Fuselli Silvia, Dupanloup Isabelle, Frigato Elena, Cruciani Fulvio, Scozzari Rosaria, Moral Pedro, Sistonen Johanna, Sajantila Antti, Barbujani Guido
Department of Biology, University of Ferrara, via Borsari 46, 44100 Ferrara, Italy.
Eur J Hum Genet. 2004 Nov;12(11):916-24. doi: 10.1038/sj.ejhg.5201243.
Despite the importance of cytochrome P450 in the metabolism of many drugs, several aspects of molecular variation at one of the main loci coding for it, CYP2D6, have never been analysed so far. Here we show that it is possible to rapidly and efficiently genotype the main European allelic variants at this locus by a SNaPshot method identifying chromosomal rearrangements and nine single-nucleotide polymorphisms. Haplotypes could be reconstructed from data on 494 chromosomes in six populations of the Mediterranean region. High levels of linkage disequilibrium were found within the chromosome region screened, suggesting that CYP2D6 may be part of a genomic recombination block, and hence that, aside from unequal crossingover that led to large chromosomal rearrangements, its haplotype diversity essentially originated through the accumulation of mutations. With the only, albeit statistically insignificant, exception of Syria, haplotype frequencies do not differ among the populations studied, despite the presence among them of three well-known genetic outliers, which could be the result of common selective pressures playing a role in shaping CYP2D6 variation over the area of Europe that we surveyed.
尽管细胞色素P450在许多药物的代谢中具有重要作用，但到目前为止，编码它的主要基因座之一CYP2D6的分子变异的几个方面从未被分析过。在这里，我们表明，通过一种识别染色体重排和9个单核苷酸多态性的SNaPshot方法，可以快速、有效地对该基因座上主要的欧洲等位基因变异进行基因分型。单倍型可以根据地中海地区六个群体中494条染色体的数据重建。在筛选的染色体区域内发现了高水平的连锁不平衡，这表明CYP2D6可能是基因组重组块的一部分，因此，除了导致大的染色体重排的不等交换外，其单倍型多样性基本上是通过突变的积累产生的。在所研究的群体中，除了叙利亚这个唯一的例外（尽管在统计学上不显著），单倍型频率没有差异，尽管其中存在三个著名的遗传异常值，这可能是共同的选择压力在我们调查的欧洲地区塑造CYP2D6变异过程中起作用的结果。
