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Sequencing of Culex quinquefasciatus
Establishes a Platform for Mosquito Comparative
Genomics
Article in Science · October 2010
DOI: 10.1126/science.1191864 · Source: PubMed
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Sequencing of Culex quinquefasciatus Establishes
a Platform for Mosquito Comparative Genomics
Peter Arensburger, et al.
Science 330, 86 (2010);
DOI: 10.1126/science.1191864
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REPORTS
References and Notes
1. United States Department of Agriculture (USDA), “The
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Sequencing of Culex quinquefasciatus
Establishes a Platform for Mosquito
Comparative Genomics
Peter Arensburger,1* Karine Megy,2 Robert M. Waterhouse,3,4 Jenica Abrudan,5 Paolo Amedeo,6
Beatriz Antelo,7 Lyric Bartholomay,8 Shelby Bidwell,9 Elisabet Caler,6 Francisco Camara,9
Corey L. Campbell,10 Kathryn S. Campbell,11 Claudio Casola,12 Marta T. Castro,13
Ishwar Chandramouliswaran,6 Sinéad B. Chapman,14 Scott Christley,5 Javier Costas,15 Eric Eisenstadt,6
Cedric Feschotte,16 Claire Fraser-Liggett,17 Roderic Guigo,9 Brian Haas,14 Martin Hammond,2
Bill S. Hansson,18 Janet Hemingway,19 Sharon R. Hill,20 Clint Howarth,14 Rickard Ignell,20
Ryan C. Kennedy,5 Chinnappa D. Kodira,21 Neil F. Lobo,5 Chunhong Mao,22 George Mayhew,23
Kristin Michel,24 Akio Mori,5 Nannan Liu,25 Horacio Naveira,26 Vishvanath Nene,17,27 Nam Nguyen,16
Matthew D. Pearson,14 Ellen J. Pritham,16 Daniela Puiu,28 Yumin Qi,22 Hilary Ranson,19
Jose M. C. Ribeiro,29 Hugh M. Roberston,30 David W. Severson,5 Martin Shumway,29 Mario Stanke,31
Robert L. Strausberg,6 Cheng Sun,16 Granger Sutton,6 Zhijian (Jake) Tu,22 Jose Manuel C. Tubio,7
Maria F. Unger,5 Dana L. Vanlandingham,33 Albert J. Vilella,2 Owen White,17 Jared R. White,14
Charles S. Wondji,19 Jennifer Wortman,17 Evgeny M. Zdobnov,3,4,33 Bruce Birren,14
Bruce M. Christensen,23 Frank H. Collins,5 Anthony Cornel,32 George Dimopoulos,35
Linda I. Hannick,6 Stephen Higgs,33 Gregory C. Lanzaro,34 Daniel Lawson,2 Norman H. Lee,36
Marc A. T. Muskavitch,14,37,38 Alexander S. Raikhel,1 Peter W. Atkinson1
Culex quinquefasciatus (the southern house mosquito) is an important mosquito vector of viruses such as
West Nile virus and St. Louis encephalitis virus, as well as of nematodes that cause lymphatic filariasis.
C. quinquefasciatus is one species within the Culex pipiens species complex and can be found throughout
tropical and temperate climates of the world. The ability of C. quinquefasciatus to take blood meals from
birds, livestock, and humans contributes to its ability to vector pathogens between species. Here, we
describe the genomic sequence of C. quinquefasciatus: Its repertoire of 18,883 protein-coding genes is
22% larger than that of Aedes aegypti and 52% larger than that of Anopheles gambiae with multiple
gene-family expansions, including olfactory and gustatory receptors, salivary gland genes, and genes
associated with xenobiotic detoxification.
M
86
osquitoes are the most important vectors of human disease and are responsible for the transmission of pathogens
that cause malaria (Anopheles), yellow fever and
dengue (Aedes), as well as lymphatic filariasis
and encephalitis viruses (Culex, Aedes, Anopheles).
1 OCTOBER 2010
VOL 330
SCIENCE
19. E. Reifenberger, E. Boles, M. Ciriacy, Eur. J. Biochem.
245, 324 (1997).
20. S. P. Voutilainen et al., Biotechnol. Bioeng. 101, 515 (2008).
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Adv. 26, 89 (2008).
22. L. C. Basso, H. V. de Amorim, A. J. de Oliveira,
M. L. Lopes, FEM. Yeast Res. 8, 1155 (2008).
23. We thank J. Doudna, M. Marletta, J. Taylor, T. Bruns, and
C. Phillips for helpful discussions and comments on the
manuscript; M. Toews for help with growth assays;
S. Bauer and A. Ibanez for help with analytical methods;
and C. Anderson for help with confocal microscopy. This
work was supported by funding from the Energy
Biosciences Institute to J.H.D.C. and N.L.G. The Regents
of the University of California, the authors, and British
Petroleum Technology Ventures (through the Energy
Biosciences Institute) have submitted a patent for the use
of cellodextrin transporters in fermenting organisms for
the use of plant biomass.
Supporting Online Material
www.sciencemag.org/cgi/content/full/science.1192838/DC1
Materials and Methods
Figs. S1 to S8
References
26 May 2010; accepted 25 August 2010
Published online 9 September 2010;
10.1126/science.1192838
Include this information when citing this paper.
Sequencing the Anopheles gambiae and Aedes
aegypti genomes has provided important insights
into the genomic diversity underlying the complexity of mosquito biology (1, 2). We describe the
sequencing of the Culex quinquefasciatus (the
southern house mosquito) genome, which offers
a reference genome from the third major taxonomic group of disease-vector mosquitoes. With
more than 1200 described species, Culex is the
most diverse and geographically widespread of
these three mosquito genera. Apart from contributing to the spread of West Nile encephalitis,
it also transmits St. Louis encephalitis and other
viral diseases and is a major vector of the parasitic Wuchereria bancrofti nematode that has
caused the majority of the 120 million current
cases of lymphatic filariasis (3).
Taxonomy of the Culex pipiens species complex is the subject of a long-standing debate, an
issue complicated by the occurrence of viable
species hybrids in many geographic areas [reviewed in (4, 5)]. We followed the standard set by
the National Center for Biotechnology Information and refer to the species sequenced here as
C. quinquefasciatus. The Johannesburg strain
of C. quinquefaciatus was established from a
single pond in Johannesburg, South Africa—an
area where the two taxa, C. quinquefasciatus and
C. pipiens, were found to be sympatric [(5) therein
described as subspecies C. pipiens quinquefasciatus
and C. pipiens pipiens] but have remained much
more genetically distinct than the same two sympatric taxa found in California.
We were able to map 9% of the C. quinquefasciatus genes (1768 genes) on the three
chromosomes with the use of published and new
C. quinquefasciatus and Ae. aegypti markers (6).
Of these mapped genes, 803 had An. gambiae
orthologs and 641 had Drosophila melanogaster
www.sciencemag.org
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[Km ≈ 100 to 1000 mM (17)] and to S. cerevisiae
hexose transporters’ apparent affinity for glucose
[Km ≈ 1000 to 10,000 mM (19)]. Therefore, the
cellodextrin transport systems should more effectively maintain soluble sugar levels below the concentration at which they inhibit fungal cellulases
[inhibition constant (Ki) of cellobiose ≈ 19 to 410
mM (20)].
With little optimization, yeast expressing cdt-1 and
gh1-1 fermented cellobiose with an ethanol yield of
0.441 T 0.001 (grams of ethanol/grams of glucose T
SD), which is 86.3% of the theoretical value (Fig.
2A) (21). This yield is close to present industrial
yields of ethanol from glucose of 90 to 93% (22).
Yeasts expressing a cellodextrin transport system
markedly improve the efficiency of SSF reactions
by reducing the steady-state concentration of both
cellobiose and glucose and by increasing the
ethanol production rate (Fig. 2, B and C). The
addition of a cellodextrin transport system to
biofuel-producing strains of yeast (Fig. 3) overcomes a major bottleneck to fermentation of
lignocellulosic feedstocks and probably will help
to make cellulosic biofuels economically viable.
REPORTS
*To whom correspondence should be addressed. E-mail:
arensburger@gmail.com
A
orthologs, consistent with the established species phylogeny (Fig. 1A). Examining correlations
between chromosomal arms indicated wholechromosome conservation between C. quinquefasciatus, An. gambiae, and D. melanogaster (Fig.
1B) (6), whereas—and as suggested from earlier
work (7)—Ae. aegypti appears to have experienced an arm exchange between the two longest
chromosomes after the Aedes/Culex divergence
(fig. S1).
A significant fraction of the assembled C.
quinquefasciatus genome (29%) was composed of
transposable elements (TEs) (fig. S2). This amount
is less than the TE fraction of Ae. aegypti (42 to
47%), but greater than that of An. gambiae (11 to
16%) (1, 2, 6), suggesting an increased level of
TE activity and/or reduced intensity of selection
against TE insertions in the two culicinae lineages
since their divergence from the An. gambiae lineage.
A comparative analysis of the age distribution of
the different TE types in the three sequenced mosquito genomes revealed that retrotransposons have
consistently been the dominant TE type in the
Ae. aegypti lineage over time (fig. S3). More recently, retrotransposons have become the predominant type of TEs active in all three species.
The C. quinquefasciatus repertoire of 18,883
protein-coding genes is 22% larger than that of
Ae. aegypti (15,419 genes) and 52% larger than
that of An. gambiae (12,457 genes) (Fig. 1C). Our
estimated gene number combines ab initio and
similarity-based predictions from three independent
automated pipelines, optimizing gene identification
(6). The relative increase in C. quinquefasciatus
gene number is explained in part by the presence
of substantially more expanded gene families, including olfactory and gustatory receptors, immunerelated genes, and genes with possible xenobiotic
B
52 – 54 mya.
145 – 200 mya.
Cq
Aa
Ag
260 mya.
Dm
C
Proteins
5,000
10,000
15,000
Cq
Aa
Ag
www.sciencemag.org
detoxification functions (table S1). Expert curation
of selected gene families revealed expansions in
cytosolic glutathione transferases and a substantial
expansion of cytochrome P450s. A large cytochrome P450 repertoire may reflect adaptations
to polluted larval habitats and may have played a
role in rendering this species particularly adaptable
to evasion of insecticide-based control programs,
with several C. quinquefasciatus P450s being associated with resistance (8, 9).
Mosquitoes are the subject of intense efforts
aimed at designing novel vector control methods
that are often based on the ability of the insect to
sense its environment (10, 11). C. quinquefasciatus
has the largest number of olfactory-receptor–related
genes (180) of all dipteran species examined to
date (table S1). This expansion may reflect culicine olfactory behavioral diversity, with particular regard to host and oviposition site choice. C.
quinquefasciatus females are opportunistic feeders,
being able to detect and feed on birds, humans, and
livestock, depending on their availability. This plasticity in feeding behavior contributes to the ability
of C. quinquefasciatus to vector pathogens, such
as West Nile virus and St. Louis encephalitis
virus, from birds to humans. The repertoire of gustatory receptors, which are known to mediate perception of both odorants and tastants (12), has also
expanded in C. quinquefasciatus, primarily through
a large alternatively spliced gene locus.
The saliva of blood-sucking arthropods contains
a complex cocktail of pharmacologically active
components that disarm host hemostasis (13). The
ability of C. quinquefasciatus to feed on birds,
humans, and livestock would suggest that it contains
an expanded number of proteins that would increase
its ability to imbibe blood from multiple host species. Consistent with this idea, a large protein family
Downloaded from www.sciencemag.org on September 30, 2010
1
Center for Disease Vector Research, University of California
Riverside, Riverside, CA 92521, USA. 2European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus,
Hinxton, Cambridge CB10 1SD, UK. 3University of Geneva
Medical School, 1 rue Michel-Servet, 1211 Geneva, Switzerland.
4
Swiss Institute of Bioinformatics, 1 rue Michel-Servet, 1211
Geneva, Switzerland. 5University of Notre Dame, Notre Dame, IN
46556, USA. 6J. Craig Venter Institute, Rockville, MD 20850, USA.
7
Complexo Hospitalario Universitario de Santiago, Santiago de
Compostela 15706, Spain. 8Iowa State University, Ames, IA
50011, USA. 9Center for Genomic Regulation, Universitat
Pompeu Fabra, E-08003 Barcelona, Catalonia, Spain. 10Colorado
State University, Fort Collins, CO 80523, USA. 11Harvard University, Cambridge, MA 02138, USA. 12Indiana University,
Bloomington, IN 47405–3700, USA. 13Programa d’Epigenètica
i Biologia del Càncer, Hospital Duran i Reynals, 08907 Hospitalet
de Llobregat, Barcelona, Spain. 14The Broad Institute, Cambridge, MA 02142, USA. 15Fundación Pública Galega de Medicina
Xenómica–Servizo Galego de Saúde, Santiago de Compostela
15706, Spain. 16University of Texas Arlington, Arlington, TX 76019,
USA. 17Institute for Genome Sciences, University of Maryland
School of Medicine, Baltimore, MD 21201, USA. 18Max Planck
Institute for Chemical Ecology, 07749 Jena, Germany. 19Liverpool
School of Tropical Medicine, Liverpool L3 5QA, UK. 20Swedish
University of Agricultural Sciences, 230 53 Alnarp, Sweden. 21454
Life Sciences, the Roche Group, Branford, CT 06405, USA. 22Virginia Polytechnic Institute and State University, Blacksburg, VA
24061, USA. 23University of Wisconsin, Madison, WI 53706, USA.
24
Kansas State University, Manhattan, KS 66506, USA. 25Auburn
University, Auburn, AL 36849, USA. 26Departamento de Bioloxía
Celular e Molecular, Universidade da Coruña, 15071 A, Coruña,
Spain. 27International Livestock Research Institute, Nairobi, Kenya.
28
Center for Bioinformatics and Computational Biology, University of Maryland, College Park, MD 20742, USA. 29National Institutes
of Health, Bethesda, MD 20892, USA. 30University of Illinois UrbanaChampaign, Urbana, IL 61801, USA. 31University of Göttingen,
37077 Göttingen, Germany. 32University of Texas Medical Branch,
Galveston, TX 77555, USA. 33Imperial College London, South
Kensington Campus, London SW7 2AZ, UK. 34University of
California Davis, Parlier, CA 93648, USA. 35Bloomberg School of
Public Health, Johns Hopkins University, Baltimore, MD 21205,
USA. 36George Washington University Medical Center, Washington,
DC 20037, USA. 37Boston College, Chestnut Hill, MA 02467, USA.
38
Harvard School of Public Health, Boston, MA 02115, USA.
Fig. 1. (A) Codon-based estimates of DNA substitutions along
the mosquito phylogeny: C. quinquefasciatus (Cq), Ae. aegypti (Aa),
and An. gambiae (Ag) with D. melanogaster (Dm) as an outgroup.
Dates of divergence were taken
from previous studies (6). mya,
million years ago. (B) Chromosomal synteny between C. quinquefasciatus, Ae. aegypti, An.
gambiae, and D. melanogaster.
Solid lines indicate main orthologous chromosomes; the dashed
line denotes secondary orthologous chromosomes. Colors indicate syntenic chromosome arms.
Chromosomes are not drawn to
scale. (C) Orthology delineation
among the protein-coding gene
repertoires of the three sequenced mosquito species. Categories of orthologous groups
with members in all three species include single-copy orthologs in each species (1:1:1)
and multicopy orthologs in all three (N:N:N), one (N in 1), or two (N in 2) species.
Remaining orthologous groups include single or multicopy groups with genes in only two
species (X:X:0, X:0:X, 0:X:X). The remaining fractions in each species (Cq/Aa/Ag-specific)
exhibit no orthology with genes in the other two mosquitoes.
SCIENCE
VOL 330
1 OCTOBER 2010
87
REPORTS
References and Notes
1. R. A. Holt et al., Science 298, 129 (2002).
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Taxonomy, Distribution, Ecology, Physiology, Genetics,
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Pathogenomics of Culex quinquefasciatus
and Meta-Analysis of Infection
Responses to Diverse Pathogens
Lyric C. Bartholomay,1* Robert M. Waterhouse,2,3,15* George F. Mayhew,4 Corey L. Campbell,5
Kristin Michel,6 Zhen Zou,7 Jose L. Ramirez,8 Suchismita Das,8 Kanwal Alvarez,7
Peter Arensburger,9 Bart Bryant,6,7 Sinead B. Chapman,10 Yuemei Dong,8 Sara M. Erickson,4
S. H. P. Parakrama Karunaratne,11,12 Vladimir Kokoza,7 Chinnappa D. Kodira,13
Patricia Pignatelli,11 Sang Woon Shin,7 Dana L. Vanlandingham,14 Peter W. Atkinson,9
Bruce Birren,10 George K. Christophides,15 Rollie J. Clem,6 Janet Hemingway,11
Stephen Higgs,14 Karine Megy,16 Hilary Ranson,11 Evgeny M. Zdobnov,2,3,15
Alexander S. Raikhel,7 Bruce M. Christensen,4 George Dimopoulos,8 Marc A. T. Muskavitch10,17,18†
The mosquito Culex quinquefasciatus poses a substantial threat to human and veterinary health as a
primary vector of West Nile virus (WNV), the filarial worm Wuchereria bancrofti, and an avian malaria
parasite. Comparative phylogenomics revealed an expanded canonical C. quinquefasciatus immune gene
repertoire compared with those of Aedes aegypti and Anopheles gambiae. Transcriptomic analysis of
C. quinquefasciatus genes responsive to WNV, W. bancrofti, and non-native bacteria facilitated an
unprecedented meta-analysis of 25 vector-pathogen interactions involving arboviruses, filarial worms,
bacteria, and malaria parasites, revealing common and distinct responses to these pathogen types in
three mosquito genera. Our findings provide support for the hypothesis that mosquito-borne pathogens
have evolved to evade innate immune responses in three vector mosquito species of major medical importance.
he Southern house mosquito, Culex
quinquefasciatus, is a geographically widespread, often abundant mosquito that is an
epidemiologically important vector for an exceptionally diverse array of pathogens, including
multiple arboviruses, filarial worms, and protozoa. C. quinquefasciatus transmits West Nile
virus (WNV), St. Louis encephalitis virus, and
other arboviruses, and acts as the most important
vector of the causative agent of lymphatic
filariasis, Wuchereria bancrofti, and Plasmodium
relictum, an avian malaria parasite. Despite the
public health importance of C. quinquefasciatus,
knowledge of the insect’s response capacities to
this diverse array of pathogens is limited.
Availability of the C. quinquefasciatus genome
sequence (1) enabled comparative phylogenomic
analyses with Aedes aegypti (2), Anopheles gambiae
T
88
(3), and Drosophila melanogaster (4) that identified 500 C. quinquefasciatus immunity genes from
39 (sub)families or processes (table S1). Conservation of C. quinquefasciatus gene family members
follows the species phylogeny, showing greatest
similarities with A. aegypti. Expansions of C-type
lectins (CTLs), fibrinogen-related proteins (FREPs),
and serine protease inhibitors (SRPNs) account
for much of the 20 to 30% increase in C. quinquefasciatus immunity gene number compared with
A. aegypti (417 genes) and A. gambiae (380 genes)
(figs. S1 to S4). This apparent diversification in immune surveillance and immune signal amplification
processes seems consistent with selection driven
by polluted, microbially complex habitats in which
C. quinquefasciatus oviposits and develops (5).
Whole genome microarray analysis revealed
dynamic changes in infection response gene
1 OCTOBER 2010
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VOL 330
SCIENCE
12. E. A. Hallem, A. Dahanukar, J. R. Carlson, Annu. Rev.
Entomol. 51, 113 (2006).
13. J. M. C. Ribeiro, B. Arcà, Adv. Insect Physiol. 37, 59
(2009).
14. This work was supported by NIH grant
HHSN266200400039C and by the National
Institute of Allergy and Infectious Diseases,
NIH, Department of Health and Human Services
under contract numbers N01-AI-30071 and
HHSN266200400001C. The assembled genome
was deposited in the GenBank database with
accession number AAWU00000000.
Supporting Online Material
www.sciencemag.org/cgi/content/full/330/6000/86/DC1
Materials and Methods
Figs. S1 to S12
Tables S1 to S14
References
5 May 2010; accepted 27 August 2010
10.1126/science.1191864
(IRG) transcription in WNV-infected mosquitoes
(fig. S5). Significant changes are observed for
22 transcripts in the midgut and 309 in the carcass (i.e., the remainder of the body) at 7 days
postinfection (dpi), with the greater number of
IRGs in the latter apparently reflecting the diversity of infected cell and tissue types in the carcass.
At 14 dpi, more IRGs are modulated in midgut
(539) and carcass (490) when WNV infection has
spread in midgut cells and has disseminated to
the salivary glands (6). Few canonical immunity
genes are represented among C. quinquefasciatus
WNV IRGs (fig. S5). Five CTL genes within a
C. quinquefasciatus–specific gene expansion (fig.
S3) are up-regulated. Several genes related to the
1
Department of Entomology, Iowa State University, Ames,
IA 50011, USA. 2Department of Genetic Medicine and Development, University of Geneva Medical School, 1 Rue MichelServet, 1211 Geneva, CH, Switzerland. 3Swiss Institute of
Bioinformatics, 1 Rue Michel-Servet, 1211 Geneva, CH, Switzerland. 4Department of Pathobiological Sciences, University of
Wisconsin, Madison, WI 53706, USA. 5Microbiology, Immunology, and Pathology Department, Colorado State University,
Fort Collins, CO 80523, USA. 6Division of Biology, Arthropod
Genomics Center, Molecular and Cellular Developmental Biology Program, Kansas State University, Manhattan, KS 66506,
USA. 7Department of Entomology, University of California,
Riverside, CA 92521, USA. 8W. Harry Feinstone Department of
Molecular Microbiology and Immunology, Malaria Research
Institute, Bloomberg School of Public Health, Johns Hopkins
University, Baltimore, MD 21205, USA. 9Department of Entomology, Center for Disease Vector Research, University of
California, Riverside, CA 92521, USA. 10The Broad Institute,
Cambridge MA 02142, USA. 11Liverpool School of Tropical Medicine, Liverpool, L3 5QA, UK. 12Faculty of Science and Department of Zoology, University of Peradeniya, Peradeniya
20400, LK, Sri Lanka. 13454 Life Sciences, Branford, CT 06405,
USA. 14Pathology Department, University of Texas Medical
Branch, Galveston, TX 77555, USA. 15Division of Cell and Molecular Biology, Department of Life Sciences, Imperial College
London, Exhibition Road, London SW7 2AZ, UK. 16European
Bioinformatics Institute (EMBL), Hinxton CB10 1SD Cambridge,
UK. 17Biology Department, Boston College, Chestnut Hill, MA
02467, USA. 18Department of Immunology and Infectious
Diseases, Harvard School of Public Health, Boston, MA 02115,
USA.
*These authors contributed equally to this work.
†To whom correspondence should be addressed. E-mail:
marc.muskavitch@bc.edu
www.sciencemag.org
Downloaded from www.sciencemag.org on September 30, 2010
unique to the Culex genus, the 16.7 kD family, was
previously discovered after salivary transcriptome
analysis (13). The genome of C. quinquefasciatus
revealed 28 additional members of this family.
We have outlined and quantified general similarity and differences at the chromosomal and genomic levels between three disease-vector mosquito
genomes, building a foundation for more in-depth
future analyses. We found substantial differences
in the relative abundance of TE classes among the
three mosquitoes with sequenced genomes. Most
unexpectedly, this study revealed numerous instances of expansion of C. quinquefasciatus gene
families compared with An. gambiae and the more
closely related Ae. aegypti. The consequent diversity in many different genes may be an important
factor that led to the wide geographic distribution
of C. quinquefasciatus.