LCR17p Repeats

Recently, we provided evidence for the existence of additional LCRs in 17p11.2-p12 termed LCR17pA, LCR17pB, LCR17pC, LCR17pD, LCR17pE, LCR17pF, and LCR17pG (19,28) (Fig. 2). Segmental duplications constitute more than 23% of approx 7.5 Mb of genome sequence in proximal 17p, approx fourfold higher than predictions based on virtual analysis of the entire human genome. Based on the genomic sequence information spanning these LCRs, we determined the size, structure, orientation, and extent of homology for and between each copy. BLAST comparisons of LCR17p repeats revealed that LCR17pA is composed of three subunits, which we termed LCR17pA/B (approx 232 kb, homologous and in an inverted orientation with respect to LCR17pB) and adjacent to it on the centromeric side two overlapping sequences LCR17pA/C (approx 79 kb), and LCR17pA/D (approx 115 kb) (both homologous and directly oriented with respect to LCR17pC [approx 91 kb] and LCR17pD [approx 118 kb], respectively). Interestingly, the LCR17pC and LCR17pD copies directly flank the proximal SMS-REP (Fig. 2).

It is remarkable that despite different sizes, locations, orientations, and, most importantly, times of origin, proximal and distal CMT1A-REPs, proximal, middle, and distal SMS-REPs, LCR17pA/B and LCR17pB, and LCR17pA/D and LCR17pD, have retained very similar (approx 98.1-98.7%) nucleotide identity. Our studies show that in contrast to LCR17pA/D-and LCR17pD-mediated NAHR, resulting in recurrent SMS chromosome deletions (29), no deletions with breakpoint within similarly sized LCR17pA/C and LCR17pC have been found (19,30). We propose that during primate evolution, the DNA sequence homology between LCR17pA/C and LCR17pC copies must have dropped below a minimal misalignment/recombination stimulating threshold (<95%?) that in turn resulted in a lack of LCR/NAHR gene conversion events and DNA homogenization and a subsequent steady decrease of nucleotide identity to the current approx 88% value (Table 1).

Fig. 2. Schematic diagram of breakpoints for DNA rearrangements in proximal chromosome 17p. (Top) Interstitial deletions and duplications are shown as horizontal arrows. Recurrent, common (approx 4 Mb) and unusual sized (approx 5 Mb) deletions are responsible for 70-80% and 4% of SMS cases, respectively. They both utilize low-copy repeats (LCRs) as substrates for nonallelic homologous recombination (NAHR). In approx 16% of SMS cases, uncommon nonrecurrent deletions have been found. Approximately half of them arise owing to NAHR mechanism between repetitive sequences and half through nonhomologous end-joining. (Bottom) LCR-associated chromosome translocations, isochromosome 17q, and marker chromosomes are depicted. The LCR17p structures are depicted in colors to better represent their positional orientation with respect to each other; the shaded rectangles and horizontal arrowheads represent the orientation of the LCRs (3,5—7,9,19,25,28—31,41—43).

Fig. 2. Schematic diagram of breakpoints for DNA rearrangements in proximal chromosome 17p. (Top) Interstitial deletions and duplications are shown as horizontal arrows. Recurrent, common (approx 4 Mb) and unusual sized (approx 5 Mb) deletions are responsible for 70-80% and 4% of SMS cases, respectively. They both utilize low-copy repeats (LCRs) as substrates for nonallelic homologous recombination (NAHR). In approx 16% of SMS cases, uncommon nonrecurrent deletions have been found. Approximately half of them arise owing to NAHR mechanism between repetitive sequences and half through nonhomologous end-joining. (Bottom) LCR-associated chromosome translocations, isochromosome 17q, and marker chromosomes are depicted. The LCR17p structures are depicted in colors to better represent their positional orientation with respect to each other; the shaded rectangles and horizontal arrowheads represent the orientation of the LCRs (3,5—7,9,19,25,28—31,41—43).

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