SINE-VNTR-Alu retrotransposons represent one class of transposable elements which contribute to the regulation and evolution of the primate genome and have the potential to be involved in genetic instability and disease progression. However, these polymorphic elements have not been extensively analysed when addressing the missing heritability of neurodegenerative diseases, including Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS). SVA_67, a retrotransposon insertion polymorphism, is located in a 1.8 Mb region of high linkage disequilibrium, called the MAPT locus, which is known to contribute to increased risk of developing PD, frontotemporal dementia and other tauopathies. To investigate the role of SVA_67 in directing differential gene expression at this locus, we characterised the impact of SVA_67 allele dosage on isoform expression of several genes in the MAPT locus using the datasets from both the Parkinson’s Progression Markers Initiative and New York Genome Center Consortium Target ALS cohort. The Parkinson’s data was from gene expression in the blood and the ALS data from a variety of CNS regions and allowed us to demonstrate that SVA_67 presence or absence correlated with both isoform- and tissue-specific expression of multiple genes at this locus. This study highlights the importance of addressing SVA polymorphism in disease genetics to gain insight into a better understanding of the role of these regulatory domains to a variety of neurodegenerative diseases.

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.

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.

Background: SINE-VNTR-Alu retrotransposons represent one class of transposable elements which contribute to the regulation and evolution of the primate genome and have the potential to be involved in genetic instability and disease progression. However, these polymorphic elements have not been extensively analysed when addressing the missing heritability of neurodegenerative diseases, including Parkinson´s disease (PD) and amyotrophic lateral sclerosis (ALS). SVA_67, a retrotransposon insertion polymorphism, is located in a 1.8 Mb region of high linkage disequilibrium, called the MAPT locus, which is known to contribute to increased risk of developing PD, frontotemporal dementia and other tauopathies. This study was conducted to investigate the role of SVA_67 in directing differential gene expression at this locus by characterising the impact of SVA_67 allele dosage on isoform expression of several genes in the MAPT locus.Methods:In this study, transcriptomic data from both the Parkinson’s Progression Markers Initiative and New York Genome Center Consortium Target ALS cohort were used. The Parkinson’s data was from gene expression in the blood and the ALS data from a variety of central nervous system (CNS) regions. The association of three different genotypes (AA, PA, PP) based on the presence (P) or absence (A) of SVA_67 was analysed. The unpaired Wilcoxon test was used to compare two independent groups of samples and to demonstrate statistical significance.Results: Using two different datasets for analysis, we could demonstrate that SVA_67 presence or absence was significantly associated with 1) changes in expression of multiple genes at this locus and 2) both differential isoform and tissue specific expression of these genes.Conclusions:This study highlights the importance of addressing SVA polymorphism in disease genetics to gain insight into a better understanding of the role of these regulatory domains to a variety of neurodegenerative diseases. Therefore, this study underlines an additional type of variation to be considered at the MAPT locus and an added layer of complexity when analysing the missing heritability of neurodegenerative diseases.