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, the non-LTR retrotransposons, which includes the Long INterspersed Element-1 (LINE-1 or L1), is currently active in humans as indicated by 96 disease-causing insertions. The autonomous LINE-1 is capable of retrotransposing not only a copy of its own RNA in cis 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.

Figure 1

Active Human Retrotransposons: The three active human retrotransposons are diagrammed with appropriate domains indicated. A) A full-length LINE-1 (L1), 6kb [111,112], in the human genome is shown. L1s have a strong promoter (black bent arrow) located in the 5’-UTR along with a weaker antisense promoter on the bottom strand [113] (smaller black bent arrow). Intact L1s contain two non-overlapping ORFs (ORF1 and ORF2) that encode a 40kDa RNA binding protein (ORF1p) [114] and a 150 kDa protein (ORF2p) with demonstrated DNA endonuclease (EN) [13] and reverse transcriptase (RT) [14] activity. L1 RNAs commonly terminate via a canonical polyA signal (AATAAA) in the 3’-UTR, but do frequently bypass this transcription termination signal for a downstream polyA signal in the 3’-flanking DNA [16,18,20,21]. On the antisense strand, human L1s have a strong polyA signal that in conjunction with the antisense promoter may result in gene-breaking if the insertion is in opposite orientation of the transcriptional unit [115]. L1 genomic insertions terminate in a polyA tail (AAAn) of varying length and are flanked by a TSD (4–16bp in length, black horizontal arrow). UTR = untranslated region, CC = coiled-coiled, RRM = RNA recognition motif, CTD = C-terminal domain, EN = endonuclease, C = cysteine-rich domain, TSD = target-site duplication. B) A full-length Alu, ~300 bp, containing an internal RNA Pol III promoter (A and B box, black boxes) at its 5’-end is shown [38]. Alus were generated from a dimerization event of two 7SL RNA sequences (Left and Right monomer). Alu genomic insertions terminate in a polyA tail and, similar to L1, are flanked by a TSD (black horizontal arrow). Alu transcripts terminate at RNA Pol III terminator sequences (TTTT) located in the downstream flanking sequence. C) A full-length canonical SINE-VNTR-Alu (SVA) consisting of in order from the 5’-end 1) CCCTCT repeat of varying length, 2) sequence sharing homology to two antisense Alu fragments (Alu-like), 3) variable number of GC-rich tandem repeats, unit size 36–42 bp and 49–51bp, and 4) a partial envelope (env) and right LTR sequence derived from an extinct HERK-K10 (SINE-R) [31,97,116,117]. SVAs are RNA PolII transcripts, however whether SVAs encode their own promoter is unknown. Transcription of SVA RNAs may occur upstream (black bent arrow) of a genomic SVA or may be initiated throughout the SVA (black bent arrow) [68,69]. Similar to L1, SVA RNAs terminate at a polyA signal (AATAAA) located at the 3’-end of the SINE-R, but may also bypass this signal for a downstream polyA signal [31, 23, 24]. Likewise, SVAs genomic insertions also terminate in a polyA tail (AAAn) and are flanked by a TSD. Note elements are not drawn to scale.