Evolutionarily recent retrotransposons contribute to schizophrenia

Abstract

Transposable elements (TEs) are mobile genetic elements that constitute half of the human genome. Recent studies suggest that polymorphic non-reference TEs (nrTEs) may contribute to cognitive diseases, such as schizophrenia, through a cis-regulatory effect. The aim of this work is to identify sets of nrTEs putatively linked to an increased risk of developing schizophrenia. To do so, we inspected the nrTE content of genomes from the dorsolateral prefrontal cortex of schizophrenic and control individuals and identified 38 nrTEs that possibly contribute to the emergence of this psychiatric disorder, two of them further confirmed with haplotype-based methods. We then performed in silico functional inferences and found that 9 of the 38 nrTEs act as expression/alternative splicing quantitative trait loci (eQTLs/sQTLs) in the brain, suggesting a possible role in shaping the human cognitive genome structure. To our knowledge, this is the first attempt at identifying polymorphic nrTEs that can contribute to the functionality of the brain. Finally, we suggest that a neurodevelopmental genetic mechanism, which involves evolutionarily young nrTEs, can be key to understanding the ethio-pathogenesis of this complex disorder.

Human Pangenomics: Promises and Challenges of a Distributed Genomic Reference

“…These changes can occur in both coding and non-coding regions and can lead to significant changes in gene expression, function, and underlying phenotype [ 70 , 71 , 72 , 73 ]. SVs are a major contributor to the diversity of the human genome, and they can cause disease when they alter important regulatory elements or disrupt essential genes [ 74 , 75 ]. The vast majority of SVs are not found in the reference genome, so their detection and characterization are challenging [ 76 , 77 , 78 , 79 ].…”

The Molecular Impacts of Retrotransposons in Development and Diseases

“…Moreover, complex phenotypes involving diverse gene regulation can also be attributed to TE polymorphism. Recently, Modenini et al investigated human polymorphic non-reference TEs (nrTEs) and identified evolutionarily young nrTE candidates that may potentially increase the risk of schizophrenia [128]. However, the underlying mechanisms remain elusive without functional validations.…”