Post-zygotic and inter-individual structural genetic variation in a presumptive enhancer element of the locus between the IL10Rβ and IFNAR1 genes.

Although historically considered as junk-DNA, tandemly repeated sequence motifs can affect human phenotype. For example, variable number tandem repeats (VNTR) with embedded enhancers have been shown to regulate gene transcription. The post-zygotic variation is the presence of genetically distinct po...

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Autores principales:	Hamid Reza Razzaghian, Lars A Forsberg, Kancherla Reddy Prakash, Szymon Przerada, Hanna Paprocka, Anna Zywicka, Maxwell P Westerman, Nancy L Pedersen, Terrance P O'Hanlon, Lisa G Rider, Frederick W Miller, Ewa Srutek, Michal Jankowski, Wojciech Zegarski, Arkadiusz Piotrowski, Devin Absher, Jan P Dumanski
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/3c2a13cdb2a84d8d9cc4928f081f6af1
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spelling	oai:doaj.org-article:3c2a13cdb2a84d8d9cc4928f081f6af12021-11-18T08:57:06ZPost-zygotic and inter-individual structural genetic variation in a presumptive enhancer element of the locus between the IL10Rβ and IFNAR1 genes.1932-620310.1371/journal.pone.0067752https://doaj.org/article/3c2a13cdb2a84d8d9cc4928f081f6af12013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24023707/?tool=EBIhttps://doaj.org/toc/1932-6203Although historically considered as junk-DNA, tandemly repeated sequence motifs can affect human phenotype. For example, variable number tandem repeats (VNTR) with embedded enhancers have been shown to regulate gene transcription. The post-zygotic variation is the presence of genetically distinct populations of cells in an individual derived from a single zygote, and this is an understudied aspect of genome biology. We report somatically variable VNTR with sequence properties of an enhancer, located upstream of IFNAR1. Initially, SNP genotyping of 63 monozygotic twin pairs and multiple tissues from 21 breast cancer patients suggested a frequent post-zygotic mosaicism. The VNTR displayed a repeated 32 bp core motif in the center of the repeat, which was flanked by similar variable motifs. A total of 14 alleles were characterized based on combinations of segments, which showed post-zygotic and inter-individual variation, with up to 6 alleles in a single subject. Somatic variation occurred in ∼24% of cases. In this hypervariable region, we found a clustering of transcription factor binding sites with strongest sequence similarity to mouse Foxg1 transcription factor binding motif. This study describes a VNTR with sequence properties of an enhancer that displays post-zygotic and inter-individual genetic variation. This element is within a locus containing four related cytokine receptors: IFNAR2, IL10Rβ, IFNAR1 and IFNGR2, and we hypothesize that it might function in transcriptional regulation of several genes in this cluster. Our findings add another level of complexity to the variation among VNTR-based enhancers. Further work may unveil the normal function of this VNTR in transcriptional control and its possible involvement in diseases connected with these receptors, such as autoimmune conditions and cancer.Hamid Reza RazzaghianLars A ForsbergKancherla Reddy PrakashSzymon PrzeradaHanna PaprockaAnna ZywickaMaxwell P WestermanNancy L PedersenTerrance P O'HanlonLisa G RiderFrederick W MillerEwa SrutekMichal JankowskiWojciech ZegarskiArkadiusz PiotrowskiDevin AbsherJan P DumanskiPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 9, p e67752 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Hamid Reza Razzaghian Lars A Forsberg Kancherla Reddy Prakash Szymon Przerada Hanna Paprocka Anna Zywicka Maxwell P Westerman Nancy L Pedersen Terrance P O'Hanlon Lisa G Rider Frederick W Miller Ewa Srutek Michal Jankowski Wojciech Zegarski Arkadiusz Piotrowski Devin Absher Jan P Dumanski Post-zygotic and inter-individual structural genetic variation in a presumptive enhancer element of the locus between the IL10Rβ and IFNAR1 genes.
description	Although historically considered as junk-DNA, tandemly repeated sequence motifs can affect human phenotype. For example, variable number tandem repeats (VNTR) with embedded enhancers have been shown to regulate gene transcription. The post-zygotic variation is the presence of genetically distinct populations of cells in an individual derived from a single zygote, and this is an understudied aspect of genome biology. We report somatically variable VNTR with sequence properties of an enhancer, located upstream of IFNAR1. Initially, SNP genotyping of 63 monozygotic twin pairs and multiple tissues from 21 breast cancer patients suggested a frequent post-zygotic mosaicism. The VNTR displayed a repeated 32 bp core motif in the center of the repeat, which was flanked by similar variable motifs. A total of 14 alleles were characterized based on combinations of segments, which showed post-zygotic and inter-individual variation, with up to 6 alleles in a single subject. Somatic variation occurred in ∼24% of cases. In this hypervariable region, we found a clustering of transcription factor binding sites with strongest sequence similarity to mouse Foxg1 transcription factor binding motif. This study describes a VNTR with sequence properties of an enhancer that displays post-zygotic and inter-individual genetic variation. This element is within a locus containing four related cytokine receptors: IFNAR2, IL10Rβ, IFNAR1 and IFNGR2, and we hypothesize that it might function in transcriptional regulation of several genes in this cluster. Our findings add another level of complexity to the variation among VNTR-based enhancers. Further work may unveil the normal function of this VNTR in transcriptional control and its possible involvement in diseases connected with these receptors, such as autoimmune conditions and cancer.
format	article
author	Hamid Reza Razzaghian Lars A Forsberg Kancherla Reddy Prakash Szymon Przerada Hanna Paprocka Anna Zywicka Maxwell P Westerman Nancy L Pedersen Terrance P O'Hanlon Lisa G Rider Frederick W Miller Ewa Srutek Michal Jankowski Wojciech Zegarski Arkadiusz Piotrowski Devin Absher Jan P Dumanski
author_facet	Hamid Reza Razzaghian Lars A Forsberg Kancherla Reddy Prakash Szymon Przerada Hanna Paprocka Anna Zywicka Maxwell P Westerman Nancy L Pedersen Terrance P O'Hanlon Lisa G Rider Frederick W Miller Ewa Srutek Michal Jankowski Wojciech Zegarski Arkadiusz Piotrowski Devin Absher Jan P Dumanski
author_sort	Hamid Reza Razzaghian
title	Post-zygotic and inter-individual structural genetic variation in a presumptive enhancer element of the locus between the IL10Rβ and IFNAR1 genes.
title_short	Post-zygotic and inter-individual structural genetic variation in a presumptive enhancer element of the locus between the IL10Rβ and IFNAR1 genes.
title_full	Post-zygotic and inter-individual structural genetic variation in a presumptive enhancer element of the locus between the IL10Rβ and IFNAR1 genes.
title_fullStr	Post-zygotic and inter-individual structural genetic variation in a presumptive enhancer element of the locus between the IL10Rβ and IFNAR1 genes.
title_full_unstemmed	Post-zygotic and inter-individual structural genetic variation in a presumptive enhancer element of the locus between the IL10Rβ and IFNAR1 genes.
title_sort	post-zygotic and inter-individual structural genetic variation in a presumptive enhancer element of the locus between the il10rβ and ifnar1 genes.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/3c2a13cdb2a84d8d9cc4928f081f6af1
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Post-zygotic and inter-individual structural genetic variation in a presumptive enhancer element of the locus between the IL10Rβ and IFNAR1 genes.

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