Genetic diversity and functional effect of common polymorphisms in genes involved in the first heterodimeric complex of the Nucleotide Excision Repair pathway

DNA Repair (Amst). 2020 Feb:86:102770. doi: 10.1016/j.dnarep.2019.102770. Epub 2019 Dec 12.

Abstract

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.

Keywords: Common regulatory polymorphism; DNA repair; Ethnic diversity; Nucleotide excision repair; Skin diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acid Phosphatase / genetics
  • Calcium-Binding Proteins / genetics
  • Cell Cycle Proteins / genetics
  • Computational Biology / methods*
  • Computer Simulation
  • DNA Repair Enzymes / genetics
  • DNA Repair*
  • DNA-Binding Proteins / genetics
  • Female
  • Gene Regulatory Networks*
  • Humans
  • Linkage Disequilibrium
  • Male
  • Polymorphism, Single Nucleotide*
  • Tunisia / ethnology
  • Xeroderma Pigmentosum / ethnology
  • Xeroderma Pigmentosum / genetics*

Substances

  • CETN2 protein, human
  • Calcium-Binding Proteins
  • Cell Cycle Proteins
  • DDB1 protein, human
  • DNA-Binding Proteins
  • RAD23A protein, human
  • XPC protein, human
  • ACP2 protein, human
  • Acid Phosphatase
  • DNA Repair Enzymes