Possible Positive Selection for an Arsenic-Protective Haplotype in Humans
Carina M. Schlebusch,1 Cecil M. Lewis Jr.,2 Marie Vahter,3 Karin Engström,4 Raúl Y. Tito,2 Alexandra J. Obregón-Tito,2 Doris Huerta,5 Susan I. Polo,2 Ángel C. Medina,6 Tom D. Brutsaert,7 Gabriela Concha,8 Mattias Jakobsson,1,9 and Karin Broberg3,4
1Department of Evolutionary Biology, Evolutionary Biology Centre, Uppsala University, Uppsala, Sweden; 2Department of Anthropology, University of Oklahoma, Norman, Oklahoma, USA; 3Section for Metals and Health, Institute for Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; 4Divison of Occupational and Environmental Medicine, Lund University, Lund, Sweden; 5Facultad de Medicina, Centro de Investigación de Bioquímica y Nutrición, Universidad Nacional Mayor de San Marcos, Lima, Peru; 6Universidad de Altiplano, Puno, Peru; 7Department of Exercise Science, Syracuse University, Syracuse, New York, USA; 8National Food Administration, Risk Benefit Assessment Department, Uppsala, Sweden; 9Science for Life Laboratory, Uppsala University, Sweden
Background: Arsenic in drinking water causes severe health effects. Indigenous people in the South American Andes have likely lived with arsenic-contaminated drinking water for thousands of years. Inhabitants of San Antonio de los Cobres (SAC) in the Argentinean highlands generally carry an AS3MT (the major arsenic-metabolizing gene) haplotype associated with reduced health risks due to rapid arsenic excretion and lower urinary fraction of the monomethylated metabolite.
Objectives: We hypothesized an adaptation to high-arsenic living conditions via a possible positive selection for protective AS3MT variants and compared AS3MT haplotype frequencies among different indigenous groups.
Methods: Indigenous groups we evaluated were a) inhabitants of SAC and villages near Salta in northern Argentina (n = 346), b) three Native American populations from the Human Genome Diversity Project (HGDP; n = 25), and c) five Peruvian populations (n = 97). The last two groups have presumably lower historical exposure to arsenic.
Results: We found a significantly higher frequency of the protective AS3MT haplotype in the SAC population (68.7%) compared with the HGDP (14.3%, p < 0.001, Fisher exact test) and Peruvian (50.5%, p < 0.001) populations. Genome-wide microsatellite (n = 671) analysis showed no detectable level of population structure between SAC and Peruvian populations (measure of population differentiation FST = 0.006) and low levels of structure between SAC and HGDP populations (FST < 0.055 for all pairs of populations compared).
Conclusions: Because population stratification seems unlikely to explain the differences in AS3MT haplotype frequencies, our data raise the possibility that, during a few thousand years, natural selection for tolerance to the environmental stressor arsenic may have increased the frequency of protective variants of AS3MT. Further studies are needed to investigate this hypothesis.
Key words: AS3MT, dimethylarsinic acid, DMA, drinking water, Human Genome Diversity Project, methylarsonic acid, MMA.
Environ Health Perspect 121:53–58 (2013). http://dx.doi.org/10.1289/ehp.1205504 [Online 16 October 2012]
Address correspondence to K. Broberg, Divison of Occupational and Environmental Medicine, Lund University, Klinikgatan 21, SE-22185, Lund, Sweden. E-mail: firstname.lastname@example.org
Supplemental Material is available online (http://dx.doi.org/10.1289/ehp.1205504).
This research was supported by grants from the Swedish Council for Working Life and Social Research, the Karolinska Institutet, the Kungliga fysiografiska sällskapet, the European Union within the Sixth Framework Programme for Research and Technological Development (“PHIME” contract FOOD-CT-2006-016253), the Wenner-Gren Foundations (grant ICRG–87), the U.S. National Science Foundation (grant 0845314), and the Swedish Research Council Formas.
The authors declare they have no actual or potential competing financial interests.
Received 22 May 2012; Accepted 12 October 2012; Online 16 October 2012.
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