Evolution of human-chimpanzee differences in malaria susceptibility: Relationship to human genetic loss of N -glycolylneuraminic acid
Open accessAbstract
Chimpanzees are the closest evolutionary cousins of humans, sharing >99% identity in most protein sequences. Plasmodium falciparum is the major worldwide cause of malaria mortality. Plasmodium reichenowi , a morphologically identical and genetically very similar parasite, infects chimpanzees but not humans. Conversely, experimental P . falciparum infection causes brief moderate parasitization and no severe infection in chimpanzees. This surprising host specificity remains unexplained. We modified and enhanced traditional methods for measuring sialic acid (Sia)-dependent recognition of glycophorins by merozoite erythrocyte-binding proteins, eliminating interference caused by endogenous Sias on transfected cells, and by using erythroleukemia cells to allow experimental manipulation of Sia content. We present evidence that these remarkable differences among such closely related host-parasite pairs is caused by species-specific erythrocyte-recognition profiles, apparently related to the human-specific loss of the common primate Sia N -glycolylneuraminic acid. The major merozoite-binding protein erythrocyte-binding antigen-175 of P . falciparum apparently evolved to take selective advantage of the excess of the Sia N -acetylneuraminic acid (the precursor of N -glycolylneuraminic acid) on human erythrocytes. The contrasting preference of P . reichenowi erythrocyte-binding antigen-175 for N -glycolylneuraminic acid is likely the ancestral condition. The surprising ability of P . falciparum to cause disease in New World Aotus monkeys (geographically isolated from P . falciparum until arrival of peoples from the Old World) can be explained by parallel evolution of a human-like Sia expression pattern in these distantly related primates. These results also have implications for the prehistory of hominids and for the genetic origins and recent emergence of P . falciparum as a major human pathogen.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Cites
The pathogenic basis of malaria
Miller, L. H., Baruch, D. I., Marsh, K., & Doumbo, O. K. (2002) · Nature · doi:10.1038/415673a · Cited by 1,754 · see citing works
Varki, A. (1994) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.91.16.7390 · Cited by 946 · see citing works
Self-citationHuman embryonic stem cells express an immunogenic nonhuman sialic acid
Martin, M. J., Muotri, A. R., Gage, F. H., & Varki, A. P. (2005) · Nature Medicine · doi:10.1038/nm1181 · Cited by 932 · see citing works
Self-citationHuman uptake and incorporation of an immunogenic nonhuman dietary sialic acid
Tangvoranuntakul, P., Gagneux, P., Diaz, S., Bardor, M., Varki, N., Varki, A., & Muchmore, E. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2131556100 · Cited by 625 · see citing works
Self-citationKin Selection, Social Structure, Gene Flow, and the Evolution of Chimpanzees
Morin, P. A., Moore, J. J., Chakraborty, R., Li, J., Goodall, J. R., & Woodruff, D. S. (1994) · Science · doi:10.1126/science.7915048 · Cited by 558 · see citing works
Receptor and Ligand Domains for Invasion of Erythrocytes by Plasmodium falciparum
Sim, B. K. L., Chitnis, C. E., Waśniowska, K., Hadley, T. J., & Miller, L. H. (1994) · Science · doi:10.1126/science.8009226 · Cited by 545 · see citing works
Evolutionary considerations in relating oligosaccharide diversity to biological function
Gagneux, P., & Varki, A. (1999) · Glycobiology · doi:10.1093/glycob/9.8.747 · Cited by 495 · see citing works
Self-citationCoatney, G. R., Collins, W. E., Warren, M., & Contacos, P. G. (1971) · Cited by 454 · see citing works
Tomita, M., Furthmayr, H., & Marchesi, V. T. (1978) · Biochemistry · doi:10.1021/bi00615a025 · Cited by 429 · see citing works
Bardor, M., Nguyen, D., Diaz, S. L., & Varki, A. P. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m412040200 · Cited by 390 · see citing works
Self-citationChou, H.-H., Hayakawa, T., Diaz, S. L., Krings, M., Indriati, E., Leakey, M. G., Pääbo, S., Satta, Y., Takahata, N., & Varki, A. P. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.182257399 · Cited by 351 · see citing works
Self-citationMitochondrial sequences show diverse evolutionary histories of African hominoids
Gagneux, P., Wills, C. J., Gerloff, U., Tautz, D., Morin, P. A., Boesch, C., Fruth, B., Hohmann, G., Ryder, O. A., & Woodruff, D. S. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.9.5077 · Cited by 351 · see citing works
Self-citationMaier, A. G., Duraisingh, M. T., Reeder, J. C., Patel, S. S., Kazura, J. W., Zimmerman, P. A., & Cowman, A. F. (2002) · Nature Medicine · doi:10.1038/nm807 · Cited by 344 · see citing works
A Plasmodium falciparum Antigen that Binds to Host Erythrocytes and Merozoites
Camus, D., & Hadley, T. J. (1985) · Science · doi:10.1126/science.3901257 · Cited by 342 · see citing works
Tolia, N. H., Enemark, E. J., Sim, B. K. L., & Joshua‐Tor, L. (2005) · Cell · doi:10.1016/j.cell.2005.05.033 · Cited by 331 · see citing works
Phylogeny of the malarial genus Plasmodium, derived from rRNA gene sequences.
Escalante, A. A., & Ayala, F. J. (1994) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.91.24.11373 · Cited by 316 · see citing works
Orlandi, P. A., Klotz, F. W., & Haynes, J. D. (1992) · The Journal of Cell Biology · doi:10.1083/jcb.116.4.901 · Cited by 249 · see citing works
The Genomic Record of Humankind's Evolutionary Roots
Goodman, M. (1999) · The American Journal of Human Genetics · doi:10.1086/302218 · Cited by 247 · see citing works
Evolutionary origin of human and primate malarias: evidence from the circumsporozoite protein gene.
Escalante, A. A., Barrio, E., & Ayala, F. J. (1995) · Molecular Biology and Evolution · doi:10.1093/oxfordjournals.molbev.a040241 · Cited by 246 · see citing works
Sequencing the chimpanzee genome: insights into human evolution and disease
Olson, M. V., & Varki, A. P. (2002) · Nature Reviews Genetics · doi:10.1038/nrg981 · Cited by 245 · see citing works
Self-citationDuraisingh, M. T., Maier, A. G., Triglia, T., et al. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0730883100 · Cited by 237 · see citing works
Simian Immunodeficiency Virus Infection of Chimpanzees
Sharp, P. M., Shaw, G. M., & Hahn, B. H. (2005) · Journal of Virology · doi:10.1128/jvi.79.7.3891-3902.2005 · Cited by 204 · see citing works
Recent Origin of Plasmodium falciparum from a Single Progenitor
Volkman, S. K., Barry, A. E., Lyons, E., Nielsen, K. M., Thomas, S. M., Choi, M., Thakore, S. S., Day, K. P., Wirth, D. F., & Hartl, D. L. (2001) · Science · doi:10.1126/science.1059878 · Cited by 203 · see citing works
Gilberger, T., Thompson, J. K., Triglia, T., et al. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m211446200 · Cited by 195 · see citing works
Mitchell, G. H., Hadley, T., McGinniss, M., et al. (1986) · Blood · doi:10.1182/blood.v67.5.1519.1519 · Cited by 184 · see citing works
McCutchan, T. F., Kissinger, J. C., Touray, M., et al. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.21.11889 · Cited by 175 · see citing works
Angata, T., & Varki, A. P. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m002775200 · Cited by 169 · see citing works
Self-citationMiller, L. H. (1969) · American Journal of Tropical Medicine and Hygiene · doi:10.4269/ajtmh.1969.18.860 · Cited by 151 · see citing works
Choe, H., Moore, M. J., Owens, C. M., Wright, P. L., Vasilieva, N., Li, W., Singh, A. P., Shakri, R., Chitnis, C. E., & Farzan, M. (2005) · Molecular Microbiology · doi:10.1111/j.1365-2958.2004.04478.x · Cited by 148 · see citing works
Gahmberg, C. G., JOKINEN, M., & Andersson, L. C. (1979) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)50339-2 · Cited by 136 · see citing works
Gingrich, J. R., Pelkey, K. A., Fam, S. R., Huang, Y., Petralia, R. S., Wenthold, R. J., & Salter, M. W. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0401413101 · Cited by 128 · see citing works
Baum, J., Thomas, A. W., & Conway, D. J. (2003) · Genetics · doi:10.1093/genetics/163.4.1327 · Cited by 126 · see citing works
Qari, S. H., Shi, Y. P., Pieniążek, N. J., et al. (1996) · Molecular Phylogenetics and Evolution · doi:10.1006/mpev.1996.0068 · Cited by 114 · see citing works
The origin of malaria: mixed messages from genetic diversity
Hartl, D. L. (2004) · Nature Reviews Microbiology · doi:10.1038/nrmicro795 · Cited by 106 · see citing works
Collins, B. E. (2000) · Glycobiology · doi:10.1093/glycob/10.1.11 · Cited by 103 · see citing works
Polymorphism in a Plasmodium falciparum Erythrocyte-binding Ligand Changes Its Receptor Specificity
Mayer, D. C. G., Mu, J., Feng, X., Su, X., & Miller, L. H. (2002) · The Journal of Experimental Medicine · doi:10.1084/jem.20020750 · Cited by 102 · see citing works
Molecular aspects of malaria pathogenesis
Rasti, N., Wahlgren, M., & Chen, Q. (2004) · FEMS Immunology & Medical Microbiology · doi:10.1016/j.femsim.2004.01.010 · Cited by 102 · see citing works
Erythrocyte Invasion Phenotypes of Plasmodium falciparum in The Gambia
Baum, J., Pinder, M., & Conway, D. J. (2003) · Infection and Immunity · doi:10.1128/iai.71.4.1856-1863.2003 · Cited by 96 · see citing works
Singh, A. P., Ozwara, H., Kocken, C. H. M., et al. (2005) · Molecular Microbiology · doi:10.1111/j.1365-2958.2005.04523.x · Cited by 85 · see citing works
Wang, H. (2003) · Molecular Biology and Evolution · doi:10.1093/molbev/msg185 · Cited by 84 · see citing works
Baruch, D. I., Gamain, B., Barnwell, J. W., Sullivan, J. S., Stowers, A. W., Galland, G. G., Miller, L. H., & Collins, W. E. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.022018399 · Cited by 82 · see citing works
Self-citationSystemic Pathology of Chimpanzees
Schmidt, R. (1978) · Journal of Medical Primatology · doi:10.1159/000459914 · Cited by 56 · see citing works
Prince, A. M., Brotman, B., Lee, D., et al. (2002) · AIDS Research and Human Retroviruses · doi:10.1089/088922202760019356 · Cited by 50 · see citing works
Studies on Malaria in Chimpanzees
Bray, R. S. (1958) · American Journal of Tropical Medicine and Hygiene · doi:10.4269/ajtmh.1958.7.20 · Cited by 50 · see citing works
Progress in Malaria Research: the Case for Phylogenetics
Rich, S. S., & Ayala, F. J. (2003) · Advances in Parasitology/Advances in parasitology · doi:10.1016/s0065-308x(03)54005-2 · Cited by 37 · see citing works
Hu, X., Javadian, A., Gagneux, P., et al. (2001) · Virus Research · doi:10.1016/s0168-1702(01)00334-3 · Cited by 33 · see citing works
Self-citationLack of Malaria Parasite Transmission between Apes and Humans in Gabon
Ollomo, B., Karch, S., Bureau, P., et al. (1997) · American Journal of Tropical Medicine and Hygiene · doi:10.4269/ajtmh.1997.56.440 · Cited by 32 · see citing works
Tanabe, K., Sakihama, N., Hattori, T., et al. (2004) · Journal of Molecular Evolution · doi:10.1007/s00239-004-2662-3 · Cited by 32 · see citing works
Schauer, R., WEMBER, M., & Tschesche, H. (1984) · Hoppe-Seyler´s Zeitschrift für physiologische Chemie · doi:10.1515/bchm2.1984.365.1.419 · Cited by 27 · see citing works
Ozwara, H., Kocken, C. H. M., Conway, D. J., et al. (2001) · Molecular and Biochemical Parasitology · doi:10.1016/s0166-6851(01)00298-5 · Cited by 24 · see citing works
Phylogenetic analysis of the genus Plasmodium based on the gene encoding adenylosuccinate lyase
Kedzierski, Ł., Escalante, A. A., Isea, R., et al. (2002) · Infection Genetics and Evolution · doi:10.1016/s1567-1348(02)00031-x · Cited by 21 · see citing works
Evolution of the glycophorin gene family in the hominoid primates
Rearden, A., Phan, H., Kudo, S., et al. (1990) · Biochemical Genetics · doi:10.1007/bf00561338 · Cited by 20 · see citing works
Tracing the dawn of Plasmodium falciparum with mitochondrial genome sequences
Conway, D. J. (2003) · Trends in Genetics · doi:10.1016/j.tig.2003.10.007 · Cited by 19 · see citing works
Conservation and divergence in erythrocyte invasion ligands: Plasmodium reichenowi EBL genes
Rayner, J. C., Huber, C. S., & Barnwell, J. W. (2004) · Molecular and Biochemical Parasitology · doi:10.1016/j.molbiopara.2004.08.008 · Cited by 19 · see citing works
Self-citationHuang, C., Xie, S.-S., Socha, W., et al. (1995) · Journal of Molecular Evolution · doi:10.1007/bf00160319 · Cited by 17 · see citing works
Ugorski, M., Blackall, D., Påhlsson, P., et al. (1993) · Blood · doi:10.1182/blood.v82.6.1913.1913 · Cited by 15 · see citing works
Storry, J. R., Coghlan, G., Poole, J., et al. (2000) · Vox Sanguinis · doi:10.1159/000031149 · Cited by 13 · see citing works
Merozoite proteins synthesized in P. falciparum schizonts.
Rf, H., Varki, A. P., & Reese, R. T. (1984) · PubMed · Cited by 3 · see citing works
Self-citationHemispheric difference in human skin color
Chaplin, G., & Jablonski, N. G. (1998) · American Journal of Physical Anthropology · doi:10.1002/(sici)1096-8644(199810)107:2
Flagged first, then by citations
Cited by
Sorted by citations
Varki, A. (2017) · Glycobiology · doi:10.1093/glycob/cww086 · Cited by 2,635 · see citing works
“Some data suggest that taxon-specific glycan losses may have played a role in protection from parasites like malaria (732, 1055), and even in speciation events, such as the origin of the genus Homo (943).”
BackgroundSelf-citationThe influence of evolutionary history on human health and disease
Benton, M. L., Abraham, A., LaBella, A. L., Abbot, P., Rokas, A., & Capra, J. A. (2021) · Nature Reviews Genetics · doi:10.1038/s41576-020-00305-9 · Cited by 291 · see citing works
Zoonotic Malaria – Global Overview and Research and Policy Needs
Ramasamy, R. (2014) · Frontiers in Public Health · doi:10.3389/fpubh.2014.00123 · Cited by 101 · see citing works
ABO blood group glycans modulate sialic acid recognition on erythrocytes
Cohen, M., Hurtado-Ziola, N., & Varki, A. (2009) · Blood · doi:10.1182/blood-2009-06-227041 · Cited by 75 · see citing works
Self-citationHuman-specific evolution of sialic acid targets: Explaining the malignant malaria mystery?
Varki, A., & Gagneux, P. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0908196106 · Cited by 62 · see citing works
Self-citation
- Authors
- Martin, M. J., Rayner, J. C., Gagneux, P., Barnwell, J. W., & Varki, A.
- Affiliations
- Glycobiology Research and Training Center and Departments of Medicine and Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093; Division of Geographic Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294; Conservation and Research for Endangered Species, Zoological Society of San Diego, San Diego, CA 92112-0551; and Malaria Branch, Division of Parasitic Diseases, National Center for Infectious Diseases, Centers for Disease...
- Zoological Society of San Diego (US)
- Corresponding author
- Varki, Ajit
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2005-08-26
- Volume
- 102
- Issue
- 36
- Pages
- 12819-12824
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC1200275
- OpenAlex
- W2142747284
- Cited by
- 193
- References
- 59
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 7 · 2023: 4 · 2022: 8 · 2021: 11 · 2020: 6 · 2019: 6 · 2018: 8 · 2017: 9 · 2016: 10 · 2015: 12 · 2014: 5 · 2013: 8 · 2012: 10
- FWCI
- 12.93
- Type
- journal article
- Language
- en
- Update notices
- correction (2006-06-20)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Gredos (University of Salamanca) (submittedVersion, cc-by-nc-nd)
- Hispana (submittedVersion, cc-by-nc-nd)
- Funders
- Vanderbilt University
- National Institutes of Health (GM32373)
- National Institute of General Medical Sciences (R01GM032373, R37GM032373, GM32373)
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Malaria Research and Control
- Health Sciences › Medicine › Hematology › Blood groups and transfusion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glycosylation and Glycoproteins Research
- Keywords
- malaria susceptibility, Plasmodium falciparum, Plasmodium reichenowi, N-glycolylneuraminic acid, sialic acid, host-parasite coevolution, chimpanzees, Aotus monkeys, glycophorin, host specificity, hominid evolution
- MeSH terms
- Animals, Cell Line, Chlorocebus aethiops, Pan troglodytes, Erythrocytes, Glycophorins, Host-Parasite Interactions, Humans, Malaria, Microscopy, Fluorescence, Neuraminic Acids, Neuraminidase, Plasmodium falciparum, Species Specificity, Transfection, Evolution, Molecular, N-Acetylneuraminic Acid, Genetic Predisposition to Disease
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
