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Evolution of mosquito preference for humans linked to an odorant receptor

Nature volume 515, pages 222–227 (2014)Cite this article

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Abstract

Female mosquitoes are major vectors of human disease and the most dangerous are those that preferentially bite humans. A ‘domestic’ form of the mosquito Aedes aegypti has evolved to specialize in biting humans and is the main worldwide vector of dengue, yellow fever, and chikungunya viruses. The domestic form coexists with an ancestral, ‘forest’ form that prefers to bite non-human animals and is found along the coast of Kenya. We collected the two forms, established laboratory colonies, and document striking divergence in preference for human versus non-human animal odour. We further show that the evolution of preference for human odour in domestic mosquitoes is tightly linked to increases in the expression and ligand-sensitivity of the odorant receptor AaegOr4, which we found recognizes a compound present at high levels in human odour. Our results provide a rare example of a gene contributing to behavioural evolution and provide insight into how disease-vectoring mosquitoes came to specialize on humans.

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Figure 1: Field collection of forest and domestic forms of Ae. aegypti in Rabai, Kenya.
Figure 2: Forest and domestic females differ in host preference.
Figure 3: Antennal gene expression is significantly associated with preference for humans.
Figure 4: Or4 responds to sulcatone, a human odorant.
Figure 5: Tight linkage of Or4 allelic expression and sulcatone sensitivity to preference for humans.

Accession codes

Primary accessions

GenBank/EMBL/DDBJ

Sequence Read Archive

Data deposits

Raw RNA-seq data are available for download at the NCBI Sequence Read Archive (accession number SRP035216). Coding sequences of AaegOr4 alleles are at GenBank (accession numbers KF801614, KF801615 and KF801617–KF801621).

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Acknowledgements

We thank M. K. N. Lawniczak, K. J. Lee, M. N. Nitabach, and the Vosshall laboratory for discussion and comments on the manuscript; J. E. Brown and J. R. Powell for discussion and coordination of field collections; W. Takken for advice regarding many aspects of this work; J.-P. Mutebi, B. Miller, and A. Ponlawat for live specimens from Uganda and Thailand; D. Beck, K. Nygaard, K. Prakash, and L. Seeholzer for expert technical assistance. We also thank X. Chen for pre-publication access to a draft Ae. albopictus genome assembly, and J. Liesch for access to Orlando strain RNA-seq data. We received valuable advice on collecting and working with forest and domestic forms of Ae. aegypti from M. Trpis, J. L. Peterson, and P. Lounibos, and on the design and use of two-port olfactometers from U. Bernier and V. Sherman. This work was funded in part by a grant to R. Axel and L.B.V. from the Foundation for the National Institutes of Health through the Grand Challenges in Global Health Initiative. This work was supported in part by the following National Institutes of Health grants: K99 award from NIDCD to C.S.M. (DC012069), an NIAID Vectorbase DBP subcontract to L.B.V. (HHSN272200900039C), and a CTSA award from NCATS (5UL1TR000043). R.I. received support from the Swedish Research Council and SLU: Insect Chemical Ecology and Evolution (IC-E3). L.B.V. is an investigator of the Howard Hughes Medical Institute.

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Author notes

  1. Carolyn S. McBride, Felix Baier, Aman B. Omondi & Sarabeth A. Spitzer

    Present address: Present addresses: Princeton Neuroscience Institute and Department of Ecology and Evolutionary Biology, Princeton University, Princeton, New Jersey 08544, USA (C.S.M.); Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 02138, USA (F.B.); Plant Protection Research Institute, Agricultural Research Council, Private Bag X134, Queenswood 0121, South Africa (A.B.O.); Harvard College, Harvard University, Cambridge, Massachusetts 02138, USA (S.A.S.).,

Authors and Affiliations

  1. Laboratory of Neurogenetics and Behavior, The Rockefeller University, New York, 10065, New York, USA

    Carolyn S. McBride, Felix Baier, Sarabeth A. Spitzer & Leslie B. Vosshall

  2. Howard Hughes Medical Institute, 1230 York Avenue, New York, 10065, New York, USA

    Carolyn S. McBride & Leslie B. Vosshall

  3. Department of Plant Protection Biology, Unit of Chemical Ecology, Swedish University of Agricultural Sciences, Box 102, Sundsvägen 14, 230 53 Alnarp, Sweden,

    Aman B. Omondi & Rickard Ignell

  4. Center for Virus Research, Kenya Medical Research Institute, PO Box 54840 – 00200, Off Mbagathi Way, Nairobi, Kenya,

    Joel Lutomiah & Rosemary Sang

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Contributions

C.S.M. and L.B.V. conceived the study. C.S.M. participated in the execution and analysis of all aspects of the study. J.L. helped coordinate mosquito collection in Rabai, Kenya under the supervision of R.S. S.A.S. helped design and carry out the morphological assays presented in Fig. 1e–i. F.B. helped clone, analyse, and genotype mosquitoes for the Or4 alleles presented in Fig. 5a–d, and construct transgenic Drosophila lines for use in single sensillum recordings. A.B.O. and R.I. designed, conducted, and analysed the GC–SSR and GC–MS experiments presented in Fig. 4 and carried out pilot experiments comprising dose–response curves and spontaneous activity analysis of alleles A and E, similar to those presented in Fig. 5e–g. C.S.M. and L.B.V. designed all other experiments, interpreted the results, designed the figures, and wrote the paper.

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Correspondence to Leslie B. Vosshall.

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Extended data figures and tables

Extended Data Figure 1 Measuring colour and scaling of adult female Ae. aegypti mosquitoes.

a, Representative photograph used to measure scale colour (Fig. 1e, g). Red dots mark the approximate position of 4 points where the colour of dark scales on the scutum was assessed. b, Representative photograph used to measure cuticle colour (Fig. 1f, h). Red dots mark the approximate position of 4 points where the colour of bare cuticle on the circular postnotum was assessed. c, Representative photographs used to assess the extent of white scaling on the first abdominal tergite (Fig. 1i), outlined with the red rectangle. Each individual is representative of the scaling score shown at the bottom.

Extended Data Figure 2 Or4 coding sequence variation in human-preferring and guinea-pig-preferring colonies from around the world.

a, Geographical origin of colonies characterized in b and c. Circle fill colour indicates preference of strains. Circle outline colour indicates origin: Purple, laboratory strain derived from USA; blue, reference genome strain derived from West Africa; orange, Uganda; red, Kenya, green, Thailand. b, Host preference assayed in the live host olfactometer. Data for Thailand, K14, K2, K4, K27, K18, K19, and Uganda are reprinted from Fig. 2g. c, Frequency of non-synonymous single nucleotide polymorphisms (SNPs) in female antennal RNA-seq reads. SNPs are defined as differences from the A reference allele. SNPs with frequency ≤ 0.1 are not shown. Vertical black and red lines indicate SNPs that were present and absent, respectively, in the major alleles subject to functional analysis.

Extended Data Figure 3 Amino acid differences of major Or4 protein alleles.

Dots represent amino acid differences with respect to the genome reference, not an inferred ancestor. Red dots indicate differences that are unique to the given allele. Blue dots indicate differences that are shared among multiple alleles. Snake plots are based on the predicted orientation and location of transmembrane domains. Extracellular loops are oriented up and cytoplasmic loops are oriented down. Allele names are indicated to the left of each snake plot.

Extended Data Figure 4 Evidence that Or4 is a single copy gene.

a, Histogram showing the number of alleles represented in the Or4-derived PacBio reads obtained for each of 270 parent and F2 hybrid mosquitoes. Alleles were only considered if they received at least 5% of an individual’s reads. b, Histogram showing the fraction of reads from individual mosquitoes assigned to individual alleles. For all 270 mosquitoes, individual alleles were represented by either very few reads (grey bars, inferred to result from allele or barcode assignment errors or polymerase chain reaction contaminants), approximately half the reads (light blue bars, inferred to represent the two alleles in heterozygotes), or over 98% of all reads (dark blue bars, inferred to represent the single allele carried by homozygotes).

Extended Data Figure 5 Response of human-preferring mosquitoes to sulcatone-scented guinea-pig odour.

a, Olfactometer apparatus in which 50 mosquitoes per trial were given a choice between guinea-pig odour/CO2 mix supplemented with solvent on one side and sulcatone 10−4 on the other side. b, Corrected preference for sulcatone vs solvent ports is indicated. Data were corrected for the daily average left–right side bias observed across 2–3 solvent vs solvent tests conducted on each day of testing. An index value of 1 indicates strong preference for the sulcatone side, whereas −1 indicates strong preference for the solvent side. Neither mosquito colony showed a preference significantly different from zero (one-sample t-test P = 0.76 for ORL, P = 0.11 for K14). The trials for each colony were performed across 4–8 days (n = 40 for ORL and n = 22 for K14).

Supplementary information

Supplementary Table 1

This file contains accession numbers and gene names (where known) for differentially expressed genes described in Fig. 3c-g. (XLSX 26 kb)

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McBride, C., Baier, F., Omondi, A. et al. Evolution of mosquito preference for humans linked to an odorant receptor. Nature 515, 222–227 (2014). https://doi.org/10.1038/nature13964

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