Active human retrotransposons: variation and disease

Abstract

Mobile DNAs, also known as transposons or “jumping genes”, are widespread in nature and comprise an estimated 45% of the human genome. Transposons are divided into two general classes based on their transposition intermediate (DNA or RNA). Only one subclass, non-LTR retrotransposons, is currently active in humans as indicated by 96 disease-causing insertions. These autonomous Long INterspersed Element-1s (LINE-1s or L1s) are capable of retrotransposing not only a copy of their own RNA but also other RNAs (Alu, SINE-VNTR-Alu (SVA), U6) in trans to new genomic locations through an element encoded reverse transcriptase. L1 can also retrotranspose cellular mRNAs, resulting in processed pseudogene formation. Here, we highlight recent reports that update our understanding of human L1 retrotransposition and their role in disease. Finally we discuss studies that provide insights into the past and current activity of these retrotransposons, and shed light on not just when, but where, retrotransposition occurs and its part in genetic variation.

Age‐associated de‐repression of retrotransposons in the Drosophila fat body, its potential cause and consequence

“…Retrotransposons represent a major population of TEs in mammals and their de‐regulation leads to many of the reported TE‐associated human diseases (Hancks & Kazazian, 2012). Since retrotransposon activation is associated with their increased transcription, we performed RNA‐seq using dissected Drosophila fat bodies (Fig.…”

Comparative validation of the D. melanogaster modENCODE transcriptome annotation

“…A classic example is the expressed pseudogene, which can arise by gene duplication followed by degeneration of one redundant copy by random accumulation of mutations (Balakirev and Ayala 2003;Zheng et al 2007). Functionless transcripts might also arise from transposon promoters (Emera and Wagner 2012;Hancks and Kazazian 2012). It is also reasonable to assume that transcriptional errors occur at a nonzero rate.…”

Homozygous deletion of DIS3L2 exon 9 due to non-allelic homologous recombination between LINE-1s in a Japanese patient with Perlman syndrome

“…L1s account for 17% of the human genome. 6 A full-length L1 is B6 kb and encodes two ORFs (ORF1 and ORF2), which are required for retrotransposition. Mobilization of L1s created several hundred species-specific insertions in humans and chimpanzees, and L1s are still actively expanding in humans, resulting in polymorphisms of L1 elements among individuals.…”

“…Twenty-five L1 retrotransposition events have been reported to result in single-gene diseases to date. 6 Although Alu-mediated NAHR contributes to a large variety of genetic disorders, L1-mediated NAHR and human endogenous retrovirus-mediated NAHR are very rare causes of human diseases. [9][10][11][12] Only three human diseasesglycogen storage disease type IXb, Alport syndrome-diffuse leiomyomatosis, and Ellis-van Creveld syndrome -have been reported to be caused by L1-mediated NAHR.…”