#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

Coordinated Evolution of Influenza A Surface Proteins


The fitness of an organism depends on the coordinated function of many genes. Thus, how a mutation in one gene affects fitness often depends on what mutations are present in other genes. This dependence is called “genetic interaction” or “epistasis”. The prevalence and type of such interactions are not well understood. Epistasis can be inferred from time-series sequencing data when a mutation in one gene is observed to facilitate the spread of a mutation in another gene. However, the situation is much more complicated when new combinations of genes are formed by processes such as recombination or reassortment. In such cases, deducing the time and order of genetic changes is difficult. Here, we devise a method to infer pairs of mutations in different genes which closely follow one another in the presence of reassortment. We apply it to evolution of two surface proteins of influenza A virus, hemagglutinin and neuraminidase, which are important targets for the human immune system and drugs. We show that mutations in one of these proteins are often facilitated by prior mutations, or compensated by subsequent mutations, in the other protein. In particular, drug-resistance mutations in neuraminidase were likely made possible by prior mutation in hemagglutinin. Knowledge of such interactions is necessary to fully understand and predict evolution.


Vyšlo v časopise: Coordinated Evolution of Influenza A Surface Proteins. PLoS Genet 11(8): e32767. doi:10.1371/journal.pgen.1005404
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1005404

Souhrn

The fitness of an organism depends on the coordinated function of many genes. Thus, how a mutation in one gene affects fitness often depends on what mutations are present in other genes. This dependence is called “genetic interaction” or “epistasis”. The prevalence and type of such interactions are not well understood. Epistasis can be inferred from time-series sequencing data when a mutation in one gene is observed to facilitate the spread of a mutation in another gene. However, the situation is much more complicated when new combinations of genes are formed by processes such as recombination or reassortment. In such cases, deducing the time and order of genetic changes is difficult. Here, we devise a method to infer pairs of mutations in different genes which closely follow one another in the presence of reassortment. We apply it to evolution of two surface proteins of influenza A virus, hemagglutinin and neuraminidase, which are important targets for the human immune system and drugs. We show that mutations in one of these proteins are often facilitated by prior mutations, or compensated by subsequent mutations, in the other protein. In particular, drug-resistance mutations in neuraminidase were likely made possible by prior mutation in hemagglutinin. Knowledge of such interactions is necessary to fully understand and predict evolution.


Zdroje

1. Palumbi SR. Humans as the world’s greatest evolutionary force. Science. 2001;293: 1786–1790. doi: 10.1126/science.293.5536.1786 11546863

2. Steinhauer DA, Holland JJ. Rapid evolution of RNA viruses. Annu Rev Microbiol. 1987;41: 409–433. doi: 10.1146/annurev.mi.41.100187.002205 3318675

3. Nobusawa E, Sato K. Comparison of the Mutation Rates of Human Influenza A and B Viruses. J Virol. 2006;80: 3675–3678. doi: 10.1128/JVI.80.7.3675-3678.2006 16537638

4. Nelson MI, Holmes EC. The evolution of epidemic influenza. Nat Rev Genet. 2007;8: 196–205. doi: 10.1038/nrg2053 17262054

5. Wilson DJ. Insights from Genomics into Bacterial Pathogen Populations. PLoS Pathog. 2012;8: e1002874. doi: 10.1371/journal.ppat.1002874 22969423

6. Maldarelli F, Kearney M, Palmer S, Stephens R, Mican J, Polis MA, et al. HIV Populations Are Large and Accumulate High Genetic Diversity in a Nonlinear Fashion. J Virol. 2013;87: 10313–10323. doi: 10.1128/JVI.01225-12 23678164

7. Wang X, Minasov G, Shoichet BK. Evolution of an antibiotic resistance enzyme constrained by stability and activity trade-offs. J Mol Biol. 2002;320: 85–95. doi: 10.1016/S0022-2836(02)00400-X 12079336

8. Bonhoeffer S, Chappey C, Parkin NT, Whitcomb JM, Petropoulos CJ. Evidence for positive epistasis in HIV-1. Science. 2004;306: 1547–1550. doi: 10.1126/science.1101786 15567861

9. Palmer AC, Kishony R. Understanding, predicting and manipulating the genotypic evolution of antibiotic resistance. Nat Rev Genet. 2013;14: 243–248. doi: 10.1038/nrg3351 23419278

10. Weinreich DM, Delaney NF, DePristo MA, Hartl DL. Darwinian Evolution Can Follow Only Very Few Mutational Paths to Fitter Proteins. Science. 2006;312: 111–114. doi: 10.1126/science.1123539 16601193

11. Schenk MF, Szendro IG, Salverda MLM, Krug J, de Visser JAGM. Patterns of Epistasis between Beneficial Mutations in an Antibiotic Resistance Gene. Mol Biol Evol. 2013;30: 1779–1787. doi: 10.1093/molbev/mst096 23676768

12. Salverda MLM, Dellus E, Gorter FA, Debets AJM, van der Oost J, Hoekstra RF, et al. Initial Mutations Direct Alternative Pathways of Protein Evolution. PLoS Genet. 2011;7: e1001321. doi: 10.1371/journal.pgen.1001321 21408208

13. Silva RF, Mendonça SCM, Carvalho LM, Reis AM, Gordo I, Trindade S, et al. Pervasive Sign Epistasis between Conjugative Plasmids and Drug-Resistance Chromosomal Mutations. PLoS Genet. 2011;7: e1002181. doi: 10.1371/journal.pgen.1002181 21829372

14. Lozovsky ER, Chookajorn T, Brown KM, Imwong M, Shaw PJ, Kamchonwongpaisan S, et al. Stepwise acquisition of pyrimethamine resistance in the malaria parasite. Proc Natl Acad Sci U S A. 2009;106: 12025–12030. doi: 10.1073/pnas.0905922106 19587242

15. Trindade S, Sousa A, Xavier KB, Dionisio F, Ferreira MG, Gordo I. Positive Epistasis Drives the Acquisition of Multidrug Resistance. Plos Genet. 2009;5: e1000578. doi: 10.1371/journal.pgen.1000578 19629166

16. Toprak E, Veres A, Michel J-B, Chait R, Hartl DL, Kishony R. Evolutionary paths to antibiotic resistance under dynamically sustained drug selection. Nat Genet. 2012;44: 101–U140. doi: 10.1038/ng.1034

17. Gong LI, Suchard MA, Bloom JD. Stability-mediated epistasis constrains the evolution of an influenza protein. eLife. 2013;2. doi: 10.7554/eLife.00631

18. Gong LI, Bloom JD. Epistatically Interacting Substitutions Are Enriched during Adaptive Protein Evolution. PLoS Genet. 2014;10: e1004328. doi: 10.1371/journal.pgen.1004328 24811236

19. Bloom JD, Gong LI, Baltimore D. Permissive secondary mutations enable the evolution of influenza oseltamivir resistance. Science. 2010;328: 1272–1275. doi: 10.1126/science.1187816 20522774

20. Hensley SE, Das SR, Bailey AL, Schmidt LM, Hickman HD, Jayaraman A, et al. Hemagglutinin Receptor Binding Avidity Drives Influenza A Virus Antigenic Drift. Science. 2009;326: 734–736. doi: 10.1126/science.1178258 19900932

21. Kryazhimskiy S, Dushoff J, Bazykin GA, Plotkin JB. Prevalence of epistasis in the evolution of influenza A surface proteins. PLoS Genet. 2011;7: e1001301. doi: 10.1371/journal.pgen.1001301 21390205

22. Wagner R, Wolff T, Herwig A, Pleschka S, Klenk HD. Interdependence of hemagglutinin glycosylation and neuraminidase as regulators of influenza virus growth: a study by reverse genetics. J Virol. 2000;74: 6316–6323. 10864641

23. Hensley SE, Das SR, Gibbs JS, Bailey AL, Schmidt LM, Bennink JR, et al. Influenza A virus hemagglutinin antibody escape promotes neuraminidase antigenic variation and drug resistance. PloS One. 2011;6: e15190. doi: 10.1371/journal.pone.0015190 21364978

24. 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: 315–321. doi: 10.1006/viro.1998.9119 9601502

25. 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. J Virol. 2000;74: 6015–6020. 10846083

26. Wagner R, Matrosovich M, Klenk H-D. Functional balance between haemagglutinin and neuraminidase in influenza virus infections. Rev Med Virol. 2002;12: 159–166. doi: 10.1002/rmv.352 11987141

27. Duan S, Govorkova EA, Bahl J, Zaraket H, Baranovich T, Seiler P, et al. Epistatic interactions between neuraminidase mutations facilitated the emergence of the oseltamivir-resistant H1N1 influenza viruses. Nat Commun. 2014;5. doi: 10.1038/ncomms6029

28. Ward MJ, Lycett SJ, Avila D, Bollback JP, Brown AJL. Evolutionary interactions between haemagglutinin and neuraminidase in avian influenza. BMC Evol Biol. 2013;13: 222. doi: 10.1186/1471-2148-13-222 24103105

29. Neverov AD, Lezhnina KV, Kondrashov AS, Bazykin GA. Intrasubtype Reassortments Cause Adaptive Amino Acid Replacements in H3N2 Influenza Genes. Malik HS, editor. PLoS Genet. 2014;10: e1004037. doi: 10.1371/journal.pgen.1004037 24415946

30. Bazykin GA, Dushoff J, Levin SA, Kondrashov AS. Bursts of nonsynonymous substitutions in HIV-1 evolution reveal instances of positive selection at conservative protein sites. Proc Natl Acad Sci. 2006;103: 19396–19401. doi: 10.1073/pnas.0609484103 17164328

31. Boni MF, de Jong MD, van Doorn HR, Holmes EC. Guidelines for identifying homologous recombination events in influenza A virus. PloS One. 2010;5: e10434. doi: 10.1371/journal.pone.0010434 20454662

32. Nagarajan N, Kingsford C. GiRaF: robust, computational identification of influenza reassortments via graph mining. Nucleic Acids Res. 2011;39: e34. doi: 10.1093/nar/gkq1232 21177643

33. 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 Biol. 2005;3: e300. doi: 10.1371/journal.pbio.0030300 16026181

34. Nelson MI, Viboud C, Simonsen L, Bennett RT, Griesemer SB, St George K, et al. Multiple reassortment events in the evolutionary history of H1N1 influenza A virus since 1918. PLoS Pathog. 2008;4: e1000012. doi: 10.1371/journal.ppat.1000012 18463694

35. Plotkin JB, Dushoff J, Levin SA. Hemagglutinin sequence clusters and the antigenic evolution of influenza A virus. Proc Natl Acad Sci U S A. 2002;99: 6263–6268. doi: 10.1073/pnas.082110799 11972025

36. Smith DJ, Lapedes AS, de Jong JC, Bestebroer TM, Rimmelzwaan GF, Osterhaus ADME, et al. Mapping the Antigenic and Genetic Evolution of Influenza Virus. Science. 2004;305: 371–376. doi: 10.1126/science.1097211 15218094

37. 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. Biol Direct. 2006;1: 34. doi: 10.1186/1745-6150-1-34 17067369

38. Strelkowa N, Lässig M. Clonal interference in the evolution of influenza. Genetics. 2012;192: 671–682. doi: 10.1534/genetics.112.143396 22851649

39. Illingworth CJR, Mustonen V. Components of Selection in the Evolution of the Influenza Virus: Linkage Effects Beat Inherent Selection. PLoS Pathog. 2012;8: e1003091. doi: 10.1371/journal.ppat.1003091 23300444

40. Lang GI, Rice DP, Hickman MJ, Sodergren E, Weinstock GM, Botstein D, et al. Pervasive genetic hitchhiking and clonal interference in forty evolving yeast populations. Nature. 2013;500: 571–574. doi: 10.1038/nature12344 23873039

41. Łuksza M, Lässig M. A predictive fitness model for influenza. Nature. 2014;507: 57–61. doi: 10.1038/nature13087 24572367

42. Wiley DC, Wilson IA, Skehel JJ. Structural identification of the antibody-binding sites of Hong Kong influenza haemagglutinin and their involvement in antigenic variation. Nature. 1981;289: 373–378. 6162101

43. Suzuki Y. Natural selection on the influenza virus genome. Mol Biol Evol. 2006;23: 1902–1911. doi: 10.1093/molbev/msl050 16818477

44. Air GM, Els MC, Brown LE, Laver WG, Webster RG. Location of antigenic sites on the three-dimensional structure of the influenza N2 virus neuraminidase. Virology. 1985;145: 237–248. 2411049

45. Gulati U, Hwang C-C, Venkatramani L, Gulati S, Stray SJ, Lee JT, et al. Antibody epitopes on the neuraminidase of a recent H3N2 influenza virus (A/Memphis/31/98). J Virol. 2002;76: 12274–12280. 12414967

46. Wan H, Gao J, Xu K, Chen H, Couzens LK, Rivers KH, et al. Molecular basis for broad neuraminidase immunity: conserved epitopes in seasonal and pandemic H1N1 as well as H5N1 influenza viruses. J Virol. 2013;87: 9290–9300. doi: 10.1128/JVI.01203-13 23785204

47. Lin YP, Xiong X, Wharton SA, Martin SR, Coombs PJ, Vachieri SG, et al. Evolution of the receptor binding properties of the influenza A(H3N2) hemagglutinin. Proc Natl Acad Sci. 2012;109: 21474–21479. doi: 10.1073/pnas.1218841110 23236176

48. Sun S, Wang Q, Zhao F, Chen W, Li Z. Glycosylation Site Alteration in the Evolution of Influenza A (H1N1) Viruses. Sambhara S, editor. PLoS ONE. 2011;6: e22844. doi: 10.1371/journal.pone.0022844 21829533

49. Steinbrück L, McHardy AC. Inference of Genotype–Phenotype Relationships in the Antigenic Evolution of Human Influenza A (H3N2) Viruses. Ferguson N, editor. PLoS Comput Biol. 2012;8: e1002492. doi: 10.1371/journal.pcbi.1002492 22532796

50. Koel BF, Burke DF, Bestebroer TM, van der Vliet S, Zondag GCM, Vervaet G, et al. Substitutions near the receptor binding site determine major antigenic change during influenza virus evolution. Science. 2013;342: 976–979. doi: 10.1126/science.1244730 24264991

51. Huang J-W, Lin W-F, Yang J-M. Antigenic sites of H1N1 influenza virus hemagglutinin revealed by natural isolates and inhibition assays. Vaccine. 2012;30: 6327–6337. doi: 10.1016/j.vaccine.2012.07.079 22885274

52. Rameix-Welti M-A, Enouf V, Cuvelier F, Jeannin P, van der Werf S. Enzymatic Properties of the Neuraminidase of Seasonal H1N1 Influenza Viruses Provide Insights for the Emergence of Natural Resistance to Oseltamivir. Manchester M, editor. PLoS Pathog. 2008;4: e1000103. doi: 10.1371/journal.ppat.1000103 18654625

53. Li Q, Qi J, Zhang W, Vavricka CJ, Shi Y, Wei J, et al. The 2009 pandemic H1N1 neuraminidase N1 lacks the 150-cavity in its active site. Nat Struct Mol Biol. 2010;17: 1266–1268. doi: 10.1038/nsmb.1909 20852645

54. McKimm-Breschkin JL, Williams J, Barrett S, Jachno K, McDonald M, Mohr PG, et al. Reduced susceptibility to all neuraminidase inhibitors of influenza H1N1 viruses with haemagglutinin mutations and mutations in non-conserved residues of the neuraminidase. J Antimicrob Chemother. 2013;68: 2210–2221. doi: 10.1093/jac/dkt205 23759505

55. Myers JL, Hensley SE. Oseltamivir-resistant influenza viruses get by with a little help from permissive mutations. Expert Rev Anti Infect Ther. 2011;9: 385–388. doi: 10.1586/eri.11.2 21504394

56. Lee HK, Tang JW-T, Kong DH-L, Loh TP, Chiang DK-L, Lam TT-Y, et al. Comparison of Mutation Patterns in Full-Genome A/H3N2 Influenza Sequences Obtained Directly from Clinical Samples and the Same Samples after a Single MDCK Passage. Digard P, editor. PLoS ONE. 2013;8: e79252. doi: 10.1371/journal.pone.0079252 24223916

57. Tamuri AU, dos Reis M, Hay AJ, Goldstein RA. Identifying Changes in Selective Constraints: Host Shifts in Influenza. Fraser C, editor. PLoS Comput Biol. 2009;5: e1000564. doi: 10.1371/journal.pcbi.1000564 19911053

58. Kobayashi Y, Suzuki Y. Evidence for N-Glycan Shielding of Antigenic Sites during Evolution of Human Influenza A Virus Hemagglutinin. J Virol. 2012;86: 3446–3451. doi: 10.1128/JVI.06147-11 22258255

59. Tharakaraman K, Raman R, Stebbins NW, Viswanathan K, Sasisekharan V, Sasisekharan R. Antigenically intact hemagglutinin in circulating avian and swine influenza viruses and potential for H3N2 pandemic. Sci Rep. 2013;3. doi: 10.1038/srep01822

60. Bradley KC, Galloway SE, Lasanajak Y, Song X, Heimburg-Molinaro J, Yu H, et al. Analysis of Influenza Virus Hemagglutinin Receptor Binding Mutants with Limited Receptor Recognition Properties and Conditional Replication Characteristics. J Virol. 2011;85: 12387–12398. doi: 10.1128/JVI.05570-11 21917953

61. Ginting TE, Shinya K, Kyan Y, Makino A, Matsumoto N, Kaneda S, et al. Amino Acid Changes in Hemagglutinin Contribute to the Replication of Oseltamivir-Resistant H1N1 Influenza Viruses. J Virol. 2012;86: 121–127. doi: 10.1128/JVI.06085-11 22013054

62. Ernst AM, Zacherl S, Herrmann A, Hacke M, Nickel W, Wieland FT, et al. Differential transport of Influenza A neuraminidase signal anchor peptides to the plasma membrane. FEBS Lett. 2013;587: 1411–1417. doi: 10.1016/j.febslet.2013.03.019 23523923

63. Da Silva DV, Nordholm J, Madjo U, Pfeiffer A, Daniels R. Assembly of Subtype 1 Influenza Neuraminidase Is Driven by Both the Transmembrane and Head Domains. J Biol Chem. 2013;288: 644–653. doi: 10.1074/jbc.M112.424150 23150659

64. Capra EJ, Perchuk BS, Skerker JM, Laub MT. Adaptive mutations that prevent crosstalk enable the expansion of paralogous signaling protein families. Cell. 2012;150: 222–232. doi: 10.1016/j.cell.2012.05.033 22770222

65. Woods RJ, Barrick JE, Cooper TF, Shrestha U, Kauth MR, Lenski RE. Second-Order Selection for Evolvability in a Large Escherichia coli Population. Science. 2011;331: 1433–1436. doi: 10.1126/science.1198914 21415350

66. Blount ZD, Borland CZ, Lenski RE. Historical contingency and the evolution of a key innovation in an experimental population of Escherichia coli. Proc Natl Acad Sci. 2008;105: 7899–7906. doi: 10.1073/pnas.0803151105 18524956

67. Bao Y, Bolotov P, Dernovoy D, Kiryutin B, Zaslavsky L, Tatusova T, et al. The influenza virus resource at the National Center for Biotechnology Information. J Virol. 2008;82: 596–601. doi: 10.1128/JVI.02005-07 17942553

68. Edgar RC. MUSCLE: multiple sequence alignment with high accuracy and high throughput. Nucleic Acids Res. 2004;32: 1792–1797. doi: 10.1093/nar/gkh340 15034147

69. Edgar RC. MUSCLE: a multiple sequence alignment method with reduced time and space complexity. BMC Bioinformatics. 2004;5: 113. doi: 10.1186/1471-2105-5-113 15318951

70. Suyama M, Torrents D, Bork P. PAL2NAL: robust conversion of protein sequence alignments into the corresponding codon alignments. Nucleic Acids Res. 2006;34: W609–612. doi: 10.1093/nar/gkl315 16845082

71. Gaydos JC, Top FH, Hodder RA, Russell PK. Swine Influenza A Outbreak, Fort Dix, New Jersey, 1976. Emerg Infect Dis. 2006;12: 23–28. doi: 10.3201/eid1201.050965 16494712

72. Han L, Lu W, Han Y, Li S, Yin J, Xie J, et al. Evolutionary characteristics of swine-origin H1N1 influenza virus that infected humans from sporadic to pandemic. J Public Health and Epidemiology. 2011;3: 254–270.

73. Influenza virus surveillance in Switzerland season 2010–2011 [Internet]. National Reference Influenza Center Laboratory of Virology University of Geneva Hospitals and Faculty of Medicine Geneva, Switzerland; 2011. Available: http://virologie.hug-ge.ch/_library/pdf/Flu2011.pdf

74. Olsen CW, Karasin AI, Carman S, Li Y, Bastien N, Ojkic D, et al. Triple reassortant H3N2 influenza A viruses, Canada, 2005. Emerg Infect Dis. 2006;12: 1132–1135. doi: 10.3201/eid1207.060268 16836834

75. Li W, Godzik A. Cd-hit: a fast program for clustering and comparing large sets of protein or nucleotide sequences. Bioinforma Oxf Engl. 2006;22: 1658–1659. doi: 10.1093/bioinformatics/btl158

76. Huelsenbeck JP, Ronquist F. MRBAYES: Bayesian inference of phylogenetic trees. Bioinforma Oxf Engl. 2001;17: 754–755.

77. Guindon S, Delsuc F, Dufayard J-F, Gascuel O. Estimating maximum likelihood phylogenies with PhyML. Methods Mol Biol Clifton NJ. 2009;537: 113–137. doi: 10.1007/978-1-59745-251-9_6

78. Pond SLK, Frost SDW, Muse SV. HyPhy: hypothesis testing using phylogenies. Bioinforma Oxf Engl. 2005;21: 676–679. doi: 10.1093/bioinformatics/bti079

79. Dutheil J, Gaillard S, Bazin E, Glémin S, Ranwez V, Galtier N, et al. Bio++: a set of C++ libraries for sequence analysis, phylogenetics, molecular evolution and population genetics. BMC Bioinformatics. 2006;7: 188. doi: 10.1186/1471-2105-7-188 16594991

80. Guéguen L, Gaillard S, Boussau B, Gouy M, Groussin M, Rochette NC, et al. Bio++: efficient extensible libraries and tools for computational molecular evolution. Mol Biol Evol. 2013;30: 1745–1750. doi: 10.1093/molbev/mst097 23699471

81. Vos RA, Caravas J, Hartmann K, Jensen MA, Miller C. BIO::Phylo-phyloinformatic analysis using perl. BMC Bioinformatics. 2011;12: 63. doi: 10.1186/1471-2105-12-63 21352572

82. Pond SLK, Frost SDW, Grossman Z, Gravenor MB, Richman DD, Brown AJL. Adaptation to different human populations by HIV-1 revealed by codon-based analyses. PLoS Comput Biol. 2006;2: e62. doi: 10.1371/journal.pcbi.0020062 16789820

83. Murrell B, Wertheim JO, Moola S, Weighill T, Scheffler K, Kosakovsky Pond SL. Detecting Individual Sites Subject to Episodic Diversifying Selection. Malik HS, editor. PLoS Genet. 2012;8: e1002764. doi: 10.1371/journal.pgen.1002764 22807683

84. Delport W, Poon AFY, Frost SDW, Kosakovsky Pond SL. Datamonkey 2010: a suite of phylogenetic analysis tools for evolutionary biology. Bioinforma Oxf Engl. 2010;26: 2455–2457. doi: 10.1093/bioinformatics/btq429

85. Pond SLK, Frost SDW. Datamonkey: rapid detection of selective pressure on individual sites of codon alignments. Bioinforma Oxf Engl. 2005;21: 2531–2533. doi: 10.1093/bioinformatics/bti320

86. Rambaut A, Drummond AJ. FigTree version 1.4 [Internet]. 2012. Available: tree.bio.ed.ac.uk/software/figtree

Štítky
Genetika Reprodukčná medicína

Článok vyšiel v časopise

PLOS Genetics


2015 Číslo 8
Najčítanejšie tento týždeň
Najčítanejšie v tomto čísle
Kurzy

Zvýšte si kvalifikáciu online z pohodlia domova

Získaná hemofilie - Povědomí o nemoci a její diagnostika
nový kurz

Eozinofilní granulomatóza s polyangiitidou
Autori: doc. MUDr. Martina Doubková, Ph.D.

Všetky kurzy
Prihlásenie
Zabudnuté heslo

Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.

Prihlásenie

Nemáte účet?  Registrujte sa

#ADS_BOTTOM_SCRIPTS#