Possible Positive Selection for an Arsenic-Protective Haplotype in Humans

Schlebusch, Carina M.; Lewis, Cecil M.; Vahter, Marie; Engström, Karin; Tito, Raúl Y.; Obregón-Tito, Alexandra J.; Huerta, Doris; Polo, Susan I.; Medina, Ángel C.; Brutsaert, Tom D.; Concha, Gabriela; Jakobsson, Mattias; Broberg, Karin

doi:10.1289/ehp.1205504

Cited by 46 publications

(38 citation statements)

References 48 publications

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“…This gene frequency value is very high compared with an 8% found in populations living in non‐arsenical areas . We expect that similarly high gene frequencies will be observed in other regions where extreme levels of natural multi elemental contamination are present in the water sources . Thus, this gene most likely facilitated the peopling of endemic arsenical areas including the Andes.…”

Section: Adaptationmentioning

confidence: 61%

“…Antonio de los Cobres in Argentina and Camarones in Chile, areas, where arsenic levels in the water reach on average 300-1,000 μg/L, respectively, are able to metabolize and more quickly eliminate this semimetal from their bodies through urination. [81][82][83] Both populations present a 68% frequency of the AS3MT gene protective variant, which allows them to methylate arsenic and prevent poisoning. [81][82][83] This gene frequency value is very high compared with an 8% found in populations living in non-arsenical areas.…”

Section: Molecular Biology Data Indicates Modern Populations From Sanmentioning

confidence: 99%

“…[81][82][83] Both populations present a 68% frequency of the AS3MT gene protective variant, which allows them to methylate arsenic and prevent poisoning. [81][82][83] This gene frequency value is very high compared with an 8% found in populations living in non-arsenical areas. 81 We expect that similarly high gene frequencies will be observed in other regions where extreme levels of natural multi elemental contamination are present in the water sources.…”

Section: Molecular Biology Data Indicates Modern Populations From Sanmentioning

confidence: 99%

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Living in poisoning environments: Invisible risks and human adaptation

Arriaza

Amarasiriwardena

Standen

et al. 2018

Evolutionary Anthropology

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This article describes the hidden natural chemical contaminants present in a unique desert environment and their health consequences on ancient populations. Currently, millions of people are affected worldwide by toxic elements such as arsenic. Using data gathered from Atacama Desert mummies, we discuss long‐term exposure and biocultural adaptation to toxic elements. The rivers that bring life to the Atacama Desert are paradoxically laden with arsenic and other minerals that are invisible and tasteless. High intake of these toxic elements results in severe health and behavioral problems, and even death. We demonstrate that Inca colonies, from Camarones 9 site, were significantly affected by chemical contaminants in their food and water. It appears however, some modern‐day Andean populations resist the elevated levels of arsenic exposure as a result of positive selection mediated via the arsenic methyltransferase enzyme and display more tolerance to high chemical doses. This article further debate the effects of natural pollution and biocultural adaptation of past populations.

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Section: Adaptationmentioning

confidence: 61%

Section: Molecular Biology Data Indicates Modern Populations From Sanmentioning

confidence: 99%

Section: Molecular Biology Data Indicates Modern Populations From Sanmentioning

confidence: 99%

See 1 more Smart Citation

Living in poisoning environments: Invisible risks and human adaptation

Arriaza

Amarasiriwardena

Standen

et al. 2018

Evolutionary Anthropology

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“…Several studies have shown marked differences in arsenic methylation patterns and genotypes based on ethnicity, and it is possible these caused the differences we identified [Engström et al, ; Fu et al, ]. Furthermore, the distribution of the protective AS3MT haplotype in the SAC population is higher than most populations around the world, making them extremely efficient arsenic metabolizers [Schlebusch et al, ]. Therefore, the contribution of N6AMT1 to arsenic metabolism within this population may differ from Chile.…”

Section: Discussionmentioning

confidence: 92%

Associations between arsenic (+3 oxidation state) methyltransferase (AS3MT) and N‐6 adenine‐specific DNA methyltransferase 1 (N6AMT1) polymorphisms, arsenic metabolism, and cancer risk in a chilean population

Rosa

Steinmaus

Akers

et al. 2017

Environ and Mol Mutagen

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Inter-individual differences in arsenic metabolism have been linked to arsenic-related disease risks. Arsenic (+3) methyltransferase (AS3MT) is the primary enzyme involved in arsenic metabolism, and we previously demonstrated in vitro that N-6 adenine-specific DNA methyltransferase 1 (N6AMT1) also methylates the toxic iAs metabolite, monomethylarsonous acid (MMA), to the less toxic dimethylarsonic acid (DMA). Here, we evaluated whether AS3MT and N6AMT1 gene polymorphisms alter arsenic methylation and impact iAs-related cancer risks. We assessed AS3MT and N6AMT1 polymorphisms and urinary arsenic metabolites (%iAs, %MMA, %DMA) in 722 subjects from an arsenic-cancer case-control study in a uniquely exposed area in northern Chile. Polymorphisms were genotyped using a custom designed multiplex, ligation-dependent probe amplification (MLPA) assay for 6 AS3MT SNPs and 14 tag SNPs in the N6AMT1 gene. We found several AS3MT polymorphisms associated with both urinary arsenic metabolite profiles and cancer risk. For example, compared to wildtypes, individuals carrying minor alleles in AS3MT rs3740393 had lower %MMA (mean difference = −1.9%, 95% CI: −3.3, −0.4), higher %DMA (mean difference = 4.0%, 95% CI: 1.5, 6.5), and lower odds ratios for bladder (OR=0.3; 95% CI: 0.1–0.6) and lung cancer (OR=0.6; 95% CI: 0.2–1.1). Evidence of interaction was also observed for both lung and bladder cancer between these polymorphisms and elevated historical arsenic exposures. Clear associations were not seen for N6AMT1. These results are the first to demonstrate a direct association between AS3MT polymorphisms and arsenic-related internal cancer risk. This research could help identify subpopulations that are particularly vulnerable to arsenic-related disease.

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“…This haplotype was associated with low %MMA and high %DMA, consistent with more efficient arsenic metabolism (Engström et al 2011). In the 34 women recruited in 2011, we genotyped AS3MT rs3740400, rs3740393, rs11191439, and rs1046778 with Taqman® SNP genotyping assays according to the manufacturer’s instructions, and inferred haplotype 2 based on the four SNPs only, as we have shown that we obtain very similar inferred AS3MT haplotypes with fewer SNPs compared with a larger number of SNPs (Schlebusch et al 2013). …”

Section: Methodsmentioning

confidence: 99%

N-6-Adenine-Specific DNA Methyltransferase 1 ( N6AMT1 ) Polymorphisms and Arsenic Methylation in Andean Women

Harari

Engström

Concha

et al. 2013

Environ Health Perspect

Self Cite

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Background: In humans, inorganic arsenic is metabolized to methylated metabolites mainly by arsenic (+3 oxidation state) methyltransferase (AS3MT). AS3MT polymorphisms are associated with arsenic metabolism efficiency. Recently, a putative N-6-adenine-specific DNA methyltransferase 1 (N6AMT1) was found to methylate arsenic in vitro.Objective: We evaluated the role of N6AMT1 polymorphisms in arsenic methylation efficiency in humans.Methods: We assessed arsenic methylation efficiency in 188 women exposed to arsenic via drinking water (~ 200 µg/L) in the Argentinean Andes by measuring the relative concentrations of arsenic metabolites in urine [inorganic arsenic, methylarsonic acid (MMA), and dimethylarsinic acid] by high-performance liquid chromatography coupled with hydride generation and inductively coupled plasma mass spectrometry. We performed genotyping for N6AMT1 and AS3MT polymorphisms by Taqman assays, and gene expression (in blood; n = 63) with Illumina HumanHT-12 v4.0.Results: Five N6AMT1 single nucleotide polymorphisms (SNPs; rs1997605, rs2205449, rs2705671, rs16983411, and rs1048546) and two N6AMT1 haplotypes were significantly associated with the percentage of MMA (%MMA) in urine, even after adjusting for AS3MT haplotype. %MMA increased monotonically according to the number of alleles for each SNP (e.g., for rs1048546, mean %MMA was 7.5% for GG, 8.8% for GT, and 9.7% for TT carriers). Three SNPs were in linkage disequilibrium (R2 > 0.8). Estimated associations for joint effects of N6AMT1 (haplotype 1) and AS3MT (haplotype 2) were generally consistent with expectations for additive effects of each haplotype on %MMA. Carriers of N6AMT1 genotypes associated with lower %MMA showed the lowest N6AMT1 expression, but associations were monotonic according to copy number for only one genotype and one haplotype.Conclusions: N6AMT1 polymorphisms were associated with arsenic methylation in Andean women, independent of AS3MT. N6AMT1 polymorphisms may be susceptibility markers for arsenic-related toxic effects.

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Possible Positive Selection for an Arsenic-Protective Haplotype in Humans

Cited by 46 publications

References 48 publications

Living in poisoning environments: Invisible risks and human adaptation

Living in poisoning environments: Invisible risks and human adaptation

Associations between arsenic (+3 oxidation state) methyltransferase (AS3MT) and N‐6 adenine‐specific DNA methyltransferase 1 (N6AMT1) polymorphisms, arsenic metabolism, and cancer risk in a chilean population

N-6-Adenine-Specific DNA Methyltransferase 1 ( N6AMT1 ) Polymorphisms and Arsenic Methylation in Andean Women

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