Home LiteratureArticle Details
PMID: 23985316 Published · epublish English Journal Article Research Support, Non-U.S. Gov't

The genome and transcriptome of Haemonchus contortus, a key model parasite for drug and vaccine discovery.

Genome biology ·Vol. 14 ·No. 8 ·2013-08-28 ·Pages R88

Laing R, Kikuchi T, Martinelli A, Tsai IJ, Beech RN, Redman E, Holroyd N, Bartley DJ, Beasley H, Britton C, Curran D, Devaney E, Gilabert A, Hunt M, Jackson F, Johnston SL, Kryukov I, Li K, Morrison AA, Reid AJ, Sargison N, Saunders GI, Wasmuth JD, Wolstenholme A, Berriman M, Gilleard JS, Cotton JA

Abstract

The small ruminant parasite Haemonchus contortus is the most widely used parasitic nematode in drug discovery, vaccine development and anthelmintic resistance research. Its remarkable propensity to develop resistance threatens the viability of the sheep industry in many regions of the world and provides a cautionary example of the effect of mass drug administration to control parasitic nematodes. Its phylogenetic position makes it particularly well placed for comparison with the free-living nematode Caenorhabditis elegans and the most economically important parasites of livestock and humans. Here we report the detailed analysis of a draft genome assembly and extensive transcriptomic dataset for H. contortus. This represents the first genome to be published for a strongylid nematode and the most extensive transcriptomic dataset for any parasitic nematode reported to date. We show a general pattern of conservation of genome structure and gene content between H. contortus and C. elegans, but also a dramatic expansion of important parasite gene families. We identify genes involved in parasite-specific pathways such as blood feeding, neurological function, and drug metabolism. In particular, we describe complete gene repertoires for known drug target families, providing the most comprehensive understanding yet of the action of several important anthelmintics. Also, we identify a set of genes enriched in the parasitic stages of the lifecycle and the parasite gut that provide a rich source of vaccine and drug target candidates. The H. contortus genome and transcriptome provide an essential platform for postgenomic research in this and other important strongylid parasites.

MeSH Terms
Animals Anthelmintics/pharmacology Antigens, Helminth/genetics Caenorhabditis elegans/classification,genetics Drug Resistance/genetics Gene Expression Regulation Genes, Helminth Genome, Helminth Haemonchiasis/parasitology,veterinary Haemonchus/classification,drug effects,genetics Host-Parasite Interactions Phylogeny Sequence Homology, Nucleic Acid Sheep Sheep Diseases/parasitology Species Specificity Transcriptome
Chemicals
Anthelmintics Antigens, Helminth
Authors & Affiliations
27 authors, click to expand affiliations / ORCID
Laing Roz
Kikuchi Taisei
Martinelli Axel
Tsai Isheng J
Beech Robin N
Redman Elizabeth
Holroyd Nancy
Bartley David J
Beasley Helen
Britton Collette
Curran David
Devaney Eileen
Gilabert Aude
Hunt Martin
Jackson Frank
Johnston Stephanie L
Kryukov Ivan
Li Keyu
Morrison Alison A
Reid Adam J
Sargison Neil
Saunders Gary I
Wasmuth James D
Wolstenholme Adrian
Berriman Matthew
Gilleard John S
Cotton James A
References (92)
92 references, click to expand
  1. Global patterns reveal strong population structure in Haemonchus contortus, a nematode parasite of domesticated ruminants.
    Int J Parasitol. 2006 Oct;36(12):1305-16 PMID: 16950266
  2. Differential expression analysis for sequence count data.
    Genome Biol. 2010;11(10):R106 PMID: 20979621
  3. DETECT--a density estimation tool for enzyme classification and its application to Plasmodium falciparum.
    Bioinformatics. 2010 Jul 15;26(14):1690-8 PMID: 20513663
  4. Vaccination with recombinant aspartic hemoglobinase reduces parasite load and blood loss after hookworm infection in dogs.
    PLoS Med. 2005 Oct;2(10):e295 PMID: 16231975
  5. WormBase 2012: more genomes, more data, new website.
    Nucleic Acids Res. 2012 Jan;40(Database issue):D735-41 PMID: 22067452
  6. Vaccines against blood-feeding nematodes of humans and livestock.
    Parasitology. 2006;133 Suppl:S63-79 PMID: 17274849
  7. Progress on vaccination against Haemonchus contortus.
    Int J Parasitol. 1995 Nov;25(11):1281-9 PMID: 8635880
  8. Sequence and genetic map of Meloidogyne hapla: A compact nematode genome for plant parasitism.
    Proc Natl Acad Sci U S A. 2008 Sep 30;105(39):14802-7 PMID: 18809916
  9. A metabolic signature of long life in Caenorhabditis elegans.
    BMC Biol. 2010 Feb 10;8:14 PMID: 20146810
  10. AUGUSTUS: ab initio prediction of alternative transcripts.
    Nucleic Acids Res. 2006 Jul 1;34(Web Server issue):W435-9 PMID: 16845043
  11. Aspartic proteases from the nematode Caenorhabditis elegans. Structural organization and developmental and cell-specific expression of asp-1.
    J Biol Chem. 2000 Aug 25;275(34):26359-69 PMID: 10854422
  12. Caenorhabditis elegans and the study of gene function in parasites.
    Trends Parasitol. 2001 Aug;17(8):387-93 PMID: 11685900
  13. Annotation of two large contiguous regions from the Haemonchus contortus genome using RNA-seq and comparative analysis with Caenorhabditis elegans.
    PLoS One. 2011;6(8):e23216 PMID: 21858033
  14. Molecular cloning and characterization of gut-derived cysteine proteinases associated with a host protective extract from Haemonchus contortus.
    Parasitology. 1999 Oct;119 ( Pt 4):405-12 PMID: 10581619
  15. Phylogeny for species of Haemonchus (Nematoda: Trichostrongyloidea): considerations of their evolutionary history and global biogeography among Camelidae and Pecora (Artiodactyla).
    J Parasitol. 2004 Oct;90(5):1085-102 PMID: 15562609
  16. Cloning, expression, purification and kinetics of trehalose-6-phosphate phosphatase of filarial parasite Brugia malayi.
    Acta Trop. 2011 Aug;119(2-3):151-9 PMID: 21658361
  17. mRNA sequences for Haemonchus contortus intestinal cathepsin B-like cysteine proteases display an extreme in abundance and diversity compared with other adult mammalian parasitic nematodes.
    Mol Biochem Parasitol. 2004 Oct;137(2):297-305 PMID: 15383300
  18. Conservation of long-range synteny and microsynteny between the genomes of two distantly related nematodes.
    Genome Biol. 2002 Sep 26;3(10):RESEARCH0057 PMID: 12372145
  19. The Pristionchus pacificus genome provides a unique perspective on nematode lifestyle and parasitism.
    Nat Genet. 2008 Oct;40(10):1193-8 PMID: 18806794
  20. Eight genes are required for functional reconstitution of the Caenorhabditis elegans levamisole-sensitive acetylcholine receptor.
    Proc Natl Acad Sci U S A. 2008 Nov 25;105(47):18590-5 PMID: 19020092
  21. A global analysis of C. elegans trans-splicing.
    Genome Res. 2011 Feb;21(2):255-64 PMID: 21177958
  22. Microsatellite analysis reveals marked genetic differentiation between Haemonchus contortus laboratory isolates and provides a rapid system of genetic fingerprinting.
    Int J Parasitol. 2008 Jan;38(1):111-22 PMID: 17727857
  23. Cloning and sequence comparisons of four distinct cysteine proteases expressed by Haemonchus contortus adult worms.
    Mol Biochem Parasitol. 1992 Apr;51(2):209-18 PMID: 1574079
  24. Genetic diversity patterns of Haemonchus placei and Haemonchus contortus populations isolated from domestic ruminants in Brazil.
    Int J Parasitol. 2012 May 1;42(5):469-79 PMID: 22787588
  25. Synergism of rotenone by piperonyl butoxide in Haemonchus contortus and Trichostrongylus colubriformis in vitro: potential for drug-synergism through inhibition of nematode oxidative detoxification pathways.
    Vet Parasitol. 2006 Mar 31;136(3-4):275-82 PMID: 16325340
  26. Vaccination against Haemonchus contortus: performance of native parasite gut membrane glycoproteins in Merino lambs grazing contaminated pasture.
    Vet Parasitol. 2008 May 31;153(3-4):302-12 PMID: 18337013
  27. A family of acetylcholine-gated chloride channel subunits in Caenorhabditis elegans.
    J Biol Chem. 2005 Feb 25;280(8):6392-8 PMID: 15579462
  28. A family of cathepsin B cysteine proteases expressed in the gut of the human hookworm, Necator americanus.
    Mol Biochem Parasitol. 2008 Aug;160(2):90-9 PMID: 18501979
  29. Understanding anthelmintic resistance: the need for genomics and genetics.
    Int J Parasitol. 2006 Oct;36(12):1227-39 PMID: 16889782
  30. Draft genome of the filarial nematode parasite Brugia malayi.
    Science. 2007 Sep 21;317(5845):1756-60 PMID: 17885136
  31. SignalP 4.0: discriminating signal peptides from transmembrane regions.
    Nat Methods. 2011 Sep 29;8(10):785-6 PMID: 21959131
  32. EFICAz2: enzyme function inference by a combined approach enhanced by machine learning.
    BMC Bioinformatics. 2009 Apr 13;10:107 PMID: 19361344
  33. Candidate anthelmintic resistance-associated gene expression and sequence polymorphisms in a triple-resistant field isolate of Haemonchus contortus.
    Mol Biochem Parasitol. 2011 Dec;180(2):99-105 PMID: 21945142
  34. Genome sequence of the metazoan plant-parasitic nematode Meloidogyne incognita.
    Nat Biotechnol. 2008 Aug;26(8):909-15 PMID: 18660804
  35. Order and specificity of the Plasmodium falciparum hemoglobin degradation pathway.
    J Clin Invest. 1994 Apr;93(4):1602-8 PMID: 8163662
  36. Isolation and characterization of four developmentally regulated cathepsin B-like cysteine protease genes from the nematode Caenorhabditis elegans.
    DNA Cell Biol. 1996 Jan;15(1):75-82 PMID: 8561899
  37. Haemonchus contortus acetylcholine receptors of the DEG-3 subfamily and their role in sensitivity to monepantel.
    PLoS Pathog. 2009 Apr;5(4):e1000380 PMID: 19360096
  38. Vitamin B12 changes in Nippostrongylus brasiliensis in its free-living and parasitic habitats with biochemical implications.
    J Parasitol. 1996 Feb;82(1):1-6 PMID: 8627475
  39. An inconvenient truth: global worming and anthelmintic resistance.
    Vet Parasitol. 2012 May 4;186(1-2):70-8 PMID: 22154968
  40. A tissue specific approach for analysis of membrane and secreted protein antigens from Haemonchus contortus gut and its application to diverse nematode species.
    Mol Biochem Parasitol. 1998 Nov 30;97(1-2):55-68 PMID: 9879887
  41. P-glycoprotein selection in strains of Haemonchus contortus resistant to benzimidazoles.
    Vet Parasitol. 2008 Mar 25;152(1-2):101-7 PMID: 18241994
  42. Genetic diversity of levamisole receptor subunits in parasitic nematode species and abbreviated transcripts associated with resistance.
    Pharmacogenet Genomics. 2010 Jul;20(7):414-25 PMID: 20531256
  43. Gene expression changes in a P-glycoprotein (Tci-pgp-9) putatively associated with ivermectin resistance in Teladorsagia circumcincta.
    Int J Parasitol. 2011 Aug 1;41(9):935-42 PMID: 21683705
  44. A new class of anthelmintics effective against drug-resistant nematodes.
    Nature. 2008 Mar 13;452(7184):176-80 PMID: 18337814
  45. Host movement and the genetic structure of populations of parasitic nematodes.
    Genetics. 1995 Nov;141(3):1007-14 PMID: 8582607
  46. A cholinergic-regulated circuit coordinates the maintenance and bi-stable states of a sensory-motor behavior during Caenorhabditis elegans male copulation.
    PLoS Genet. 2011 Mar;7(3):e1001326 PMID: 21423722
  47. Abundant variation in microsatellites of the parasitic nematode Trichostrongylus tenuis and linkage to a tandem repeat.
    Mol Biochem Parasitol. 2006 Aug;148(2):210-8 PMID: 16765463
  48. Using existing drugs as leads for broad spectrum anthelmintics targeting protein kinases.
    PLoS Pathog. 2013 Feb;9(2):e1003149 PMID: 23459584
  49. Gene ontology: tool for the unification of biology. The Gene Ontology Consortium.
    Nat Genet. 2000 May;25(1):25-9 PMID: 10802651
  50. Purification and evaluation of the integral membrane protein H11 as a protective antigen against Haemonchus contortus.
    Int J Parasitol. 1993 Apr;23(2):271-80 PMID: 8496010
  51. KAAS: an automatic genome annotation and pathway reconstruction server.
    Nucleic Acids Res. 2007 Jul;35(Web Server issue):W182-5 PMID: 17526522
  52. Cytochrome P450 monooxygenase activity in Haemonchus contortus (Nematoda).
    Int J Parasitol. 1997 Jan;27(1):33-40 PMID: 9076527
  53. Association of ion-channel genotype and macrocyclic lactone sensitivity traits in Haemonchus contortus.
    Mol Biochem Parasitol. 2010 Jun;171(2):74-80 PMID: 20211658
  54. Population genetics of anthelmintic resistance in parasitic nematodes.
    Parasitology. 2007;134(Pt 8):1133-47 PMID: 17608973
  55. Identification of secreted cysteine proteases from the parasitic nematode Haemonchus contortus detected by biotinylated inhibitors.
    Infect Immun. 2006 Mar;74(3):1989-93 PMID: 16495580
  56. Candidate genes affecting Drosophila life span identified by integrating microarray gene expression analysis and QTL mapping.
    Mech Ageing Dev. 2007 Mar;128(3):237-49 PMID: 17196240
  57. ATP-binding cassette transporters are required for efficient RNA interference in Caenorhabditis elegans.
    Mol Biol Cell. 2006 Aug;17(8):3678-88 PMID: 16723499
  58. Genomic insights into the origin of parasitism in the emerging plant pathogen Bursaphelenchus xylophilus.
    PLoS Pathog. 2011 Sep;7(9):e1002219 PMID: 21909270
  59. CEGMA: a pipeline to accurately annotate core genes in eukaryotic genomes.
    Bioinformatics. 2007 May 1;23(9):1061-7 PMID: 17332020
  60. Caenorhabditis elegans: how good a model for veterinary parasites?
    Vet Parasitol. 2001 Nov 22;101(3-4):371-86 PMID: 11707307
  61. Computational analysis of Plasmodium falciparum metabolism: organizing genomic information to facilitate drug discovery.
    Genome Res. 2004 May;14(5):917-24 PMID: 15078855
  62. TopHat: discovering splice junctions with RNA-Seq.
    Bioinformatics. 2009 May 1;25(9):1105-11 PMID: 19289445
  63. Haemonchus contortus: selection at a glutamate-gated chloride channel gene in ivermectin- and moxidectin-selected strains.
    Exp Parasitol. 1998 Sep;90(1):42-8 PMID: 9709029
  64. Intestinal transcriptomes of nematodes: comparison of the parasites Ascaris suum and Haemonchus contortus with the free-living Caenorhabditis elegans.
    PLoS Negl Trop Dis. 2008 Aug 06;2(8):e269 PMID: 18682827
  65. Characterisation of Teladorsagia circumcincta microsatellites and their development as population genetic markers.
    Mol Biochem Parasitol. 2006 Aug;148(2):181-9 PMID: 16687182
  66. A multi-enzyme cascade of hemoglobin proteolysis in the intestine of blood-feeding hookworms.
    J Biol Chem. 2004 Aug 20;279(34):35950-7 PMID: 15199048
  67. Mycobacterium tuberculosis RmlC epimerase (Rv3465): a promising drug-target structure in the rhamnose pathway.
    Acta Crystallogr D Biol Crystallogr. 2004 May;60(Pt 5):895-902 PMID: 15103135
  68. Immunisation of sheep with an integral membrane glycoprotein complex of Haemonchus contortus and with its major polypeptide components.
    Res Vet Sci. 1996 Jan;60(1):1-6 PMID: 8745246
  69. Glutamate-gated chloride channels of Haemonchus contortus restore drug sensitivity to ivermectin resistant Caenorhabditis elegans.
    PLoS One. 2011;6(7):e22390 PMID: 21818319
  70. The nature and prospects for gut membrane proteins as vaccine candidates for Haemonchus contortus and other ruminant trichostrongyloids.
    Int J Parasitol. 2003 Sep 30;33(11):1129-37 PMID: 13678629
  71. InterProScan--an integration platform for the signature-recognition methods in InterPro.
    Bioinformatics. 2001 Sep;17(9):847-8 PMID: 11590104
  72. A research agenda for helminth diseases of humans: intervention for control and elimination.
    PLoS Negl Trop Dis. 2012;6(4):e1549 PMID: 22545163
  73. Introgression of ivermectin resistance genes into a susceptible Haemonchus contortus strain by multiple backcrossing.
    PLoS Pathog. 2012 Feb;8(2):e1002534 PMID: 22359506
  74. Microsatellites of the parasitic nematode Haemonchus contortus: polymorphism and linkage with a direct repeat.
    Mol Biochem Parasitol. 1997 Oct;89(1):97-107 PMID: 9297704
  75. The transcriptional response of Caenorhabditis elegans to Ivermectin exposure identifies novel genes involved in the response to reduced food intake.
    PLoS One. 2012;7(2):e31367 PMID: 22348077
  76. The nicotinic acetylcholine receptor gene family of the nematode Caenorhabditis elegans: an update on nomenclature.
    Invert Neurosci. 2007 Jun;7(2):129-31 PMID: 17503100
  77. EGASP: the human ENCODE Genome Annotation Assessment Project.
    Genome Biol. 2006;7 Suppl 1:S2.1-31 PMID: 16925836
  78. Automated eukaryotic gene structure annotation using EVidenceModeler and the Program to Assemble Spliced Alignments.
    Genome Biol. 2008 Jan 11;9(1):R7 PMID: 18190707
  79. Haemonchus contortus: HcGluCla expressed in Xenopus oocytes forms a glutamate-gated ion channel that is activated by ibotenate and the antiparasitic drug ivermectin.
    Mol Biochem Parasitol. 2003 Jun;129(1):115-21 PMID: 12798512
  80. Measurements of blood loss caused by Haemonchus contortus infection in sheep.
    Am J Vet Res. 1962 Sep;23:977-80 PMID: 13879671
  81. The use of Caenorhabditis elegans in parasitic nematode research.
    Parasitology. 2004;128 Suppl 1:S49-70 PMID: 16454899
  82. Flow cytometry for parasite nematode genome size measurement.
    Mol Biochem Parasitol. 2003 Apr 25;128(1):91-3 PMID: 12706802
  83. Development and evaluation of an in vivo assay in Caenorhabditis elegans for screening of compounds for their effect on cytochrome P450 expression.
    J Biosci. 2008 Jun;33(2):269-77 PMID: 18535361
  84. Functional reconstitution of Haemonchus contortus acetylcholine receptors in Xenopus oocytes provides mechanistic insights into levamisole resistance.
    Br J Pharmacol. 2011 Nov;164(5):1421-32 PMID: 21486278
  85. Cytochrome P450 metabolism and inhibition: analysis for drug discovery.
    Prog Med Chem. 2009;47:239-63 PMID: 19328293
  86. A molecular evolutionary framework for the phylum Nematoda.
    Nature. 1998 Mar 5;392(6671):71-5 PMID: 9510248
  87. Genetic variability following selection of Haemonchus contortus with anthelmintics.
    Trends Parasitol. 2001 Sep;17(9):445-53 PMID: 11530357
  88. The epidemiology of abomasal nematodes of sheep in Sweden, with particular reference to over-winter survival strategies.
    Vet Parasitol. 2004 Jul 14;122(3):207-20 PMID: 15219362
  89. Characterization and comparative analysis of the complete Haemonchus contortus β-tubulin gene family and implications for benzimidazole resistance in strongylid nematodes.
    Int J Parasitol. 2013 May;43(6):465-75 PMID: 23416426
  90. Chromosomal clustering of muscle-expressed genes in Caenorhabditis elegans.
    Nature. 2002 Aug 29;418(6901):975-9 PMID: 12214599
  91. Xenobiotic detoxification in the nematode Caenorhabditis elegans.
    J Exp Zool A Comp Exp Biol. 2006 Sep 1;305(9):720-30 PMID: 16902959
  92. Drug resistance in nematodes of veterinary importance: a status report.
    Trends Parasitol. 2004 Oct;20(10):477-81 PMID: 15363441
Article Info
Journal
Genome biology
Abbr.
Genome Biol
ISSN
1474-760X
Published
2013-08-28
Epub
2013-00-28
Pages
R88
Language
English
Region
England
NLM ID
100960660
PMCID
PMC4054779
Subset
IM
Grants
Biotechnology and Biological Sciences Research Council · BB/E018130/1 · United Kingdom
Wellcome Trust · 067811 · United Kingdom
CIHR · 230927 · Canada
Wellcome Trust · 098051 · United Kingdom
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com