Haplotype diversity and linkage disequilibrium at human G6PD: recent origin of alleles that confer malarial resistance.

Department of Biology, Biology/Psychology Building, University of Maryland, College Park, MD 20742, USA.
Science (Impact Factor: 31.48). 08/2001; 293(5529):455-62. DOI: 10.1126/science.1061573
Source: PubMed

ABSTRACT 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.


Available from: Giuseppe Tagarelli, Jun 16, 2015
1 Follower
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Placental malaria is a special form of malaria that causes up to 200,000 maternal and infant deaths every year. Previous studies show that two receptor molecules, hyaluronic acid and chondroitin sulphate A, are mediating the adhesion of parasite-infected erythrocytes in the placenta of patients, which is believed to be a key step in the pathogenesis of the disease. In this study, we aimed at identifying sites of malaria-induced adaptation by scanning for signatures of natural selection in 24 genes in the complete biosynthesis pathway of these two receptor molecules. We analyzed a total of 24 Mb of publicly available polymorphism data from the International HapMap project for three human populations with European, Asian and African ancestry, with the African population from a region of presently and historically high malaria prevalence. Using the methods based on allele frequency distributions, genetic differentiation between populations, and on long-range haplotype structure, we found only limited evidence for malaria-induced genetic adaptation in this set of genes in the African population; however, we identified one candidate gene with clear evidence of selection in the Asian population. Although historical exposure to malaria in this population cannot be ruled out, we speculate that it might be caused by other pathogens, as there is growing evidence that these molecules are important receptors in a variety of host-pathogen interactions. We propose to use the present methods in a systematic way to help identify candidate regions under positive selection as a consequence of malaria.
    Human Genetics 06/2008; 123(4):343-57. DOI:10.1007/s00439-008-0483-y · 4.52 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Several lines of evidence have confirmed the importance of Nod2 mutations for disease susceptibility in Crohn's disease. For tracing Nod2 evolution, exons 4a, 4e, 8, and 12 mutations were screened in a collection of 1,064 DNA samples from 52 worldwide populations. The overall allele frequency was 7.5% for single nucleotide polymorphism (SNP)5, 0.2% for SNP8, 0.3% for SNP12, and 0.4% for SNP13. Nod2 mutations are mainly Caucasian alleles with strong distribution dissimilarity between single populations and major geographical regions. This regional diversity of Nod2 mutations within Europe points to the regional existence of selection pressure (possibly through dairy-associated bacterial infections within Neolithic cattle farming populations). The SNP5 gradient between Africa and the Middle East and its absence in Asian and Native American populations indicate that the evolution of this variant occurred in the Middle East. As mutations in exons 4e, 8, and 12 were only found in association with SNP5, this variant may have allowed selection pressure to arise.
    Immunogenetics 03/2008; 60(2):115-20. DOI:10.1007/s00251-008-0274-6 · 2.49 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Accumulating evidence indicates that some deleterious mutations responsible for genetic diseases may offer benefits for human to prevent other diseases. Therefore, human genetic diseases and evolution were tentatively regarded as the two sides of the same coin, which stimulated our interest to explore how similar are amino acid mutations in human genetic diseases and evolution. Through a large-scale analysis on amino acid mutation patterns of genetic diseases and evolution of Hominidae (Homo sapiens and Pan troglodytes), it was found that there exist significant correlations between two mutation patterns. Besides, there also exist some evident differences between both mutations, especially those associated with four amino acids C, G, R, and L. These findings are of significance to understanding the subtle connections between human genetic diseases and evolution.
    Biochemical and Biophysical Research Communications 11/2007; 362(2):233-7. DOI:10.1016/j.bbrc.2007.07.141 · 2.28 Impact Factor