Evidence for Balancing Selection from Nucleotide Sequence Analyses of Human G6PD

Sapienza University of Rome, Roma, Latium, Italy
The American Journal of Human Genetics (Impact Factor: 10.93). 12/2002; 71(5):1112-28. DOI: 10.1086/344345
Source: PubMed


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.

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    • "Indeed, studies have shown that AAs have higher CRP and IL6 levels than EAs [11,12]. Because of evolution over millennia in Africa, and adaptation to endemic infectious diseases, it is possible that innate immune factors may differ by ancestry, with a more robust inflammatory response among AAs [13–15], which could contribute to the differential risk between AA and EA women of developing more aggressive breast cancer phenotypes. "
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    ABSTRACT: African American (AA) women are more likely than European American (EA) women to be diagnosed with early, aggressive breast cancer. Possible differences in innate immune pathways (e.g., inflammatory responses) have received little attention as potential mechanisms underlying this disparity. We evaluated distributions of selected genetic variants in innate immune pathways in AA and EA women, and examined their associations with breast cancer risk within the Women's Circle of Health Study (WCHS). In stage I of the study (864 AA and 650 EA women) we found that genotype frequencies for 35 of 42 tested SNPs (18 candidate genes) differed between AAs and EAs (corroborated by ancestry informative markers). Among premenopausal AA women, comparing variant allele carriers to non-carriers, reduced breast cancer risk was associated with CXCL5-rs425535 (OR=0.61, P=0.02), while among EA women, there were associations with TNFA-rs1799724 (OR =2.31, P =0.002) and CRP-rs1205 (OR=0.54, P=0.01). For postmenopausal women, IL1B-rs1143627 (OR=1.80, P=0.02) and IL1B-rs16944 (OR=1.85, P =0.02) were associated with risk among EA women, with significant associations for TNFA-rs1799724 limited to estrogen receptor (ER) positive cancers (OR=2.0, P =0.001). However, none of the SNPs retained significance after Bonferroni adjustment for multiple testing at the level of P0.0012 (0.05/42) except for TNFA-rs1799724 in ER positive cancers. In a stage II validation (1,365 AA and 1,307 EA women), we extended evaluations for four SNPs (CCL2-rs4586, CRP-rs1205, CXCL5-rs425535, and IL1RN-rs4251961), which yielded similar results. In summary, distributions of variants in genes involved in innate immune pathways were found to differ between AA and EA populations, and showed differential associations with breast cancer according to menopausal or ER status. These results suggest that immune adaptations suited to ancestral environments may differentially influence breast cancer risk among EA and AA women.
    Full-text · Article · Aug 2013 · PLoS ONE
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    • "In their work, Fumagalli and coworkers [9] also indicated that the effect of distinct pathogens can at least in part be disentangled, although infectious agents were grouped into macrocategories (i.e., viruses, bacteria, helminths, and protozoa). Indeed, in his observations about thalassemia, Haldane chose a lucky rare example: the specific characteristics of Plasmodium infection and the strong selective pressure the parasite exerted allowed to draw a direct link between the infectious agent and specific loci showing very strong evidence of natural selection (e.g., DARC and G6PD [10] [11]). This has proved unfeasible for the large majority of human genes, whereby signatures of natural selection are described, but the underlying selective pressure (i.e., the specific pathogen) remains unknown. "
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    ABSTRACT: Infectious diseases and epidemics have always accompanied and characterized human history, representing one of the main causes of death. Even today, despite progress in sanitation and medical research, infections are estimated to account for about 15% of deaths. The hypothesis whereby infectious diseases have been acting as a powerful selective pressure was formulated long ago, but it was not until the availability of large-scale genetic data and the development of novel methods to study molecular evolution that we could assess how pervasively infectious agents have shaped human genetic diversity. Indeed, recent evidences indicated that among the diverse environmental factors that acted as selective pressures during the evolution of our species, pathogen load had the strongest influence. Beside the textbook example of the major histocompatibility complex, selection signatures left by pathogen-exerted pressure can be identified at several human loci, including genes not directly involved in immune response. In the future, high-throughput technologies and the availability of genetic data from different populations are likely to provide novel insights into the evolutionary relationships between the human host and its pathogens. Hopefully, this will help identify the genetic determinants modulating the susceptibility to infectious diseases and will translate into new treatment strategies.
    Full-text · Article · Mar 2013
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    • "Wood et al. (2005) 38–120 950–3000 — Modiano et al. (2008) E 100.3 (62–222) 2508 (1550–5550) 0.079 (0.035–0.099) Ohashi et al., 2004 G6PD A- 254.3 6357 (3840–11 760) 0.044 Tishkoff et al. (2001) A- 93 2325 (1200–3862) — Sabeti et al. (2002) A- 1800 45 000 (25 000–65 000) — Verrelli et al. (2002) A- 40 1000 0.25 Slatkin (2008) Med 133.2 3330 (1600–6640) 0.034 Tishkoff et al. (2001) Med 400 10 000 (0–35 000) — Verrelli et al. (2002) Mahidol 63 1575 0.23 Louicharoen et al. (2009) Duffy ES (null) 1323 33 075 (6500–97 200) — Hamblin and Di Rienzo, 2000 ES (null) 310 7750 (3625–13 125 — Seixas et al. (2002) ES (null) 490 12 250 (4250–26 500) — Seixas et al. (2002) ABO O01 — 1.15 million — Calafell et al. (2008) O02 — 2.5 million — Calafell et al. (2008) HLA-B B53 100 2500 0.028* Hill et al., 1991 B53 86 2150 0.041* This paper "
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    ABSTRACT: The high mortality and widespread impact of malaria have resulted in this disease being the strongest evolutionary selective force in recent human history, and genes that confer resistance to malaria provide some of the best-known case studies of strong positive selection in modern humans. I begin by reviewing JBS Haldane's initial contribution to the potential of malaria genetic resistance in humans. Further, I discuss the population genetics aspects of many of the variants, including globin, G6PD deficiency, Duffy, ovalocytosis, ABO and human leukocyte antigen variants. Many of the variants conferring resistance to malaria are 'loss-of-function' mutants and appear to be recent polymorphisms from the last 5000-10 000 years or less. I discuss estimation of selection coefficients from case-control data and make predictions about the change for S, C and G6PD-deficiency variants. In addition, I consider the predicted joint changes when the two β-globin alleles S and C are both variable in the same population and when there is a variation for α-thalassemia and S, two unlinked, but epistatic variants. As more becomes known about genes conferring genetic resistance to malaria in humans, population genetics approaches can contribute both to investigating past selection and predicting the consequences in future generations for these variants.
    Preview · Article · Mar 2011 · Heredity
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