Poster Presentation 44th Lorne Genome Conference 2023

Variable number tandem repeat (VNTR) allele genotype of an SVA retrotransposon correlates with differential gene expression at the MAPT locus (#174)

Alexander Fröhlich 1 , Abigail L Pfaff 2 3 , Ben Middlehurst 1 , Vivien J Bubb 1 , Sulev Koks 2 3 , John P Quinn 1
  1. Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, United Kingdom
  2. Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Perth, WA, Australia
  3. Perron Institute for Neurological and Translational Science, Perth, WA, Australia

SINE-VNTR-Alu (SVA) retrotransposons are transposable elements which are capable of propagating throughout the genome and hence represent a source of genetic variation. We previously demonstrated that presence or absence of a human-specific SVA, termed SVA_67, correlated with both isoform- and tissue-specific expression of multiple genes at the MAPT locus, a locus associated with several neurodegenerative diseases including Parkinson's disease, frontotemporal dementia and other tauopathies. A problem in defining regulatory associations is that this region is contained within a large genomic inversion termed H1/H2. We have identified that SVA _67 tags the H1 inversion and we are extending our analysis to distinguish the SVA specific regulation from that associated with the inversion. In the current study we show that SVA_67 is not only a retrotransposon insertion polymorphism (RIP), but also variable in the size of its variable number tandem repeat (VNTR) domain. Four different alleles of the SVA_67 VNTR were identified which demonstrated differential properties of a regulatory domain in a reporter gene assay. We expanded these findings by correlating SVA_67 allele genotypes with expression of genes located around this SVA in the MAPT locus using transcriptomic datasets from the Parkinson’s Progression Markers Initiative (PPMI) cohort. Variation of the SVA_67 VNTR domain was associated with differential expression of multiple genes including KANSL1. As part of the nonspecific lethal complex, KANSL1 was previously identified as an essential gene for autophagy, a key machinery to maintain proteostasis, and dysregulation has been considered to play major roles in neurodegenerative diseases including amyotrophic lateral sclerosis and Parkinson’s disease. This study highlights the potential of SVA_67 to act in concert with other regulatory domains to modulate gene expression leading to phenotypic variation in a population and an additional type of variation to be taken into account when investigating the missing heritability of neurodegenerative diseases.