Oxamniquine resistance alleles are widespread in Old World Schistosoma mansoni and predate drug deployment


Autoři: Frédéric D. Chevalier aff001;  Winka Le Clec’h aff001;  Marina McDew-White aff001;  Vinay Menon aff001;  Meghan A. Guzman aff002;  Stephen P. Holloway aff003;  Xiaohang Cao aff003;  Alexander B. Taylor aff003;  Safari Kinung'hi aff005;  Anouk N. Gouvras aff006;  Bonnie L. Webster aff006;  Joanne P. Webster aff006;  Aidan M. Emery aff006;  David Rollinson aff006;  Amadou Garba Djirmay aff009;  Khalid M. Al Mashikhi aff011;  Salem Al Yafae aff011;  Mohamed A. Idris aff012;  Hélène Moné aff013;  Gabriel Mouahid aff013;  P. John Hart aff003;  Philip T. LoVerde aff002;  Timothy J. C. Anderson aff001
Působiště autorů: Texas Biomedical Research Institute, San Antonio, Texas, United States of America aff001;  Departments of Pathology and University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America aff002;  Biochemistry & Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America aff003;  X-ray Crystallography Core Laboratory, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America aff004;  National Institute for Medical Research, Mwanza, United Republic of Tanzania aff005;  London Centre for Neglected Tropical Disease Research (LCNDTR), Imperial Collge, London, United Kingdom aff006;  Wolfson Wellcome Biomedical Laboratories, Natural History Museum, London, United Kingdom aff007;  Centre for Emerging, Endemic and Exotic Diseases (CEEED), Royal Veterinary College, University of London, United Kingdom aff008;  Réseau International Schistosomiases Environnemental Aménagement et Lutte (RISEAL), Niamey, Niger aff009;  World Health Organization, Geneva, Switzerland aff010;  Directorate General of Health Services, Dhofar Governorate, Salalah, Sultanate of Oman aff011;  Sultan Qaboos University, Muscat, Sultanate of Oman aff012;  Host-Pathogen-Environment Interactions laboratory, University of Perpignan, Perpignan, France aff013
Vyšlo v časopise: Oxamniquine resistance alleles are widespread in Old World Schistosoma mansoni and predate drug deployment. PLoS Pathog 15(10): e32767. doi:10.1371/journal.ppat.1007881
Kategorie: Research Article
doi: 10.1371/journal.ppat.1007881

Souhrn

Do mutations required for adaptation occur de novo, or are they segregating within populations as standing genetic variation? This question is key to understanding adaptive change in nature, and has important practical consequences for the evolution of drug resistance. We provide evidence that alleles conferring resistance to oxamniquine (OXA), an antischistosomal drug, are widespread in natural parasite populations under minimal drug pressure and predate OXA deployment. OXA has been used since the 1970s to treat Schistosoma mansoni infections in the New World where S. mansoni established during the slave trade. Recessive loss-of-function mutations within a parasite sulfotransferase (SmSULT-OR) underlie resistance, and several verified resistance mutations, including a deletion (p.E142del), have been identified in the New World. Here we investigate sequence variation in SmSULT-OR in S. mansoni from the Old World, where OXA has seen minimal usage. We sequenced exomes of 204 S. mansoni parasites from West Africa, East Africa and the Middle East, and scored variants in SmSULT-OR and flanking regions. We identified 39 non-synonymous SNPs, 4 deletions, 1 duplication and 1 premature stop codon in the SmSULT-OR coding sequence, including one confirmed resistance deletion (p.E142del). We expressed recombinant proteins and used an in vitro OXA activation assay to functionally validate the OXA-resistance phenotype for four predicted OXA-resistance mutations. Three aspects of the data are of particular interest: (i) segregating OXA-resistance alleles are widespread in Old World populations (4.29–14.91% frequency), despite minimal OXA usage, (ii) two OXA-resistance mutations (p.W120R, p.N171IfsX28) are particularly common (>5%) in East African and Middle-Eastern populations, (iii) the p.E142del allele has identical flanking SNPs in both West Africa and Puerto Rico, suggesting that parasites bearing this allele colonized the New World during the slave trade and therefore predate OXA deployment. We conclude that standing variation for OXA resistance is widespread in S. mansoni.

Klíčová slova:

Africa – Alleles – Deletion mutation – Haplotypes – Mutation – Parasitic diseases – Schistosoma mansoni – Schistosoma


Zdroje

1. Barrett RDH, Schluter D. Adaptation from standing genetic variation. Trends in ecology & evolution. 2008;23: 38–44. doi: 10.1016/j.tree.2007.09.008 18006185

2. Hermisson J, Pennings PS. Soft sweeps: molecular population genetics of adaptation from standing genetic variation. Genetics. 2005;169: 2335–2352. doi: 10.1534/genetics.104.036947 15716498

3. Messer PW, Petrov DA. Population genomics of rapid adaptation by soft selective sweeps. Trends Ecol Evol. 2013;28: 659–669. doi: 10.1016/j.tree.2013.08.003 24075201

4. Orr HA, Betancourt AJ. Haldane’s sieve and adaptation from the standing genetic variation. Genetics. 2001;157: 875–884. 11157004

5. Hawkins NJ, Bass C, Dixon A, Neve P. The evolutionary origins of pesticide resistance. Biological reviews of the Cambridge Philosophical Society. 2018; doi: 10.1111/brv.12440 29971903

6. Doyle SR, Bourguinat C, Nana-Djeunga HC, Kengne-Ouafo JA, Pion SDS, Bopda J, et al. Genome-wide analysis of ivermectin response by Onchocerca volvulus reveals that genetic drift and soft selective sweeps contribute to loss of drug sensitivity. PLoS neglected tropical diseases. 2017;11: e0005816. doi: 10.1371/journal.pntd.0005816 28746337

7. Diawara A, Schwenkenbecher JM, Kaplan RM, Prichard RK. Molecular and biological diagnostic tests for monitoring benzimidazole resistance in human soil-transmitted helminths. The American journal of tropical medicine and hygiene. 2013;88: 1052–1061. doi: 10.4269/ajtmh.12-0484 23458960

8. Pullan RL, Smith JL, Jasrasaria R, Brooker SJ. Global numbers of infection and disease burden of soil transmitted helminth infections in 2010. Parasites & vectors. 2014;7: 37. doi: 10.1186/1756-3305-7-37 24447578

9. Pica-Mattoccia L, Novi A, Cioli D. Enzymatic basis for the lack of oxamniquine activity in Schistosoma haematobium infections. Parasitol Res. 1997;83: 687–689. doi: 10.1007/s004360050320 9272559

10. Valentim CLL, Cioli D, Chevalier FD, Cao X, Taylor AB, Holloway SP, et al. Genetic and molecular basis of drug resistance and species-specific drug action in Schistosome parasites. Science. 2013;342: 1385–1389. doi: 10.1126/science.1243106 24263136

11. Rogers SH, Bueding E. Hycanthone resistance: development in Schistosoma mansoni. Science. 1971;172: 1057–1058. doi: 10.1126/science.172.3987.1057 5103321

12. Pica-Mattoccia L, Dias LC, Cioli D. Genetic complementation analysis of two independently isolated hycanthone-resistant strains of Schistosoma mansoni. Mem Inst Oswaldo Cruz. 1992;87 Suppl 4: 211–214. doi: 10.1590/S0074-02761992000800032 1343897

13. Chevalier FD, Le Clec’h W, Eng N, Rugel AR, Assis RR de, Oliveira G, et al. Independent origins of loss-of-function mutations conferring oxamniquine resistance in a Brazilian schistosome population. Int J Parasitol. 2016;46: 417–424. doi: 10.1016/j.ijpara.2016.03.006 27073078

14. Coura JR, Amaral RS. Epidemiological and control aspects of schistosomiasis in Brazilian endemic areas. Mem Inst Oswaldo Cruz. 2004;99: 13–19. doi: 10.1590/S0074-02762004000900003 15486629

15. Foster R. A review of clinical experience with oxamniquine. Transactions of the Royal Society of Tropical Medicine and Hygiene. 1987;81: 55–59. doi: 10.1016/0035-9203(87)90282-3 3127959

16. Hotez PJ, Bundy DA, Beegle K, Brooker S, Drake L, de Silva N, et al. Disease Control Priorities in Developing Countries. In: Jamison D, Breman J, AR, M, et al., editors. 2nd ed. Washington (DC): Oxford University Press & World Bank; 2006. pp. 467–482. Available: http://www.ncbi.nlm.nih.gov/books/NBK11748/

17. Emery AM, Allan FE, Rabone ME, Rollinson D. Schistosomiasis collection at NHM (SCAN). Parasit Vectors. 2012;5: 185. doi: 10.1186/1756-3305-5-185 22943137

18. Cioli D, Pica-Mattoccia L, Moroni R. Schistosoma mansoni: hycanthone/oxamniquine resistance is controlled by a single autosomal recessive gene. Exp Parasitol. 1992;75: 425–432. doi: 10.1016/0014-4894(92)90255-9 1493874

19. Eltis D, Richardson D, Blight DW. Atlas of the Transatlantic Slave Trade [Internet]. Yale University Press; 2010. Available: http://www.jstor.org/stable/j.ctt5vm1s4

20. Katz N, Pellegrino J, Grinbaum E, Chaves A, Zicker F. Preliminary clinical trials with oxamniquine, a new antischistosomal agent. Rev Inst Med Trop Sao Paulo. 1973;15: 25–29. 4574207

21. Katz N, Dias EP, Araújo N, Souza CP. Estudo de uma cepa humana de Schistosoma mansoni resistente a agentes esquistossomicidas. Rev Soc Bras Med Trop. 1973;7: 381–387. doi: 10.1590/S0037-86821973000600008

22. Dias L. C. de S. Pedro R. J. Rigo E. Goto M. M. F. Mafra G. L. Linhagem humana de Schistosoma mansoni resistente a esquistossomicidas. Revista de Saúde Pública. 1978;12: 110–110. doi: 10.1590/S0034-89101978000100013 675134

23. Coles GC, Mutahi WT, Kinoti GK, Bruce JI, Katz N. Tolerance of Kenyan Schistosoma mansoni to oxamniquine. Transactions of the Royal Society of Tropical Medicine and Hygiene. 1987;81: 782–785. doi: 10.1016/0035-9203(87)90032-0 3130689

24. Gupta KK. Schistosoma mansoni treatment with oral oxamniquine in Zambia. East African medical journal. 1984;61: 641–644. 6399028

25. Omer AH. Oxamniquine for treating Schistosoma mansoni infection in Sudan. British medical journal. 1978;2: 163–165. doi: 10.1136/bmj.2.6131.163 678831

26. Ongom VL, Wamboka GW, Kadil AUK. Oxamniquine (UK 4271): a potential antischistosomal drug in the treatment of Schistosoma mansoni infections in Uganda. The East African medical journal. 1976;53: 505.

27. Pitchford RJ, Lewis M. Oxamniquine in the treatment of various schistosome infections in South Africa. S Afr Med J. 1978;53: 677–680. 354047

28. World Health Organization. WHO model prescribing information: drugs used in parasitic diseases [Internet]. World Health Organization; 1995. Available: http://apps.who.int/medicinedocs/en/d/Jh2922e/

29. Daneshmend TK, Homeida MA. Oxamniquine pharmacokinetics in hepatosplenic schistosomiasis in the Sudan. The Journal of antimicrobial chemotherapy. 1987;19: 87–93. doi: 10.1093/jac/19.1.87 3104279

30. Kokwaro GO, Taylor G. Oxamniquine pharmacokinetics in healthy Kenyan African volunteers. East African medical journal. 1991;68: 359–364. 1935730

31. Rugel A, Tarpley RS, Lopez A, Menard T, Guzman MA, Taylor AB, et al. Design, Synthesis, and Characterization of Novel Small Molecules as Broad Range Antischistosomal Agents. ACS medicinal chemistry letters. 2018;9: 967–973. doi: 10.1021/acsmedchemlett.8b00257 30344901

32. Hahnel SR, Zdraljevic S, Rodriguez BC, Zhao Y, McGrath PT, Andersen EC. Extreme allelic heterogeneity at a Caenorhabditis elegans beta-tubulin locus explains natural resistance to benzimidazoles. PLoS pathogens. 2018;14: e1007226. doi: 10.1371/journal.ppat.1007226 30372484

33. Délye C, Deulvot C, Chauvel B. DNA analysis of herbarium Specimens of the grass weed Alopecurus myosuroides reveals herbicide resistance pre-dated herbicides. PloS one. 2013;8: e75117. doi: 10.1371/journal.pone.0075117 24146749

34. D’Costa VM, King CE, Kalan L, Morar M, Sung WWL, Schwarz C, et al. Antibiotic resistance is ancient. Nature. 2011;477: 457–461. doi: 10.1038/nature10388 21881561

35. Perry J, Waglechner N, Wright G. The Prehistory of Antibiotic Resistance. Cold Spring Harbor perspectives in medicine. 2016;6. doi: 10.1101/cshperspect.a025197 27252395

36. Silvestre A, Humbert JF. Diversity of benzimidazole-resistance alleles in populations of small ruminant parasites. Int J Parasitol. 2002;32: 921–928. doi: 10.1016/s0020-7519(02)00032-2 12062563

37. Redman E, Whitelaw F, Tait A, Burgess C, Bartley Y, Skuce PJ, et al. The emergence of resistance to the benzimidazole anthlemintics in parasitic nematodes of livestock is characterised by multiple independent hard and soft selective sweeps. PLoS Negl Trop Dis. 2015;9: e0003494. doi: 10.1371/journal.pntd.0003494 25658086

38. Geerts S, Gryseels B. Drug resistance in human helminths: current situation and lessons from livestock. Clinical microbiology reviews. 2000;13: 207–222. doi: 10.1128/cmr.13.2.207-222.2000 10755998

39. Crellen T, Allan F, David S, Durrant C, Huckvale T, Holroyd N, et al. Whole genome resequencing of the human parasite Schistosoma mansoni reveals population history and effects of selection. Scientific Reports. 2016;6: 20954. doi: 10.1038/srep20954 26879532

40. Organization WH. Artemisinin resistance and artemisinin-based combination therapy efficacy: status report [Internet]. Organization WH, editor. World Health Organization; 2018. Available: https://apps.who.int/iris/bitstream/handle/10665/274362/WHO-CDS-GMP-2018.18-eng.pdf

41. Nair S, Williams JT, Brockman A, Paiphun L, Mayxay M, Newton PN, et al. A selective sweep driven by pyrimethamine treatment in southeast asian malaria parasites. Molecular biology and evolution. 2003;20: 1526–1536. doi: 10.1093/molbev/msg162 12832643

42. Anderson TJC, Nair S, McDew-White M, Cheeseman IH, Nkhoma S, Bilgic F, et al. Population Parameters Underlying an Ongoing Soft Sweep in Southeast Asian Malaria Parasites. Molecular biology and evolution. 2017;34: 131–144. doi: 10.1093/molbev/msw228 28025270

43. Negishi M, Pedersen LG, Petrotchenko E, Shevtsov S, Gorokhov A, Kakuta Y, et al. Structure and function of sulfotransferases. Archives of biochemistry and biophysics. 2001;390: 149–157. doi: 10.1006/abbi.2001.2368 11396917

44. Rothman DM, Gao X, George E, Rasmusson T, Bhatia D, Alimov I, et al. Metabolic Enzyme Sulfotransferase 1A1 Is the Trigger for N-Benzyl Indole Carbinol Tumor Growth Suppression. Chemistry & Biology. 2015;22: 1228–1237. doi: 10.1016/j.chembiol.2015.06.025 26364931

45. Pica-Mattoccia L, Carlini D, Guidi A, Cimica V, Vigorosi F, Cioli D. The schistosome enzyme that activates oxamniquine has the characteristics of a sulfotransferase. Mem Inst Oswaldo Cruz. 2006;101 Suppl 1: 307–312. doi: 10.1590/S0074-02762006000900048 17308787

46. Nsanzabana C, Djalle D, Guérin PJ, Ménard D, González IJ. Tools for surveillance of anti-malarial drug resistance: an assessment of the current landscape. Malaria journal. 2018;17: 75. doi: 10.1186/s12936-018-2185-9 29422048

47. Keating P, Pharris A, Leitmeyer K, De Angelis S, Wensing A, Amato-Gauci AJ, et al. Assessment of HIV molecular surveillance capacity in the European Union, 2016. Eurosurveillance. 2017;22. doi: 10.2807/1560-7917.ES.2017.22.49.17–00269

48. Fenwick A. Praziquantel: do we need another antischistosoma treatment? Future medicinal chemistry. 2015;7: 677–680. doi: 10.4155/fmc.15.16 25996058

49. Fallon PG, Doenhoff MJ. Drug-resistant schistosomiasis: resistance to praziquantel and oxamniquine induced in Schistosoma mansoni in mice is drug specific. Am J Trop Med Hyg. 1994;51: 83–88. doi: 10.4269/ajtmh.1994.51.83 8059919

50. Couto FFB, Coelho PMZ, Araújo N, Kusel JR, Katz N, Jannotti-Passos LK, et al. Schistosoma mansoni: a method for inducing resistance to praziquantel using infected Biomphalaria glabrata snails. Mem Inst Oswaldo Cruz. 2011;106: 153–157. doi: 10.1590/s0074-02762011000200006 21537673

51. Lotfy WM, Hishmat MG, El Nashar AS, Abu El Einin HM. Evaluation of a method for induction of praziquantel resistance in Schistosoma mansoni. Pharmaceutical biology. 2015;53: 1214–1219. doi: 10.3109/13880209.2014.970289 25609146

52. Pinto-Almeida A, Mendes T, Armada A, Belo S, Carrilho E, Viveiros M, et al. The Role of Efflux Pumps in Schistosoma mansoni Praziquantel Resistant Phenotype. PloS one. 2015;10: e0140147. doi: 10.1371/journal.pone.0140147 26445012

53. Lamberton PHL, Faust CL, Webster JP. Praziquantel decreases fecundity in Schistosoma mansoni adult worms that survive treatment: evidence from a laboratory life-history trade-offs selection study. Infectious diseases of poverty. 2017;6: 110. doi: 10.1186/s40249-017-0324-0 28622767

54. Sanchez MC, Cupit PM, Bu L, Cunningham C. Transcriptomic analysis of reduced sensitivity to praziquantel in Schistosoma mansoni. Molecular and biochemical parasitology. 2019;228: 6–15. doi: 10.1016/j.molbiopara.2018.12.005 30658180

55. Lewis FA, Stirewalt MA, Souza CP, Gazzinelli G. Large-scale laboratory maintenance of Schistosoma mansoni, with observations on three schistosome/snail host combinations. J Parasitol. 1986;72: 813–829. 3546654

56. Utzinger J, Brattig NW, Kristensen TK. Schistosomiasis research in Africa: how the CONTRAST alliance made it happen. Acta Tropica. 2013;128: 182–195. doi: 10.1016/j.actatropica.2013.08.011 23973364

57. Webster BL, Webster JP, Gouvras AN, Garba A, Lamine MS, Diaw OT, et al. DNA “barcoding” of Schistosoma mansoni across sub-Saharan Africa supports substantial within locality diversity and geographical separation of genotypes. Acta Trop. 2013;128: 250–260. doi: 10.1016/j.actatropica.2012.08.009 22935316

58. Gower CM, Gouvras AN, Lamberton PHL, Deol A, Shrivastava J, Mutombo PN, et al. Population genetic structure of Schistosoma mansoni and Schistosoma haematobium from across six sub-Saharan African countries: Implications for epidemiology, evolution and control. Acta Trop. 2013;128: 261–274. doi: 10.1016/j.actatropica.2012.09.014 23041540

59. Ezeamama AE, He C-L, Shen Y, Yin X-P, Binder SC, Campbell CH, et al. Gaining and sustaining schistosomiasis control: study protocol and baseline data prior to different treatment strategies in five African countries. BMC Infect Dis. 2016;16: 229. doi: 10.1186/s12879-016-1575-2 27230666

60. Gower CM, Shrivastava J, Lamberton PHL, Rollinson D, Webster BL, Emery A, et al. Development and application of an ethically and epidemiologically advantageous assay for the multi-locus microsatellite analysis of Schistosoma mansoni. Parasitology. 2007;134: 523–536. doi: 10.1017/S0031182006001685 17096873

61. Moné H, Holtfreter MC, Allienne J-F, Mintsa-Nguéma R, Ibikounlé M, Boissier J, et al. Introgressive hybridizations of Schistosoma haematobium by Schistosoma bovis at the origin of the first case report of schistosomiasis in Corsica (France, Europe). Parasitology research. 2015;114: 4127–4133. doi: 10.1007/s00436-015-4643-4 26268566

62. Mouahid G, Mintsa Nguema R, Al Mashikhi KM, Al Yafae SA, Idris MA, Moné H. Host-parasite life-histories of the diurnal vs. nocturnal chronotypes of Schistosoma mansoni: adaptive significance. Tropical medicine & international health: TM & IH. 2019; doi: 10.1111/tmi.13227 30851235

63. Duvall RH, DeWitt WB. An improved perfusion technique for recovering adult schistosomes from laboratory animals. Am J Trop Med Hyg. 1967;16: 483–486. doi: 10.4269/ajtmh.1967.16.483 4952149

64. Le Clec’h W, Chevalier FD, McDew-White M, Allan F, Webster BL, Gouvras AN, et al. Whole genome amplification and exome sequencing of archived schistosome miracidia. Parasitology. 2018; 1–9. doi: 10.1017/S0031182018000811 29806576

65. Garrison E, Marth G. Haplotype-based variant detection from short-read sequencing. 2012; Available: http://arxiv.org/pdf/1207.3907v2

66. Danecek P, Auton A, Abecasis G, Albers CA, Banks E, DePristo MA, et al. The variant call format and VCFtools. Bioinformatics. 2011;27: 2156–2158. doi: 10.1093/bioinformatics/btr330 21653522

67. Tan A, Abecasis GR, Kang HM. Unified representation of genetic variants. Bioinformatics (Oxford, England). 2015;31: 2202–2204. doi: 10.1093/bioinformatics/btv112 25701572

68. Browning SR, Browning BL. Rapid and accurate haplotype phasing and missing-data inference for whole-genome association studies by use of localized haplotype clustering. American journal of human genetics. 2007;81: 1084–1097. doi: 10.1086/521987 17924348

69. R Core Team. R: A Language and Environment for Statistical Computing [Internet]. Vienna, Austria; 2015. Available: http://www.R-project.org/

70. Knaus BJ, Grünwald NJ. VCFR: a package to manipulate and visualize variant call format data in R. Molecular ecology resources. 2017;17: 44–53. doi: 10.1111/1755-0998.12549 27401132

71. Kamvar ZN, Tabima JF, Grünwald NJ. Poppr: an R package for genetic analysis of populations with clonal, partially clonal, and/or sexual reproduction. PeerJ. 2014;2: e281. doi: 10.7717/peerj.281 24688859

72. Kamvar ZN, Brooks JC, Grünwald NJ. Novel R tools for analysis of genome-wide population genetic data with emphasis on clonality. Frontiers in genetics. 2015;6: 208. doi: 10.3389/fgene.2015.00208 26113860

73. Li H. A statistical framework for SNP calling, mutation discovery, association mapping and population genetical parameter estimation from sequencing data. Bioinformatics. 2011;27: 2987–2993. doi: 10.1093/bioinformatics/btr509 21903627

74. Sievers F, Wilm A, Dineen D, Gibson TJ, Karplus K, Li W, et al. Fast, scalable generation of high-quality protein multiple sequence alignments using Clustal Omega. Mol Syst Biol. 2011;7: 539. doi: 10.1038/msb.2011.75 21988835

75. Rozas J, Ferrer-Mata A, Sánchez-DelBarrio JC, Guirao-Rico S, Librado P, Ramos-Onsins SE, et al. DnaSP 6: DNA Sequence Polymorphism Analysis of Large Data Sets. Molecular Biology and Evolution. 2017;34: 3299–3302. doi: 10.1093/molbev/msx248 29029172

76. O’Boyle NM, Banck M, James CA, Morley C, Vandermeersch T, Hutchison GR. Open Babel: An open chemical toolbox. Journal of Cheminformatics. 2011;3: 33. doi: 10.1186/1758-2946-3-33 21982300

77. Kellogg EH, Leaver-Fay A, Baker D. Role of conformational sampling in computing mutation-induced changes in protein structure and stability. Proteins. 2011;79: 830–838. doi: 10.1002/prot.22921 21287615

78. Battey C. Cjbattey/Driftr: Driftr_V1.3 [Internet]. Zenodo; 2017. doi: 10.5281/zenodo.345172

79. Ogino S, Gulley ML, den Dunnen JT, Wilson RB, Association for Molecular Patholpogy Training, Committtee E. Standard mutation nomenclature in molecular diagnostics: practical and educational challenges. J Mol Diagn. 2007;9: 1–6. doi: 10.2353/jmoldx.2007.060081 17251329

Štítky
Hygiena a epidemiologie Infekční lékařství Laboratoř

Článek vyšel v časopise

PLOS Pathogens


2019 Číslo 10

Nejčtenější v tomto čísle

Tomuto tématu se dále věnují…


Kurzy

Zvyšte si kvalifikaci online z pohodlí domova

Farmaceutická péče o pacienta s inhalační terapií
nový kurz
Autoři: Mgr. Ondřej Šimandl

Revmatoidní artritida: včas a k cíli
Autoři: MUDr. Heřman Mann

Jistoty a nástrahy antikoagulační léčby aneb kardiolog - neurolog - farmakolog - nefrolog - právník diskutují
Autoři: doc. MUDr. Štěpán Havránek, Ph.D., prof. MUDr. Roman Herzig, Ph.D., doc. MUDr. Karel Urbánek, Ph.D., prim. MUDr. Jan Vachek, MUDr. et Mgr. Jolana Těšínová, Ph.D.

Léčba akutní pooperační bolesti
Autoři: doc. MUDr. Jiří Málek, CSc.

Nové antipsychotikum kariprazin v léčbě schizofrenie
Autoři: prof. MUDr. Cyril Höschl, DrSc., FRCPsych.

Všechny kurzy
Přihlášení
Zapomenuté heslo

Nemáte účet?  Registrujte se

Zapomenuté heslo

Zadejte e-mailovou adresu se kterou jste vytvářel(a) účet, budou Vám na ni zaslány informace k nastavení nového hesla.

Přihlášení

Nemáte účet?  Registrujte se