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

Identifieur interne : 000634 ( Main/Exploration ); précédent : 000633; suivant : 000635

Genetic 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 :

RBID : pubmed:31865061

Descripteurs français

English descriptors

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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Le document en format XML

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<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>
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<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>
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<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>
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<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>
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<name sortKey="Hamdi, Yosr" sort="Hamdi, Yosr" uniqKey="Hamdi Y" first="Yosr" last="Hamdi">Yosr Hamdi</name>
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<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 Chouchane</name>
</noRegion>
</country>
</tree>
</affiliations>
</record>

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{{Explor lien
   |wiki=    Wicri/Sante
   |area=    MaghrebDataLibMedV2
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   |texte=   Genetic diversity and functional effect of common polymorphisms in genes involved in the first heterodimeric complex of the Nucleotide Excision Repair pathway.
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