Alu pair exclusions in the human genome

Abstract

BackgroundThe human genome contains approximately one million Alu elements which comprise more than 10% of human DNA by mass. Alu elements possess direction, and are distributed almost equally in positive and negative strand orientations throughout the genome. Previously, it has been shown that closely spaced Alu pairs in opposing orientation (inverted pairs) are found less frequently than Alu pairs having the same orientation (direct pairs). However, this imbalance has only been investigated for Alu pairs separated by 650 or fewer base pairs (bp) in a study conducted prior to the completion of the draft human genome sequence.ResultsWe performed a comprehensive analysis of all (> 800,000) full-length Alu elements in the human genome. This large sample size permits detection of small differences in the ratio between inverted and direct Alu pairs (I:D). We have discovered a significant depression in the full-length Alu pair I:D ratio that extends to repeat pairs separated by ≤ 350,000 bp. Within this imbalance bubble (those Alu pairs separated by ≤ 350,000 bp), direct pairs outnumber inverted pairs. Using PCR, we experimentally verified several examples of inverted Alu pair exclusions that were caused by deletions.ConclusionsOver 50 million full-length Alu pairs reside within the I:D imbalance bubble. Their collective impact may represent one source of Alu element-related human genomic instability that has not been previously characterized.

Widespread occurrence of power-law distributions in inter-repeat distances shaped by genome dynamics

“…It has been shown that inverted Alus, even at 86% identity, efficiently stimulate recombination when separated by b20 nt, while recombination still occurs at 80% identity (Lobachev et al, 2000;Stenger et al, 2001). In a recent work evidence is presented about deletions of Alu repeat pairs in inverse orientation separated by long distances, up to 350,000 nt (Cook et al, 2011). Fig.…”

Multiple cellular mechanisms prevent chromosomal rearrangements involving repetitive DNA

“…These repeats can also be interspersed throughout the genome, and can be arranged in direct or inverted orientations. However, inverted repeats are extremely unstable because they can form secondary structures that disrupt DNA replication, and consequently, are rarely seen (Cook et al, 2011; Kurahashi et al, 2009; Paek et al, 2009; Lobachev et al, 2002). Many tandem and interspersed repeats are active transposons such as Ty elements in yeast, or have their origins in transposable elements, the most common of which are Alu and LINE elements in humans.…”

A Comparison of 100 Human Genes Using an Alu Element-Based Instability Model

“…Recombinant inverted Alu pairs have been shown to be unstable in genetically engineered yeast experiments when separated by up to 100 base pair (bp) and are potential sources of chromosome instability when separated by up to 350,000 bp in humans [18]–[20]. Furthermore, fusions of inverted Alu pairs previously separated by 1–5 kb have been recently identified at the breakpoints of high copy number loci in cancer cells [13].…”