The genetic etiologies of many complex psychiatric conditions, neurodevelopmental defects, and neurodegenerative disorders are poorly understood. Although genome wide association studies (GWAS) have linked thousands of genetic loci with many brain disorders, most causal variants remain to be discovered. Mobile DNA, which comprises ~45% of the genome, consists of multiple copies of different types of transposable elements (TE; e.g., LINE1, Alu, SVA, HERV) and other repetitive sequences [1]. Traditionally labeled Junk DNA, TE induce germline, somatic DNA, and epigenetic changes that are strongly implicated in development, cancer, and other genetic diseases [2]. TE are highly active in the developing brain and expressed in specific brain tissues in adults under normal and disease states. However, they are understudied in neurological and neuropsychiatric conditions due to many challenges, including: differences between the germline and brain genomes within an individual; somatic mosaicism within the brain, which necessitates sequencing small numbers of cells from specific brain tissues; genomic sequencing limitations of repetitive DNA; and lack of inclusion in GWAS detection strategies [1]. Here we discuss evidence that TEs are emerging candidates for brain disorders.

Highly polymorphic Alu elements are disproportionately identified through GWAS [3]. Payer et al. tested the hypothesis that Alu elements modulate disease risk through co-opting mRNA splicing. They found an AluY insertion in CD58 that is in strong linkage disequilibrium (r2 > 0.9) with a risk allele for multiple sclerosis [4]. The AluY insertion causes aberrant splicing of CD58, resulting in a frameshift. This data plausibly links Alu elements with disease risk, as reduced CD58 expression is associated with increased risk for multiple sclerosis [4].

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