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. 2002 May;12(5):729-38.
doi: 10.1101/gr.82802.

Structure and evolution of the Smith-Magenis syndrome repeat gene clusters, SMS-REPs

Sung-Sup Park  1 , Paweł Stankiewicz, Weimin Bi, Christine Shaw, Jessica Lehoczky, Ken Dewar, Bruce Birren, James R Lupski
Affiliations

Structure and evolution of the Smith-Magenis syndrome repeat gene clusters, SMS-REPs

Sung-Sup Park et al. Genome Res. 2002 May.

Abstract

An approximately 4-Mb genomic segment on chromosome 17p11.2, commonly deleted in patients with the Smith-Magenis syndrome (SMS) and duplicated in patients with dup(17)(p11.2p11.2) syndrome, is flanked by large, complex low-copy repeats (LCRs), termed proximal and distal SMS-REP. A third copy, the middle SMS-REP, is located between them. SMS-REPs are believed to mediate nonallelic homologous recombination, resulting in both SMS deletions and reciprocal duplications. To delineate the genomic structure and evolutionary origin of SMS-REPs, we constructed a bacterial artificial chromosome/P1 artificial chromosome contig spanning the entire SMS region, including the SMS-REPs, determined its genomic sequence, and used fluorescence in situ hybridization to study the evolution of SMS-REP in several primate species. Our analysis shows that both the proximal SMS-REP (approximately 256 kb) and the distal copy (approximately 176 kb) are located in the same orientation and derived from a progenitor copy, whereas the middle SMS-REP (approximately 241 kb) is inverted and appears to have been derived from the proximal copy. The SMS-REP LCRs are highly homologous (>98%) and contain at least 14 genes/pseudogenes each. SMS-REPs are not present in mice and were duplicated after the divergence of New World monkeys from pre-monkeys approximately 40-65 million years ago. Our findings potentially explain why the vast majority of SMS deletions and dup(17)(p11.2p11.2) occur at proximal and distal SMS-REPs and further support previous observations that higher-order genomic architecture involving LCRs arose recently during primate speciation and may predispose the human genome to both meiotic and mitotic rearrangements.

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Figures

Figure 1
Figure 1
An example of a cis-morphism among three SMS-REPs. Southern blotting with CLP cDNA probe on HindIII-digested large-insert genomic clones revealed an 8.1-kb band for the distal SMS-REP (lanes 3 and 4 for yeast artificial chromosomes [YACs]; lanes 7 and 8 for bacterial artificial chromosomes [BACs]) and 5.1 kb and 0.9 kb for the proximal SMS-REP (lanes 5 and 6 for YACs; lanes 9 and 10 for BACs). Hybridization to total genomic DNA (gDNA in lanes 1 and 2) reveals additional cross-hybridizing bands, which map to different genomic locations.
Figure 2
Figure 2
Bacterial artificial chromosome/P1 artificial chromosome (BAC/PAC) contig map spanning three SMS-REPs. Thick bold lines represent minimal-tiling-path, large-insert clones utilized for genomic finished sequence of SMS-REPs. Clones are designated with their clone name and their GenBank accession number. Markers in boxes represent SMS-REP-flanking sequences used to determine SMS-REP orientations. Final orientation was determined by the construction of a complete BAC/PAC contig spanning the common deletion (Bi et al. 2002).
Figure 3
Figure 3
Human metaphase chromosome 17 and G2 interphase nucleus after fluorescence in situ hybridization (FISH) with SMS-REP-specific bacterial artificial chromosome (BAC) RP11–158M20. To the left is a human-chromosome-17 ideogram with the positions of hybridization signals (green) shown next to specific cytological bands. White horizontal arrows show specific locations of FISH signals with BACs containing the genomic segments listed above the arrows. To the right of the figure is a G2 interphase FISH analysis (the G2 phase of the nucleus was determined without an internal control probe). Note the three copies of SMS-REP (arrows in interphase nucleus) and SMS-REP-like sequences.
Figure 4
Figure 4
Sequence-based genomic structure of the SMS-REPs. There are four regions of sequence identity >95% between the proximal and the distal SMS-REPs (A, B, C, and D). The A (red), B (black), and C (yellow) sequence blocks have >98% identity between distal and proximal REPs; the D regions (green) show >95% identity. Blue represents the regions of homology between proximal and middle SMS-REPs. The proximal copy is the largest and is localized in the same orientations as the distal copy. The middle SMS-REP shows almost the same sequence and structure as the proximal copy except for two terminal deletions, an UPF3A gene interstitial deletion and a small (∼2 kb) insertional duplication. However, it is inverted with respect to proximal and distal SMS-REPs. SMS-REP-specific CLP, TRE, and SRP cis-morphisms (Table 1) were confirmed by DNA sequencing. Fourteen genes/pseudogenes were found and are summarized in Table 2. The two additional KER copies in distal SMS-REP represent repeated fragments of the KER pseudogenes, the accession numbers of which are given in Table 2. Crosshatched areas (NOS2A in the proximal and KER [M22927] in the distal) denote two genes spanning the high homology and nonhomology area between the distal and proximal, which suggest a three-step event for the hypothetical model of the evolution of the SMS-REPs (see text). At the bottom, the chromosome 17 distribution of fragments of SMS-REP, which constitutes a chromosome 17 low-copy repeat, LCR17, is shown. The above data were obtained through BLAST analysis of sequence database.
Figure 5
Figure 5
Schematic representation of low-copy repeats (LCRs; >10 kb) in proximal 17p, including SMS and CMT1A chromosome regions. Colored boxes represent positions of highly similar sequence of LCR structures. Note that the at least 410-kb repeat, LCR17pA, flanking the proximal CMT1A-REP has three partial copies: LCR17pB, proximally adjacent to the middle SMS-REP, and LCR17pC and LCR17pD (also described as PSFS; Stankiewicz et al. 2001) flanking the proximal SMS-REP.
Figure 6
Figure 6
FISH analyses for evolutionary studies. (A) Metaphase and interphase cells of chimpanzee, gorilla, orangutan, gibbon, baboon, and rhesus after hybridization with SMS-REP bacterial artificial chromosome (BAC) RP11–158M20. (B) The interphase nuclei of New World squirrel monkey after cohybridization of differentially labeled SMS-REP-specific BAC (RP11–158M20) and a P1 artificial chromosome clone that directly flanks SMS-REP (RP1–178F10). Note the single yellow foci, indicating the <100-kb physical vicinity of the clones. Similar results were obtained using five other clones directly flanking individual SMS-REPs, showing the presence of three copies of SMS-REPs.
Figure 6
Figure 6
FISH analyses for evolutionary studies. (A) Metaphase and interphase cells of chimpanzee, gorilla, orangutan, gibbon, baboon, and rhesus after hybridization with SMS-REP bacterial artificial chromosome (BAC) RP11–158M20. (B) The interphase nuclei of New World squirrel monkey after cohybridization of differentially labeled SMS-REP-specific BAC (RP11–158M20) and a P1 artificial chromosome clone that directly flanks SMS-REP (RP1–178F10). Note the single yellow foci, indicating the <100-kb physical vicinity of the clones. Similar results were obtained using five other clones directly flanking individual SMS-REPs, showing the presence of three copies of SMS-REPs.
Figure 7
Figure 7
Hypothetical model for evolution of SMS-REPs. Our data indicate that in the first step, a progenitor SMS-REP must have arisen in an ancient chromosome. Its structure was almost the same as the proximal SMS-REP at the present time, but included the B region flanking sequences on both sides similar to the distal SMS-REP. The distal SMS-REP resulted from the deletions of two large areas between the A and B, and C and D regions. Secondly, deletion of both flanking sequences of the B region in the progenitor resulted in the proximal SMS-REP. Finally, two terminal deletions and one interstial deletion involving the UPF3A gene accompanied by interchromosomal insertional duplication together with an inversion generated the middle SMS-REP.
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