Abstract
Examination of the human transcriptome reveals higher levels of RNA editing than in any other organism tested to date. This is indicative of extensive double-stranded RNA (dsRNA) formation within the human transcriptome. Most of the editing sites are located in the primate-specific retrotransposed element called Alu. A large fraction of Alus are found in intronic sequences, implying extensive Alu-Alu dsRNA formation in mRNA precursors. Yet, the effect of these intronic Alus on splicing of the flanking exons is largely unknown. Here, we show that more Alus flank alternatively spliced exons than constitutively spliced ones; this is especially notable for those exons that have changed their mode of splicing from constitutive to alternative during human evolution. This implies that Alu insertions may change the mode of splicing of the flanking exons. Indeed, we demonstrate experimentally that two Alu elements that were inserted into an intron in opposite orientation undergo base-pairing, as evident by RNA editing, and affect the splicing patterns of a downstream exon, shifting it from constitutive to alternative. Our results indicate the importance of intronic Alus in influencing the splicing of flanking exons, further emphasizing the role of Alus in shaping of the human transcriptome.
Highlights
Alternative splicing enhances transcriptomic diversity and presumably leads to speciation and higher organism complexity, especially in mammals [1,2,3]
A large fraction of Alu elements are located within intronic sequences
Over 90% of the editing sites in the human transcriptome are found within Alu sequences
Summary
Alternative splicing enhances transcriptomic diversity and presumably leads to speciation and higher organism complexity, especially in mammals [1,2,3]. There are four major types of alternative splicing: exon skipping, which is the most prevalent form in higher vertebrates; alternative 59 and 39 splice site (59ss and 39ss) selection; and intron retention, which is the rarest form in both vertebrates and invertebrates [4,5]. Understanding the changes in the genome that dictate fixation of beneficial alternative splicing events or deleterious events (e.g., mutations leading to genetic disorders or cancer), or aberrant splicing events (noise in the system) is of great interest. One mechanism responsible for the shift from constitutive to alternative splicing is accumulation of mutations in the 59 splice site region. We set out to examine additional mechanisms involved in the transition from constitutive to alternative splicing
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