Variable number tandem repeats – Their emerging role in sickness and health

Marshall, Jack N G; Lopez, Ana Illera; Pfaff, Abigail L; Kõks, Sulev; Quinn, John P.; Bubb, Vivien J.

doi:10.1177/15353702211003511

Cited by 17 publications

(13 citation statements)

References 76 publications

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“…The latter variation affects age of onset in XDP [42]. VNTRs more generally have been studied extensively as both biomarkers and functional elements in the context of complex genetics for many years, and these elements have been shown to have tissue-specific and stimulus-inducible regulatory properties, which are modified further by polymorphism in the VNTR itself [43]. We would expect such polymorphism to play a role in the variable function of the RIP on gene expression in that it is not solely due to the presence/absence of polymorphism but also the RIP sequence.…”

Section: Discussionmentioning

confidence: 99%

Expression Quantitative Trait Loci (eQTLs) Associated with Retrotransposons Demonstrate their Modulatory Effect on the Transcriptome

Kõks

Pfaff

Bubb

et al. 2021

IJMS

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Transposable elements (TEs) are repetitive elements that belong to a variety of functional classes and have an important role in shaping genome evolution. Around 50% of the human genome contains TEs, and they have been termed the “dark matter” of the genome because relatively little is known about their function. While TEs have been shown to participate in aberrant gene regulation and the pathogenesis of diseases, only a few studies have explored the systemic effect of TEs on gene expression. In the present study, we analysed whole genome sequences and blood whole transcriptome data from 570 individuals within the Parkinson’s Progressive Markers Initiative (PPMI) cohort to identify expression quantitative trait loci (eQTL) regulating genome-wide gene expression associated with TEs. We identified 2132 reference TEs that were polymorphic for their presence or absence in our study cohort. The presence or absence of the TE element could change the expression of the gene or gene clusters from zero to tens of thousands of copies of RNA. The main finding is that many TEs possess very strong regulatory effects, and they have the potential to modulate large genetic networks with hundreds of target genes over the genome. We illustrate the plethora of regulatory mechanisms using examples of their action at the HLA gene cluster and data showing different TEs' convergence to modulate WFS1 gene expression. In conclusion, the presence or absence of polymorphisms of TEs has an eminent genome-wide regulatory function with large effect size at the level of the whole transcriptome. The role of TEs in explaining, in part, the missing heritability for complex traits is convincing and should be considered.

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Section: Discussionmentioning

confidence: 99%

Expression Quantitative Trait Loci (eQTLs) Associated with Retrotransposons Demonstrate their Modulatory Effect on the Transcriptome

Kõks

Pfaff

Bubb

et al. 2021

IJMS

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“…It has been established that VNTRs can be both biomarkers for disease risk and also functional regulatory domains affecting both transcription and post-transcriptional mechanisms as reviewed recently (Marshall et al, 2021 ). These latter transcriptional properties can be exhibited together for the same VNTR as in the case of the monoamine oxidase A ( MAOA ) gene (Manca et al, 2018 ) and a VNTR in the mir137 gene (Warburton et al, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

A polymorphic transcriptional regulatory domain in the amyotrophic lateral sclerosis risk gene CFAP410 correlates with differential isoform expression

Marshall

Fröhlich

et al. 2022

Front. Mol. Neurosci.

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We describe the characterisation of a variable number tandem repeat (VNTR) domain within intron 1 of the amyotrophic lateral sclerosis (ALS) risk gene CFAP410 (Cilia and flagella associated protein 410) (previously known as C21orf2), providing insight into how this domain could support differential gene expression and thus be a modulator of ALS progression or risk. We demonstrated the VNTR was functional in a reporter gene assay in the HEK293 cell line, exhibiting both the properties of an activator domain and a transcriptional start site, and that the differential expression was directed by distinct repeat number in the VNTR. These properties embedded in the VNTR demonstrated the potential for this VNTR to modulate CFAP410 expression. We extrapolated these findings in silico by utilisation of tagging SNPs for the two most common VNTR alleles to establish a correlation with endogenous gene expression. Consistent with in vitro data, CFAP410 isoform expression was found to be variable in the brain. Furthermore, although the number of matched controls was low, there was evidence for one specific isoform being correlated with lower expression in those with ALS. To address if the genotype of the VNTR was associated with ALS risk, we characterised the variation of the CFAP410 VNTR in ALS cases and matched controls by PCR analysis of the VNTR length, defining eight alleles of the VNTR. No significant difference was observed between cases and controls, we noted, however, the cohort was unlikely to contain sufficient power to enable any firm conclusion to be drawn from this analysis. This data demonstrated that the VNTR domain has the potential to modulate CFAP410 expression as a regulatory element that could play a role in its tissue-specific and stimulus-inducible regulation that could impact the mechanism by which CFAP410 is involved in ALS.

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“…2 –6 These functional studies have shown that TEs like Alu repeats, LINE1s, and composite SINE-VNTR-Alu (SVA) can modify gene expression and be a part of the disease mechanism. 7,8 Most importantly, analysis of the variability of the TEs offers a unique opportunity to identify the hidden genetic mechanisms of disease, often referred simply as the missing heritability. 9 Genome-wide association studies (GWAS) based on single nucleotide polymorphism (SNP) genotyping have enjoyed significant success in defining the genetics of complex diseases.…”

Section: Introductionmentioning

confidence: 99%

Non-reference genome transposable elements (TEs) have a significant impact on the progression of the Parkinson’s disease

Kõks

Pfaff

Singleton

et al. 2022

Exp Biol Med (Maywood)

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The pathophysiology of Parkinson’s disease (PD) is a complex process of the interaction between genetic and environmental factors. Studies on the genetic component of PD have predominantly focused on single nucleotide polymorphisms (SNPs) using a cross-sectional case–control design in large genome-wide association studies. This approach while giving insight into a significant portion of the genetics of PD does not fully account for all the genetic components resulting in missing heritability. In this study, we approached this problem by focusing on the non-reference genome transposable elements (TEs) and their impact on the progression of PD using a longitudinal study design within the Parkinson’s progression markers initiative (PPMI) cohort. We analyzed 2886 Alu repeats, 360 LINE1 and 128 SINE-VNTR-Alus (SVAs) that were called from the whole-genome sequence data which are not within the reference genome. The presence or absence of these non-reference TE variants is known as a retrotransposon insertion polymorphism, and measuring this polymorphism describes the impact of TEs on the traits. The variations for the presence or absence of the non-reference TE elements were modeled to align with the changes in the 114 outcome measures during the five-year follow-up period of the PPMI cohort. Linear mixed-effects models were used, and many TEs were found to have a highly significant effect on the longitudinal changes in the clinically important PD outcomes such as UPDRS subscale II, UPDRS total scores, and modified Schwab and England ADL scale. In addition, the progression of several imaging and functional measures, including the Caudate/Putamen ratio and levodopa equivalent daily dose (LEDD) were also significantly affected by the TEs. In conclusion, this study identified the overwhelming effect of the non-reference TEs on the progression of PD and is a good example of the impact the variations in the “junk DNA” have on complex diseases.

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Variable number tandem repeats – Their emerging role in sickness and health

Cited by 17 publications

References 76 publications

Expression Quantitative Trait Loci (eQTLs) Associated with Retrotransposons Demonstrate their Modulatory Effect on the Transcriptome

Expression Quantitative Trait Loci (eQTLs) Associated with Retrotransposons Demonstrate their Modulatory Effect on the Transcriptome

A polymorphic transcriptional regulatory domain in the amyotrophic lateral sclerosis risk gene CFAP410 correlates with differential isoform expression

Non-reference genome transposable elements (TEs) have a significant impact on the progression of the Parkinson’s disease

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