Article

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.

Full-text

Available from: Giuseppe Tagarelli, Apr 21, 2015
1 Follower
 · 
164 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Tafenoquine (TQ), a new synthetic analog of primaquine, has relatively poor bioavailability and associated toxicity in glucose-6-phosphate dehydrogenase (G6PD)-deficient individuals. A microemulsion formulation of TQ (MTQ) with sizes <20 nm improved the solubility of TQ and enhanced the oral bioavailability from 55% to 99% in healthy mice (area under the curve 0 to infinity: 11,368±1,232 and 23,842±872 min·μmol/L) for reference TQ and MTQ, respectively. Average parasitemia in Plasmodium berghei-infected mice was four- to tenfold lower in the MTQ-treated group. In vitro antiplasmodial activities against chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum indicated no change in half maximal inhibitory concentration, suggesting that the microemulsion did not affect the inherent activity of TQ. In a humanized mouse model of G6PD deficiency, we observed reduction in toxicity of TQ as delivered by MTQ at low but efficacious concentrations of TQ. We hereby report an enhancement in the solubility, bioavailibility, and efficacy of TQ against blood stages of Plasmodium parasites without a corresponding increase in toxicity.
    International Journal of Nanomedicine 02/2015; 10:1493-1503. DOI:10.2147/IJN.S76317 · 4.20 Impact Factor
  • Source
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: This review explores the limitations of self-reported race, ethnicity, and genetic ancestry in biomedical research. Various terminologies are used to classify human differences in genomic research including race, ethnicity, and ancestry. Although race and ethnicity are related, race refers to a person¿s physical appearance, such as skin color and eye color. Ethnicity, on the other hand, refers to communality in cultural heritage, language, social practice, traditions, and geopolitical factors. Genetic ancestry inferred using ancestry informative markers (AIMs) is based on genetic/genomic data. Phenotype-based race/ethnicity information and data computed using AIMs often disagree. For example, self-reporting African Americans can have drastically different levels of African or European ancestry. Genetic analysis of individual ancestry shows that some self-identified African Americans have up to 99% of European ancestry, whereas some self-identified European Americans have substantial admixture from African ancestry. Similarly, African ancestry in the Latino population varies between 3% in Mexican Americans to 16% in Puerto Ricans. The implication of this is that, in African American or Latino populations, self-reported ancestry may not be as accurate as direct assessment of individual genomic information in predicting treatment outcomes. To better understand human genetic variation in the context of health disparities, we suggest using ¿ancestry¿ (or biogeographical ancestry) to describe actual genetic variation, ¿race¿ to describe health disparity in societies characterized by racial categories, and ¿ethnicity¿ to describe traditions, lifestyle, diet, and values. We also suggest using ancestry informative markers for precise characterization of individuals¿ biological ancestry. Understanding the sources of human genetic variation and the causes of health disparities could lead to interventions that would improve the health of all individuals.
    Human genomics 01/2015; 9(1):1. DOI:10.1186/PREACCEPT-2695828013752627