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aFrom the May 2004 genome assembly (http://genome.ucsc.edu/). bATP, adenosine-5'-triphosphate; GTP, guanosine-5'-triphosphate.

aFrom the May 2004 genome assembly (http://genome.ucsc.edu/). bATP, adenosine-5'-triphosphate; GTP, guanosine-5'-triphosphate.

Fig. 2. The structure of the NF1-REP paralogs. (A) The structure of NF1-REP-P1 (131 kb) and a partial structure of NF1-REP-M (see B for complete structure) are shown. These serve as paralogous recombination substrates for the common 1.4-Mb NF1 microdeletion. The 51-kb high sequence identity region, designated NF1-REP-51 harbors the recombination hotpots PRS1 and PRS2. Gray blocks indicate the KIAA0563rel functional gene and related pseudogene (y) fragments with numbered black bars designating exons or exon-derived sequences. White boxes with arrows inside KIAA0563rel sequences designate the orientation of a 5.9-kb inverted repeats with two copies in NF1-REP-P1 and one in NF1-REP-M. STS in KIAA0563rel are shown as landmarks. Open blocks with bold margins are SMURF2-derived pseudogene (y) fragments. The arrow at the telomeric end of NF1-REP-P1 indicates that it is truncated; see panel B for full-length structure. NF1-REP-P2 is a partial NF1-REP with fragments derived from SMURF2 and KIAA0563 pseudogenes. Figures are oriented from centromere (left) to telomere. BAC identities and accession numbers for each NF1-REP are given in Forbes et al. (24). (B) Comparison of NF1-REP-P1 and NF1-REP-E19, at chromosome 19p13.13. Boxes are labeled as in (A), in addition to LEC2 and its pseudogene (open blocks with borders of multiple lines) and non-coding sequences between PRS2 and LEC2 (blocks filled with diagonal lines); sequence orientations are shown with arrows. The SMURF2, non-coding, and LEC2 sequences flanking the 51-kb repeat are considered part of NF1-REP-P1 based on paralogy with NF1-REP-P2 and NF1-REP-E19. BAC identities and accession numbers for each NF1-REP are given in Forbes et al. (24). Note difference in scales between panels A and B. (Adapted with permission from ref. 24.)

tion between chromosome 17 NFl-REPs and NF1-REP-E19, although NF1-REP-P1-51 and NF1-REP-E19 share 94-95% sequence identity that includes the recombination hotspots PRS1 and PRS2 (see next section) (Fig. 2) (24). Additional NF1-REP-like elements with KIAA0563 fragments are at chromosome 17q12 and 17q24, but they do not share any other sequences with NF1-REP-P1, -P2, or -M (11,24,25). Whether these LCRs mediate chromosomal rearrangements is unknown. Similar to those of other LCRs that mediate genomic disorders on chromosome 17, the segmental duplications giving rise to NF1-REPs originated in recent hominoid evolution about 25 million years ago before the separation of orangutan from the human lineage (25). Fluorescent in situ hybridization (FISH) studies showed the presence of NF1-REP-P1 and NF1-REP-M orthologs flanking the NF1 gene in the Great Apes (27).

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