Non-canonical roles of transposable elements in human evolution and disease

Abstract

Transposable elements (TEs) are large repetitive sequence elements with a past and, in some cases, present ability to insert themselves or copies of themselves into the genome. As with other types of insertional mutagens, TE insertions have been largely studied in terms of their disruption to the integrity of non-coding cis-regulatory elements and protein coding regions or their introduction of new substrates. Functionally, the consequences of such insertions reveal changes in gene expression or changes in protein function–most often loss of function. The post-insertional role of TEs in mediating large-scale recombination events has also been appreciated, and their catastrophic effects in disease have been described. However, the full repertoire of TE activity, including TE insertions and TE machinery, beyond insertional and recombinogenic mutagenesis remains elusive. We hypothesize that TEs shape human evolution and disease in a multitude of ways distinct from their canonical mutagenesis through insertion and recombination. The two non-canonical roles impacting the genome and transcriptome that we explore in this work are: 1) the formation of RNA secondary structures arising from TE sequence complementary that influence splicing decisions; and 2) the generation of DNA damage at non-insertion genomic sites by TE proteins. By performing statistical analysis, developing computational pipelines, and leveraging deep learning models, we reveal new insights into the ability of TEs to regulate gene expression and increase genetic diversity.