Biased Distribution of Inverted and Direct Alus in the Human Genome: Implications for Insertion, Exclusion, and Genome Stability

Abstract

Alu sequences, the most abundant class of large dispersed DNA repeats in human chromosomes, contribute to human genome dynamics. Recently we reported that long inverted repeats, including human Alus, can be strong initiators of genetic change in yeast. We proposed that the potential for interactions between adjacent, closely related Alus would influence their stability and this would be reflected in their distribution. We have undertaken an extensive computational analysis of all Alus (the database is at http://dir.niehs.nih.gov/ALU) to better understand their distribution and circumstances under which Alu sequences might affect genome stability. Alus separated by <650 bp were categorized according to orientation, length of regions sharing high sequence identity, distance between highly identical regions, and extent of sequence identity. Nearly 50% of all Alu pairs have long alignable regions (>275 bp), corresponding to nearly full-length Alus, regardless of orientation. There are dramatic differences in the distributions and character of Alu pairs with closely spaced, nearly identical regions. For Alu pairs that are directly repetitive, ∼30% have highly identical regions separated by <20 bp, but only when the alignments correspond to near full-size or half-size Alus. The opposite is found for the distribution of inverted repeats: Alu pairs with aligned regions separated by <20 bp are rare. Furthermore, closely spaced direct and inverted Alus differ in their truncation patterns, suggesting differences in the mechanisms of insertion. At larger distances, the direct and inverted Alu pairs have similar distributions. We propose that sequence identity, orientation, and distance are important factors determining insertion of adjacent Alus, the frequency and spectrum of Alu-associated changes in the genome, and the contribution of Alu pairs to genome instability. Based on results in model systems and the present analysis, closely spaced inverted Alu pairs with long regions of alignment are likely at-risk motifs (ARMs) for genome instability.

Absence of close-facing retrotransposons: A comparison of molecular data and theory

“…The efficiency of removal through this mechanism is expected to increase with the size of the LTR (Bennetzen, 2005) and also with an inverse of the length of the intervening sequence, and could well be the mechanism behind the removal of close facing retroelement insertions. In humans, Alu repeats constitute 10% of the genome and even though they have a different mechanism of integration to the copialike retroelements, closely spaced and inverted Alu elements are extremely unstable (Lobachev et al, 2000;Rowold and Herrera, 2000;Stenger et al, 2001). Similarly the findings of this study suggest that close proximity retroelement insertion is a similarly unstable event.…”

Intrastrand Annealing Leads to the Formation of a Large DNA Palindrome and Determines the Boundaries of Genomic Amplification in Human Cancer

“…A study by Warburton et al identified a number of DNA IRs in the human genome with more than 8 kb in each arm length and 99% identity between the arms (41). In addition, Alu sequences often form DNA IRs with a high degree of homology (Ͼ80%) and substantial alignment (Ͼ275 bp) when present next to each other in the genome (33). Second, a DNA IR also serves either as an "at-risk-motif" or a "fragile site" to regulate large palindrome formation in S. cerevisiae when DNA replication, repair, and checkpoint function are compromised (14,18).…”

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

“…Instability-Multiple studies have demonstrated the particularly unstable nature of nearby TE copies that are in inverted orientation relative to one another [45,70,71]. Closely located, inverted Alu elements are extremely rare in the human genome [66].…”