Repetitive Elements and Human Disorders

Abstract

Repetitive sequences, consisting largely of transposable elements (TEs), comprise almost two‐thirds of the human genome. Non‐long‐terminal repeat (non‐LTR) TEs such as L1s, Alus and SVAs are still actively multiplying. Ongoing proliferation of these non‐LTR TEs results in a significant level of disease‐causing mutations through insertional mutagenesis, non‐allelic recombination (NAR) and the induction of genomic instability. NAR between Alu elements represents a major form of genetic instability leading to deletions, duplications and complex rearrangements. Between these different mechanisms, TEs have not only contributed a great deal to the evolution of the genome but also continue to generate germline mutations that cause a variety of diseases and potentially the progression of somatic diseases like cancer. With the advent of sequencing technologies, the future holds the promise of uncovering this role. Key Concepts Transposable elements (TEs) are DNA segments that are able to create new copies within the genome. These TEs are known to cause a variety of germline diseases through insertional mutagenesis and mutagenic recombination. TEs provide opportunities for non‐allelic recombination events to cause DNA rearrangements. There is a sharp increase in TE insertions in most epithelial cancers as well as increased opportunities for non‐allelic recombination. The overall impact of these TEs in a number of somatic diseases, particularly epithelial cancers, is under investigation. High‐throughput sequencing approaches are being utilised to better understand mobile element biology.

Altered DNA repair creates novel Alu/Alu repeat‐mediated deletions

“…With over 1 million copies in the human genome (about 11% of the overall mass of DNA), Alu elements are distributed across all chromosomes, though they tend to cluster in gene-rich regions (Lander et al, 2001). This means that Alu element-related instability frequently results in genomic rearrangements that influence gene function (Kaul et al, 2017;Sen et al, 2006;Xing et al, 2007). Alu-related RMDs in germ cells have been linked to many diseases, including Parkinson's disease, several cancers, and pulmonary artery hypertension .…”