Objective: The transition from food collection to food production modified the nature of selective pressures, and several studies illustrate that genetic adaptation to new lifestyle has occurred in humans since the agricultural revolution. Here we test the hypothesis that high levels of genetic variation at CYP2D6, a locus coding for a detoxifying enzyme of the cytochrome P450 complex, reflect this change. Methods: We compared DNA sequences and predicted levels of enzyme activity across 10 African, Asian and European populations, 6 of which currently rely on hunting and gathering (HG) while 4 on food production (FP). Results and conclusions: HG and FP showed similar levels of CYP2D6 diversity, but displayed different substitution patterns at coding DNA sites possibly related to selective differences. Comparison with variation at presumably neutral independent loci confirmed this finding, despite the confounding effects of population history, resulting in higher overall variation in Africans than in Eurasians. The differences between HG and FP populations suggest that new lifestyle and dietary habits acquired in the transition to agriculture affected the variation pattern at CYP2D6, leading to an increase in FP populations of the frequency of alleles that are associated with a slower rate of metabolism. These alleles reached a balanced co-existence with other important and previously selected variants. We suggest that the pronounced substrate-dependent activity of most of these enzymes expanded the spectrum of the metabolic response.
Evolution of detoxifying systems: the role of environment and population history in shaping genetic diversity at human CYP2D6 locus.
FUSELLI, Silvia;BARBUJANI, Guido;BERTORELLE, Giorgio;
2010
Abstract
Objective: The transition from food collection to food production modified the nature of selective pressures, and several studies illustrate that genetic adaptation to new lifestyle has occurred in humans since the agricultural revolution. Here we test the hypothesis that high levels of genetic variation at CYP2D6, a locus coding for a detoxifying enzyme of the cytochrome P450 complex, reflect this change. Methods: We compared DNA sequences and predicted levels of enzyme activity across 10 African, Asian and European populations, 6 of which currently rely on hunting and gathering (HG) while 4 on food production (FP). Results and conclusions: HG and FP showed similar levels of CYP2D6 diversity, but displayed different substitution patterns at coding DNA sites possibly related to selective differences. Comparison with variation at presumably neutral independent loci confirmed this finding, despite the confounding effects of population history, resulting in higher overall variation in Africans than in Eurasians. The differences between HG and FP populations suggest that new lifestyle and dietary habits acquired in the transition to agriculture affected the variation pattern at CYP2D6, leading to an increase in FP populations of the frequency of alleles that are associated with a slower rate of metabolism. These alleles reached a balanced co-existence with other important and previously selected variants. We suggest that the pronounced substrate-dependent activity of most of these enzymes expanded the spectrum of the metabolic response.I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
