Human Genomic Deletions Mediated by Recombination between Alu Elements

Abstract

Recombination between Alu elements results in genomic deletions associated with many human genetic disorders. Here, we compare the reference human and chimpanzee genomes to determine the magnitude of this recombination process in the human lineage since the human-chimpanzee divergence approximately 6 million years ago. Combining computational data mining and wet-bench experimental verification, we identified 492 human-specific deletions (for a total of approximately 400 kb) attributable to this process, a significant component of the insertion/deletion spectrum of the human genome. The majority of the deletions (295 of 492) coincide with known or predicted genes (including 3 that deleted functional exons, as compared with orthologous chimpanzee genes), which implicates this process in creating a substantial portion of the genomic differences between humans and chimpanzees. Overall, we found that Alu recombination-mediated genomic deletion has had a much higher impact than was inferred from previously identified isolated events and that it continues to contribute to the dynamic nature of the human genome.

Inviting instability: Transposable elements, double-strand breaks, and the maintenance of genome integrity

“…If the targeted sequence is on the same chromosomal strand as the repair site, the intervening sequence can be inverted ( Figure 2). As discussed below, most of the Alu-mediated deletion events in humans are consistent with either NAHR or SSA mechanisms [37].…”

“…While there is extensive support for the DSBR model described above for meiotic cells, a number of inconsistencies with experimental results were observed for mitotically dividing systems [32,37,41]. As a result, several alternative conservative HRR models have been put forward to accommodate the experimental data, including a SDSA and BIR (Reviewed in [26,41]).…”

“…In addition, a large number of the observed smaller-scale deletion events in humans are consistent with the SSA pathway [4], and the use of SSA in preference to recombination based mechanisms would be consistent with the general tendency of mammalian lineages, as opposed to yeast, to suppress crossover during repair. Although the relatively short average size of Alu-Alu mediated deletions in humans (~806 bp) [37] is suggestive of an SSA model where limited resection is involved, the somewhat larger size of disease rearrangements involving Alu [3] indicates that larger events that are occurring may be rapidly purged from the genome. As a consequence, we should be cautious about extrapolating much from the characteristics of instability events that have already been heavily filtered by natural selection.…”

Repetitive sequence environment distinguishes housekeeping genes

“…Indeed, there are numerous reports of disease-causing deletions resulting from recombination between Alu elements (Batzer and Deininger, 2002;Nishimura et al, 2005;Casarin et al, 2006;Has et al, 2006;Kozak et al, 2006;Li et al, 2006;Matejas et al, 2006;Nissen et al, 2006;Sen et al, 2006;Shabbeer et al, 2006;Uddin et al, 2006;Xie et al, 2006;Zhang et al, 2006). If a large proportion of Alu elements indeed fosters euchromatic domains as suggested by the aforementioned study (Willoughby et al, 2000), then flanking sequences may also be destabilized.…”

Down-regulation of 21A Alu RNA as a tool to boost proliferation maintaining the tissue regeneration potential of progenitor cells

“…[1][2][3] In this scenario, a significant fraction of RNA molecules is ascribable to the Alu class of repetitive sequences that represents about one-tenth of the whole human genome. 4 Up to date, a long series of biological roles have been attributed to Alu short transcripts 5 including RNA editing, 6 alternative splicing regulation, 7 chromosomal recombination, 8 gene-expression regulation, 9 cell stress response, 10,11 putative miRNA targets. 12 Notably, the observation that the transcription of Alu elements is dependent on RNA polymerase (pol) III highlights a previously unexpected role in gene-expression regulation of this machinery that deserves further investigations.…”