Possible Positive Selection for an Arsenic-Protective Haplotype in Humans

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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 micro-satellite (n = 671) analysis showed no detectable level of population structure between SAC and Peruvian populations (measure of population differentiation F-ST = 0.006) and low levels of structure between SAC and HGDP populations (F-ST < 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.


  • Carina M. Schlebusch
  • Cecil M. Jr. Lewis
  • Marie Vahter
  • Karin Engström
  • Raul Y. Tito
  • Alexandra J. Obregon-Tito
  • Doris Huerta
  • Susan I. Polo
  • Angel C. Medina
  • Tom D. Brutsaert
  • Gabriela Concha
  • Mattias Jakobsson
  • Karin Broberg Palmgren
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Environmental Health and Occupational Health


  • AS3MT, dimethylarsinic acid, DMA, drinking water, Human Genome Diversity, Project, methylarsonic acid, MMA
Original languageEnglish
Pages (from-to)53-58
JournalEnvironmental Health Perspectives
Issue number1
Publication statusPublished - 2013
Publication categoryResearch

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