Letter | Published:

Evolution of a malaria resistance gene in wild primates

Nature 460, 388–391 (16 July 2009) | Download Citation

Subjects

Abstract

The ecology, behaviour and genetics of our closest living relatives, the nonhuman primates, should help us to understand the evolution of our own lineage. Although a large amount of data has been amassed on primate ecology and behaviour, much less is known about the functional and evolutionary genetic aspects of primate biology, especially in wild primates. As a result, even in well-studied populations in which nongenetic factors that influence adaptively important characteristics have been identified, we have almost no understanding of the underlying genetic basis for such traits. Here, we report on the functional consequences of genetic variation at the malaria-related FY (DARC) gene in a well-studied population of yellow baboons (Papio cynocephalus) living in Amboseli National Park in Kenya. FY codes for a chemokine receptor normally expressed on the erythrocyte surface that is the known entry point for the malarial parasite Plasmodium vivax1,2,3. We identified variation in the cis-regulatory region of the baboon FY gene that was associated with phenotypic variation in susceptibility to Hepatocystis, a malaria-like pathogen that is common in baboons4,5. Genetic variation in this region also influenced gene expression in vivo in wild individuals, a result we confirmed using in vitro reporter gene assays. The patterns of genetic variation in and around this locus were also suggestive of non-neutral evolution, raising the possibility that the evolution of the FY cis-regulatory region in baboons has exhibited both mechanistic and selective parallels with the homologous region in humans6,7,8. Together, our results represent the first reported association and functional characterization linking genetic variation and a complex trait in a natural population of nonhuman primates.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

Rent or Buy

All prices are NET prices.

Accessions

Data deposits

Sequence data have been deposited in NCBI GenBank under the accession numbers FJ952954–FJ955880, FJ955882–FJ955885, FJ955887–FJ955896 and FJ955899–FJ956699.

References

  1. 1.

    , & In vitro evaluation of the role of the Duffy blood group in erythrocyte invasion by Plasmodium vivax. J. Exp. Med. 169, 1795–1802 (1989)

  2. 2.

    , , & Resistance factor to Plasmodium vivax in blacks—Duffy blood group genotype Fyfy. New Engl. J. Med. 295, 302–304 (1976)

  3. 3.

    , , , & Erythrocyte receptors for Plasmodium knowlesi malaria—Duffy blood group determinants. Science 189, 561–563 (1975)

  4. 4.

    Malaria Parasites and Other Haemosporidia (Blackwell, 1966)

  5. 5.

    & A checklist of parasites reported for the baboon. Primates 6, 137–194 (1965)

  6. 6.

    & Detection of the signature of natural selection in humans: evidence from the Duffy blood group locus. Am. J. Hum. Genet. 66, 1669–1679 (2000)

  7. 7.

    , & Complex signatures of natural selection at the Duffy blood group locus. Am. J. Hum. Genet. 70, 369–383 (2002)

  8. 8.

    et al. Positive natural selection in the human lineage. Science 312, 1614–1620 (2006)

  9. 9.

    , , & Disruption of a GATA motif in the Duffy gene promoter abolishes erythroid gene expression in Duffy negative individuals. Nature Genet. 10, 224–228 (1995)

  10. 10.

    et al. Duffy-null promoter heterozygosity reduces DARC expression and abrogates adhesion of the P.vivax ligand required for blood-stage infection. FEBS Lett. 495, 111–114 (2001)

  11. 11.

    et al. Emergence of FY*A(null) in a Plasmodium vivax-endemic region of Papua New Guinea. Proc. Natl Acad. Sci. USA 96, 13973–13977 (1999)

  12. 12.

    , & Sexual selection in wild baboons: from mating opportunities to paternity success. Anim. Behav. 72, 1177–1196 (2006)

  13. 13.

    , , & True paternal care in a multi-male primate society. Nature 425, 179–181 (2003)

  14. 14.

    , , , & Genetic evidence reveals temporal change in hybridization patterns in a wild baboon population. Mol. Ecol. 17, 1998–2011 (2008)

  15. 15.

    & A molecular phylogeny of malarial parasites recovered from cytochrome b gene sequences. J. Parasitol. 88, 972–978 (2002)

  16. 16.

    , , , & Culicoides adersi Ingram and Macfie, 1923, a presumed vector of Hepatocystis ( = Plasmodium) kochi (Laveran, 1899). Nature 190, 739–741 (1961)

  17. 17.

    , & Evolutionary changes in cis and trans gene regulation. Nature 430, 85–88 (2004)

  18. 18.

    , , , & Allelic variation in human gene expression. Science 297, 1143 (2002)

  19. 19.

    et al. Reduced neutrophil count in people of African descent is due to a regulatory variant in the Duffy antigen receptor for chemokines gene. PLoS Genet. 5, e1000360 (2009)

  20. 20.

    , , , & Ancient polymorphism and functional variation in the primate MHC-DQA1 5' cis-regulatory region. Proc. Natl Acad. Sci. USA 103, 16331–16336 (2006)

  21. 21.

    et al. Independent evolution of bitter-taste sensitivity in humans and chimpanzees. Nature 440, 930–934 (2006)

  22. 22.

    Evolutionary Genetics of Immune System Genes in a Wild Primate Population. PhD thesis, Duke Univ. (2007)

  23. 23.

    , & Microsatellite variation and evolution of the human Duffy blood group polymorphism. Mol. Biol. Evol. 19, 1802–1806 (2002)

  24. 24.

    & Entopolyploides macaci Mayer, 1934 in the African baboon (Papio cynocephalus L. 1766). J. Med. Primatol. 4, 1–7 (1975)

  25. 25.

    , , & Genetic interactions between polymorphisms that affect gene expression in yeast. Nature 436, 701–703 (2005)

  26. 26.

    & Gene-environment interaction in yeast gene expression. PLoS Biol. 6, e83 (2008)

  27. 27.

    , , , & DNA polymorphism analyses by the coalescent and other methods. Bioinformatics 19, 2496–2497 (2003)

  28. 28.

    et al. Behavior predicts genetic structure in a wild primate group. Proc. Natl Acad. Sci. USA 93, 5797–5801 (1996)

  29. 29.

    , & A new statistical method for haplotype reconstruction from population data. Am. J. Hum. Genet. 68, 978–989 (2001)

  30. 30.

    , & Arlequin version 3.0: an integrated software package for population genetics data analysis. Evol. Bioinform. Online 1, 47–50 (2005)

Download references

Acknowledgements

We thank the Office of the President of the Republic of Kenya and the Kenya Wildlife Service for permission to work in Amboseli National Park, and the Institute of Primate Research for local sponsorship. We thank the wardens and staff of Amboseli National Park, and the pastoral communities of Amboseli and Longido for cooperation. We thank J. Altmann for providing access to long-term data and contributing samples, and J. Altmann and Y. Gilad for providing comments on the manuscript. R. S. Mututua, S. Sayialel, and J. K. Warutere assisted with sample collection. The Integrated Primate Biomaterials and Information Resource, the Coriell Institute, J. Rogers and R. Sapolsky provided access to DNA samples from Mikumi and Masai Mara respectively. G. Gibson, T. F. C. Mackay, L. Goering and D. Tan provided access to a pyrosequencer at NC State University. M. Akinyi assisted with sample collection and analysis. A. D. Pfefferle assisted with sequencing. S. Mukherjee advised and assisted with statistical tests. Financial support came from the National Science Foundation (to S.C.A. and J.T.); the American Society of Primatologists (to J.T.); Duke University and the Duke chapter of Sigma Xi (to J.T.); and the Duke Institute for Genome Sciences and Policy (to G.A.W.).

Author Contributions J.T., S.C.A. and G.A.W. designed the study, analysed the results, and wrote the paper. J.T. and S.C.A. collected blood samples; S.C.A. provided the long-term data on Amboseli National Park. J.T. gathered the allelic imbalance and sequence data; A.P., T.F.S. and J.T. collected the transfection assay data; T.F.S. and J.T. collected the genotyping data; A.J.B. and J.T. collected the Hepatocystis data. G.A.W. and S.C.A. provided funding support.

Author information

    • Susan C. Alberts
    •  & Gregory A. Wray

    These authors contributed equally to this work.

Affiliations

  1. Department of Biology, Duke University,

    • Jenny Tung
    • , Alexander Primus
    • , Andrew J. Bouley
    • , Susan C. Alberts
    •  & Gregory A. Wray

  2. Institute for Genome Sciences and Policy, Duke University,

    • Jenny Tung
    • , Alexander Primus
    • , Tonya F. Severson
    • , Susan C. Alberts
    •  & Gregory A. Wray

  3. Department of Evolutionary Anthropology, Duke University, Durham, North Carolina 27708, USA

    • Susan C. Alberts
    •  & Gregory A. Wray

  4. Institute of Primate Research, National Museums of Kenya, Nairobi, Kenya

    • Susan C. Alberts

Authors

  1. Search for Jenny Tung in:

  2. Search for Alexander Primus in:

  3. Search for Andrew J. Bouley in:

  4. Search for Tonya F. Severson in:

  5. Search for Susan C. Alberts in:

  6. Search for Gregory A. Wray in:

Corresponding author

Correspondence to Jenny Tung.

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    This file contains Supplementary Figures 1-4 with Legends, Supplementary Methods, Supplementary Tables 1-4 and Supplementary References.

To obtain permission to re-use content from this article visit RightsLink.

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/nature08149

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.