The effective rate of influenza reassortment is limited during human infection

PLoS Pathogens

Volumn 13, Issue 2, 2017, Pages

  Sobel Leonard, Ashley ^a   McClain, Micah T ^b   Smith, Gavin J D ^c   Wentworth, David E ^d,h   Halpin, Rebecca A ^d   Lin, Xudong ^d   Ransier, Amy ^d   Stockwell, Timothy B ^d   Das, Suman R ^d   Gilbert, Anthony S ^e   Lambkin Williams, Rob ^e   Ginsburg, Geoffrey S ^b   Woods, Christopher W ^b   Koelle, Katia ^a   Illingworth, Christopher J R ^f,g  

^a DUKE UNIVERSITY   (United States)

^b DUKE UNIVERSITY SCHOOL OF MEDICINE   (United States)

^c DUKE NUS MEDICAL SCHOOL   (Singapore)

^d J CRAIG VENTER INSTITUTE   (United States)

^e QUEEN MARY UNIVERSITY OF LONDON   (United Kingdom)

^f UNIVERSITY OF CAMBRIDGE   (United Kingdom)

^g UNIVERSITY OF CAMBRIDGE   (United Kingdom)

^h CENTERS FOR DISEASE CONTROL AND PREVENTION   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

OSELTAMIVIR;

AMINO ACID SUBSTITUTION; ARTICLE; BAYES THEOREM; DISPERSITY; DRUG RESISTANCE; GENE FREQUENCY; GENE LOCUS; GENETIC ASSOCIATION; GENETIC REASSORTMENT; HAPLOTYPE; HUMAN; HUMAN CELL; INFLUENZA; MUTATION; NONHUMAN; SIMULATION; SINGLE NUCLEOTIDE POLYMORPHISM; VALIDATION PROCESS; VIRUS LOAD; BIOLOGICAL MODEL; GENETIC SELECTION; GENETICS; ORTHOMYXOVIRIDAE; VIROLOGY;

HUMANS; INFLUENZA, HUMAN; MODELS, GENETIC; ORTHOMYXOVIRIDAE; SELECTION, GENETIC;

EID: 85014077124     PISSN: 15537366     EISSN: 15537374     Source Type: Journal    
DOI: 10.1371/journal.ppat.1006203     Document Type: Article

References (93)

1. Fitch WM, Bush RM, Bender CA, Cox NJ, Long Term Trends in the Evolution of H(3) HA1 Human Influenza Type A. Proceedings of the National Academy of Sciences of the United States of America. 1997;94(15):7712–7718. doi: 10.1073/pnas.94.15.77129223253
2. Wolf YI, Viboud C, Holmes EC, Koonin EV, Lipman DJ, Long intervals of stasis punctuated by bursts of positive selection in the seasonal evolution of influenza A virus. Biology direct. 2006;1:34. doi: 10.1186/1745-6150-1-3417067369
3. Strelkowa N, Lässig M, Clonal interference in the evolution of influenza. Genetics. 2012;192(2):671–682. doi: 10.1534/genetics.112.14339622851649
4. Illingworth CJR, Mustonen V, Components of Selection in the Evolution of the Influenza Virus: Linkage Effects Beat Inherent Selection. PLoS Pathogens. 2012;8(12):e1003091. doi: 10.1371/journal.ppat.100309123300444
5. Koelle K, Rasmussen DA, The effects of a deleterious mutation load on patterns of influenza A/H3N2’s antigenic evolution in humans. eLife. 2015;4:e07361. doi: 10.7554/eLife.0736126371556
6. Nelson MI, Simonsen L, Viboud C, Miller MA, Holmes EC, Phylogenetic Analysis Reveals the Global Migration of Seasonal Influenza A Viruses. PLoS Pathogens. 2007;3(9):e131. doi: 10.1371/journal.ppat.0030131
7. Bedford T, Cobey S, Beerli P, Pascual M, Global Migration Dynamics Underlie Evolution and Persistence of Human Influenza A (H3N2). PLoS Pathogens. 2010;6(5):e1000918. doi: 10.1371/journal.ppat.100091820523898
8. Bedford T, Riley S, Barr IG, Broor S, Chadha M, Cox NJ, et al. Global circulation patterns of seasonal influenza viruses vary with antigenic drift. Nature. 2015;523(7559):217–220. doi: 10.1038/nature1446026053121
9. Bush RM, Bender CA, Subbarao K, Cox NJ, Fitch WM, Predicting the evolution of human influenza A. Science. 1999;286(5446):1921–1925. doi: 10.1126/science.286.5446.192110583948
10. Łuksza M, Lässig M, A predictive fitness model for influenza. Nature. 2014;507(7490):57–61. doi: 10.1038/nature1308724572367
11. Neher RA, Russell CA, Shraiman BI, Predicting evolution from the shape of genealogical trees. eLife. 2014;3:e03568. doi: 10.7554/eLife.03568
12. Murcia PR, Baillie GJ, Daly J, Elton D, Jervis C, Mumford JA, et al. Intra- and Interhost Evolutionary Dynamics of Equine Influenza Virus. Journal of Virology. 2010;84(14):6943–6954. doi: 10.1128/JVI.00112-1020444896
13. Varble A, Albrecht RA, Backes S, Crumiller M, Bouvier NM, Sachs D, et al. Influenza A Virus Transmission Bottlenecks Are Defined by Infection Route and Recipient Host. Cell Host and Microbe. 2014;16(5):691–700. doi: 10.1016/j.chom.2014.09.02025456074
14. Murcia PR, Hughes J, Battista P, Lloyd L, Baillie GJ, Ramirez-Gonzalez RH, et al. Evolution of an Eurasian Avian-like Influenza Virus in Naïve and Vaccinated Pigs. PLoS Pathogens. 2012;8(5):e1002730. doi: 10.1371/journal.ppat.100273022693449
15. Sobel Leonard A, McClain M, Smith G, Wentworth D, Halpin R, Lin X, et al. Deep Sequencing of Influenza A Virus from a Human Challenge Study Reveals a Selective Bottleneck and Only Limited Intrahost Genetic Diversification. J Virol, in press. 2016;. doi: 10.1128/JVI.01657-1627707932
16. Dinis JM, Florek NW, Fatola OO, Moncla LH, Mutschler JP, Charlier OK, et al. Deep Sequencing Reveals Potential Antigenic Variants at Low Frequencies in Influenza A Virus-Infected Humans. Journal of Virology. 2016;90(7):3355–3365. doi: 10.1128/JVI.03248-1526739054
17. Imai M, Watanabe T, Hatta M, Das SC, Ozawa M, Shinya K, et al. Experimental adaptation of an influenza H5 HA confers respiratory droplet transmission to a reassortant H5 HA/H1N1 virus in ferrets. Nature. 2012;486(7403):420–428. doi: 10.1038/nature1083122722205
18. Herfst S, Schrauwen EJA, Linster M, Chutinimitkul S, de Wit E, Munster VJ, et al. Airborne Transmission of Influenza A/H5N1 Virus Between Ferrets. Science. 2012;336(6088):1534–1541. doi: 10.1126/science.121336222723413
19. Lakdawala SS, Jayaraman A, Halpin RA, Lamirande EW, Shih AR, Stockwell TB, et al. The soft palate is an important site of adaptation for transmissible influenza viruses. Nature. 2015;526(7571):122–125. doi: 10.1038/nature1537926416728
20. Moncla LH, Zhong G, Nelson CW, Dinis JM, Mutschler J, Hughes AL, et al. Selective Bottlenecks Shape Evolutionary Pathways Taken during Mammalian Adaptation of a 1918-like Avian Influenza Virus. Cell Host and Microbe. 2016;19(2):169–180. doi: 10.1016/j.chom.2016.01.01126867176
21. Koel BF, van der Vliet S, Burke DF, Bestebroer TM, Bharoto EE, Yasa IWW, et al. Antigenic variation of clade 2.1 H5N1 virus is determined by a few amino acid substitutions immediately adjacent to the receptor binding site. mBio. 2014;5(3):e01070–14. doi: 10.1128/mBio.01070-1424917596
22. Gong LI, Bloom JD, Epistatically Interacting Substitutions Are Enriched during Adaptive Protein Evolution. PLoS Genetics. 2014;10(5):e1004328–10. doi: 10.1371/journal.pgen.100432824811236
23. Gong LI, Suchard MA, Bloom JD, Stability-mediated epistasis constrains the evolution of an influenza protein. eLife. 2013;2:e00631. doi: 10.7554/eLife.0063123682315
24. Kryazhimskiy S, Dushoff J, Bazykin GA, Plotkin JB, Prevalence of Epistasis in the Evolution of Influenza A Surface Proteins. PLoS Genetics. 2011;7(2):e1001301. doi: 10.1371/journal.pgen.100130121390205
25. Kaverin NV, Gambaryan AS, Bovin NV, Rudneva IA, Shilov AA, Khodova OM, et al. Postreassortment changes in influenza A virus hemagglutinin restoring HA-NA functional match. Virology. 1998;244(2):315–321. doi: 10.1006/viro.1998.91199601502
26. Mitnaul LJ, Matrosovich MN, Castrucci MR, Tuzikov AB, Bovin NV, Kobasa D, et al. Balanced hemagglutinin and neuraminidase activities are critical for efficient replication of influenza A virus. Journal of Virology. 2000;74(13):6015–6020. doi: 10.1128/JVI.74.13.6015-6020.200010846083
27. Xu R, Zhu X, McBride R, Nycholat CM, Yu W, Paulson JC, et al. Functional balance of the hemagglutinin and neuraminidase activities accompanies the emergence of the 2009 H1N1 influenza pandemic. Journal of Virology. 2012;86(17):9221–9232. doi: 10.1128/JVI.00697-1222718832
28. Zeldovich KB, Liu P, Renzette N, Foll M, Pham ST, Venev SV, et al. Positive Selection Drives Preferred Segment Combinations during Influenza Virus Reassortment. Molecular Biology and Evolution. 2015; p. 1–14.
29. Holmes EC, Ghedin E, Miller N, Taylor J, Bao Y, St George K, et al. Whole-Genome Analysis of Human Influenza A Virus Reveals Multiple Persistent Lineages and Reassortment among Recent H3N2 Viruses. PLoS Biology. 2005;3(9):e300. doi: 10.1371/journal.pbio.003030016026181
30. Ince WL, Gueye-Mbaye A, Bennink JR, Yewdell JW, Reassortment complements spontaneous mutation in influenza A virus NP and M1 genes to accelerate adaptation to a new host. Journal of Virology. 2013;87(8):4330–4338. doi: 10.1128/JVI.02749-1223365443
31. Marshall N, Priyamvada L, Ende Z, Steel J, Lowen AC, Influenza Virus Reassortment Occurs with High Frequency in the Absence of Segment Mismatch. PLoS Pathogens. 2013;9(6):e1003421. doi: 10.1371/journal.ppat.100342123785286
32. Tao H, Steel J, Lowen AC, Intrahost Dynamics of Influenza Virus Reassortment. Journal of Virology. 2014;88(13):7485–7492. doi: 10.1128/JVI.00715-1424741099
33. Tao H, Li L, White MC, Steel J, Lowen AC, Influenza A Virus Coinfection through Transmission Can Support High Levels of Reassortment. Journal of Virology. 2015;89(16):8453–8461. doi: 10.1128/JVI.01162-1526041285
34. Murillo LN, Murillo MS, Perelson AS, Towards multiscale modeling of influenza infection. Journal of Theoretical Biology. 2013;332(C):267–290. doi: 10.1016/j.jtbi.2013.03.02423608630
35. Kryazhimskiy S, Plotkin JB, The Population Genetics of dN/dS. PLoS Genetics. 2008;4(12):e1000304. doi: 10.1371/journal.pgen.100030419081788
36. Mugal CF, Wolf JBW, Kaj I, Why Time Matters: Codon Evolution and the Temporal Dynamics of dN/dS. Molecular Biology and Evolution. 2013;31(1):212–231. doi: 10.1093/molbev/mst19224129904
37. Boni MF, Zhou Y, Taubenberger JK, Holmes EC, Homologous recombination is very rare or absent in human influenza A virus. Journal of Virology. 2008;82(10):4807–4811. doi: 10.1128/JVI.02683-0718353939
38. Han GZ, Worobey M, Homologous recombination in negative sense RNA viruses. Viruses. 2011;3(8):1358–1373. doi: 10.3390/v308135821994784
39. Lam TTY, Chong YL, Shi M, Hon CC, Li J, Martin DP, et al. Systematic phylogenetic analysis of influenza A virus reveals many novel mosaic genome segments. Infection, genetics and evolution: journal of molecular epidemiology and evolutionary genetics in infectious diseases. 2013;18:367–378. doi: 10.1016/j.meegid.2013.03.01523548803
40. de Visser JAGM, Krug J, Empirical fitness landscapes and the predictability of evolution. Nature Reviews Genetics. 2014;15(7):480–490. doi: 10.1038/nrg374424913663
41. Illingworth CJR, Fischer A, Mustonen V, Identifying selection in the within-host evolution of influenza using viral sequence data. PLoS Computational Biology. 2014;10(7):e1003755. doi: 10.1371/journal.pcbi.100375525080215
42. Illingworth CJR, Fitness Inference from Short-Read Data: Within-Host Evolution of a Reassortant H5N1 Influenza Virus. Molecular Biology and Evolution. 2015;32(11):3012–3026. doi: 10.1093/molbev/msv17126243288
43. Iqbal M, Essen SC, Xiao H, Brookes SM, Brown IH, McCauley JW, Selection of variant viruses during replication and transmission of H7N1 viruses in chickens and turkeys. Virology. 2012;433(2):282–295. doi: 10.1016/j.virol.2012.08.00122944111
44. Hoelzer K, Murcia PR, Baillie GJ, Wood JLN, Metzger SM, Osterrieder N, et al. Intrahost evolutionary dynamics of canine influenza virus in naive and partially immune dogs. Journal of Virology. 2010;84(10):5329–5335. doi: 10.1128/JVI.02469-0920219907
45. Murcia PR, Baillie GJ, Stack JC, Jervis C, Elton D, Mumford JA, et al. Evolution of Equine Influenza Virus in Vaccinated Horses. Journal of Virology. 2013;87(8):4768–4771. doi: 10.1128/JVI.03379-1223388708
46. Easterday BC, Animals in the Influenza World. Philosophical Transactions of the Royal Society B: Biological Sciences. 1980;288(1029):433–437. doi: 10.1098/rstb.1980.0020
47. Belser JA, Katz JM, Tumpey TM, The ferret as a model organism to study influenza A virus infection. Disease models & mechanisms. 2011;4(5):575–579. doi: 10.1242/dmm.007823
48. Buhnerkempe MG, Gostic K, Park M, Ahsan P, Mapping influenza transmission in the ferret model to transmission in humans. eLife. 2015;4:e07969. doi: 10.7554/eLife.07969
49. Zaas AK, Chen M, Varkey J, Veldman T, Hero AO, Lucas J, et al. Gene expression signatures diagnose influenza and other symptomatic respiratory viral infections in humans. Cell Host and Microbe. 2009;6(3):207–217. doi: 10.1016/j.chom.2009.07.00619664979
50. Huang Y, Zaas AK, Rao A, Dobigeon N, Woolf PJ, Veldman T, et al. Temporal dynamics of host molecular responses differentiate symptomatic and asymptomatic influenza a infection. PLoS Genetics. 2011;7(8):e1002234. doi: 10.1371/journal.pgen.100223421901105
51. Moody MA, Zhang R, Walter EB, Woods CW, Ginsburg GS, McClain MT, et al. H3N2 influenza infection elicits more cross-reactive and less clonally expanded anti-hemagglutinin antibodies than influenza vaccination. PLoS ONE. 2011;6(10):e25797. doi: 10.1371/journal.pone.002579722039424
52. Wilkinson TM, Li CKF, Chui CSC, Huang AKY, Perkins M, Liebner JC, et al. Preexisting influenza-specific CD4+ T cells correlate with disease protection against influenza challenge in humans. Nature Medicine. 2012;18(2):274–280. doi: 10.1038/nm.261222286307
53. Zaas AK, Burke T, Chen M, McClain M, Nicholson B, Veldman T, et al. A host-based RT-PCR gene expression signature to identify acute respiratory viral infection. Science Translational Medicine. 2013;5(203):203ra126. doi: 10.1126/scitranslmed.300628024048524
54. Woods CW, McClain MT, Chen M, Zaas AK, Nicholson BP, Varkey J, et al. A host transcriptional signature for presymptomatic detection of infection in humans exposed to influenza H1N1 or H3N2. PLoS ONE. 2013;8(1):e52198. doi: 10.1371/journal.pone.005219823326326
55. Greenbaum BD, Ghedin E, ScienceDirectViral evolution: beyond drift and shift. Current Opinion in Microbiology. 2015;26:109–115. doi: 10.1016/j.mib.2015.06.01526189048
56. Zaas AK, Chen M, Varkey J, Veldman T, Hero AO, IIILucas J, et al. Gene Expression Signatures Diagnose Influenza and Other Symptomatic Respiratory Viral Infections in Humans. Cell Host and Microbe. 2009;6(3):207–217. doi: 10.1016/j.chom.2009.07.00619664979
57. Moody MA, Zhang R, Walter EB, Woods CW, Ginsburg GS, McClain MT, et al. H3N2 influenza infection elicits more cross-reactive and less clonally expanded anti-hemagglutinin antibodies than influenza vaccination. PLoS ONE. 2011;6(10):e25797. doi: 10.1371/journal.pone.002579722039424
58. Huang Y, Zaas AK, Rao A, Dobigeon N, Woolf PJ, Veldman T, et al. Temporal dynamics of host molecular responses differentiate symptomatic and asymptomatic influenza a infection. PLoS Genetics. 2011;7(8):e1002234. doi: 10.1371/journal.pgen.100223421901105
59. Zhou B, Donnelly ME, Scholes DT, St George K, Hatta M, Kawaoka Y, et al. Single-reaction genomic amplification accelerates sequencing and vaccine production for classical and swine origin human influenza A viruses. Journal of Virology. 2009;83(19):10309–10313. doi: 10.1128/JVI.01109-0919605485
60. Zhou B, Wentworth DE, Influenza A virus molecular virology techniques. Methods in molecular biology (Clifton, NJ). 2012;865:175–192. doi: 10.1007/978-1-61779-621-0_11
61. Foll M, Poh YP, Renzette N, Ferrer-Admetlla A, Bank C, Shim H, et al. Influenza Virus Drug Resistance: A Time-Sampled Population Genetics Perspective. PLoS Genetics. 2014;10(2):e1004185. doi: 10.1371/journal.pgen.100418524586206
62. Ghedin E, Holmes EC, DePasse JV, Pinilla LT, Fitch A, Hamelin ME, et al. Presence of oseltamivir-resistant pandemic A/H1N1 minor variants before drug therapy with subsequent selection and transmission. The Journal of infectious diseases. 2012;206(10):1504–1511. doi: 10.1093/infdis/jis57122966122
63. Illingworth CJR. SAMFIRE: multi-locus variant calling for time-resolved sequence data. Bioinformatics. 2016; p. btw205.
64. Stevens J, Chen LM, Carney PJ, Garten R, Foust A, Le J, et al. Receptor specificity of influenza A H3N2 viruses isolated in mammalian cells and embryonated chicken eggs. Journal of Virology. 2010;84(16):8287–8299. doi: 10.1128/JVI.00058-1020519409
65. Skowronski DM, Janjua NZ, De Serres G, Sabaiduc S, Eshaghi A, Dickinson JA, et al. Low 2012–13 Influenza Vaccine Effectiveness Associated with Mutation in the Egg-Adapted H3N2 Vaccine Strain Not Antigenic Drift in Circulating Viruses. PLoS ONE. 2014;9(3):e92153–15. doi: 10.1371/journal.pone.009215324667168
66. Nakowitsch S, Wolschek M, Morokutti A, Ruthsatz T, Krenn BM, Ferko B, et al. Mutations affecting the stability of the haemagglutinin molecule impair the immunogenicity of live attenuated H3N2 intranasal influenza vaccine candidates lacking NS1. Vaccine. 2011;29(19):3517–3524. doi: 10.1016/j.vaccine.2011.02.10021406268
67. Kass RE, Raftery AE, Bayes factors. Journal of the American Statistical Association. 1995;90(430):773–795. doi: 10.1080/01621459.1995.10476572
68. Kiso M, Mitamura K, Sakai-Tagawa Y, Shiraishi K, Kawakami C, Kimura K, et al. Resistant influenza A viruses in children treated with oseltamivir: descriptive study. The Lancet. 2004;364(9436):759–765. doi: 10.1016/S0140-6736(04)16934-1
69. McClain MT, Nicholson BP, Park LP, Liu TY, Hero AO, Tsalik EL, et al. A Genomic Signature of Influenza Infection Shows Potential for Presymptomatic Detection, Guiding Early Therapy, and Monitoring Clinical Responses. Open forum infectious diseases. 2016;3(1):ofw007. doi: 10.1093/ofid/ofw00726933666
70. Fujii Y, Goto H, Watanabe T, Yoshida T, Kawaoka Y, Selective incorporation of influenza virus RNA segments into virions. Proceedings of the National Academy of Sciences of the United States of America. 2003;100(4):2002–2007. doi: 10.1073/pnas.043777210012574509
71. Marsh GA, Rabadan R, Levine AJ, Palese P, Highly conserved regions of influenza A virus polymerase gene segments are critical for efficient viral RNA packaging. Journal of Virology. 2008;82(5):2295–2304. doi: 10.1128/JVI.02267-0718094182
72. Hutchinson EC, von Kirchbach JC, Gog JR, Digard P, Genome packaging in influenza A virus. Journal of General Virology. 2010;91(Pt 2):313–328. doi: 10.1099/vir.0.017608-019955561
73. Gultyaev AP, Foucher RAM, Olsthoorn RCL, Influenza virus RNA Structure: Unique and Common Features. International Reviews of Immunology. 2010;29(6):533–556. doi: 10.3109/08830185.2010.50782820923332
74. Brower-Sinning R, Carter DM, Crevar CJ, Ghedin E, Ross TM, Benos PV, The role of RNA folding free energy in the evolution of the polymerase genes of the influenza A virus. Genome Biology. 2009;10(2):R18. doi: 10.1186/gb-2009-10-2-r1819216739
75. Soszynska-Jozwiak M, Michalak P, Moss WN, Kierzek R, Kierzek E, A Conserved Secondary Structural Element in the Coding Region of the Influenza A Virus Nucleoprotein (NP) mRNA Is Important for the Regulation of Viral Proliferation. PLoS ONE. 2015;10(10):e0141132–16. doi: 10.1371/journal.pone.014113226488402
76. Moss WN, Priore SF, Turner DH, Identification of potential conserved RNA secondary structure throughout influenza A coding regions. RNA. 2011;17(6):991–1011. doi: 10.1261/rna.261951121536710
77. Lubeck MD, Palese P, Schulman JL, Nonranom association of parental genes in influenza A virus recombinants. Virology. 1979;95(1):269–274. doi: 10.1016/0042-6822(79)90430-6442543
78. Greenbaum BD, Li OTW, Poon LLM, Levine AJ, Rabadan R, Viral reassortment as an information exchange between viral segments. Proceedings of the National Academy of Sciences of the United States of America. 2012;109(9):3341–3346. doi: 10.1073/pnas.111330010922331898
79. Rabadan R, Levine AJ, Krasnitz M, Non-random reassortment in human influenza A viruses. Influenza and Other Respiratory Viruses. 2008;2(1):9–22. doi: 10.1111/j.1750-2659.2007.00030.x19453489
80. Dudas G, Bedford T, Lycett S, Rambaut A, Reassortment between Influenza B Lineages and the Emergence of a Coadapted PB1-PB2-HA Gene Complex. Molecular Biology and Evolution. 2014;32(1):162–172. doi: 10.1093/molbev/msu28725323575
81. Zeldovich KB, Liu P, Renzette N, Foll M, Pham ST, Venev SV, et al. Positive Selection Drives Preferred Segment Combinations during Influenza Virus Reassortment. Molecular Biology and Evolution. 2015;32(6):1519–1532. doi: 10.1093/molbev/msv04425713211
82. Khiabanian H, Trifonov V, Rabadan R, Reassortment Patterns in Swine Influenza Viruses. PLoS ONE. 2009;4(10):e7366–7. doi: 10.1371/journal.pone.000736619809504
83. Frost SD, Dumaurier MJ, Wain-Hobson S, Brown AJ, Genetic drift and within-host metapopulation dynamics of HIV-1 infection. Proceedings of the National Academy of Sciences of the United States of America. 2001;98(12):6975–6980. doi: 10.1073/pnas.13105699811381143
84. Lythgoe KA, Blanquart F, Pellis L, Fraser C, Large Variations in HIV-1 Viral Load Explained by Shifting-Mosaic Metapopulation Dynamics. PLoS Biology. 2016;14(10):e1002567–25. doi: 10.1371/journal.pbio.100256727706164
85. Baer A, Kehn-Hall K, Viral concentration determination through plaque assays: using traditional and novel overlay systems. Journal of visualized experiments: JoVE. 2014;(93):e52065. doi: 10.3791/5206525407402
86. Schwarz G, Estimating the Dimension of a Model. The Annals of Statistics. 1978;6(2):461–464. doi: 10.1214/aos/1176344136
87. Baccam P, Beauchemin C, Macken CA, Hayden FG, Perelson AS, Kinetics of Influenza A Virus Infection in Humans. Journal of Virology. 2006;80(15):7590–7599. doi: 10.1128/JVI.01623-0516840338
88. Hill WG, Robertson A, The effect of linkage on limits to artificial selection. Genetics Research. 1966;8(3):269–294. doi: 10.1017/S0016672300010156
89. Illingworth CJR, Mustonen V, Distinguishing Driver and Passenger Mutations in an Evolutionary History Categorized by Interference. Genetics. 2011;189(3):989–1000. doi: 10.1534/genetics.111.13397521900272
90. Sanjuan R, Nebot MR, Chirico N, Mansky LM, Belshaw R, Viral Mutation Rates. Journal of Virology. 2010;84(19):9733–9748. doi: 10.1128/JVI.00694-1020660197
91. Rogers MB, Song T, Sebra R, Greenbaum BD, Hamelin ME, Fitch A, et al. Intrahost Dynamics of Antiviral Resistance in Influenza A Virus Reflect Complex Patterns of Segment Linkage, Reassortment, and Natural Selection. mBio. 2015;6(2):e02464–14–8. doi: 10.1128/mBio.02464-1425852163
92. McDonald SM, Nelson MI, Turner PE, Patton JT, Reassortment in segmented RNA viruses: mechanisms and outcomes. Nature Publishing Group. 2016;14(7):448–460.
93. Wright S, Evolution in Mendelian Populations. Genetics. 1931;16(2):97–159. 17246615