Possible positive selection for an arsenic-protective haplotype in humans.
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.


OBJECTIVE
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.
Department of Evolutionary Biology, Evolutionary Biology Centre, Uppsala University, Uppsala, Sweden.
Carina M
CM
Schlebusch
Cecil M
CM
Lewis
Marie
M
Vahter
Karin
K
Engström
Raúl Y
RY
Tito
Alexandra J
AJ
Obregón-Tito
Doris
D
Huerta
Susan I
SI
Polo
Ángel C
ÁC
Medina
Tom D
TD
Brutsaert
Gabriela
G
Concha
Mattias
M
Jakobsson
Karin
K
Broberg
D001118:Argentina; D001151:Arsenic / Q000633:toxicity*; D020261:Arsenic Poisoning / Q000235:genetics*; D005787:Gene Frequency / Q000235:genetics; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D008780:Methyltransferases / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D014874:Water Pollutants, Chemical / Q000633:toxicity*
D014874:Water Pollutants, Chemical; D008780:Methyltransferases; C505756:AS3MT protein, human; D001151:Arsenic