 193.196 m 581.250 193.196 l 581.250 193.946 l 26.250 193.946 l f q 155.250 0 0 225.000 35.250 277.060 cm /I12 Do Q q 35.250 204.446 537.000 66.614 re W n 0.271 0.267 0.267 rg BT 35.250 261.536 Td /F4 9.8 Tf [(Fig. 1: The maximum clade credibility \(MCC\) tree of H1N1pdm.)] TJ ET BT 35.250 242.166 Td /F1 9.8 Tf [(In blue is the marginal posterior probability density of the time of the most recent common ancestors of the sampled )] TJ ET BT 35.250 228.429 Td /F1 9.8 Tf [(lineages \(95% credible interval shown by darker blue\). Clades are labelled with their posterior probability where greater )] TJ ET BT 35.250 214.693 Td /F1 9.8 Tf [(than 0.5. Lineages are coloured using a parsimonious reconstruction based on the locations of the sampled viruses.)] TJ ET Q 0.267 0.267 0.267 rg BT 26.250 176.172 Td /F1 9.8 Tf [(PDF version with isolate names)] TJ ET 0.271 0.267 0.267 rg BT 26.250 156.767 Td /F1 9.8 Tf [(The color-coded branches highlight the rapid spatial diffusion of H1N1pdm, which multiple entries into countries from Asia and )] TJ ET BT 26.250 144.863 Td /F1 9.8 Tf [(Europe. Such a spatial mixing is typical for influenza A virus )] TJ ET 0.267 0.267 0.267 rg BT 286.351 144.863 Td /F1 9.8 Tf [([7])] TJ ET 0.271 0.267 0.267 rg BT 297.193 144.863 Td /F1 9.8 Tf [( and suggests that H1N1pdm exhibits similar spatial dynamics to )] TJ ET BT 26.250 132.958 Td /F1 9.8 Tf [(those of seasonal influenza. It is also notable that multiple lineages of H1N1pdm are circulating in a single geographical region )] TJ ET BT 26.250 121.053 Td /F1 9.8 Tf [(\(with the United States a notable example\), providing the raw material for intra-subtype reassortment.)] TJ ET BT 26.250 101.648 Td /F1 9.8 Tf [(The population growth rates and epidemic doubling times inferred here are similar to those estimated previously for H1N1pdm )] TJ ET 0.267 0.267 0.267 rg BT 26.250 89.744 Td /F1 9.8 Tf [([4])] TJ ET 0.271 0.267 0.267 rg BT 37.092 89.744 Td /F1 9.8 Tf [( and suggest that the virus will continue to spread globally. However, it is difficult to compare these coalescent-based )] TJ ET BT 26.250 77.839 Td /F1 9.8 Tf [(estimates of epidemiological dynamics with those of seasonal influenza viruses, as multiple introductions into any locality in any )] TJ ET BT 26.250 65.934 Td /F1 9.8 Tf [(season )] TJ ET 0.267 0.267 0.267 rg BT 60.395 65.934 Td /F1 9.8 Tf [([8])] TJ ET BT 71.237 65.934 Td /F1 9.8 Tf [([9])] TJ ET 0.271 0.267 0.267 rg BT 82.078 65.934 Td /F1 9.8 Tf [( mean that equivalent point-source outbreaks are rarely observed.)] TJ ET Q q 15.000 18.901 577.500 758.099 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F1 9.8 Tf [(approximately the first 7 weeks of 2009\). In sum, this means that there was a period of up to about 3 months where the virus )] TJ ET BT 26.250 755.571 Td /F1 9.8 Tf [(was circulating in humans prior to initial characterization \(cryptic transmission\).)] TJ ET BT 26.250 736.167 Td /F1 9.8 Tf [(The substitution rate for H1N1pdm is significantly higher than that estimated by Smith )] TJ ET BT 396.906 736.167 Td /F5 9.8 Tf [(et al.)] TJ ET 0.267 0.267 0.267 rg BT 418.044 736.167 Td /F1 9.8 Tf [( [2])] TJ ET 0.271 0.267 0.267 rg BT 431.596 736.167 Td /F1 9.8 Tf [( for each of the genomic )] TJ ET BT 26.250 724.262 Td /F1 9.8 Tf [(segments for a panel of related swine viruses \(at ~3 x 10 )] TJ ET BT 273.637 728.150 Td /F1 8.7 Tf [(-3)] TJ ET BT 281.341 724.262 Td /F1 9.8 Tf [( substitutions/site/year\). This higher rate in H1N1pdm was noted by )] TJ ET BT 26.250 712.357 Td /F1 9.8 Tf [(Smith )] TJ ET BT 53.882 712.357 Td /F5 9.8 Tf [(et al.)] TJ ET BT 75.019 712.357 Td /F1 9.8 Tf [( , and as an explanation it was suggested that the rapid epidemic spread and short timescale had resulted in a )] TJ ET BT 26.250 700.452 Td /F1 9.8 Tf [(proportion of mildly-deleterious mutations being maintained in the population. It will be possible to test this hypothesis when )] TJ ET BT 26.250 688.548 Td /F1 9.8 Tf [(H1N1pdm sequences are sampled over a longer time-period.)] TJ ET BT 26.250 669.143 Td /F4 9.8 Tf [(Table 1)] TJ ET BT 59.849 669.143 Td /F4 9.8 Tf [(. )] TJ ET BT 65.269 669.143 Td /F1 9.8 Tf [( Marginal posterior estimates of model parameters.)] TJ ET 1.000 1.000 1.000 rg 26.250 592.524 555.000 66.738 re f 0.267 0.267 0.267 rg 26.625 658.137 128.929 0.750 re f 26.625 624.043 0.750 34.844 re f 154.804 658.137 123.439 0.750 re f 154.804 624.043 0.750 34.844 re f 0.271 0.267 0.267 rg BT 176.967 648.282 Td /F1 9.8 Tf [(Rate of molecular )] TJ ET BT 195.658 640.651 Td /F1 9.8 Tf [(evolution )] TJ ET BT 168.781 630.659 Td /F1 9.8 Tf [(\(x10 )] TJ ET BT 190.455 633.224 Td /F1 8.7 Tf [(-3)] TJ ET BT 198.160 630.659 Td /F1 9.8 Tf [( subs/site/year\))] TJ ET 0.267 0.267 0.267 rg 277.493 658.137 114.292 0.750 re f 277.493 624.043 0.750 34.844 re f 0.271 0.267 0.267 rg BT 290.744 648.282 Td /F1 9.8 Tf [(Date of most recent )] TJ ET BT 295.897 640.651 Td /F1 9.8 Tf [(common ancestor)] TJ ET 0.267 0.267 0.267 rg 391.035 658.137 104.001 0.750 re f 391.035 624.043 0.750 34.844 re f 0.271 0.267 0.267 rg BT 400.223 648.282 Td /F1 9.8 Tf [(Exponential growth )] TJ ET BT 434.636 640.651 Td /F1 9.8 Tf [(rate)] TJ ET 0.267 0.267 0.267 rg 494.286 658.137 86.589 0.750 re f 494.286 624.043 0.750 34.844 re f 580.125 624.043 0.750 34.844 re f 0.271 0.267 0.267 rg BT 506.424 648.282 Td /F1 9.8 Tf [(Doubling time )] TJ ET BT 524.038 640.651 Td /F1 9.8 Tf [(\(days\))] TJ ET 0.267 0.267 0.267 rg 26.625 624.043 128.929 0.750 re f 26.625 592.899 128.929 0.750 re f 26.625 592.899 0.750 31.894 re f 0.271 0.267 0.267 rg BT 48.277 614.188 Td /F1 9.8 Tf [(mean estimate and )] TJ ET BT 35.548 606.556 Td /F1 9.8 Tf [(Bayesian credible interval)] TJ ET 0.267 0.267 0.267 rg 154.804 624.043 123.439 0.750 re f 154.804 592.899 123.439 0.750 re f 154.804 592.899 0.750 31.894 re f 0.271 0.267 0.267 rg BT 205.681 614.188 Td /F1 9.8 Tf [(5.02 )] TJ ET BT 191.592 606.556 Td /F1 9.8 Tf [(\(4.17, 5.95\))] TJ ET 0.267 0.267 0.267 rg 277.493 624.043 114.292 0.750 re f 277.493 592.899 114.292 0.750 re f 277.493 592.899 0.750 31.894 re f 0.271 0.267 0.267 rg BT 305.915 614.188 Td /F1 9.8 Tf [(27-Jan-2009 )] TJ ET BT 285.060 606.556 Td /F1 9.8 Tf [(\(30-Dec-2008, 22-Feb-)] TJ ET BT 322.174 598.925 Td /F1 9.8 Tf [(2009\))] TJ ET 0.267 0.267 0.267 rg 391.035 624.043 104.001 0.750 re f 391.035 592.899 104.001 0.750 re f 391.035 592.899 0.750 31.894 re f 0.271 0.267 0.267 rg BT 429.483 614.188 Td /F1 9.8 Tf [(14.92 )] TJ ET BT 412.684 606.556 Td /F1 9.8 Tf [(\(10.44, 19.61\))] TJ ET 0.267 0.267 0.267 rg 494.286 624.043 86.589 0.750 re f 494.286 592.899 86.589 0.750 re f 494.286 592.899 0.750 31.894 re f 580.125 592.899 0.750 31.894 re f 0.271 0.267 0.267 rg BT 526.739 614.188 Td /F1 9.8 Tf [(17.0 )] TJ ET BT 512.650 606.556 Td /F1 9.8 Tf [(\(12.9, 24.2\))] TJ ET BT 26.250 545.500 Td /F1 9.8 Tf [(Figure 1 shows the maximum clade credibility tree \(the tree sampled from the MCMC with the highest product of individual clade )] TJ ET BT 26.250 533.595 Td /F1 9.8 Tf [(probabilities\). This tree is intended as a representative tree from the posterior sample; however, the ages of each node in the )] TJ ET BT 26.250 521.690 Td /F1 9.8 Tf [(tree are set to the mean across the entire sample.)] TJ ET 0.965 0.965 0.965 rg 26.250 193.196 555.000 318.614 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 511.810 m 581.250 511.810 l 581.250 511.060 l 26.250 511.060 l f 26.250 193.196 m 581.250 193.196 l 581.250 193.946 l 26.250 193.946 l f q 155.250 0 0 225.000 35.250 277.060 cm /I14 Do Q q 35.250 204.446 537.000 66.614 re W n 0.271 0.267 0.267 rg BT 35.250 261.536 Td /F4 9.8 Tf [(Fig. 1: The maximum clade credibility \(MCC\) tree of H1N1pdm.)] TJ ET BT 35.250 242.166 Td /F1 9.8 Tf [(In blue is the marginal posterior probability density of the time of the most recent common ancestors of the sampled )] TJ ET BT 35.250 228.429 Td /F1 9.8 Tf [(lineages \(95% credible interval shown by darker blue\). Clades are labelled with their posterior probability where greater )] TJ ET BT 35.250 214.693 Td /F1 9.8 Tf [(than 0.5. Lineages are coloured using a parsimonious reconstruction based on the locations of the sampled viruses.)] TJ ET Q 0.267 0.267 0.267 rg BT 26.250 176.172 Td /F1 9.8 Tf [(PDF version with isolate names)] TJ ET 0.271 0.267 0.267 rg BT 26.250 156.767 Td /F1 9.8 Tf [(The color-coded branches highlight the rapid spatial diffusion of H1N1pdm, which multiple entries into countries from Asia and )] TJ ET BT 26.250 144.863 Td /F1 9.8 Tf [(Europe. Such a spatial mixing is typical for influenza A virus )] TJ ET 0.267 0.267 0.267 rg BT 286.351 144.863 Td /F1 9.8 Tf [([7])] TJ ET 0.271 0.267 0.267 rg BT 297.193 144.863 Td /F1 9.8 Tf [( and suggests that H1N1pdm exhibits similar spatial dynamics to )] TJ ET BT 26.250 132.958 Td /F1 9.8 Tf [(those of seasonal influenza. It is also notable that multiple lineages of H1N1pdm are circulating in a single geographical region )] TJ ET BT 26.250 121.053 Td /F1 9.8 Tf [(\(with the United States a notable example\), providing the raw material for intra-subtype reassortment.)] TJ ET BT 26.250 101.648 Td /F1 9.8 Tf [(The population growth rates and epidemic doubling times inferred here are similar to those estimated previously for H1N1pdm )] TJ ET 0.267 0.267 0.267 rg BT 26.250 89.744 Td /F1 9.8 Tf [([4])] TJ ET 0.271 0.267 0.267 rg BT 37.092 89.744 Td /F1 9.8 Tf [( and suggest that the virus will continue to spread globally. However, it is difficult to compare these coalescent-based )] TJ ET BT 26.250 77.839 Td /F1 9.8 Tf [(estimates of epidemiological dynamics with those of seasonal influenza viruses, as multiple introductions into any locality in any )] TJ ET BT 26.250 65.934 Td /F1 9.8 Tf [(season )] TJ ET 0.267 0.267 0.267 rg BT 60.395 65.934 Td /F1 9.8 Tf [([8])] TJ ET BT 71.237 65.934 Td /F1 9.8 Tf [([9])] TJ ET 0.271 0.267 0.267 rg BT 82.078 65.934 Td /F1 9.8 Tf [( mean that equivalent point-source outbreaks are rarely observed.)] TJ ET Q q 155.250 0 0 225.000 35.250 277.060 cm /I16 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 88 0 obj << /Type /Font /Subtype /Type1 /Name /F5 /BaseFont /Helvetica-Oblique /Encoding /WinAnsiEncoding >> endobj 89 0 obj << /Type /Annot /Subtype /Link /A 90 0 R /Border [0 0 0] /H /I /Rect [ 418.0440 735.2648 431.5965 745.1854 ] >> endobj 90 0 obj << /Type /Action >> endobj 91 0 obj << /Type /Annot /Subtype /Link /A 92 0 R /Border [0 0 0] /H /I /Rect [ 35.2500 277.0595 190.5000 502.0595 ] >> endobj 92 0 obj << /Type /Action /S /URI /URI (http://currents.plos.org/influenza/files/2009/08/genomes.hkyg_.ucln_.egc_.mcc_.tree2_.png) >> endobj 93 0 obj << /Type /XObject /Subtype /Image /Width 207 /Height 300 /Filter /FlateDecode /DecodeParms << /Predictor 15 /Colors 1 /Columns 207 /BitsPerComponent 8>> /ColorSpace /DeviceGray /BitsPerComponent 8 /Length 9529>> stream xDk?f&df2dd$d$II$II2I$d$Wf8ccff$Wsvnu~{^}={?z|SuZAU" T2Q9Q"IX3v;v:uK -&$EDLE`K. 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B=t`E(<˅‘ba,Hjjjj3*MB>Oh 7v5wp=IC=J!PJ!$blf$S"!@8tPQf,B !Ɏd?c<|.j24M)QBc׎P2jMql6OHէNRB)d8%Q/d2#=Bf|> >YɌ H<0e/ G+PJRRJ(tt$H$$JL8@#}l֬:PJ %ϯQ[WWRZJQB٬RT(!>?Lե(e޲}["$ ˏvm߹pȲwDܹM><acL x,z^Q UI*U{7\Lc`42sQB;>fᮔ[7m!N?zsX‘-7jݽzq/3~/~׏dFjj%*R)[lٍ?)g>:zhn=U$*IT2.D%YcלӴ!P"tp{h`L Ȳ|1pN魩L[vD ѻCv 3ÅBξ'zꚱpZJq&:٧;+=8_]]=&u,=\l>z谢$-hĊU++Tj"Q j b͔/o_hhl:rpq-5!L&v0U۶]:rH*r1$dY&'(IL%AgA [ )x2NBd28T5dODW֥ܴ5\ tn4*3Z[@Owdḱt,\_WW748H[g*Ξ3gΔ$Iqeeg [Prk֭d߿k箵h$*jz̎ByL}EfuΎdkjjbx(2_Q[a{THiV;>vͮت+KRf?oJ,$-'ጱMp$r-1Dh ^=9vxss$ɄfBVILy;mb׾ }%;`rv ZRɪH$^q)^u,#5McJ ctTS41iLcӘ4>/ endstream endobj 139 0 obj << /Type /Page /Parent 3 0 R /Annots [ 141 0 R 143 0 R 145 0 R 147 0 R 149 0 R 151 0 R 153 0 R 155 0 R 157 0 R 159 0 R 161 0 R 163 0 R ] /Contents 140 0 R >> endobj 140 0 obj << /Length 17062 >> stream 0.271 0.267 0.267 rg q 15.000 100.010 577.500 676.990 re W n 0.271 0.267 0.267 rg BT 26.250 750.278 Td /F4 12.0 Tf [(Acknowledgments)] TJ ET BT 26.250 730.324 Td /F1 9.8 Tf [(Thanks to Gytis Dudas for help with collating the sequence data.)] TJ ET BT 26.250 693.722 Td /F4 12.0 Tf [(Funding information)] TJ ET BT 26.250 673.767 Td /F1 9.8 Tf [(AR was funded by The Royal Society of London and the Interdisciplinary Centre for Human and Avian Influenza Research )] TJ ET BT 26.250 661.863 Td /F1 9.8 Tf [(\(ICHAIR\). ECH was funded by NIH grant R01 GM080533. Both AR and ECH thank the Fogarty International Center, NIH, for )] TJ ET BT 26.250 649.958 Td /F1 9.8 Tf [(continued support.)] TJ ET BT 26.250 613.355 Td /F4 12.0 Tf [(Competing interests)] TJ ET BT 26.250 593.401 Td /F1 9.8 Tf [(The authors have declared that no competing interests exist.)] TJ ET BT 26.250 556.799 Td /F4 12.0 Tf [(References)] TJ ET BT 26.250 529.344 Td /F1 9.8 Tf [(1.)] TJ ET BT 38.132 529.344 Td /F1 9.8 Tf [(Novel Swine-Origin Influenza A \(H1N1\) Virus Investigation Team, Dawood FS, Jain S, Finelli L, Shaw MW, Lindstrom S, )] TJ ET BT 26.250 517.440 Td /F1 9.8 Tf [(Garten RJ, Gubareva LV, Xu X, Bridges CB, Uyeki TM. Emergence of a novel swine-origin influenza A \(H1N1\) virus in humans. )] TJ ET BT 26.250 505.535 Td /F1 9.8 Tf [(N Engl J Med. 2009 Jun 18;360\(25\):2605-15. Epub 2009 May 7. Erratum in: N Engl J Med. 2009 Jul 2;361\(1\):102. )] TJ ET 0.267 0.267 0.267 rg BT 26.250 497.049 Td /F1 7.5 Tf [(REFERENCE LINK)] TJ ET 0.271 0.267 0.267 rg BT 26.250 478.499 Td /F1 9.8 Tf [(2.)] TJ ET BT 38.132 478.499 Td /F1 9.8 Tf [(Smith GJ, Vijaykrishna D, Bahl J, Lycett SJ, Worobey M, Pybus OG, Ma SK, Cheung CL, Raghwani J, Bhatt S, Peiris JS, )] TJ ET BT 26.250 466.594 Td /F1 9.8 Tf [(Guan Y, Rambaut A. Origins and evolutionary genomics of the 2009 swine-origin H1N1 influenza A epidemic. Nature. 2009 Jun )] TJ ET BT 26.250 454.689 Td /F1 9.8 Tf [(25;459\(7250\):1122-5. )] TJ ET 0.267 0.267 0.267 rg BT 26.250 446.204 Td /F1 7.5 Tf [(REFERENCE LINK)] TJ ET 0.271 0.267 0.267 rg BT 26.250 427.653 Td /F1 9.8 Tf [(3.)] TJ ET BT 38.132 427.653 Td /F1 9.8 Tf [(World Health Organization \(2009\) Pandemic \(H1N1\) 2009 - update 61. August 12th 2009.)] TJ ET 0.267 0.267 0.267 rg BT 26.250 419.168 Td /F1 7.5 Tf [(REFERENCE LINK)] TJ ET 0.271 0.267 0.267 rg BT 26.250 400.617 Td /F1 9.8 Tf [(4.)] TJ ET BT 38.132 400.617 Td /F1 9.8 Tf [(Fraser C, Donnelly CA, Cauchemez S, Hanage WP, Van Kerkhove MD, Hollingsworth TD, Griffin J, Baggaley RF, Jenkins )] TJ ET BT 26.250 388.713 Td /F1 9.8 Tf [(HE, Lyons EJ, Jombart T, Hinsley WR, Grassly NC, Balloux F, Ghani AC, Ferguson NM, Rambaut A, Pybus OG, Lopez-Gatell )] TJ ET BT 26.250 376.808 Td /F1 9.8 Tf [(H, Alpuche-Aranda CM, Chapela IB, Zavala EP, Guevara DM, Checchi F, Garcia E, Hugonnet S, Roth C; WHO Rapid )] TJ ET BT 26.250 364.903 Td /F1 9.8 Tf [(Pandemic Assessment Collaboration. Pandemic potential of a strain of influenza A \(H1N1\): early findings. Science. 2009 Jun )] TJ ET BT 26.250 352.998 Td /F1 9.8 Tf [(19;324\(5934\):1557-61. Epub 2009 May 11.)] TJ ET 0.267 0.267 0.267 rg BT 26.250 344.513 Td /F1 7.5 Tf [(REFERENCE LINK)] TJ ET 0.271 0.267 0.267 rg BT 26.250 325.962 Td /F1 9.8 Tf [(5.)] TJ ET BT 38.132 325.962 Td /F1 9.8 Tf [(Drummond AJ, Rambaut A. BEAST: Bayesian evolutionary analysis by sampling trees. BMC Evol Biol. 2007 Nov 8;7:214. )] TJ ET BT 26.250 314.058 Td /F1 9.8 Tf [([http://beast.bio.ed.ac.uk/], [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2247476/], )] TJ ET BT 26.250 302.153 Td /F1 9.8 Tf [([http://www.ncbi.nlm.nih.gov/pubmed/17996036])] TJ ET BT 26.250 282.748 Td /F1 9.8 Tf [(6.)] TJ ET BT 38.132 282.748 Td /F1 9.8 Tf [(Drummond AJ, Ho SY, Phillips MJ, Rambaut A. Relaxed phylogenetics and dating with confidence. PLoS Biol. 2006 )] TJ ET BT 26.250 270.843 Td /F1 9.8 Tf [(May;4\(5\):e88. Epub 2006 Mar 14. [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1395354/], )] TJ ET BT 26.250 258.939 Td /F1 9.8 Tf [([http://www.ncbi.nlm.nih.gov/pubmed/16683862])] TJ ET BT 26.250 239.534 Td /F1 9.8 Tf [(7.)] TJ ET BT 38.132 239.534 Td /F1 9.8 Tf [(Nelson MI, Simonsen L, Viboud C, Miller MA, Holmes EC. Phylogenetic analysis reveals the global migration of seasonal )] TJ ET BT 26.250 227.629 Td /F1 9.8 Tf [(influenza A viruses. PLoS Pathog. 2007 Sep 14;3\(9\):1220-8. [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2323296/], )] TJ ET BT 26.250 215.724 Td /F1 9.8 Tf [([http://www.ncbi.nlm.nih.gov/pubmed/17941707])] TJ ET BT 26.250 196.320 Td /F1 9.8 Tf [(8.)] TJ ET BT 38.132 196.320 Td /F1 9.8 Tf [(Holmes EC, Ghedin E, Miller N, Taylor J, Bao Y, St George K, Grenfell BT, Salzberg SL, Fraser CM, Lipman DJ, )] TJ ET BT 26.250 184.415 Td /F1 9.8 Tf [(Taubenberger JK. Whole-genome analysis of human influenza A virus reveals multiple persistent lineages and reassortment )] TJ ET BT 26.250 172.510 Td /F1 9.8 Tf [(among recent H3N2 viruses. PLoS Biol. 2005 Sep;3\(9\):e300. Epub 2005 Jul 26. )] TJ ET BT 26.250 160.605 Td /F1 9.8 Tf [([http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1180517/], [http://www.ncbi.nlm.nih.gov/pubmed/16026181])] TJ ET BT 26.250 141.201 Td /F1 9.8 Tf [(9.)] TJ ET BT 38.132 141.201 Td /F1 9.8 Tf [(Rambaut A, Pybus OG, Nelson MI, Viboud C, Taubenberger JK, Holmes EC. The genomic and epidemiological dynamics of )] TJ ET BT 26.250 129.296 Td /F1 9.8 Tf [(human influenza A virus. Nature. 2008 May 29;453\(7195\):615-9. Epub 2008 Apr 16. )] TJ ET BT 26.250 117.391 Td /F1 9.8 Tf [([http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2441973/], [http://www.ncbi.nlm.nih.gov/pubmed/18418375])] TJ ET Q q 15.000 100.010 577.500 676.990 re W n 0.271 0.267 0.267 rg BT 26.250 750.278 Td /F4 12.0 Tf [(Acknowledgments)] TJ ET BT 26.250 730.324 Td /F1 9.8 Tf [(Thanks to Gytis Dudas for help with collating the sequence data.)] TJ ET BT 26.250 693.722 Td /F4 12.0 Tf [(Funding information)] TJ ET BT 26.250 673.767 Td /F1 9.8 Tf [(AR was funded by The Royal Society of London and the Interdisciplinary Centre for Human and Avian Influenza Research )] TJ ET BT 26.250 661.863 Td /F1 9.8 Tf [(\(ICHAIR\). ECH was funded by NIH grant R01 GM080533. Both AR and ECH thank the Fogarty International Center, NIH, for )] TJ ET BT 26.250 649.958 Td /F1 9.8 Tf [(continued support.)] TJ ET BT 26.250 613.355 Td /F4 12.0 Tf [(Competing interests)] TJ ET BT 26.250 593.401 Td /F1 9.8 Tf [(The authors have declared that no competing interests exist.)] TJ ET BT 26.250 556.799 Td /F4 12.0 Tf [(References)] TJ ET BT 26.250 529.344 Td /F1 9.8 Tf [(1.)] TJ ET BT 38.132 529.344 Td /F1 9.8 Tf [(Novel Swine-Origin Influenza A \(H1N1\) Virus Investigation Team, Dawood FS, Jain S, Finelli L, Shaw MW, Lindstrom S, )] TJ ET BT 26.250 517.440 Td /F1 9.8 Tf [(Garten RJ, Gubareva LV, Xu X, Bridges CB, Uyeki TM. Emergence of a novel swine-origin influenza A \(H1N1\) virus in humans. )] TJ ET BT 26.250 505.535 Td /F1 9.8 Tf [(N Engl J Med. 2009 Jun 18;360\(25\):2605-15. Epub 2009 May 7. Erratum in: N Engl J Med. 2009 Jul 2;361\(1\):102. )] TJ ET 0.267 0.267 0.267 rg BT 26.250 497.049 Td /F1 7.5 Tf [(REFERENCE LINK)] TJ ET 0.271 0.267 0.267 rg BT 26.250 478.499 Td /F1 9.8 Tf [(2.)] TJ ET BT 38.132 478.499 Td /F1 9.8 Tf [(Smith GJ, Vijaykrishna D, Bahl J, Lycett SJ, Worobey M, Pybus OG, Ma SK, Cheung CL, Raghwani J, Bhatt S, Peiris JS, )] TJ ET BT 26.250 466.594 Td /F1 9.8 Tf [(Guan Y, Rambaut A. Origins and evolutionary genomics of the 2009 swine-origin H1N1 influenza A epidemic. Nature. 2009 Jun )] TJ ET BT 26.250 454.689 Td /F1 9.8 Tf [(25;459\(7250\):1122-5. )] TJ ET 0.267 0.267 0.267 rg BT 26.250 446.204 Td /F1 7.5 Tf [(REFERENCE LINK)] TJ ET 0.271 0.267 0.267 rg BT 26.250 427.653 Td /F1 9.8 Tf [(3.)] TJ ET BT 38.132 427.653 Td /F1 9.8 Tf [(World Health Organization \(2009\) Pandemic \(H1N1\) 2009 - update 61. August 12th 2009.)] TJ ET 0.267 0.267 0.267 rg BT 26.250 419.168 Td /F1 7.5 Tf [(REFERENCE LINK)] TJ ET 0.271 0.267 0.267 rg BT 26.250 400.617 Td /F1 9.8 Tf [(4.)] TJ ET BT 38.132 400.617 Td /F1 9.8 Tf [(Fraser C, Donnelly CA, Cauchemez S, Hanage WP, Van Kerkhove MD, Hollingsworth TD, Griffin J, Baggaley RF, Jenkins )] TJ ET BT 26.250 388.713 Td /F1 9.8 Tf [(HE, Lyons EJ, Jombart T, Hinsley WR, Grassly NC, Balloux F, Ghani AC, Ferguson NM, Rambaut A, Pybus OG, Lopez-Gatell )] TJ ET BT 26.250 376.808 Td /F1 9.8 Tf [(H, Alpuche-Aranda CM, Chapela IB, Zavala EP, Guevara DM, Checchi F, Garcia E, Hugonnet S, Roth C; WHO Rapid )] TJ ET BT 26.250 364.903 Td /F1 9.8 Tf [(Pandemic Assessment Collaboration. Pandemic potential of a strain of influenza A \(H1N1\): early findings. Science. 2009 Jun )] TJ ET BT 26.250 352.998 Td /F1 9.8 Tf [(19;324\(5934\):1557-61. Epub 2009 May 11.)] TJ ET 0.267 0.267 0.267 rg BT 26.250 344.513 Td /F1 7.5 Tf [(REFERENCE LINK)] TJ ET 0.271 0.267 0.267 rg BT 26.250 325.962 Td /F1 9.8 Tf [(5.)] TJ ET BT 38.132 325.962 Td /F1 9.8 Tf [(Drummond AJ, Rambaut A. BEAST: Bayesian evolutionary analysis by sampling trees. BMC Evol Biol. 2007 Nov 8;7:214. )] TJ ET BT 26.250 314.058 Td /F1 9.8 Tf [([http://beast.bio.ed.ac.uk/], [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2247476/], )] TJ ET BT 26.250 302.153 Td /F1 9.8 Tf [([http://www.ncbi.nlm.nih.gov/pubmed/17996036])] TJ ET BT 26.250 282.748 Td /F1 9.8 Tf [(6.)] TJ ET BT 38.132 282.748 Td /F1 9.8 Tf [(Drummond AJ, Ho SY, Phillips MJ, Rambaut A. Relaxed phylogenetics and dating with confidence. PLoS Biol. 2006 )] TJ ET BT 26.250 270.843 Td /F1 9.8 Tf [(May;4\(5\):e88. Epub 2006 Mar 14. [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1395354/], )] TJ ET BT 26.250 258.939 Td /F1 9.8 Tf [([http://www.ncbi.nlm.nih.gov/pubmed/16683862])] TJ ET BT 26.250 239.534 Td /F1 9.8 Tf [(7.)] TJ ET BT 38.132 239.534 Td /F1 9.8 Tf [(Nelson MI, Simonsen L, Viboud C, Miller MA, Holmes EC. Phylogenetic analysis reveals the global migration of seasonal )] TJ ET BT 26.250 227.629 Td /F1 9.8 Tf [(influenza A viruses. PLoS Pathog. 2007 Sep 14;3\(9\):1220-8. [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2323296/], )] TJ ET BT 26.250 215.724 Td /F1 9.8 Tf [([http://www.ncbi.nlm.nih.gov/pubmed/17941707])] TJ ET BT 26.250 196.320 Td /F1 9.8 Tf [(8.)] TJ ET BT 38.132 196.320 Td /F1 9.8 Tf [(Holmes EC, Ghedin E, Miller N, Taylor J, Bao Y, St George K, Grenfell BT, Salzberg SL, Fraser CM, Lipman DJ, )] TJ ET BT 26.250 184.415 Td /F1 9.8 Tf [(Taubenberger JK. Whole-genome analysis of human influenza A virus reveals multiple persistent lineages and reassortment )] TJ ET BT 26.250 172.510 Td /F1 9.8 Tf [(among recent H3N2 viruses. PLoS Biol. 2005 Sep;3\(9\):e300. Epub 2005 Jul 26. )] TJ ET BT 26.250 160.605 Td /F1 9.8 Tf [([http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1180517/], [http://www.ncbi.nlm.nih.gov/pubmed/16026181])] TJ ET BT 26.250 141.201 Td /F1 9.8 Tf [(9.)] TJ ET BT 38.132 141.201 Td /F1 9.8 Tf [(Rambaut A, Pybus OG, Nelson MI, Viboud C, Taubenberger JK, Holmes EC. The genomic and epidemiological dynamics of )] TJ ET BT 26.250 129.296 Td /F1 9.8 Tf [(human influenza A virus. Nature. 2008 May 29;453\(7195\):615-9. Epub 2008 Apr 16. )] TJ ET BT 26.250 117.391 Td /F1 9.8 Tf [([http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2441973/], [http://www.ncbi.nlm.nih.gov/pubmed/18418375])] TJ ET Q q 15.000 100.010 577.500 676.990 re W n 0.271 0.267 0.267 rg BT 26.250 750.278 Td /F4 12.0 Tf [(Acknowledgments)] TJ ET BT 26.250 730.324 Td /F1 9.8 Tf [(Thanks to Gytis Dudas for help with collating the sequence data.)] TJ ET BT 26.250 693.722 Td /F4 12.0 Tf [(Funding information)] TJ ET BT 26.250 673.767 Td /F1 9.8 Tf [(AR was funded by The Royal Society of London and the Interdisciplinary Centre for Human and Avian Influenza Research )] TJ ET BT 26.250 661.863 Td /F1 9.8 Tf [(\(ICHAIR\). ECH was funded by NIH grant R01 GM080533. Both AR and ECH thank the Fogarty International Center, NIH, for )] TJ ET BT 26.250 649.958 Td /F1 9.8 Tf [(continued support.)] TJ ET BT 26.250 613.355 Td /F4 12.0 Tf [(Competing interests)] TJ ET BT 26.250 593.401 Td /F1 9.8 Tf [(The authors have declared that no competing interests exist.)] TJ ET BT 26.250 556.799 Td /F4 12.0 Tf [(References)] TJ ET BT 26.250 529.344 Td /F1 9.8 Tf [(1.)] TJ ET BT 38.132 529.344 Td /F1 9.8 Tf [(Novel Swine-Origin Influenza A \(H1N1\) Virus Investigation Team, Dawood FS, Jain S, Finelli L, Shaw MW, Lindstrom S, )] TJ ET BT 26.250 517.440 Td /F1 9.8 Tf [(Garten RJ, Gubareva LV, Xu X, Bridges CB, Uyeki TM. Emergence of a novel swine-origin influenza A \(H1N1\) virus in humans. )] TJ ET BT 26.250 505.535 Td /F1 9.8 Tf [(N Engl J Med. 2009 Jun 18;360\(25\):2605-15. Epub 2009 May 7. Erratum in: N Engl J Med. 2009 Jul 2;361\(1\):102. )] TJ ET 0.267 0.267 0.267 rg BT 26.250 497.049 Td /F1 7.5 Tf [(REFERENCE LINK)] TJ ET 0.271 0.267 0.267 rg BT 26.250 478.499 Td /F1 9.8 Tf [(2.)] TJ ET BT 38.132 478.499 Td /F1 9.8 Tf [(Smith GJ, Vijaykrishna D, Bahl J, Lycett SJ, Worobey M, Pybus OG, Ma SK, Cheung CL, Raghwani J, Bhatt S, Peiris JS, )] TJ ET BT 26.250 466.594 Td /F1 9.8 Tf [(Guan Y, Rambaut A. Origins and evolutionary genomics of the 2009 swine-origin H1N1 influenza A epidemic. Nature. 2009 Jun )] TJ ET BT 26.250 454.689 Td /F1 9.8 Tf [(25;459\(7250\):1122-5. )] TJ ET 0.267 0.267 0.267 rg BT 26.250 446.204 Td /F1 7.5 Tf [(REFERENCE LINK)] TJ ET 0.271 0.267 0.267 rg BT 26.250 427.653 Td /F1 9.8 Tf [(3.)] TJ ET BT 38.132 427.653 Td /F1 9.8 Tf [(World Health Organization \(2009\) Pandemic \(H1N1\) 2009 - update 61. August 12th 2009.)] TJ ET 0.267 0.267 0.267 rg BT 26.250 419.168 Td /F1 7.5 Tf [(REFERENCE LINK)] TJ ET 0.271 0.267 0.267 rg BT 26.250 400.617 Td /F1 9.8 Tf [(4.)] TJ ET BT 38.132 400.617 Td /F1 9.8 Tf [(Fraser C, Donnelly CA, Cauchemez S, Hanage WP, Van Kerkhove MD, Hollingsworth TD, Griffin J, Baggaley RF, Jenkins )] TJ ET BT 26.250 388.713 Td /F1 9.8 Tf [(HE, Lyons EJ, Jombart T, Hinsley WR, Grassly NC, Balloux F, Ghani AC, Ferguson NM, Rambaut A, Pybus OG, Lopez-Gatell )] TJ ET BT 26.250 376.808 Td /F1 9.8 Tf [(H, Alpuche-Aranda CM, Chapela IB, Zavala EP, Guevara DM, Checchi F, Garcia E, Hugonnet S, Roth C; WHO Rapid )] TJ ET BT 26.250 364.903 Td /F1 9.8 Tf [(Pandemic Assessment Collaboration. Pandemic potential of a strain of influenza A \(H1N1\): early findings. Science. 2009 Jun )] TJ ET BT 26.250 352.998 Td /F1 9.8 Tf [(19;324\(5934\):1557-61. Epub 2009 May 11.)] TJ ET 0.267 0.267 0.267 rg BT 26.250 344.513 Td /F1 7.5 Tf [(REFERENCE LINK)] TJ ET 0.271 0.267 0.267 rg BT 26.250 325.962 Td /F1 9.8 Tf [(5.)] TJ ET BT 38.132 325.962 Td /F1 9.8 Tf [(Drummond AJ, Rambaut A. BEAST: Bayesian evolutionary analysis by sampling trees. BMC Evol Biol. 2007 Nov 8;7:214. )] TJ ET BT 26.250 314.058 Td /F1 9.8 Tf [([http://beast.bio.ed.ac.uk/], [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2247476/], )] TJ ET BT 26.250 302.153 Td /F1 9.8 Tf [([http://www.ncbi.nlm.nih.gov/pubmed/17996036])] TJ ET BT 26.250 282.748 Td /F1 9.8 Tf [(6.)] TJ ET BT 38.132 282.748 Td /F1 9.8 Tf [(Drummond AJ, Ho SY, Phillips MJ, Rambaut A. Relaxed phylogenetics and dating with confidence. PLoS Biol. 2006 )] TJ ET BT 26.250 270.843 Td /F1 9.8 Tf [(May;4\(5\):e88. Epub 2006 Mar 14. [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1395354/], )] TJ ET BT 26.250 258.939 Td /F1 9.8 Tf [([http://www.ncbi.nlm.nih.gov/pubmed/16683862])] TJ ET BT 26.250 239.534 Td /F1 9.8 Tf [(7.)] TJ ET BT 38.132 239.534 Td /F1 9.8 Tf [(Nelson MI, Simonsen L, Viboud C, Miller MA, Holmes EC. Phylogenetic analysis reveals the global migration of seasonal )] TJ ET BT 26.250 227.629 Td /F1 9.8 Tf [(influenza A viruses. PLoS Pathog. 2007 Sep 14;3\(9\):1220-8. [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2323296/], )] TJ ET BT 26.250 215.724 Td /F1 9.8 Tf [([http://www.ncbi.nlm.nih.gov/pubmed/17941707])] TJ ET BT 26.250 196.320 Td /F1 9.8 Tf [(8.)] TJ ET BT 38.132 196.320 Td /F1 9.8 Tf [(Holmes EC, Ghedin E, Miller N, Taylor J, Bao Y, St George K, Grenfell BT, Salzberg SL, Fraser CM, Lipman DJ, )] TJ ET BT 26.250 184.415 Td /F1 9.8 Tf [(Taubenberger JK. Whole-genome analysis of human influenza A virus reveals multiple persistent lineages and reassortment )] TJ ET BT 26.250 172.510 Td /F1 9.8 Tf [(among recent H3N2 viruses. PLoS Biol. 2005 Sep;3\(9\):e300. Epub 2005 Jul 26. )] TJ ET BT 26.250 160.605 Td /F1 9.8 Tf [([http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1180517/], [http://www.ncbi.nlm.nih.gov/pubmed/16026181])] TJ ET BT 26.250 141.201 Td /F1 9.8 Tf [(9.)] TJ ET BT 38.132 141.201 Td /F1 9.8 Tf [(Rambaut A, Pybus OG, Nelson MI, Viboud C, Taubenberger JK, Holmes EC. The genomic and epidemiological dynamics of )] TJ ET BT 26.250 129.296 Td /F1 9.8 Tf [(human influenza A virus. Nature. 2008 May 29;453\(7195\):615-9. Epub 2008 Apr 16. )] TJ ET BT 26.250 117.391 Td /F1 9.8 Tf [([http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2441973/], [http://www.ncbi.nlm.nih.gov/pubmed/18418375])] TJ ET 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 141 0 obj << /Type /Annot /Subtype /Link /A 142 0 R /Border [0 0 0] /H /I /Rect [ 26.2500 496.3553 91.2600 503.9865 ] >> endobj 142 0 obj << /Type /Action /S /URI /URI (http://www.ncbi.nlm.nih.gov/pubmed/19423869) >> endobj 143 0 obj << /Type /Annot /Subtype /Link /A 144 0 R /Border [0 0 0] /H /I /Rect [ 26.2500 445.5098 91.2600 453.1410 ] >> endobj 144 0 obj << /Type /Action /S /URI /URI (http://www.ncbi.nlm.nih.gov/pubmed/19516283) >> endobj 145 0 obj << /Type /Annot /Subtype /Link /A 146 0 R /Border [0 0 0] /H /I /Rect [ 26.2500 418.4738 91.2600 426.1050 ] >> endobj 146 0 obj << /Type /Action /S /URI /URI (http://www.who.int/csr/don/2009_08_12/en/index.html) >> 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