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

Area of Science:

• Genomics
• Molecular Biology
• Human Genetics

Background:

• Transposable elements (TEs) comprise ~50% of the human genome, often termed 'genomic dark matter' due to limited functional understanding.
• While implicated in disease, systemic effects of TEs on gene expression remain underexplored.
• TEs are crucial for genome evolution and can influence gene regulation.

Purpose of the Study:

• To investigate the genome-wide regulatory effects of transposable elements on gene expression.
• To identify expression quantitative trait loci (eQTLs) associated with TE polymorphisms.
• To explore the role of TEs in modulating gene networks and complex trait heritability.

Main Methods:

• Analysis of whole genome sequences and whole transcriptome data from 570 individuals in the Parkinson's Progressive Markers Initiative (PPMI) cohort.
• Identification of polymorphic transposable elements (TEs) present or absent in the study cohort.
• Association analysis to link TE presence/absence with gene expression levels (eQTLs).

Main Results:

• Identified 2132 reference TEs polymorphic for presence/absence in the cohort.
• Demonstrated that TE presence/absence can drastically alter gene or gene cluster expression (0 to tens of thousands of RNA copies).
• Revealed that many TEs exert strong regulatory effects, modulating large genetic networks with hundreds of target genes.

Conclusions:

• Polymorphisms in transposable elements possess significant genome-wide regulatory functions with large effect sizes on the transcriptome.
• TEs demonstrate potent regulatory mechanisms, exemplified by their action at the HLA gene cluster and modulation of WFS1 expression.
• TEs are a convincing factor in explaining the missing heritability of complex traits and warrant further consideration.