Freudenberg-Hua Yun, Freudenberg Jan, Kluck Nadine, Cichon Sven, Propping Peter, Nöthen Markus M
Institute of Human Genetics, University of Bonn, D-53111 Bonn, Germany.
Genome Res. 2003 Oct;13(10):2271-6. doi: 10.1101/gr.1299703.
The detailed investigation of variation in functionally important regions of the human genome is expected to promote understanding of genetically complex diseases. We resequenced 65 candidate genes for CNS disorders in an average of 85 European individuals. The minor allele frequency (MAF), an indicator of weak purifying selection, was lowest in radical amino acid alterations, whereas similar MAF was observed for synonymous variants and conservative amino acid alterations. In noncoding sequences, variants located in CpG islands tended to have a lower MAF than those outside CpG islands. The transition/transversion ratio was increased among both synonymous and conservative variants compared with noncoding variants. Conversely, the transition/transversion ratio was lowest among radical amino acid alterations. Furthermore, among nonsynonymous variants, transversions displayed lower MAF than did transitions. This suggests that transversions are associated with functionally important amino acid alterations. By comparing our data with public SNP databases, we found that variants with lower allele frequency are underrepresented in these databases. Therefore, radical variants obtain distinctively lower database coverage. However, those variants appear to be under weak purifying selection and thus could play a role in the etiology of genetically complex diseases.
对人类基因组功能重要区域变异的详细研究有望促进对基因复杂疾病的理解。我们对平均85名欧洲个体的65个中枢神经系统疾病候选基因进行了重测序。作为弱纯化选择指标的次要等位基因频率（MAF）在发生氨基酸根本改变时最低，而同义变体和保守氨基酸改变的MAF则相近。在非编码序列中，位于CpG岛的变体往往比位于CpG岛外的变体具有更低的MAF。与非编码变体相比，同义变体和保守变体中的转换/颠换比均有所增加。相反，在氨基酸根本改变中转换/颠换比最低。此外，在非同义变体中，颠换的MAF低于转换。这表明颠换与功能重要的氨基酸改变有关。通过将我们的数据与公共SNP数据库进行比较，我们发现等位基因频率较低的变体在这些数据库中的代表性不足。因此，根本变体的数据库覆盖率明显较低。然而，这些变体似乎受到弱纯化选择，因此可能在基因复杂疾病的病因学中起作用。
