Widespread RNA Editing of EmbeddedAluElements in the Human Transcriptome

Abstract

More than one million copies of the ∼300-bp Alu element are interspersed throughout the human genome, with up to 75% of all known genes having Alu insertions within their introns and/or UTRs. Transcribed Alu sequences can alter splicing patterns by generating new exons, but other impacts of intragenic Alu elements on their host RNA are largely unexplored. Recently, repeat elements present in the introns or 3′-UTRs of 15 human brain RNAs have been shown to be targets for multiple adenosine to inosine (A-to-I) editing. Using a statistical approach, we find that editing of transcripts with embedded Alu sequences is a global phenomenon in the human transcriptome, observed in 2674 (∼2%) of all publicly available full-length human cDNAs (n = 128,406), from >250 libraries and >30 tissue sources. In the vast majority of edited RNAs, A-to-I substitutions are clustered within transcribed sense or antisense Alu sequences. Edited bases are primarily associated with retained introns, extended UTRs, or with transcripts that have no corresponding known gene. Therefore, Alu-associated RNA editing may be a mechanism for marking nonstandard transcripts, not destined for translation

Editor meets silencer: crosstalk between RNA editing and RNA interference

“…Alu repeats are short interspersed elements (SINEs) that are unique to primates. However, SINE elements that are 8,72 . This substantial reduction in frequency might be explained by the differences in repeat length (∼300 bp versus ∼150 bp for human Alu and mouse SINE, respectively) and higher sequence homogeneity among human Alu repeats compared with mouse SINEs 8,72 .…”

“…Several groups have recently developed a systematic, computational analysis method for the genome-wide identification of new A→I RNA editing sites [6][7][8][9] . Reverse transcriptase recognizes inosine as if it were guanosine (FIG.…”

“…This is followed by the elimination of single nucleotide polymorphisms (SNPs) and the evaluation of data quality. With this technique, a much larger than expected number of human A→I RNA editing sites has been identified [6][7][8][9] . Most surprisingly, almost all of these new sites that were identified in the human transcriptome (∼15,000 sites, mapped in ∼2,000 different genes) reside in non-coding regions that consist of inversely oriented repetitive elements (FIG.…”

“…However, SINE elements that are considered to have a common evolutionary origin with Alu repeats do exist in other organisms. Therefore, computational analyses have been carried out to search for A→I RNA editing sites in mouse EST databases 8,72 . The editing level in SINEs in mouse is at least an order of magnitude lower compared with Alu repeats in humans 8,72 .…”

“…A→I RNA editing of a short dsRNA that has formed between a coding exon and nearby intron sequences can lead to a codon change and an alteration in the protein function. However, it was recently discovered that the most frequent targets of A→I RNA editing seem to be long, but partially double-stranded, RNAs that are formed from inverted Alu repeats and long interspersed element (LINE) repeats located in introns and untranslated regions (UTRs) of mRNAs [6][7][8][9] . Global editing of non-coding RNA might control the expression of genes that harbour these repeat sequences of retrotransposon origin.…”