Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Published Online June 21, 2001
Science DOI: 10.1126/science.1061573

Research Articles

Submitted on April 12, 2001
Accepted on June 7, 2001

Haplotype Diversity and Linkage Disequilibrium at Human G6PD: Recent Origin of Alleles That Confer Malarial Resistance

Sarah A. Tishkoff 1*, Robert Varkonyi 2, Nelie Cahinhinan 2, Salem Abbes 3, George Argyropoulos 4, Giovanni Destro-Bisol 5, Anthi Drousiotou 6, Bruce Dangerfield 7, Gerard Lefranc 8, Jacques Loiselet 9, Anna Piro 10, Mark Stoneking 11, Antonio Tagarelli 10, Giuseppe Tagarelli 10, Elias H. Touma 9, Scott M. Williams 12, Andrew G. Clark 2

1 Department of Biology, Biology/Psychology Building, University of Maryland, College Park, MD 20742, USA; Institute of Evolutionary Genetics, Department of Biology, Pennsylvania State University, University Park, PA, USA.
2 Institute of Evolutionary Genetics, Department of Biology, Pennsylvania State University, University Park, PA, USA.
3 Faculty of Medicine and Pasteur Institute, Tunis, Tunisia.
4 Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA, USA.
5 Department of Human and Animal Biology, University "La Sapienza," Rome, Italy.
6 Department of Biochemical Genetics, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.
7 Department of Human Genetics, South African Institute of Medical Research, University of the Witwatersrand, Johannesburg, South Africa.
8 University of Sciences and CNRS, Montpellier, France.
9 University St. Joseph, Beirut, Lebanon.
10 Istituto di Medicina Sperimentale e Biotecnologie-CNR, Mangone (Cosenza), Italy.
11 Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany.
12 Montreal Genome Center, Montreal General Hospital Research Institute, Montreal, Quebec, Canada; Department of Microbiology, Meharry Medical College, Nashville, TN, USA.

* To whom correspondence should be addressed. E-mail: st130{at}umail.umd.edu.

The frequencies of low-activity alleles of glucose-6-phosphate dehydrogenase in humans are highly correlated with the prevalence of malaria. These "deficiency" alleles are thought to provide reduced risk from infection by the Plasmodium parasite and are maintained at high frequency despite the hemopathologies that they cause. Haplotype analysis of "A-" and "Med" mutations at this locus indicates that they have evolved independently and have increased in frequency at a rate that is too rapid to be explained by random genetic drift. Statistical modeling indicates that the A- allele arose within the past 3840 to 11,760 years and the Med allele arose within the past 1600 to 6640 years. These results support the hypothesis that malaria has had a major impact on humans only since the introduction of agriculture within the past 10,000 years and provide a striking example of the signature of selection on the human genome.


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Genome-wide scans for footprints of natural selection.
T. K. Oleksyk, M. W. Smith, and S. J. O'Brien (2010)
Phil Trans R Soc B 365, 185-205
   Abstract »    Full Text »    PDF »
Positively Selected G6PD-Mahidol Mutation Reduces Plasmodium vivax Density in Southeast Asians.
C. Louicharoen, E. Patin, R. Paul, I. Nuchprayoon, B. Witoonpanich, C. Peerapittayamongkol, I. Casademont, T. Sura, N. M. Laird, P. Singhasivanon, et al. (2009)
Science 326, 1546-1549
   Abstract »    Full Text »    PDF »
Glucose-6-phosphate Dehydrogenase Deficiency and Malaria: Cytochemical Detection of Heterozygous G6PD Deficiency in Women.
A. L. Peters and C. J.F. Van Noorden (2009)
J. Histochem. Cytochem. 57, 1003-1011
   Abstract »    Full Text »    PDF »
From the Cover: The origin of malignant malaria.
S. M. Rich, F. H. Leendertz, G. Xu, M. LeBreton, C. F. Djoko, M. N. Aminake, E. E. Takang, J. L. D. Diffo, B. L. Pike, B. M. Rosenthal, et al. (2009)
PNAS 106, 14902-14907
   Abstract »    Full Text »    PDF »
Human-specific evolution of sialic acid targets: Explaining the malignant malaria mystery?.
A. Varki and P. Gagneux (2009)
PNAS 106, 14739-14740
   Full Text »    PDF »
Population Genomic Analysis of ALMS1 in Humans Reveals a Surprisingly Complex Evolutionary History.
L. B. Scheinfeldt, S. Biswas, J. Madeoy, C. F. Connelly, E. E. Schadt, and J. M. Akey (2009)
Mol. Biol. Evol. 26, 1357-1367
   Abstract »    Full Text »    PDF »
Constructing genomic maps of positive selection in humans: Where do we go from here?.
J. M. Akey (2009)
Genome Res. 19, 711-722
   Abstract »    Full Text »    PDF »
Different Selective Pressures Shape the Molecular Evolution of Color Vision in Chimpanzee and Human Populations.
B. C. Verrelli, C. M. Lewis Jr, A. C. Stone, and G. H. Perry (2008)
Mol. Biol. Evol. 25, 2735-2743
   Abstract »    Full Text »    PDF »
Hereditary red cell disorders and malaria resistance.
P. M. Durand and T. L. Coetzer (2008)
Haematologica 93, 961-963
   Full Text »    PDF »
Detecting Local Adaptation Using the Joint Sampling of Polymorphism Data in the Parental and Derived Populations.
H. Innan and Y. Kim (2008)
Genetics 179, 1713-1720
   Abstract »    Full Text »    PDF »
Ustilago maydis populations tracked maize through domestication and cultivation in the Americas.
A. B Munkacsi, S. Stoxen, and G. May (2008)
Proc R Soc B 275, 1037-1046
   Abstract »    Full Text »    PDF »
Glucose-6-phosphate dehydrogenase deficiency: a historical perspective.
E. Beutler (2008)
Blood 111, 16-24
   Abstract »    Full Text »    PDF »
Mutations and haplotype diversity in 70 Portuguese G6PD-deficient individuals: an overview on the origin and evolution of mutated alleles.
L. Manco, P. Goncalves, P. Antunes, F. Maduro, A. Abade, and M. L. Ribeiro (2007)
Haematologica 92, 1713-1714
   Abstract »    Full Text »    PDF »
New Interventions for Malaria: Mining the Human and Parasite Genomes.
F. Ntoumi, D. P. Kwiatkowski, M. Diakite, T. K. Mutabingwa, and P. E. Duffy (2007)
Am J Trop Med Hyg 77, 270-275
   Abstract »    Full Text »    PDF »
Century-scale Holocene processes as a source of natural selection pressure in human evolution: Holocene climate and the Human Genome Project.
A. J. Smith (2007)
The Holocene 17, 689-695
   Abstract »    PDF »
Estimation of Multilocus Linkage Disequilibria in Diploid Populations With Dominant Markers.
Y. Li, Y. Li, S. Wu, K. Han, Z. Wang, W. Hou, Y. Zeng, and R. Wu (2007)
Genetics 176, 1811-1821
   Abstract »    Full Text »    PDF »
Sequence Diversity at the Proximal 14q32.1 SERPIN Subcluster: Evidence for Natural Selection Favoring the Pseudogenization of SERPINA2.
S. Seixas, G. Suriano, F. Carvalho, R. Seruca, J. Rocha, and A. Di Rienzo (2007)
Mol. Biol. Evol. 24, 587-598
   Abstract »    Full Text »    PDF »
Genomic signatures of positive selection in humans and the limits of outlier approaches.
J. L. Kelley, J. Madeoy, J. C. Calhoun, W. Swanson, and J. M. Akey (2006)
Genome Res. 16, 980-989
   Abstract »    Full Text »    PDF »
Contrasting Histories of G6PD Molecular Evolution and Malarial Resistance in Humans and Chimpanzees.
B. C. Verrelli, S. A. Tishkoff, A. C. Stone, and J. W. Touchman (2006)
Mol. Biol. Evol. 23, 1592-1601
   Abstract »    Full Text »    PDF »
TRPV6 exhibits unusual patterns of polymorphism and divergence in worldwide populations.
J. M. Akey, W. J. Swanson, J. Madeoy, M. Eberle, and M. D. Shriver (2006)
Hum. Mol. Genet. 15, 2106-2113
   Abstract »    Full Text »    PDF »
Positive natural selection in the human lineage..
P. C. Sabeti, S. F. Schaffner, B. Fry, J. Lohmueller, P. Varilly, O. Shamovsky, A. Palma, T. S. Mikkelsen, D. Altshuler, and E. S. Lander (2006)
Science 312, 1614-1620
   Abstract »    Full Text »    PDF »
Interpreting Disparate Responses to Cancer Therapy: The Role of Human Population Genetics.
M. L. Maitland, A. DiRienzo, and M. J. Ratain (2006)
J. Clin. Oncol. 24, 2151-2157
   Abstract »    Full Text »    PDF »
Neutral and adaptive variation in gene expression.
A. Whitehead and D. L. Crawford (2006)
PNAS 103, 5425-5430
   Abstract »    Full Text »    PDF »
Genetic Resistance to Brucella abortus in the Water Buffalo (Bubalus bubalis).
G. Borriello, R. Capparelli, M. Bianco, D. Fenizia, F. Alfano, F. Capuano, D. Ercolini, A. Parisi, S. Roperto, and D. Iannelli (2006)
Infect. Immun. 74, 2115-2120
   Abstract »    Full Text »    PDF »
From DNA to Fitness Differences: Sequences and Structures of Adaptive Variants of Colias Phosphoglucose Isomerase (PGI).
C. W. Wheat, W. B. Watt, D. D. Pollock, and P. M. Schulte (2006)
Mol. Biol. Evol. 23, 499-512
   Abstract »    Full Text »    PDF »
Influence of human genetic variation on nutritional requirements.
P. J Stover (2006)
Am. J. Clinical Nutrition 83, 436S-442S
   Abstract »    Full Text »    PDF »
Global landscape of recent inferred Darwinian selection for Homo sapiens.
E. T. Wang, G. Kodama, P. Baldi, and R. K. Moyzis (2006)
PNAS 103, 135-140
   Abstract »    Full Text »    PDF »
The Extent of Linkage Disequilibrium Caused by Selection on G6PD in Humans.
M. A. Saunders, M. Slatkin, C. Garner, M. F. Hammer, and M. W. Nachman (2005)
Genetics 171, 1219-1229
   Abstract »    Full Text »    PDF »
Microcephalin, a Gene Regulating Brain Size, Continues to Evolve Adaptively in Humans.
P. D. Evans, S. L. Gilbert, N. Mekel-Bobrov, E. J. Vallender, J. R. Anderson, L. M. Vaez-Azizi, S. A. Tishkoff, R. R. Hudson, and B. T. Lahn (2005)
Science 309, 1717-1720
   Abstract »    Full Text »    PDF »
Chromosome speciation: Humans, Drosophila, and mosquitoes.
F. J. Ayala and M. Coluzzi (2005)
PNAS 102, 6535-6542
   Abstract »    Full Text »    PDF »
Red Cell Enzymes.
J. T. Prchal and X. T. Gregg (2005)
Hematology 2005, 19-23
   Abstract »    Full Text »    PDF »
Positive selection on the human genome.
E. J. Vallender and B. T. Lahn (2004)
Hum. Mol. Genet. 13, R245-R254
   Abstract »    Full Text »    PDF »
Genome Scans of DNA Variability in Humans Reveal Evidence for Selective Sweeps Outside of Africa.
J. F. Storz, B. A. Payseur, and M. W. Nachman (2004)
Mol. Biol. Evol. 21, 1800-1811
   Abstract »    Full Text »    PDF »
Comparative Evaluation of a New Effective Population Size Estimator Based on Approximate Bayesian Computation.
D. A. Tallmon, G. Luikart, and M. A. Beaumont (2004)
Genetics 167, 977-988
   Abstract »    Full Text »    PDF »
Patterns of ethnic diversity among the genes that influence AIDS.
C. Winkler, P. An, and S. J. O'Brien (2004)
Hum. Mol. Genet. 13, R9-19
   Abstract »    Full Text »    PDF »
Rapidly Evolving Genes in Human. I. The Glycophorins and Their Possible Role in Evading Malaria Parasites.
H.-Y. Wang, H. Tang, C.-K. J. Shen, and C.-I Wu (2003)
Mol. Biol. Evol. 20, 1795-1804
   Abstract »    Full Text »    PDF »
Adaptive Evolution of MRG, a Neuron-Specific Gene Family Implicated in Nociception.
S. S. Choi and B. T. Lahn (2003)
Genome Res. 13, 2252-2259
   Abstract »    Full Text »    PDF »
A Selective Sweep Driven by Pyrimethamine Treatment in Southeast Asian Malaria Parasites.
S. Nair, J. T. Williams, A. Brockman, L. Paiphun, M. Mayxay, P. N. Newton, J.-P. Guthmann, F. M. Smithuis, T. T. Hien, N. J. White, et al. (2003)
Mol. Biol. Evol. 20, 1526-1536
   Abstract »    Full Text »    PDF »
Estimating the Time Since the Fixation of a Beneficial Allele.
M. Przeworski (2003)
Genetics 164, 1667-1676
   Abstract »    Full Text »    PDF »
A Genome Scan to Detect Candidate Regions Influenced by Local Natural Selection in Human Populations.
M. Kayser, S. Brauer, and M. Stoneking (2003)
Mol. Biol. Evol. 20, 893-900
   Abstract »    Full Text »    PDF »
Balancing Selection at the Prion Protein Gene Consistent with Prehistoric Kurulike Epidemics.
S. Mead, M. P. H. Stumpf, J. Whitfield, J. A. Beck, M. Poulter, T. Campbell, J. B. Uphill, D. Goldstein, M. Alpers, E. M. C. Fisher, et al. (2003)
Science 300, 640-643
   Abstract »    Full Text »    PDF »
Population Differences in the Human Functional Olfactory Repertoire.
Y. Gilad and D. Lancet (2003)
Mol. Biol. Evol. 20, 307-314
   Abstract »    Full Text »    PDF »
Structure of Linkage Disequilibrium in Humans: Genome Factors and Population Stratification.
J. BERTRANPETIT, F. CALAFELL, D. COMAS, A. GONZALEZ-NEIRA, and A. NAVARRO (2003)
Cold Spring Harb Symp Quant Biol 68, 79-88
   Abstract »    PDF »
Interrogating a High-Density SNP Map for Signatures of Natural Selection.
J. M. Akey, G. Zhang, K. Zhang, L. Jin, and M. D. Shriver (2002)
Genome Res. 12, 1805-1814
   Abstract »    Full Text »    PDF »
Discovery of Novel Targets of Quinoline Drugs in the Human Purine Binding Proteome.
P. R. Graves, J. J. Kwiek, P. Fadden, R. Ray, K. Hardeman, A. M. Coley, M. Foley, and T. A. J. Haystead (2002)
Mol. Pharmacol. 62, 1364-1372
   Abstract »    Full Text »    PDF »
Nucleotide Variability at G6pd and the Signature of Malarial Selection in Humans.
M. A. Saunders, M. F. Hammer, and M. W. Nachman (2002)
Genetics 162, 1849-1861
   Abstract »    Full Text »    PDF »
Approximate Bayesian Computation in Population Genetics.
M. A. Beaumont, W. Zhang, and D. J. Balding (2002)
Genetics 162, 2025-2035
   Abstract »    Full Text »    PDF »
A Polytene Chromosome Analysis of the Anopheles gambiae Species Complex.
M. Coluzzi, A. Sabatini, A. della Torre, M. A. Di Deco, and V. Petrarca (2002)
Science 298, 1415-1418
   Abstract »    Full Text »    PDF »
A Comparison between Crop Domestication, Classical Plant Breeding, and Genetic Engineering.
P. Gepts (2002)
Crop Sci. 42, 1780-1790
   Abstract »    Full Text »    PDF »
Evolutionary and Historical Aspects of the Burden of Malaria.
R. Carter and K. N. Mendis (2002)
Clin. Microbiol. Rev. 15, 564-594
   Abstract »    Full Text »    PDF »
Susceptibility to malaria as a complex trait: big pressure from a tiny creature.
A. Fortin, M.M. Stevenson, and P. Gros (2002)
Hum. Mol. Genet. 11, 2469-2478
   Abstract »    Full Text »    PDF »
Microsatellite Variation and Evolution of the Human Duffy Blood Group Polymorphism.
S. Seixas, N. Ferrand, and J. Rocha (2002)
Mol. Biol. Evol. 19, 1802-1806
   Full Text »    PDF »
Coevolutionary Genetics of Plasmodium Malaria Parasites and Their Human Hosts.
A. G. Evans and T. E. Wellems (2002)
Integr. Comp. Biol. 42, 401-407
   Abstract »    Full Text »    PDF »
Malaria and the Red Cell.
D. J. Weatherall, L. H. Miller, D. I. Baruch, K. Marsh, O. K. Doumbo, C. Casals-Pascual, and D. J. Roberts (2002)
Hematology 2002, 35-57
   Abstract »    Full Text »


To Advertise     Find Products

Science. ISSN 0036-8075 (print), 1095-9203 (online)