Department of Biology and Evolution, University of Ferrara, Ferrara, Italy.
Pharmacogenet Genomics. 2010 Aug;20(8):485-99. doi: 10.1097/FPC.0b013e32833bba25.
The transition from food collection to food production (FP) 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.
We compared DNA sequences and predicted the levels of enzyme activity across 10 African, Asian and European populations, six of which currently rely on hunting and gathering (HG) while four on food production (FP).
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.
从食物采集到食物生产（FP）的转变改变了选择压力的性质，有几项研究表明，自从农业革命以来，人类发生了适应新的生活方式的遗传适应性。在这里，我们检验了以下假设，即 CYP2D6 这一编码细胞色素 P450 复合酶解毒酶的基因座中存在高水平的遗传变异，反映了这种变化。
我们比较了 10 个非洲、亚洲和欧洲人群的 DNA 序列，并预测了 10 个非洲、亚洲和欧洲人群的酶活性水平，其中 6 个人群目前依赖狩猎和采集（HG），4 个人群依赖食物生产（FP）。
HG 和 FP 显示出相似的 CYP2D6 多样性水平，但在编码 DNA 位点的替代模式上存在差异，这可能与选择性差异有关。与假定的中性独立位点的变异进行比较证实了这一发现，尽管存在种群历史的混杂效应，导致非洲人的总体变异高于欧亚人。HG 和 FP 人群之间的差异表明，向农业的过渡带来的新的生活方式和饮食习惯影响了 CYP2D6 的变异模式，导致 FP 人群中与代谢率较慢相关的等位基因频率增加。这些等位基因与其他重要的、以前选择的变体达到了平衡共存。我们认为，这些酶中大多数的明显的底物依赖性活性扩大了代谢反应的范围。
