title: Post-zygotic and inter-individual structural genetic variation in a presumptive enhancer element of the locus between the IL10Rβ and IFNAR1 genes.
abstract: 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.
authors.affiliation: Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
authors.forename: Hamid Reza
authors.initials: HR
authors.lastname: Razzaghian
authors.forename: Lars A
authors.initials: LA
authors.lastname: Forsberg
authors.forename: Kancherla Reddy
authors.initials: KR
authors.lastname: Prakash
authors.forename: Szymon
authors.initials: S
authors.lastname: Przerada
authors.forename: Hanna
authors.initials: H
authors.lastname: Paprocka
authors.forename: Anna
authors.initials: A
authors.lastname: Zywicka
authors.forename: Maxwell P
authors.initials: MP
authors.lastname: Westerman
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Pedersen
authors.forename: Terrance P
authors.initials: TP
authors.lastname: O'Hanlon
authors.forename: Lisa G
authors.initials: LG
authors.lastname: Rider
authors.forename: Frederick W
authors.initials: FW
authors.lastname: Miller
authors.forename: Ewa
authors.initials: E
authors.lastname: Srutek
authors.forename: Michal
authors.initials: M
authors.lastname: Jankowski
authors.forename: Wojciech
authors.initials: W
authors.lastname: Zegarski
authors.forename: Arkadiusz
authors.initials: A
authors.lastname: Piotrowski
authors.forename: Devin
authors.initials: D
authors.lastname: Absher
authors.forename: Jan P
authors.initials: JP
authors.lastname: Dumanski
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D019295:Computational Biology / Q000379:methods; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D005260:Female; D056426:Genetic Loci / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics; D005838:Genotype; D006801:Humans; D053710:Interleukin-10 Receptor beta Subunit / Q000235:genetics*; D008297:Male; D018598:Minisatellite Repeats / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D053633:Receptor, Interferon alpha-beta / Q000235:genetics*; D055815:Young Adult
chemical_list: C081846:IL10RB protein, human; D053710:Interleukin-10 Receptor beta Subunit; D053633:Receptor, Interferon alpha-beta
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