Abstract
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.
Highlights
Neurodegenerative diseases, including Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS), are complex disorders involving interaction of genetic and environmental factors (Emamzadeh and Surguchov, 2018)
As non-coding retrotransposon insertion polymorphism (RIP) may lead to interpersonal differences in expression patterns, we aimed to extend our previous findings (Pfaff et al, 2021) by analysing the association of the SVA_67 RIP with isoform expression of six genes located in the block at the microtubule-associated protein tau (MAPT) locus including MAPT, KAT8 regulatory NSL complex subunit 1 (KANSL1), corticotropin releasing hormone receptor 1 (CRHR1), leucine rich repeat containing 37A (LRRC37A), pleckstrin homology and RUN domain containing M1 (PLEKHM1) and ADP ribosylation factor like GTPase 17A (ARL17A)
Upon inspection of the primary sequence of these elements we excluded these elements with a length of 58, 127 and 128 bp, respectively, because their sequences did not align with characteristic structures (e.g., CT element, variable number tandem repeat (VNTR) or 3 poly A) of SVA elements
Summary
Neurodegenerative diseases, including Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS), are complex disorders involving interaction of genetic and environmental factors (Emamzadeh and Surguchov, 2018). Dismissed as “junk” DNA, TEs are known to contribute to the regulation and evolution of the genome as well as to be involved in genetic instability and disease progression (Ayarpadikannan and Kim, 2014). Based on their transposition strategy and intermediates formed, TEs are split into two families named DNA transposons and retrotransposons (Savage et al, 2019). SINE-VNTR-Alu (SVA) elements, approximately 0.7–4 kb in length, are one member of the non-LTR (long terminal repeat) retrotransposon family with 2,700–3,000 copies present in the reference human genome They consist of a 5 CT-rich hexamer domain (CT element), an antisense Alu-like region, a central GC-rich variable number tandem repeat (VNTR, each repeat typically 30–50 bp in length), a SINE-R domain and a 3 poly A tail (Figure 1A; Hancks and Kazazian, 2010; Gianfrancesco et al, 2017). It should be noted that the evolutionarily youngest classes of SVAs (D-F1) may be of special interest for human physiology, health and evolution since they have introduced hominid-specific insertions which can exert novel regulatory potential to specific genomic loci (Vasieva et al, 2017)
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