Evidence for Balancing Selection from Nucleotide Sequence Analyses of Human G6PD

Glucose-6-phosphate dehydrogenase ( G6PD) mutations that result in reduced enzyme activity have been implicated in malarial resistance and constitute one of the best examples of selection in the human genome. In the present study, we characterize the nucleotide diversity across a 5.2-kb region of G6...

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Published inAmerican journal of human genetics Vol. 71; no. 5; pp. 1112 - 1128
Main Authors Verrelli, Brian C., McDonald, John H., Argyropoulos, George, Destro-Bisol, Giovanni, Froment, Alain, Drousiotou, Anthi, Lefranc, Gerard, Helal, Ahmed N., Loiselet, Jacques, Tishkoff, Sarah A.
Format Journal Article
LanguageEnglish
Published Chicago, IL Elsevier Inc 01.11.2002
University of Chicago Press
The American Society of Human Genetics
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Abstract Glucose-6-phosphate dehydrogenase ( G6PD) mutations that result in reduced enzyme activity have been implicated in malarial resistance and constitute one of the best examples of selection in the human genome. In the present study, we characterize the nucleotide diversity across a 5.2-kb region of G6PD in a sample of 160 Africans and 56 non-Africans, to determine how selection has shaped patterns of DNA variation at this gene. Our global sample of enzymatically normal B alleles and A, A−, and Med alleles with reduced enzyme activities reveals many previously uncharacterized silent-site polymorphisms. In comparison with the absence of amino acid divergence between human and chimpanzee G6PD sequences, we find that the number of G6PD amino acid polymorphisms in human populations is significantly high. Unlike many other G6PD-activity alleles with reduced activity, we find that the age of the A variant, which is common in Africa, may not be consistent with the recent emergence of severe malaria and therefore may have originally had a historically different adaptive function. Overall, our observations strongly support previous genotype-phenotype association studies that proposed that balancing selection maintains G6PD deficiencies within human populations. The present study demonstrates that nucleotide sequence analyses can reveal signatures of both historical and recent selection in the genome and may elucidate the impact that infectious disease has had during human evolution.
AbstractList Glucose-6-phosphate dehydrogenase ( G6PD ) mutations that result in reduced enzyme activity have been implicated in malarial resistance and constitute one of the best examples of selection in the human genome. In the present study, we characterize the nucleotide diversity across a 5.2-kb region of G6PD in a sample of 160 Africans and 56 non-Africans, to determine how selection has shaped patterns of DNA variation at this gene. Our global sample of enzymatically normal B alleles and A, A−, and Med alleles with reduced enzyme activities reveals many previously uncharacterized silent-site polymorphisms. In comparison with the absence of amino acid divergence between human and chimpanzee G6PD sequences, we find that the number of G6PD amino acid polymorphisms in human populations is significantly high. Unlike many other G6PD-activity alleles with reduced activity, we find that the age of the A variant, which is common in Africa, may not be consistent with the recent emergence of severe malaria and therefore may have originally had a historically different adaptive function. Overall, our observations strongly support previous genotype-phenotype association studies that proposed that balancing selection maintains G6PD deficiencies within human populations. The present study demonstrates that nucleotide sequence analyses can reveal signatures of both historical and recent selection in the genome and may elucidate the impact that infectious disease has had during human evolution.
Glucose-6-phosphate dehydrogenase ( G6PD) mutations that result in reduced enzyme activity have been implicated in malarial resistance and constitute one of the best examples of selection in the human genome. In the present study, we characterize the nucleotide diversity across a 5.2-kb region of G6PD in a sample of 160 Africans and 56 non-Africans, to determine how selection has shaped patterns of DNA variation at this gene. Our global sample of enzymatically normal B alleles and A, A−, and Med alleles with reduced enzyme activities reveals many previously uncharacterized silent-site polymorphisms. In comparison with the absence of amino acid divergence between human and chimpanzee G6PD sequences, we find that the number of G6PD amino acid polymorphisms in human populations is significantly high. Unlike many other G6PD-activity alleles with reduced activity, we find that the age of the A variant, which is common in Africa, may not be consistent with the recent emergence of severe malaria and therefore may have originally had a historically different adaptive function. Overall, our observations strongly support previous genotype-phenotype association studies that proposed that balancing selection maintains G6PD deficiencies within human populations. The present study demonstrates that nucleotide sequence analyses can reveal signatures of both historical and recent selection in the genome and may elucidate the impact that infectious disease has had during human evolution.
Glucose-6-phosphate dehydrogenase (G6PD) mutations that result in reduced enzyme activity have been implicated in malarial resistance and constitute one of the best examples of selection in the human genome. In the present study, we characterize the nucleotide diversity across a 5.2-kb region of G6PD in a sample of 160 Africans and 56 non-Africans, to determine how selection has shaped patterns of DNA variation at this gene. Our global sample of enzymatically normal B alleles and A, A-, and Med alleles with reduced enzyme activities reveals many previously uncharacterized silent-site polymorphisms. In comparison with the absence of amino acid divergence between human and chimpanzee G6PD sequences, we find that the number of G6PD amino acid polymorphisms in human populations is significantly high. Unlike many other G6PD-activity alleles with reduced activity, we find that the age of the A variant, which is common in Africa, may not be consistent with the recent emergence of severe malaria and therefore may have originally had a historically different adaptive function. Overall, our observations strongly support previous genotype-phenotype association studies that proposed that balancing selection maintains G6PD deficiencies within human populations. The present study demonstrates that nucleotide sequence analyses can reveal signatures of both historical and recent selection in the genome and may elucidate the impact that infectious disease has had during human evolution.
Author Loiselet, Jacques
Verrelli, Brian C.
Destro-Bisol, Giovanni
Froment, Alain
Argyropoulos, George
Drousiotou, Anthi
McDonald, John H.
Tishkoff, Sarah A.
Lefranc, Gerard
Helal, Ahmed N.
AuthorAffiliation 1 Department of Biology, University of Maryland, College Park; 2 Department of Biological Sciences, University of Delaware, Newark; 3 Pennington Biomedical Research Center, Louisiana State University, Baton Rouge; 4 Department of Animal and Human Biology, University “La Sapienza,” Rome; 5 UR 092, IRD, Orléans, France; 6 Department of Biochemical Genetics, Institute of Neurology and Genetics, Nicosia, Cyprus; 7 University of Sciences and CNRS, Montpellier, France; 8 Immunogenetics Laboratory, Faculty of Pharmacy, Monastir, Tunisia; and 9 Unit of Medical Genetics, University St. Joseph, Beirut
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  organization: Immunogenetics Laboratory, Faculty of Pharmacy, Monastir, Tunisia
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DocumentTitleAlternate Balancing Selection at G6PD
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Issue 5
Keywords Pathogenesis
Biological evolution
Monkey
Hemopathy
Founder effect
Enzymopathy
Genetic determinism
Hemolytic anemia
Enzymatic activity
Primates
Human
Glucose-6-phosphate 1-dehydrogenase
Enzyme
Deficiency
Genetic variant
Metabolic diseases
Genotype
Ethnic group
Genetic disease
Vertebrata
Allele
Phenotype
Mammalia
Animal
Oxidoreductases
Comparative study
Language English
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Snippet Glucose-6-phosphate dehydrogenase ( G6PD) mutations that result in reduced enzyme activity have been implicated in malarial resistance and constitute one of...
Glucose-6-phosphate dehydrogenase (G6PD) mutations that result in reduced enzyme activity have been implicated in malarial resistance and constitute one of the...
Glucose-6-phosphate dehydrogenase ( G6PD ) mutations that result in reduced enzyme activity have been implicated in malarial resistance and constitute one of...
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StartPage 1112
SubjectTerms Africa South of the Sahara
African Continental Ancestry Group - genetics
Biological and medical sciences
Carbohydrates (enzymatic deficiencies). Glycogenosis
Errors of metabolism
Evolution, Molecular
Glucosephosphate Dehydrogenase - genetics
Humans
Immunity, Innate - genetics
Linkage Disequilibrium
Malaria - genetics
Medical sciences
Metabolic diseases
Molecular Sequence Data
Mutagenesis, Site-Directed
Phylogeny
Polymorphism, Genetic
Selection, Genetic
Sequence Analysis, DNA
Tropical medicine
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Title Evidence for Balancing Selection from Nucleotide Sequence Analyses of Human G6PD
URI https://dx.doi.org/10.1086/344345
https://www.ncbi.nlm.nih.gov/pubmed/12378426
https://search.proquest.com/docview/18624218
https://pubmed.ncbi.nlm.nih.gov/PMC385087
Volume 71
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