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Vol. 12, Issue 5, 729-738, May 2002

Structure and Evolution of the Smith-Magenis Syndrome Repeat Gene Clusters, SMS-REPs

Sung-Sup Park,1,5,6 Paweł Stankiewicz,1,5 Weimin Bi,1 Christine Shaw,1 Jessica Lehoczky,4 Ken Dewar,4 Bruce Birren,4 and James R. Lupski1,2,3,7

Departments of 1 Molecular and Human Genetics and 2 Pediatrics, Baylor College of Medicine, 3 Texas Children's Hospital, Houston, Texas, 77030, USA; 4 Whitehead Institute for Biomedical Research/MIT Center for Genome Research, Cambridge, Massachusetts 02141, USA

An ~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 artifical 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 (~256 kb) and the distal copy (~176 kb) are located in the same orientation and derived from a progenitor copy, whereas the middle SMS-REP (~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 ~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.

5 These authors contributed equally to this work.

6 Present address: Department of Clinical Pathology, Seoul National University Hospital, Seoul 110-744, South Korea.

7 Corresponding author.

12:729-738 ©2002 by Cold Spring Harbor Laboratory Press  ISSN 1088-9051/02 $5.00
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