Nucleotide excision repair is a multistep process that recognizes and eliminates a spectrum of DNA damages. Five proteins, namely XPC, RAD23, Centrin 2, DDB1 and DDB2 act as a heterodimeric complex at the early steps of the NER pathway and play a crucial role in the removal of DNA lesions. Several exonic mutations on genes coding for these proteins have been identified as associated with Xeroderma-pigmentosum (XP), a rare monogenic disorder. However, the role of regulatory polymorphisms in disease development and inter-ethnic diversity is still not well documented. Due to the high incidence rate of XP in Tunisia, we performed a genotyping analysis of 140 SNPs found on these 5 genes in a set of 135-subjects representing the general Tunisian-population. An inter-ethnic comparison based on the genotype frequency of these SNPs have been also conducted. For the most relevant variants, we performed a comprehensive assessment of their functional effects. Linkage disequilibrium and principal component analysis showed that the Tunisian-population is an admixed and intermediate population between Sub-Saharan Africans and Europeans. Using variable factor maps, we identified a list of 20 polymorphisms that contribute considerably to the inter-ethnic diversity of the NER complex. In-silico functional analysis showed that SNPs on XPC, DDB1 and DDB2 are associated with eQTLs mainly DDB2-rs10838681 that seems to decrease significantly the expression level of ACP2 (p = 6.1 × 10-26). Statistical analysis showed that the allelic frequency of DDB2-rs10838681 in Tunisia is significantly different from all other populations. Using rVarBase, we identified 5 variants on XPC, DDB1 and DDB2 that seem to alter the binding sites of several transcription factors considered as key players in DNA-repair pathways. Results presented in this study provide the first report on regulatory polymorphisms of the NER-complex genes in Tunisia. These results may also help to establish a baseline database for future association and functional studies.

中文翻译：

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核苷酸切除修复途径的第一个异源二聚体复合体基因中常见多态性的遗传多样性和功能效应。

核苷酸切除修复是一个多步骤过程，可识别并消除一系列DNA损伤。XPC，RAD23，Centrin 2，DDB1和DDB2这五种蛋白质在NER途径的早期阶段起异二聚体复合物的作用，在去除DNA损伤中起关键作用。已经鉴定出编码这些蛋白质的基因上的几个外显子突变与一种罕见的单基因性疾病-干皮症-黑皮病（XP）有关。然而，调控多态性在疾病发展和种族间多样性中的作用仍未得到很好的证明。由于突尼斯XP的高发率，我们对代表突尼斯人的135个对象进行了这5个基因的140个SNP的基因分型分析。还根据这些SNP的基因型频率进行了种族间比较。对于最相关的变体，我们对其功能效果进行了全面评估。连锁不平衡和主成分分析表明，突尼斯人是撒哈拉以南非洲人和欧洲人之间的混合和中间人口。使用可变因子图谱，我们确定了20种多态性的列表，这些多态性极大地促进了NER复合物的族裔多样性。电子功能分析表明，XPC，DDB1和DDB2上的SNP与主要是DDB2-rs10838681的eQTL相关，这似乎显着降低了ACP2的表达水平（p = 6.1×10-26）。统计分析表明，突尼斯DDB2-rs10838681的等位基因频率与所有其他人群均存在显着差异。使用rVarBase，我们在XPC上确定了5个变体，DDB1和DDB2似乎改变了几种转录因子的结合位点，这些转录因子被认为是DNA修复途径中的关键角色。这项研究中提出的结果首次提供了关于突尼斯NER复杂基因调控多态性的报告。这些结果也可能有助于建立基线数据库，以用于将来的关联和功能研究。