February 9, 2016
Tick genome reveals inner workings of a versatile blood-guzzler
Deer ticks can transmit a number of illnesses including Lyme disease. (Andrew Nuss)
WEST LAFAYETTE, Ind. - An international team of scientists led by Purdue University has sequenced the genome of the tick that transmits Lyme disease, the most common vector-borne illness in North America.
The decadelong project, involving 93 authors from 46 institutions, decodes the biology of an arachnid with sophisticated spit, barbed mouthparts and millions of years of successful parasitism. The genome of Ixodes scapularis, known as the deer tick or blacklegged tick, also sheds light on how ticks acquire and transmit pathogens and offers tick-specific targets for control.
"The genome provides a foundation for a whole new era in tick research," said Catherine Hill, lead author of the paper, Purdue professor of medical entomology and Showalter Faculty Scholar. "Now that we've cracked the tick's code, we can begin to design strategies to control ticks, to understand how they transmit disease and to interfere with that process."
Purdue medical entomologist Catherine Hill led a decadelong effort to sequence the tick genome. (Purdue Agricultural Communication photo/Tom Campbell)
I. scapularis is the first tick species to have its genome sequenced.
The principle genome paper was published in Nature Communications on Tuesday (Feb. 9) and is available at http://dx.doi.org/
Genomic Resources for Tick-Borne Diseases
Tick-borne illnesses cause thousands of human and animal deaths annually, and ticks transmit a wider variety of pathogens and parasites than any other arthropod. They primarily spread disease by creating a feeding wound in the skin of their hosts, regurgitating infected saliva into the wound as they ingest blood.
Despite ticks' capacity to acquire and pass on an array of pathogens, research on ticks has lagged behind that of other arthropod vectors, such as mosquitoes, largely because of a lack of genetic and molecular tools and resources.
"Ticks are underappreciated as vectors - until you get Lyme disease," Hill said.
About 30,000 cases of Lyme disease cases are reported in the U.S. annually, most concentrated in the Northeast and upper Midwest. But the Centers for Disease Control estimates the actual number of cases is 329,000 a year, many of which are unreported or misdiagnosed.
While not fatal, Lyme disease can be permanently debilitating if the infection is not treated before it reaches the chronic phase.
The deer tick also vectors human granulocytic anaplasmosis, babesiosis and the potentially lethal Powassan virus. Other tick species transmit a number of flaviviruses, including some that cause hemorrhaging and inflammation of the brain and the membrane that covers the brain and spinal cord. Less is known about the tick-borne flaviviruses than Lyme disease, Hill said, but they are particularly important diseases in Europe and parts of Asia and represent global threats to human health.
"Genomic resources for the tick were desperately needed," she said. "These enable us to look at tick biology in a systems way."
The genome provides two lines of valuable biological resources, Hill said: the genes and proteins that make ticks successful parasites and excellent vectors of parasites and pathogens.
Identifying the proteins involved in the transmission of tick-borne diseases could help researchers develop strategies to halt this process.
Researchers pinpointed some of the proteins that play key roles in the interactions between deer ticks and the bacterium that causes Lyme disease and proteins associated with the transmission of human granulocytic anaplasmosis, an emerging disease.
A companion paper published in PLoS Neglected Tropical Diseases identified proteins and biochemical pathways associated with infection and replication of the encephalitis-causing Langat virus, another pathogen transmitted by Ixodes ticks. These proteins could be candidates for drugs and vaccines and give clues to how the virus affects the tick.
"This study opens the door to understanding how tick-borne viruses exploit their hosts and offers unique insights from ticks that could be applicable to humans," said Richard Kuhn, Purdue professor and head of the Department of Biological Sciences, lead author of the virus study and director of the Purdue Institute for Inflammation, Immunology and Infectious Diseases. "Once you know which host proteins are critical for virus replication, you can manipulate those proteins to interfere with the growth and development of the virus."
An Inside Look at Tick Biology
The genome also provides insights into unique aspects of tick biology.
Tick saliva, for example, teems with antimicrobials, pain inhibitors, cement, anticoagulants and immune suppressors, all designed to help the tick feed on its host undetected for days or weeks.
The genome reveals that tick saliva contains thousands of compounds - compared with mere hundreds in mosquito saliva - a diversity that presumably allows ticks to exploit a wide range of hosts and stay attached for a long time, Hill said.
The researchers also identified genes that could be linked to ticks' ability to synthesize new armorlike cuticle as they feed, allowing them to expand over 100 times.
The team searched for clues to how ticks digest blood, a toxic food source due to its high concentrations of iron. The genome points to a number of proteins that link with iron-containing heme molecules, the byproducts of blood digestion, to make them less toxic.
"Ticks have an amazing number of detoxification enzymes, and we don't know why," Hill said. "We've got our eye on this because these enzymes are also involved in detoxifying insecticides. As we develop new chemicals to control ticks, we'll be going up against this massive arsenal of detoxification enzymes, far more than insects have."
One of the major findings of the genome project is that about 20 percent of the genes appear to be unique to ticks. These genes could provide researchers with tick-specific targets for control.
"We don't see the equivalent of these genes in a mosquito or human," Hill said. "That's a fascinating collection of molecules, and as a scientist, I can't wait to get into that pot of gold and find out what these are and what they do."
Unique Features of the Genome
One of the main challenges the research team faced was the complexity of the tick genome, one of the larger arthropod genomes sequenced to date. Another obstacle was the unusual amount of repetitive DNA, which comprises about 70 percent of the genome, an aspect further explored in a companion paper published in BMC Genomics.
While copies of duplicated genes are often eliminated, the tick genome has retained these repeated genes. Many of them have mutated, suggesting that the two copies of a gene are associated with different functions and give the tick an evolutionary advantage. These duplicated genes could also be targets for new tick control measures.
"We estimate those gene duplications took place probably just after the last Ice Age when tick populations would have been expanding into new habitats," Hill said.
The project also included the first genome-wide analysis of tick population structure in North America, resolving a long-standing debate over whether deer ticks in the North and South are actually two different species. According to Hill, the genome offers convincing evidence that the two populations are the same species, despite their genetic differences. Because the majority of Lyme disease cases occur in the North, there might be a genetic component to ticks' ability to transmit Lyme disease that a comparison of the two populations could illuminate.
"Now we've got the script to help us work out what proteins the tick's genes are making, what these proteins do and whether we can exploit them to control the tick," Hill said.
Co-principal investigators for the project are Claire Fraser of the University of Maryland's Institute for Genome Sciences; Frank Collins of the University of Notre Dame's Department of Biological Sciences; Bruce Birren of the Broad Institute of the Massachusetts Institute of Technology and Harvard University; and Karen Nelson of the J. Craig Venter Institute. The JCVI and VectorBase annotated the genome.
The National Institutes of Health, the National Institute of Allergy and Infectious Diseases and the U.S. Department of Health and Human Services provided principle funding for the project. NIAID scientist and co-author Jose M. Ribeiro was supported through the NIAID intramural research program.
The genome project produced six companion papers:
* Grabowski, J. et al. Changes in the proteome of Langat-infected Ixodes scapularis ISE6 cells: metabolic pathways associated with flavivirus infection. PLoS Neglected Tropical Diseases. http://dx.doi.org/10.1371/journal.pntd.0004180
* Van Zee, J. P. et al. Paralog analyses reveal gene duplication events and genes under positive selection in Ixodes scapularis and other ticks. BMC Genomics. http://dx.doi.org/10.1186/s12864-015-2314-6
* Egekwu, N. I. et al. Comparing synganglion neuropeptides, neuropeptide receptors and neurotransmitter receptors and their gene expression in response to feeding in Ixodes scapularis (Ixodidae) versus Ornithodoros turicata (Argasidae). Insect Mol. Biol. http://dx.doi.org/10.1111/imb.12202
* Zhu, J. et al. Mevalonate-farnesol pathway in ticks: comparative synganglion transcriptomics and a new perspective. PLoS One. http://dx.doi.org/10.1371/journal.pone.0141084
* Carr, A. L. & Roe, R.M. Acarine attractants: chemoreception, bioassay, chemistry and control. Pest. Biochem. Physiol. http://dx.doi.org/10.1016/j.pestbp.2015.12.009
* Carr, A. L. et al. Evidence of female sex pheromones and characterization of the cuticular lipids of unfed, adult male versus female blacklegged ticks, Ixodes scapularis. Exp. Appl. Acarol. http://dx.doi.org/10.1007/s10493-015-0009-y
Writer: Natalie van Hoose, 765-496-2050, firstname.lastname@example.org
Sources: Catherine Hill, 765-496-6157, email@example.com
Richard Kuhn, 765-494-4407, firstname.lastname@example.org
Department of Health and Human Services, NIH and NIAID grants and contracts used in support of this research include N01-AI30071, HHSN272200900007C, HHSN266200400001C, 5R01GM77117-5, HHSN266200400039C, HHSN272200900039C, NIH-1R01AI090062, NIH 1R21AI096268, TL1 TR000162, HHSN272200900040C, R01AI017828 and R01AI043006.
Genetic clues to a unique parasitic lifestyle in the Lyme disease tick, Ixodes scapularis
Monika Gulia-Nuss1,¥,#, Andrew B. Nuss1,π,#, Jason M. Meyer1,§,#, Daniel E. Sonenshine2, R. Michael Roe3, Robert M. Waterhouse4,5,6,7, David B. Sattelle8, José de la Fuente9,10, Jose M. Ribeiro11, Karine Megy12,◊, Jyothi Thimmapuram13, Jason R. Miller14, Brian P. Walenz14,†, Sergey Koren14,†, Jessica B. Hostetler14,ζ, Mathangi Thiagarajan14,β, Vinita S. Joardar14,∞, Linda I. Hannick14,β, Shelby Bidwell14, Martin P. Hammond12,**, Sarah Young15, Qiandong Zeng15, Jenica L. Abrudan16,∆, Francisca C. Almeida17, Nieves Ayllón9, Ketaki Bhide13, Brooke W. Bissinger3,Ÿ, Elena Bonzon-Kulichenko18, Steven D. Buckingham8, Daniel R. Caffrey19, Melissa J. Caimano20, Vincent Croset21,δ, Timothy Driscoll22,θ, Don Gilbert23, Joseph J. Gillespie22,α, Gloria I. Giraldo-Calderón1,16, Jeffrey M. Grabowski1,24,∫, David Jiang25, Sayed M.S. Khalil26, Donghun Kim27,¶, Katherine M. Kocan10, Juraj Koči28,√, Richard J. Kuhn24, Timothy J. Kurtti29, Kristin Lees30,£, Emma G. Lang1, Ryan C. Kennedy31, Hyeogsun Kwon27,œ, Rushika Perera24,Ω, Yumin Qi25, Justin D. Radolf20, Joyce M. Sakamoto32, Alejandro Sánchez-Gracia17, Maiara S. Severo33,∑, Neal Silverman19, Ladislav Šimo28,€, Marta Tojo34,35, Cristian Tornador36, Janice P. Van Zee1, Jesús Vázquez18, Filipe G. Vieira17, Margarita Villar9, Adam R. Wespiser19, Yunlong Yang27, Jiwei Zhu3, Peter Arensburger37, Patricia V. Pietrantonio27, Stephen C. Barker38, Renfu Shao39, Evgeny M. Zdobnov4,5, Frank Hauser40, Cornelis J.P. Grimmelikhuijzen40, Yoonseong Park28, Julio Rozas17, Richard Benton21, Joao H.F. Pedra33,α, David R. Nelson41, Maria F. Unger16, Jose M.C. Tubio42,43, Zhijian Tu25, Hugh M. Robertson44, Martin Shumway14, ‡, Granger Sutton14, Jennifer R. Wortman14,η, Daniel Lawson12, Stephen K. Wikel45, Vishvanath M. Nene14,+, Claire M. Fraser46, Frank H. Collins16, Bruce Birren7, Karen E. Nelson14, Elizabet Caler14,ε, Catherine A. Hill1,*
1Department of Entomology, Purdue University, West Lafayette, IN 47907, USA.
2Department of Biological Sciences, Old Dominion University, Norfolk, VA 23529, USA.
3Department of Entomology, North Carolina State University, Raleigh, NC 27695, USA.
4Department of Genetic Medicine and Development, University of Geneva Medical School, 1211 Geneva, Switzerland.
5Swiss Institute of Bioinformatics, 1211 Geneva, Switzerland.
6Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
7The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
8Division of Medicine, University College London, The Rayne Building, London WC1E 6JF, UK.
9SaBio, Instituto de Investigación en Recursos Cinegéticos, IREC-CSIC-UCLM-JCCM, Ronda de Toledo sn, Ciudad Real 13005, Spain.
10Department of Veterinary Pathobiology, Center for Veterinary Health Sciences, Oklahoma State University, 250 McElroy Hall, Stillwater, OK 74078, USA.
11Laboratory of Malaria and Vector Research, NIAID, Rockville, MD 20852, USA.
12VectorBase/EMBL-EBI, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SD, United Kingdom.
13Bioinformatics Core, Purdue University, West Lafayette, IN 47907, USA.
14J. Craig Venter Institute, Rockville, MD 20850, USA.
15Genome Sequencing and Analysis Program, Broad Institute, Cambridge MA 02142, USA.
16Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556, USA.
17Departament de Genètica & Institut de Recerca de la Biodiversitat (IRBio), Universitat de Barcelona, Barcelona E-08028, Spain.
18Centro Nacional de Investigaciones Cardiovasculares, Madrid 28029, Spain.
19Department of Medicine, Division of Infectious Diseases, University of Massachusetts Medical School, Worcester, MA 01605, USA.
20Department of Medicine, UConn Health, Farmington, CT 06030, USA.
21Center for Integrative Genomics, Faculty of Biology and Medicine, University of Lausanne, CH-1015, Lausanne, Switzerland.
22Virginia Bioinformatics Institute at Virginia Tech, Blacksburg, VA 24061, USA.
23Department of Biology, Indiana University, Bloomington, IN 47405, USA.
24Markey Center for Structural Biology, Department Biological Sciences, Purdue University, West Lafayette, IN 47907, USA.
25Department of Biochemistry, Virginia Tech, Blacksburg, VA 24061, USA.
26Department of Microbial Molecular Biology, Agricultural Genetic Engineering Research Institute, Giza 12619, Egypt.
27Department of Entomology, Texas A&M University, College Station, TX 77843, USA.
28Department of Entomology, Kansas State University, Manhattan, KS 66506, USA.
29Department of Entomology, University of Minnesota, St. Paul, MN 55108, USA.
30Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United Kingdom.
31Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA 94143, USA.
32Department of Entomology, The Pennsylvania State University, University Park, PA 16802, USA.
33Center for Disease Vector Research and Department of Entomology, University of California, Riverside, CA, 92506, USA.
34Department of Pathology, Cambridge Genomic Services, University of Cambridge, Cambridge CB2 1QP, United Kingdom.
35Department of Physiology, School of Medicine-CIMUS-Instituto de Investigaciones Sanitarias, University of Santiago de Compostela, Santiago de Compostela, Spain.
36Universidad Pompeu Fabra, E-08002 Barcelona, Spain.
37Department of Biological Sciences, California State Polytechnic University, Pomona, CA 91768, USA.
38Parasitology Section, School of Chemistry & Molecular Biosciences, University of Queensland, Brisbane, Queensland 4072, Australia.
39GeneCology Research Centre, Faculty of Science, Health, Education and Engineering, University of the Sunshine Coast, Maroochydore, Queensland 4556, Australia.
40Department of Biology, Center for Functional and Comparative Insect Genomics, University of Copenhagen, DK-2100 Copenhagen, Denmark.
41Department of Microbiology, Immunology & Biochemistry, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
42Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, United Kingdom.
43Department of Biochemistry, Genetics and Immunology, University of Vigo, Vigo 36310, Spain.
44Department of Entomology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
45Department of Medical Sciences, Frank H. Netter MD School of Medicine at Quinnipiac University, Hamden, CT 06518, USA.
46Institute for Genome Sciences, University of Maryland, School of Medicine, Baltimore, MD 21201, USA.
¥Department of Biochemistry and Molecular Biology, University of Nevada, Reno, NV 89503, USA.
πDepartment of Agriculture, Nutrition, and Veterinary Science, University of Nevada, Reno, NV 89557, USA.
§Department of Biotechnology, Monsanto Company, Chesterfield, MO 63017, USA.
◊Department of Haematology, University of Cambridge, NHSBT Building, Long Road, Cambridge CB2 0PT, UK.
†Genome Informatics Section, Computational and Statistical Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA
ζLaboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
βLeidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
∞National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD 20894, USA.
∆Nevada Institute of Personalized Medicine, University of Nevada, Las Vegas, Las Vegas, NV, 89154, USA.
ŸAgBiome, Inc., Research Triangle Park, NC 27709, USA.
δCentre for Neural Circuits and Behaviour, University of Oxford, Oxford OX1 3SR, United Kingdom.
θDepartment of Biology, West Virginia University, Morgantown, WV 26505
αDepartment of Microbiology & Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
£Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119074.
œDepartment of Entomology, Iowa State University, Ames, IA 50011, USA.
∫Rocky Mountain Laboratories, Biology of Vector-Borne Viruses Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840, USA.
¶Department of Entomology, Kansas State University, Manhattan, KS 66506, USA.
√Department of Veterinary Medicine, University of Maryland, School of Medicine, Baltimore, MD 21201, USA.
ΩDepartment of Microbiology, Immunology, and Pathology, Arthropod-borne & Infectious Diseases Laboratory, Colorado State University, Fort Collins, CO 80523, USA.
∑Department of Vector Biology, Max-Planck-Institut für Infektionsbiologie, Charitéplatz 1, 10117 Berlin, Germany.
€French National Institute of Agricultural Research, UMR-BIPAR INRA-ANSES-ENVA, Maisons-Alfort, France.
‡National Library of Medicine, Bethesda, MD 20894, USA.
ηSeres Therapeutics, Cambridge, MA 02142, USA.
+International Livestock Research Institute, Nairobi 00100, Kenya
εNational Heart, Lung, and Blood Institute, Division of Lung Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
#authors contributed equally
Ticks transmit more pathogens to humans and animals than any other arthropod. We describe the 2.1 Gbp nuclear genome of the tick, Ixodes scapularis (Say), which vectors pathogens that cause Lyme disease, human granulocytic anaplasmosis, babesiosis, and other diseases. The large genome reflects extensive accumulation of repetitive DNA, new lineages of retro-transposons, and gene architecture patterns resembling ancient eukaryotes rather than pancrustaceans. Annotation revealed 20,486 protein-coding genes and expansions of gene families associated with tick-host interactions. Genome analyses provided insights into parasitic processes unique to ticks, including host "questing," prolonged feeding, cuticle synthesis, blood meal concentration, novel methods of hemoglobin digestion, heme detoxification, vitellogenesis, reproduction, oviposition, and prolonged off-host survival. Proteins associated with the agent of transmission of human granulocytic anaplasmosis, an emerging disease, and the encephalitis-causing Langat virus, were identified. SNP analysis revealed a population structure correlated to life-history traits and transmission of the Lyme disease agent.