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. 2016 Feb 9;7:10507.
doi: 10.1038/ncomms10507.

Genomic Insights Into the Ixodes Scapularis Tick Vector of Lyme Disease

Monika Gulia-Nuss  1 Andrew B Nuss  1 Jason M Meyer  1 Daniel E Sonenshine  2 R Michael Roe  3 Robert M Waterhouse  4   5   6   7 David B Sattelle  8 José de la Fuente  9   10 Jose M Ribeiro  11 Karine Megy  12 Jyothi Thimmapuram  13 Jason R Miller  14 Brian P Walenz  14 Sergey Koren  14 Jessica B Hostetler  14 Mathangi Thiagarajan  14 Vinita S Joardar  14 Linda I Hannick  14 Shelby Bidwell  14 Martin P Hammond  12 Sarah Young  15 Qiandong Zeng  15 Jenica L Abrudan  16 Francisca C Almeida  17 Nieves Ayllón  9 Ketaki Bhide  13 Brooke W Bissinger  3 Elena Bonzon-Kulichenko  18 Steven D Buckingham  8 Daniel R Caffrey  19 Melissa J Caimano  20 Vincent Croset  21 Timothy Driscoll  22 Don Gilbert  23 Joseph J Gillespie  22 Gloria I Giraldo-Calderón  1   16 Jeffrey M Grabowski  1   24 David Jiang  25 Sayed M S Khalil  26 Donghun Kim  27 Katherine M Kocan  10 Juraj Koči  28 Richard J Kuhn  24 Timothy J Kurtti  29 Kristin Lees  30 Emma G Lang  1 Ryan C Kennedy  31 Hyeogsun Kwon  27 Rushika Perera  24 Yumin Qi  25 Justin D Radolf  20 Joyce M Sakamoto  32 Alejandro Sánchez-Gracia  17 Maiara S Severo  33 Neal Silverman  19 Ladislav Šimo  28 Marta Tojo  34   35 Cristian Tornador  36 Janice P Van Zee  1 Jesús Vázquez  18 Filipe G Vieira  17 Margarita Villar  9 Adam R Wespiser  19 Yunlong Yang  27 Jiwei Zhu  3 Peter Arensburger  37 Patricia V Pietrantonio  27 Stephen C Barker  38 Renfu Shao  39 Evgeny M Zdobnov  4   5 Frank Hauser  40 Cornelis J P Grimmelikhuijzen  40 Yoonseong Park  28 Julio Rozas  17 Richard Benton  21 Joao H F Pedra  33 David R Nelson  41 Maria F Unger  16 Jose M C Tubio  42   43 Zhijian Tu  25 Hugh M Robertson  44 Martin Shumway  14 Granger Sutton  14 Jennifer R Wortman  14 Daniel Lawson  12 Stephen K Wikel  45 Vishvanath M Nene  14 Claire M Fraser  46 Frank H Collins  16 Bruce Birren  7 Karen E Nelson  14 Elisabet Caler  14 Catherine A Hill  1
Free PMC article

Genomic Insights Into the Ixodes Scapularis Tick Vector of Lyme Disease

Monika Gulia-Nuss et al. Nat Commun. .
Free PMC article


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 accumulation of repetitive DNA, new lineages of retro-transposons, and gene architecture patterns resembling ancient metazoans rather than pancrustaceans. Annotation of scaffolds representing ∼57% of the genome, reveals 20,486 protein-coding genes and expansions of gene families associated with tick-host interactions. We report insights from genome analyses into parasitic processes unique to ticks, including host 'questing', prolonged feeding, cuticle synthesis, blood meal concentration, novel methods of haemoglobin digestion, haem detoxification, vitellogenesis and prolonged off-host survival. We identify proteins associated with the agent of human granulocytic anaplasmosis, an emerging disease, and the encephalitis-causing Langat virus, and a population structure correlated to life-history traits and transmission of the Lyme disease agent.


Figure 1
Figure 1. Genes associated with the unique parasitic lifestyle of Ixodes scapularis.
(a) Host detection. Ticks spend long periods off-host and locate hosts by ‘questing' from vegetation. The Haller's organ, located on the first pair of tarsi, is the major sensory appendage. The tick has a relatively small repertoire of visual and chemosensory genes and an expansion of detoxification genes, presumably to counteract environmental toxicants. (b) Attachment and blood feeding. The tick creates a wound cavity and injects saliva containing cement, vasodilators, pain inhibitors, anticoagulants and immune-suppressing factors to facilitate long periods of attachment and blood feeding. (c) Engorgement. Blood engorgement takes place over days to weeks and includes slow and rapid phases (dotted lines indicate increase in body volume). New cuticle is putatively synthesized to accommodate ingestion of the large (∼100-fold increase in body weight) blood meal. The tick has an expansion of neuropeptide receptors to regulate diuresis and concentrate the blood meal. (d) Digestion. The processes of haemoglobin digestion in intracellular vesicles of midgut cells and haem sequestration involving specialized storage proteins are unique to ticks. Haemolyzed erythrocytes are absorbed by midgut epithelial cells by pinocytosis. Digestion is accomplished by fusion with lysosomes containing digestive enzymes (see text) and sequential breakdown of proteins (1) liberating haem and 8–11 kDa peptide fragments, (2) ∼5–7 kDa fragments, (3) 3–5 kDa peptides and finally (4) dipeptides and free amino acids. Amino acids are transcytosed from the digestive cells into haemolymph and haem is transported by haem-binding proteins to haemosomes for detoxification. Absorbed nutrients are converted to storage proteins (CP) throughout development or to vitellogenin in adult females for yolk provisioning of the egg just before oviposition. AMP, antimicrobial peptide; CAT, cathepsin; CP, haemlipoglyco-carrier protein; CYP450, cytochrome P450; GR, gustatory receptor; IR/iGluR, ionotropic receptor/ionotropic glutamate receptor; LAP, lysosomal aspartic protease; OBP, odorant binding protein; OR, odorant receptor; SCP, serine cysteine protease; Vg, vitellogenin.
Figure 2
Figure 2. Organization of DNA on the Ixodes scapularis chromosomes.
Families of tandem repeats (TRs) comprise approximately 40% of the genome and were localized by fluorescent in situ hybridization (FISH) to ISE18 cell line mitotic chromosome spreads. (a) Representative FISH image of Cot-1 DNA (green) at the heterochromatic terminal region of the DAPI-stained chromosomes (blue), presumed to represent the centromere. (b) Representative FISH of a telomeric repeat probe (TTAGG)n. Not all DAPI-stained chromosomes (blue) in this image show the ‘two-spot' telomeric hybridization signal (green) at both ends due to the limited depth of field possible during imaging. (c) Representative FISH of a BAC clone (BAC ID: 192414) in red and the ISR-2a 95 bp tandem repeat in green. BAC clone hybridization signals are dispersed throughout the presumed euchromatic regions of the DAPI-stained chromosomes (blue). Hybridization of the 95 bp tandem repeat is prevalent at one end of most of the chromosomes that is believed to represent the centromeres. (df) FISH using probes from clones in a small-insert gDNA library containing tandem repeats; Clone O-21 (d); Clone B-20 (e); Clone B-01 (f). Note that the hybridization signals (red) are dispersed among the presumed euchromatic regions of the DAPI-stained chromosomes (blue) and not at the heterochromatic termini thought to represent the centromeres. (g) Ideogram showing the relative arrangement of tandemly repetitive DNA based on FISH to the presumed acro- or telocentric chromosomes. The 13 autosomes and the X and Y sex determining chromosomes are shown. Brackets indicate groups of chromosomes sharing similar hybridization patterns. The individual chromosomes within these groups could not be distinguished based on relative size or distribution of tandemly repetitive DNA. Chromosomes are drawn to scale based on the representative example. Variability in the relative sizes of ISE18 chromosomes among different chromosome spreads prevented development of a standard karyotype where chromosomes are assigned numbers based on size and FISH marker distribution.
Figure 3
Figure 3. Molecular and intron evolution of Ixodes scapularis orthologs.
(a) The species phylogeny computed from the concatenated alignment of single-copy orthologous protein-coding genes confirms the position of the Subphylum Chelicerata at the base of the arthropod radiation, an outgroup to the clade Pancrustacea that contains crustaceans and hexapods. The average rate of I. scapularis molecular evolution is slower than that in the fast-evolving dipterans (Anopheles gambiae and Drosophila melanogaster), comparable to other representative arthropods for which genome sequences are available, and faster than that of vertebrates. (b) Quantification of the proportions of shared and unique intron positions from well-aligned regions of universal orthologs reveals that, compared with the crustacean, Daphnia pulex, I. scapularis shares more than 10 times as many introns exclusively with at least one of the five outgroup species (from Cnidaria and Vertebrata) (dotted box, 13.8% versus 1.1%). Conversely, D. pulex has more intron positions exclusively in common with the representative insects (dashed box, 2.3% versus 0.6%). (c) I. scapularis intron lengths are more similar to those of introns from orthologous genes in the vertebrates Homo sapiens and Mus musculus, and are an order of magnitude longer than introns from the pancrustacean species analysed. The intron length distributions are shown for ancient introns found in both I. scapularis and D. pulex and at least one of the five outgroup species and at least one insect; boxplots indicate medians, first and third quartiles, and whiskers.
Figure 4
Figure 4. Model of neuroendocrine processes controlling mating and egg production in Ixodes scapularis.
(1) Mating takes place off or on the host (before or during blood feeding), but is required for rapid blood feeding. The male attaches to the genital pore of the female via its mouthparts (evidence suggests the potential involvement of female specific cuticular lipids and a non-volatile mounting pheromone in I. scapularis), then transfers sperm and gonadotropins (unidentified at present), among other seminal components, including the spermatophore, (2) Gonadotropins initiate the synganglion to release EDTH, stimulate rapid engorgement, initiate synthesis of neuropeptides which in insects regulate moulting and synthesis of new cuticle (tick functions unknown), and release of allatostatins and allatotropins (which may stimulate or inhibit the mevalonate-farnesal pathway), (3) EDTH initiates production of ecdysteroids by the epidermis, (4) High ecdysteroid titres activate transcription factors for VgR in the ovaries, are stored in developing eggs and, as 20-E, activates transcription factors for Vg in the fat body and specialized cells of the midgut, (5) Vg is taken up via VgR-receptor mediated endocytosis by developing oocytes and incorporated into the yolk as vitellin, and (6) The female produces a single batch of ∼3,000 mature eggs from the genital pore that are passed forward to the mouthparts for coating with wax released from the Gene's organ. Biochemical and genomic evidence suggests that I. scapularis do not make JH III although the genes for the preceding mevalonate and parts of the farnesal pathway were identified. Dashed lines indicate proposed pathways and factors. 20-E, 20-hydroxyecdysone; CAP, cardioactive peptide; EDTH, hypothesized epidermal trophic hormone; Vg, vitellogenin (yolk protein in haemolymph before egg uptake); VgR, vitellogenin receptor.
Figure 5
Figure 5. Key features of pathogen transmission by Ixodes scapularis.
The tick life stages involved in the transmission of a typical pathogen (outer ring) and critical physical/physiological barriers to pathogen acquisition, replication and transmission (inner circle) are depicted. Representative pathogens: (a) Borrelia spp.; (b) Anaplasma phagocytophilum; (c) Tick-borne flavivirus (e.g., Langat virus, LGTV). The different strategies employed by a parasite to navigate from the midgut to the salivary glands, and tick and parasite derived factors known to facilitate these processes are shown. IMD, Immunodeficiency; JAK-STAT, Janus Kinase/Signal Transsducers and Activators of Transcription; OspA, Borrelia outer surface protein A; Salp15/16, salivary gland protein 15/16; tHRF, tick histamine-release factor; TROPSA, tick receptor for OspA; TSLP1, tick salivary lectin pathway inhibitor.
Figure 6
Figure 6. Population structure of Ixodes scapularis across North America.
(a) Tick sampling sites in Indiana (IN), Massachusetts (MA), Maine (ME), North Carolina (NC), New Hampshire (NH), Wisconsin (WI), Florida (FL) and Virginia (VA) overlaid against reported Lyme disease cases in 2012 (modified from CDC:; (b) Membership probabilities in bar plots for individual I. scapularis comprising different clusters and showing separation of genetic groups based on 34,693 RADtag SNP markers. SNP, single-nucleotide polymorphism; WK, I. scapularis WIKEL reference strain.
Figure 7
Figure 7. De-orphanizing Ixodes scapularis receptors as candidate targets for the development of new acaricides.
The newly identified I. scapularis dicysteine-loop, ligand-gated anion channel subunit (IscaGluCl1, KR107244) contains the ‘PAR' motif centred on the 0' position in the second transmembrane region (TM2), characteristic of ligand-gated anion channels and is aligned with a brown dog tick Rhipicephalus sanguineus GluCl (RsGluCl1, ACX33155) and human glycine receptor α-subunit (P23415) (a). Using the Xenopus laevis oocyte receptor expression vehicle, IscaGluCl1 yielded robust chloride currents in response to 10−4 M L-glutamate (b) and ibotenate (c) but only weak currents in response to the same concentration of D-glutamate (c); ibotentate and D-glutamate responses are depicted relative to L-glutamate (n=6, 8; error bars represent±1 s.e.m.). No response was detected in the presence of 10−4 M acetylcholine (ACh), γ-amino butyric acid (GABA), dopamine, histamine, serotonin, tyramine or glycine. The subunit is therefore identified as an Ixodes scapularis homomer-forming GluCl subunit, (IscaGluCl1), illustrated by a schematic of a homomeric GluCl showing two of the five subunits and the position of the PAR motif in yellow (d).

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    1. Lindgren E. & Jaenson T. G. T. Lyme borreliosis in Europe: influences of climate and climate change, epidemiology, ecology and adaptation measures World Health Organization (2006)
    1. MMWR. Morbidity and Mortality Weekly Report. Report No. 61, 1-124 (Centers for Disease Control and Prevention (CDC), Atlanta, GA, USA, 2014)
    1. Walker D. Tick-transmitted infectious diseases in the United States. Annu. Rev. Public Health 19, 237–269 (1998) . - PubMed
    1. Rizzoli A. et al. . Lyme borreliosis in Europe. Eurosurveillance 16, : pii 19906 (2011) .
    1. Wormser G. P. et al. . The clinical assessment, treatment, and prevention of Lyme disease, human granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious Diseases Society of America. Clin. Infect. Dis. 43, 1089–1134 (2006) . - PubMed

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