Adapting to Arsenic

Andean communities may have evolved the ability to metabolize arsenic, a trait that could be the first documented example of a toxic substance acting as an agent of natural selection in humans.

By | June 1, 2015

TOXIC SELECTION: Arsenic exposure can be deadly, but high in the Andes, drinking water laced with the chemical may have driven genetic adaptation in local populations.© ISTOCK.COM/ANDREASKERMANN

In parts of Argentina, people have been drinking poison—arsenic, to be specific—for thousands of years. The river running through the Andean village of San Antonio de los Cobres (SAC) has arsenic levels up to 80 times the safe limit established by the World Health Organization (WHO); it seeps into the groundwater from volcanic bedrock. Arsenic levels in the region’s tap water were as high as 20 times the WHO’s limit before 2012, when a filtration system was installed. The villagers are descended from indigenous Atacameño people who have lived and drunk the water in northern Argentina for as long as 11,000 years. Since 1994, Swedish biologist Karin Broberg, of Stockholm’s Karolinska Institute, and colleagues at Uppsala and Lund Universities have been trying to figure out how generations of SAC’s now nearly 6,000 residents have been able to survive this chronic arsenic exposure.

Previous studies of arsenic-exposed populations in Bangladesh, Mexico, and Taiwan established AS3MT, located on chromosome 10, as the main gene involved in arsenic metabolism in humans (PLOS Genet, 8:e1002522, 2012; J Appl Toxicol, 30:260-70, 2010; Cancer Causes Control, 20:1653-61, 2009). AS3MT encodes an enzyme that methylates inorganic arsenic to form mono- and dimethylated forms, which are less toxic than the naked element. The ratio of methylated to total arsenic in a urine sample indicates an individual’s ability to metabolize the element and, for researchers, is a key measure of arsenic tolerance.

Broberg and her colleagues hypothesized that the remarkable arsenic tolerance of SAC residents might be due to particular variants of AS3MT that confer better arsenic metabolism. They wondered, further, if thousands of years of arsenic exposure had given a survival advantage to individuals with these metabolism-driving alleles and had increased the frequencies of these genetic variants.

At altitudes of 3,800 meters, the team traversed unpaved roads collecting samples of blood and urine from study participants. They faced many challenges preserving and transporting the samples and shipping them, safely frozen, all the way to Sweden. But the hassles and high-altitude adventures paid off with what may prove to be the first persuasive evidence in humans of natural selection driven by chronic exposure to a poison.  A 2013 analysis of the data the team collected over many trips to the Andes found that residents of SAC had higher levels of AS3MT alleles linked to efficient arsenic metabolism than other Native American and Asian populations, suggesting that exposure to arsenic in the environment might have driven the selection for arsenic-protective alleles (Environ Health Perspect, 121:53-58, 2013).

To test the selection hypothesis, the group homed in on a subset of 124 women from their earlier study who all had similar levels of arsenic exposure, in order to minimize the variable of intake and focus on genetic factors. The researchers analyzed single-nucleotide polymorphisms using DNA from the blood samples, measured the levels of methylated arsenic in the subjects’ urine, and performed a genome-wide association analysis to look for genes influencing arsenic metabolism. As they had predicted, there was a strong association between an individual’s AS3MT allele and urinary levels of methylated arsenic.

In order to rule out the possibility that something other than selection, such as genetic drift among South American populations, led to the increased frequencies of these protective AS3MT variants, the researchers examined publicly available genomic data from people in Peru and Colombia—countries with much lower arsenic exposure. If frequencies of AS3MT variants differed markedly between the Argentine and comparison populations, it was likely that arsenic was exerting a selective pressure on the SAC population.

Overall, Broberg says, their genetic analyses revealed that the SAC and comparison populations were genetically similar. The SAC and Peruvian populations were about as alike as, say, the French and the Italians, says evolutionary biologist Rasmus Nielsen of the University of California, Berkeley, who was not involved in the study. The Columbian population, which also had more European ancestry, was a bit more divergent. In the area around AS3MT, however, the SAC population differed dramatically from both comparison populations. Not only did the SAC women have higher levels of protective AS3MT alleles, but these alleles also had longer stretches of homozygosity—a telltale sign of selection (Mol Bio Evol, 32:1544-55, 2015).

“There is an extremely strong difference in allele frequency,” says Nielsen. “This pattern is almost certainly caused by selection. This is a very convincing study that provides a new and interesting example of human adaptation to the local environment.”

The University of Chicago’s Habibul Ahsan, who led the first genome-wide association study of arsenic metabolism, says that Broberg and her colleagues “are showing some evidence” for selection of AS3MT protective variants in the SAC population, but he notes that the study was limited by its small sample size and by the fact that the comparison groups differ from the Argentine populations in important ways—such as nationality, ethnicity, and culture—that go beyond historical arsenic exposure.

University of Arizona researcher Walter Klimecki, who has studied factors affecting arsenic susceptibility, also urged caution about Broberg’s conclusions regarding selection, but admitted that the study could spark important insights into human evolution. “If these findings are confirmed to the level where there’s general acceptance that this represents an instance of a toxic compound acting as a selecting agent in natural selection in a human population,” he says, “this would be the first report [of that] in a human population, and so there’s obvious interest from that standpoint.”

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Avatar of: savvyone2

savvyone2

Posts: 1

June 4, 2015

As the Andes were the likely beginning for the humble potato as a primary staple/ food source for the world, it is no surprise that these cultures adapted to their surroundings and the associated food sources' uptake of the environment’s soil content.  I suspect there are other yet undiscovered metabolic properties of regional populations who have long inhabited other remote areas, serving as a sort of human comp to the Galapagos Islands’ well documented  and unmitigated evolution of its wildlife inhabitants.

 

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