Mechanisms of disease-associated SINE-VNTR-Alus

Pfaff, Abigail L; Singleton, Lewis M; Kõks, Sulev

doi:10.1177/15353702221082612

Cited by 17 publications

(11 citation statements)

References 90 publications

(131 reference statements)

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“…In association with the duplications and inversion, we detected a non-reference (both GRCh38 and T2T) SINE insertion at one of the breakpoints, disrupting one of the copies of the DMRT1 gene. SINE is a transposable element and its mobilization has long been associated with evolution and human diseases ( Akrami and Habibi 2014 ; Pfaff, Singleton, and Kõks 2022 ). Several cases linked with SINE-VNTR-Alus rearrangements induce aberrant splicing patterns, and we cannot exclude the possibility that this insertion alters the DMRT1 expression pattern.…”

Section: Discussionmentioning

confidence: 99%

A germline chimeric KANK1-DMRT1 transcript derived from a complex structural variant is associated with a congenital heart defect segregating across five generations

Costa,

Fishman,

Pinheiro

et al. 2023

Preprint

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Structural variants (SVs) pose a challenge to detect and interpret, but their study provides novel biological insights and molecular diagnosis underlying rare diseases. The aim of this study was to resolve a 9p24 rearrangement segregating in a family through five generations with a congenital heart defect (congenital pulmonary and aortic valvular stenosis, and pulmonary artery stenosis), by applying a combined genomic analysis. The analysis involved multiple techniques, including karyotype, chromosomal microarray analysis (CMA), FISH, whole-genome sequencing (WGS), RNA-seq and optical genome mapping (OGM). A complex 9p24 SV was hinted at by CMA results, showing three interspersed duplicated segments. Combined WGS and OGM analyses revealed that the 9p24 duplications constitute a complex SV, on which a set of breakpoints match the boundaries of the CMA duplicated sequences. The proposed structure for this complex rearrangement implies three duplications associated with an inversion of ~ 2Mb region on chromosome 9 with a SINE element insertion at the more distal breakpoint. Interestingly, this hypothesized genomic structure of rearrangement forms a chimeric transcript of the KANK1/DMRT1 loci, which was confirmed by RNA-seq on blood from 9p24 rearrangement carriers. Altogether with breakpoint amplification and FISH analysis, this combined approach allowed a deep characterization of this complex rearrangement. Although the genotype-phenotype correlation remains elusive from the molecular mechanism point of view, this study identified a large genomic rearrangement at 9p segregating with a familial congenital clinical trait, revealing a genetic biomarker that was successfully applied for embryo selection, changing the reproductive perspective of affected individuals.

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Section: Discussionmentioning

confidence: 99%

A germline chimeric KANK1-DMRT1 transcript derived from a complex structural variant is associated with a congenital heart defect segregating across five generations

Costa,

Fishman,

Pinheiro

et al. 2023

Preprint

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“…This insertion not only led to reduced TAF1 mRNA expression by intron retention, but additionally, variation within the CT hexamer repeat (ranging between 35 and 52 repeats) of this class F SVA inversely correlated with age at onset (AAO) of the disease 20 – 22 . To date, at least 24 disease-causing SVA insertions were reported which highlights the impact of SVA elements on gene function and genetic processing ultimately leading to pathogenesis and phenotypic differences within a population 13 , 23 , 24 .…”

Section: Introductionmentioning

confidence: 99%

Deciphering the role of a SINE-VNTR-Alu retrotransposon polymorphism as a biomarker of Parkinson’s disease progression

Fröhlich,

Pfaff,

Middlehurst

et al. 2024

Sci Rep

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SINE-VNTR-Alu (SVA) retrotransposons are transposable elements which represent a source of genetic variation. We previously demonstrated that the presence/absence of a human-specific SVA, termed SVA_67, correlated with the progression of Parkinson’s disease (PD). In the present study, we demonstrate that SVA_67 acts as expression quantitative trait loci, thereby exhibiting a strong regulatory effect across the genome using whole genome and transcriptomic data from the Parkinson’s progression markers initiative cohort. We further show that SVA_67 is polymorphic for its variable number tandem repeat domain which correlates with both regulatory properties in a luciferase reporter gene assay in vitro and differential expression of multiple genes in vivo. Additionally, this variation’s utility as a biomarker is reflected in a correlation with a number of PD progression markers. These experiments highlight the plethora of transcriptomic and phenotypic changes associated with SVA_67 polymorphism which should be considered when investigating the missing heritability of neurodegenerative diseases.

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“…This insertion not only led to reduced TAF1 mRNA expression by intron retention, but additionally, variation within the CT hexamer repeat (ranging between 35 and 52 repeats) of this class F SVA inversely correlated with age at onset (AAO) of the disease [19][20][21] . To date, at least 24 disease-causing SVA insertions were reported which highlights the impact of SVA elements on gene function and genetic processing ultimately leading to pathogenesis and phenotypic differences within a population 12,22,23 .…”

Section: Introductionmentioning

confidence: 99%

Deciphering the role of a SINE-VNTR-Alu retrotransposon polymorphism as a biomarker of Parkinson’s disease progression

Fröhlich

Pfaff

Middlehurst

et al. 2023

Preprint

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SINE-VNTR-Alu (SVA) retrotransposons are transposable elements which represent a source of genetic variation. We previously demonstrated that the presence/absence of a human-specific SVA, termed SVA_67, correlated with the progression of Parkinson´s Disease (PD). In the present study, we demonstrate that SVA_67 acts as expression quantitative trait loci, thereby exhibiting a strong regulatory effect across the genome using whole genome and transcriptomic data from the Parkinson’s Progression Markers Initiative cohort. We further show that SVA_67 is polymorphic for its variable number tandem repeat domain which correlates with both regulatory properties in a luciferase reporter gene assay in vitro and differential expression of multiple genes in vivo. Additionally, this variation’s utility as a biomarker is reflected in a correlation with a number of PD progression markers. These experiments highlight the plethora of transcriptomic and phenotypic changes associated with SVA_67 polymorphism which should be considered when investigating the missing heritability of neurodegenerative diseases.

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Mechanisms of disease-associated SINE-VNTR-Alus

Cited by 17 publications

References 90 publications

A germline chimeric KANK1-DMRT1 transcript derived from a complex structural variant is associated with a congenital heart defect segregating across five generations

A germline chimeric KANK1-DMRT1 transcript derived from a complex structural variant is associated with a congenital heart defect segregating across five generations

Deciphering the role of a SINE-VNTR-Alu retrotransposon polymorphism as a biomarker of Parkinson’s disease progression

Deciphering the role of a SINE-VNTR-Alu retrotransposon polymorphism as a biomarker of Parkinson’s disease progression

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