Genetic diversity and functional effect of common polymorphisms in genes involved in the first heterodimeric complex of the Nucleotide Excision Repair pathway.
Identifieur interne : 000141 ( Main/Exploration ); précédent : 000140; suivant : 000142Genetic diversity and functional effect of common polymorphisms in genes involved in the first heterodimeric complex of the Nucleotide Excision Repair pathway.
Auteurs : Yosr Hamdi [Tunisie] ; Manel Jerbi [Tunisie] ; Lilia Romdhane [Tunisie] ; Mariem Ben Rekaya [Tunisie] ; Houda El Benna [Tunisie] ; Lotfi Chouchane [Qatar] ; Mohamed Samir Boubaker [Tunisie] ; Sonia Abdelhak [Tunisie] ; Houda Yacoub-Youssef [Tunisie]Source :
- DNA repair [ 1568-7856 ] ; 2020.
Descripteurs français
- KwdFr :
- Acid phosphatase (génétique), Biologie informatique (méthodes), Déséquilibre de liaison (MeSH), Enzymes de réparation de l'ADN (génétique), Femelle (MeSH), Humains (MeSH), Mâle (MeSH), Polymorphisme de nucléotide simple (MeSH), Protéines de liaison au calcium (génétique), Protéines de liaison à l'ADN (génétique), Protéines du cycle cellulaire (génétique), Réparation de l'ADN (MeSH), Réseaux de régulation génique (MeSH), Simulation numérique (MeSH), Tunisie (ethnologie), Xeroderma pigmentosum (ethnologie), Xeroderma pigmentosum (génétique).
- MESH :
- ethnologie : Tunisie, Xeroderma pigmentosum.
- génétique : Acid phosphatase, Enzymes de réparation de l'ADN, Protéines de liaison au calcium, Protéines de liaison à l'ADN, Protéines du cycle cellulaire, Xeroderma pigmentosum.
- méthodes : Biologie informatique.
- Déséquilibre de liaison, Femelle, Humains, Mâle, Polymorphisme de nucléotide simple, Réparation de l'ADN, Réseaux de régulation génique, Simulation numérique.
- Wicri :
- geographic : Tunisie.
English descriptors
- KwdEn :
- Acid Phosphatase (genetics), Calcium-Binding Proteins (genetics), Cell Cycle Proteins (genetics), Computational Biology (methods), Computer Simulation (MeSH), DNA Repair (MeSH), DNA Repair Enzymes (genetics), DNA-Binding Proteins (genetics), Female (MeSH), Gene Regulatory Networks (MeSH), Humans (MeSH), Linkage Disequilibrium (MeSH), Male (MeSH), Polymorphism, Single Nucleotide (MeSH), Tunisia (ethnology), Xeroderma Pigmentosum (ethnology), Xeroderma Pigmentosum (genetics).
- MESH :
- chemical , genetics : Acid Phosphatase, Calcium-Binding Proteins, Cell Cycle Proteins, DNA Repair Enzymes, DNA-Binding Proteins.
- geographic , ethnology : Tunisia.
- ethnology : Xeroderma Pigmentosum.
- genetics : Xeroderma Pigmentosum.
- methods : Computational Biology.
- Computer Simulation, DNA Repair, Female, Gene Regulatory Networks, Humans, Linkage Disequilibrium, Male, Polymorphism, Single Nucleotide.
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.
DOI: 10.1016/j.dnarep.2019.102770
PubMed: 31865061
Affiliations:
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Department of Biology, Faculty of Science of Bizerte, Université Tunis Carthage, Tunisia.</nlm:affiliation><country xml:lang="fr">Tunisie</country><wicri:regionArea>Laboratory of Biomedical Genomics and Oncogenetics, LR16IPT05, Institut Pasteur de Tunis, University of Tunis El Manar, Tunis, Tunisia; Department of Biology, Faculty of Science of Bizerte, Université Tunis Carthage</wicri:regionArea><wicri:noRegion>Université Tunis Carthage</wicri:noRegion></affiliation></author><author><name sortKey="Ben Rekaya, Mariem" sort="Ben Rekaya, Mariem" uniqKey="Ben Rekaya M" first="Mariem" last="Ben Rekaya">Mariem Ben Rekaya</name><affiliation wicri:level="3"><nlm:affiliation>Laboratory of Biomedical Genomics and Oncogenetics, LR16IPT05, Institut Pasteur de Tunis, University of Tunis El Manar, Tunis, Tunisia; Theranostic Biomarkers in Cancer, UR17ES15, Faculty of Medicine of Tunis, University of Tunis El Manar, Tunis, Tunisia.</nlm:affiliation><country xml:lang="fr">Tunisie</country><wicri:regionArea>Laboratory of Biomedical Genomics and Oncogenetics, LR16IPT05, Institut Pasteur de Tunis, University of Tunis El Manar, Tunis, Tunisia; Theranostic Biomarkers in Cancer, UR17ES15, Faculty of Medicine of Tunis, University of Tunis El Manar, Tunis</wicri:regionArea><placeName><settlement type="city">Tunis</settlement><region nuts="2">Gouvernorat de Tunis</region></placeName></affiliation></author><author><name sortKey="El Benna, Houda" sort="El Benna, Houda" uniqKey="El Benna H" first="Houda" last="El Benna">Houda El Benna</name><affiliation wicri:level="1"><nlm:affiliation>Department of medical Oncology, Abderrahman Mami Hospital, Ariana, Tunisia.</nlm:affiliation><country xml:lang="fr">Tunisie</country><wicri:regionArea>Department of medical Oncology, Abderrahman Mami Hospital, Ariana</wicri:regionArea><wicri:noRegion>Ariana</wicri:noRegion></affiliation></author><author><name sortKey="Chouchane, Lotfi" sort="Chouchane, Lotfi" uniqKey="Chouchane L" first="Lotfi" last="Chouchane">Lotfi Chouchane</name><affiliation wicri:level="1"><nlm:affiliation>Department of Genetic Medicine, Weill Cornell Medicine, New York, NY 10065, USA; Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY 10065, USA; Laboratory of Genetic Medicine and Immunology, Weill Cornell Medicine-Qatar, Doha, Qatar.</nlm:affiliation><country xml:lang="fr">Qatar</country><wicri:regionArea>Department of Genetic Medicine, Weill Cornell Medicine, New York, NY 10065, USA; Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY 10065, USA; Laboratory of Genetic Medicine and Immunology, Weill Cornell Medicine-Qatar, Doha</wicri:regionArea><wicri:noRegion>Doha</wicri:noRegion></affiliation></author><author><name sortKey="Boubaker, Mohamed Samir" sort="Boubaker, Mohamed Samir" uniqKey="Boubaker M" first="Mohamed Samir" last="Boubaker">Mohamed Samir Boubaker</name><affiliation wicri:level="3"><nlm:affiliation>Laboratory of Biomedical Genomics and Oncogenetics, LR16IPT05, Institut Pasteur de Tunis, University of Tunis El Manar, Tunis, Tunisia.</nlm:affiliation><country xml:lang="fr">Tunisie</country><wicri:regionArea>Laboratory of Biomedical Genomics and Oncogenetics, LR16IPT05, Institut Pasteur de Tunis, University of Tunis El Manar, Tunis</wicri:regionArea><placeName><settlement type="city">Tunis</settlement><region nuts="2">Gouvernorat de Tunis</region></placeName></affiliation></author><author><name sortKey="Abdelhak, Sonia" sort="Abdelhak, Sonia" uniqKey="Abdelhak S" first="Sonia" last="Abdelhak">Sonia Abdelhak</name><affiliation wicri:level="3"><nlm:affiliation>Laboratory of Biomedical Genomics and Oncogenetics, LR16IPT05, Institut Pasteur de Tunis, University of Tunis El Manar, Tunis, Tunisia.</nlm:affiliation><country xml:lang="fr">Tunisie</country><wicri:regionArea>Laboratory of Biomedical Genomics and Oncogenetics, LR16IPT05, Institut Pasteur de Tunis, University of Tunis El Manar, Tunis</wicri:regionArea><placeName><settlement type="city">Tunis</settlement><region nuts="2">Gouvernorat de Tunis</region></placeName></affiliation></author><author><name sortKey="Yacoub Youssef, Houda" sort="Yacoub Youssef, Houda" uniqKey="Yacoub Youssef H" first="Houda" last="Yacoub-Youssef">Houda Yacoub-Youssef</name><affiliation wicri:level="3"><nlm:affiliation>Laboratory of Biomedical Genomics and Oncogenetics, LR16IPT05, Institut Pasteur de Tunis, University of Tunis El Manar, Tunis, Tunisia.</nlm:affiliation><country xml:lang="fr">Tunisie</country><wicri:regionArea>Laboratory of Biomedical Genomics and Oncogenetics, LR16IPT05, Institut Pasteur de Tunis, University of Tunis El Manar, Tunis</wicri:regionArea><placeName><settlement type="city">Tunis</settlement><region nuts="2">Gouvernorat de Tunis</region></placeName></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2020">2020</date><idno type="RBID">pubmed:31865061</idno><idno type="pmid">31865061</idno><idno type="doi">10.1016/j.dnarep.2019.102770</idno><idno type="wicri:Area/Main/Corpus">000186</idno><idno type="wicri:explorRef" wicri:stream="Main" wicri:step="Corpus" wicri:corpus="PubMed">000186</idno><idno type="wicri:Area/Main/Curation">000186</idno><idno type="wicri:explorRef" wicri:stream="Main" wicri:step="Curation">000186</idno><idno type="wicri:Area/Main/Exploration">000186</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Genetic diversity and functional effect of common polymorphisms in genes involved in the first heterodimeric complex of the Nucleotide Excision Repair pathway.</title><author><name sortKey="Hamdi, Yosr" sort="Hamdi, Yosr" uniqKey="Hamdi Y" first="Yosr" last="Hamdi">Yosr Hamdi</name><affiliation wicri:level="3"><nlm:affiliation>Laboratory of Biomedical Genomics and Oncogenetics, LR16IPT05, Institut Pasteur de Tunis, University of Tunis El Manar, Tunis, Tunisia. Electronic address: Yosr.hamdi@pasteur.tn.</nlm:affiliation><country xml:lang="fr">Tunisie</country><wicri:regionArea>Laboratory of Biomedical Genomics and Oncogenetics, LR16IPT05, Institut Pasteur de Tunis, University of Tunis El Manar, Tunis</wicri:regionArea><placeName><settlement type="city">Tunis</settlement><region nuts="2">Gouvernorat de Tunis</region></placeName></affiliation></author><author><name sortKey="Jerbi, Manel" sort="Jerbi, Manel" uniqKey="Jerbi M" first="Manel" last="Jerbi">Manel Jerbi</name><affiliation wicri:level="3"><nlm:affiliation>Laboratory of Biomedical Genomics and Oncogenetics, LR16IPT05, Institut Pasteur de Tunis, University of Tunis El Manar, Tunis, Tunisia.</nlm:affiliation><country xml:lang="fr">Tunisie</country><wicri:regionArea>Laboratory of Biomedical Genomics and Oncogenetics, LR16IPT05, Institut Pasteur de Tunis, University of Tunis El Manar, Tunis</wicri:regionArea><placeName><settlement type="city">Tunis</settlement><region nuts="2">Gouvernorat de Tunis</region></placeName></affiliation></author><author><name sortKey="Romdhane, Lilia" sort="Romdhane, Lilia" uniqKey="Romdhane L" first="Lilia" last="Romdhane">Lilia Romdhane</name><affiliation wicri:level="1"><nlm:affiliation>Laboratory of Biomedical Genomics and Oncogenetics, LR16IPT05, Institut Pasteur de Tunis, University of Tunis El Manar, Tunis, Tunisia; Department of Biology, Faculty of Science of Bizerte, Université Tunis Carthage, Tunisia.</nlm:affiliation><country xml:lang="fr">Tunisie</country><wicri:regionArea>Laboratory of Biomedical Genomics and Oncogenetics, LR16IPT05, Institut Pasteur de Tunis, University of Tunis El Manar, Tunis, Tunisia; Department of Biology, Faculty of Science of Bizerte, Université Tunis Carthage</wicri:regionArea><wicri:noRegion>Université Tunis Carthage</wicri:noRegion></affiliation></author><author><name sortKey="Ben Rekaya, Mariem" sort="Ben Rekaya, Mariem" uniqKey="Ben Rekaya M" first="Mariem" last="Ben Rekaya">Mariem Ben Rekaya</name><affiliation wicri:level="3"><nlm:affiliation>Laboratory of Biomedical Genomics and Oncogenetics, LR16IPT05, Institut Pasteur de Tunis, University of Tunis El Manar, Tunis, Tunisia; Theranostic Biomarkers in Cancer, UR17ES15, Faculty of Medicine of Tunis, University of Tunis El Manar, Tunis, Tunisia.</nlm:affiliation><country xml:lang="fr">Tunisie</country><wicri:regionArea>Laboratory of Biomedical Genomics and Oncogenetics, LR16IPT05, Institut Pasteur de Tunis, University of Tunis El Manar, Tunis, Tunisia; Theranostic Biomarkers in Cancer, UR17ES15, Faculty of Medicine of Tunis, University of Tunis El Manar, Tunis</wicri:regionArea><placeName><settlement type="city">Tunis</settlement><region nuts="2">Gouvernorat de Tunis</region></placeName></affiliation></author><author><name sortKey="El Benna, Houda" sort="El Benna, Houda" uniqKey="El Benna H" first="Houda" last="El Benna">Houda El Benna</name><affiliation wicri:level="1"><nlm:affiliation>Department of medical Oncology, Abderrahman Mami Hospital, Ariana, Tunisia.</nlm:affiliation><country xml:lang="fr">Tunisie</country><wicri:regionArea>Department of medical Oncology, Abderrahman Mami Hospital, Ariana</wicri:regionArea><wicri:noRegion>Ariana</wicri:noRegion></affiliation></author><author><name sortKey="Chouchane, Lotfi" sort="Chouchane, Lotfi" uniqKey="Chouchane L" first="Lotfi" last="Chouchane">Lotfi Chouchane</name><affiliation wicri:level="1"><nlm:affiliation>Department of Genetic Medicine, Weill Cornell Medicine, New York, NY 10065, USA; Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY 10065, USA; Laboratory of Genetic Medicine and Immunology, Weill Cornell Medicine-Qatar, Doha, Qatar.</nlm:affiliation><country xml:lang="fr">Qatar</country><wicri:regionArea>Department of Genetic Medicine, Weill Cornell Medicine, New York, NY 10065, USA; Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY 10065, USA; Laboratory of Genetic Medicine and Immunology, Weill Cornell Medicine-Qatar, Doha</wicri:regionArea><wicri:noRegion>Doha</wicri:noRegion></affiliation></author><author><name sortKey="Boubaker, Mohamed Samir" sort="Boubaker, Mohamed Samir" uniqKey="Boubaker M" first="Mohamed Samir" last="Boubaker">Mohamed Samir Boubaker</name><affiliation wicri:level="3"><nlm:affiliation>Laboratory of Biomedical Genomics and Oncogenetics, LR16IPT05, Institut Pasteur de Tunis, University of Tunis El Manar, Tunis, Tunisia.</nlm:affiliation><country xml:lang="fr">Tunisie</country><wicri:regionArea>Laboratory of Biomedical Genomics and Oncogenetics, LR16IPT05, Institut Pasteur de Tunis, University of Tunis El Manar, Tunis</wicri:regionArea><placeName><settlement type="city">Tunis</settlement><region nuts="2">Gouvernorat de Tunis</region></placeName></affiliation></author><author><name sortKey="Abdelhak, Sonia" sort="Abdelhak, Sonia" uniqKey="Abdelhak S" first="Sonia" last="Abdelhak">Sonia Abdelhak</name><affiliation wicri:level="3"><nlm:affiliation>Laboratory of Biomedical Genomics and Oncogenetics, LR16IPT05, Institut Pasteur de Tunis, University of Tunis El Manar, Tunis, Tunisia.</nlm:affiliation><country xml:lang="fr">Tunisie</country><wicri:regionArea>Laboratory of Biomedical Genomics and Oncogenetics, LR16IPT05, Institut Pasteur de Tunis, University of Tunis El Manar, Tunis</wicri:regionArea><placeName><settlement type="city">Tunis</settlement><region nuts="2">Gouvernorat de Tunis</region></placeName></affiliation></author><author><name sortKey="Yacoub Youssef, Houda" sort="Yacoub Youssef, Houda" uniqKey="Yacoub Youssef H" first="Houda" last="Yacoub-Youssef">Houda Yacoub-Youssef</name><affiliation wicri:level="3"><nlm:affiliation>Laboratory of Biomedical Genomics and Oncogenetics, LR16IPT05, Institut Pasteur de Tunis, University of Tunis El Manar, Tunis, Tunisia.</nlm:affiliation><country xml:lang="fr">Tunisie</country><wicri:regionArea>Laboratory of Biomedical Genomics and Oncogenetics, LR16IPT05, Institut Pasteur de Tunis, University of Tunis El Manar, Tunis</wicri:regionArea><placeName><settlement type="city">Tunis</settlement><region nuts="2">Gouvernorat de Tunis</region></placeName></affiliation></author></analytic><series><title level="j">DNA repair</title><idno type="eISSN">1568-7856</idno><imprint><date when="2020" type="published">2020</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Acid Phosphatase (genetics)</term><term>Calcium-Binding Proteins (genetics)</term><term>Cell Cycle Proteins (genetics)</term><term>Computational Biology (methods)</term><term>Computer Simulation (MeSH)</term><term>DNA Repair (MeSH)</term><term>DNA Repair Enzymes (genetics)</term><term>DNA-Binding Proteins (genetics)</term><term>Female (MeSH)</term><term>Gene Regulatory Networks (MeSH)</term><term>Humans (MeSH)</term><term>Linkage Disequilibrium (MeSH)</term><term>Male (MeSH)</term><term>Polymorphism, Single Nucleotide (MeSH)</term><term>Tunisia (ethnology)</term><term>Xeroderma Pigmentosum (ethnology)</term><term>Xeroderma Pigmentosum (genetics)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Acid phosphatase (génétique)</term><term>Biologie informatique (méthodes)</term><term>Déséquilibre de liaison (MeSH)</term><term>Enzymes de réparation de l'ADN (génétique)</term><term>Femelle (MeSH)</term><term>Humains (MeSH)</term><term>Mâle (MeSH)</term><term>Polymorphisme de nucléotide simple (MeSH)</term><term>Protéines de liaison au calcium (génétique)</term><term>Protéines de liaison à l'ADN (génétique)</term><term>Protéines du cycle cellulaire (génétique)</term><term>Réparation de l'ADN (MeSH)</term><term>Réseaux de régulation génique (MeSH)</term><term>Simulation numérique (MeSH)</term><term>Tunisie (ethnologie)</term><term>Xeroderma pigmentosum (ethnologie)</term><term>Xeroderma pigmentosum (génétique)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Acid Phosphatase</term><term>Calcium-Binding Proteins</term><term>Cell Cycle Proteins</term><term>DNA Repair Enzymes</term><term>DNA-Binding Proteins</term></keywords><keywords scheme="MESH" type="geographic" qualifier="ethnology" xml:lang="en"><term>Tunisia</term></keywords><keywords scheme="MESH" qualifier="ethnologie" xml:lang="fr"><term>Tunisie</term><term>Xeroderma pigmentosum</term></keywords><keywords scheme="MESH" qualifier="ethnology" xml:lang="en"><term>Xeroderma Pigmentosum</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Xeroderma Pigmentosum</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Acid phosphatase</term><term>Enzymes de réparation de l'ADN</term><term>Protéines de liaison au calcium</term><term>Protéines de liaison à l'ADN</term><term>Protéines du cycle cellulaire</term><term>Xeroderma pigmentosum</term></keywords><keywords scheme="MESH" qualifier="methods" xml:lang="en"><term>Computational Biology</term></keywords><keywords scheme="MESH" qualifier="méthodes" xml:lang="fr"><term>Biologie informatique</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Computer Simulation</term><term>DNA Repair</term><term>Female</term><term>Gene Regulatory Networks</term><term>Humans</term><term>Linkage Disequilibrium</term><term>Male</term><term>Polymorphism, Single Nucleotide</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Déséquilibre de liaison</term><term>Femelle</term><term>Humains</term><term>Mâle</term><term>Polymorphisme de nucléotide simple</term><term>Réparation de l'ADN</term><term>Réseaux de régulation génique</term><term>Simulation numérique</term></keywords><keywords scheme="Wicri" type="geographic" xml:lang="fr"><term>Tunisie</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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<sup>-26</sup>). 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.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">31865061</PMID><DateCompleted><Year>2020</Year><Month>11</Month><Day>04</Day></DateCompleted><DateRevised><Year>2020</Year><Month>11</Month><Day>04</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1568-7856</ISSN><JournalIssue CitedMedium="Internet"><Volume>86</Volume><PubDate><Year>2020</Year><Month>02</Month></PubDate></JournalIssue><Title>DNA repair</Title><ISOAbbreviation>DNA Repair (Amst)</ISOAbbreviation></Journal><ArticleTitle>Genetic diversity and functional effect of common polymorphisms in genes involved in the first heterodimeric complex of the Nucleotide Excision Repair pathway.</ArticleTitle><Pagination><MedlinePgn>102770</MedlinePgn></Pagination><ELocationID EIdType="pii" ValidYN="Y">S1568-7864(19)30185-5</ELocationID><ELocationID EIdType="doi" ValidYN="Y">10.1016/j.dnarep.2019.102770</ELocationID><Abstract><AbstractText>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<sup>-26</sup>). 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.</AbstractText><CopyrightInformation>Copyright © 2019 Elsevier B.V. All rights reserved.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Hamdi</LastName><ForeName>Yosr</ForeName><Initials>Y</Initials><AffiliationInfo><Affiliation>Laboratory of Biomedical Genomics and Oncogenetics, LR16IPT05, Institut Pasteur de Tunis, University of Tunis El Manar, Tunis, Tunisia. Electronic address: Yosr.hamdi@pasteur.tn.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Jerbi</LastName><ForeName>Manel</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Laboratory of Biomedical Genomics and Oncogenetics, LR16IPT05, Institut Pasteur de Tunis, University of Tunis El Manar, Tunis, Tunisia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Romdhane</LastName><ForeName>Lilia</ForeName><Initials>L</Initials><AffiliationInfo><Affiliation>Laboratory of Biomedical Genomics and Oncogenetics, LR16IPT05, Institut Pasteur de Tunis, University of Tunis El Manar, Tunis, Tunisia; Department of Biology, Faculty of Science of Bizerte, Université Tunis Carthage, Tunisia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Ben Rekaya</LastName><ForeName>Mariem</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Laboratory of Biomedical Genomics and Oncogenetics, LR16IPT05, Institut Pasteur de Tunis, University of Tunis El Manar, Tunis, Tunisia; Theranostic Biomarkers in Cancer, UR17ES15, Faculty of Medicine of Tunis, University of Tunis El Manar, Tunis, Tunisia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>El Benna</LastName><ForeName>Houda</ForeName><Initials>H</Initials><AffiliationInfo><Affiliation>Department of medical Oncology, Abderrahman Mami Hospital, Ariana, Tunisia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Chouchane</LastName><ForeName>Lotfi</ForeName><Initials>L</Initials><AffiliationInfo><Affiliation>Department of Genetic Medicine, Weill Cornell Medicine, New York, NY 10065, USA; Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY 10065, USA; Laboratory of Genetic Medicine and Immunology, Weill Cornell Medicine-Qatar, Doha, Qatar.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Boubaker</LastName><ForeName>Mohamed Samir</ForeName><Initials>MS</Initials><AffiliationInfo><Affiliation>Laboratory of Biomedical Genomics and Oncogenetics, LR16IPT05, Institut Pasteur de Tunis, University of Tunis El Manar, Tunis, Tunisia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Abdelhak</LastName><ForeName>Sonia</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Laboratory of Biomedical Genomics and Oncogenetics, LR16IPT05, Institut Pasteur de Tunis, University of Tunis El Manar, Tunis, Tunisia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Yacoub-Youssef</LastName><ForeName>Houda</ForeName><Initials>H</Initials><AffiliationInfo><Affiliation>Laboratory of Biomedical Genomics and Oncogenetics, LR16IPT05, Institut Pasteur de Tunis, University of Tunis El Manar, Tunis, Tunisia.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2019</Year><Month>12</Month><Day>12</Day></ArticleDate></Article><MedlineJournalInfo><Country>Netherlands</Country><MedlineTA>DNA Repair (Amst)</MedlineTA><NlmUniqueID>101139138</NlmUniqueID><ISSNLinking>1568-7856</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C472752">CETN2 protein, human</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D002135">Calcium-Binding Proteins</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D018797">Cell Cycle Proteins</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C091435">DDB1 protein, human</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D004268">DNA-Binding Proteins</NameOfSubstance></Chemical><Chemical><RegistryNumber>156533-33-4</RegistryNumber><NameOfSubstance UI="C086985">RAD23A protein, human</NameOfSubstance></Chemical><Chemical><RegistryNumber>156533-34-5</RegistryNumber><NameOfSubstance UI="C086984">XPC protein, human</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 3.1.3.2</RegistryNumber><NameOfSubstance UI="C520783">ACP2 protein, human</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 3.1.3.2</RegistryNumber><NameOfSubstance UI="D000135">Acid Phosphatase</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 6.5.1.-</RegistryNumber><NameOfSubstance UI="D045643">DNA Repair Enzymes</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000135" MajorTopicYN="N">Acid Phosphatase</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D002135" MajorTopicYN="N">Calcium-Binding Proteins</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D018797" MajorTopicYN="N">Cell Cycle Proteins</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D019295" MajorTopicYN="N">Computational Biology</DescriptorName><QualifierName UI="Q000379" MajorTopicYN="Y">methods</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D003198" MajorTopicYN="N">Computer Simulation</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D004260" MajorTopicYN="Y">DNA Repair</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D045643" MajorTopicYN="N">DNA Repair Enzymes</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D004268" MajorTopicYN="N">DNA-Binding Proteins</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D005260" MajorTopicYN="N">Female</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D053263" MajorTopicYN="Y">Gene Regulatory Networks</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D015810" MajorTopicYN="N">Linkage Disequilibrium</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008297" MajorTopicYN="N">Male</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D020641" MajorTopicYN="Y">Polymorphism, Single Nucleotide</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D014416" MajorTopicYN="N" Type="Geographic">Tunisia</DescriptorName><QualifierName UI="Q000208" MajorTopicYN="N">ethnology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D014983" MajorTopicYN="N">Xeroderma Pigmentosum</DescriptorName><QualifierName UI="Q000208" MajorTopicYN="N">ethnology</QualifierName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName></MeshHeading></MeshHeadingList><KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="Y">Common regulatory polymorphism</Keyword><Keyword MajorTopicYN="Y">DNA repair</Keyword><Keyword MajorTopicYN="Y">Ethnic diversity</Keyword><Keyword MajorTopicYN="Y">Nucleotide excision repair</Keyword><Keyword MajorTopicYN="Y">Skin diseases</Keyword></KeywordList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2019</Year><Month>06</Month><Day>27</Day></PubMedPubDate><PubMedPubDate PubStatus="revised"><Year>2019</Year><Month>11</Month><Day>25</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2019</Year><Month>12</Month><Day>09</Day></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2019</Year><Month>12</Month><Day>23</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2020</Year><Month>11</Month><Day>5</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2019</Year><Month>12</Month><Day>23</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">31865061</ArticleId><ArticleId IdType="pii">S1568-7864(19)30185-5</ArticleId><ArticleId IdType="doi">10.1016/j.dnarep.2019.102770</ArticleId></ArticleIdList></PubmedData></pubmed><affiliations><list><country><li>Qatar</li><li>Tunisie</li></country><region><li>Gouvernorat de Tunis</li></region><settlement><li>Tunis</li></settlement></list><tree><country name="Tunisie"><region name="Gouvernorat de Tunis"><name sortKey="Hamdi, Yosr" sort="Hamdi, Yosr" uniqKey="Hamdi Y" first="Yosr" last="Hamdi">Yosr Hamdi</name></region><name sortKey="Abdelhak, Sonia" sort="Abdelhak, Sonia" uniqKey="Abdelhak S" first="Sonia" last="Abdelhak">Sonia Abdelhak</name><name sortKey="Ben Rekaya, Mariem" sort="Ben Rekaya, Mariem" uniqKey="Ben Rekaya M" first="Mariem" last="Ben Rekaya">Mariem Ben Rekaya</name><name sortKey="Boubaker, Mohamed Samir" sort="Boubaker, Mohamed Samir" uniqKey="Boubaker M" first="Mohamed Samir" last="Boubaker">Mohamed Samir Boubaker</name><name sortKey="El Benna, Houda" sort="El Benna, Houda" uniqKey="El Benna H" first="Houda" last="El Benna">Houda El Benna</name><name sortKey="Jerbi, Manel" sort="Jerbi, Manel" uniqKey="Jerbi M" first="Manel" last="Jerbi">Manel Jerbi</name><name sortKey="Romdhane, Lilia" sort="Romdhane, Lilia" uniqKey="Romdhane L" first="Lilia" last="Romdhane">Lilia Romdhane</name><name sortKey="Yacoub Youssef, Houda" sort="Yacoub Youssef, Houda" uniqKey="Yacoub Youssef H" first="Houda" last="Yacoub-Youssef">Houda Yacoub-Youssef</name></country><country name="Qatar"><noRegion><name sortKey="Chouchane, Lotfi" sort="Chouchane, Lotfi" uniqKey="Chouchane L" first="Lotfi" last="Chouchane">Lotfi 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