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

  1. Sung-Sup Park1,5,6,
  2. Paweł Stankiewicz1,5,
  3. Weimin Bi1,
  4. Christine Shaw1,
  5. Jessica Lehoczky4,
  6. Ken Dewar4,
  7. Bruce Birren4, and
  8. James R. Lupski1,2,3,7
  1. Departments of 1Molecular and Human Genetics and 2Pediatrics, Baylor College of Medicine, 3Texas Children's Hospital, Houston, Texas, 77030, USA; 4Whitehead Institute for Biomedical Research/MIT Center for Genome Research, Cambridge, Massachusetts 02141, USA

Abstract

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.

Footnotes

  • 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.

  • E-MAIL jlupski{at}bcm.tmc.edu; FAX (713) 798-5073.

  • Article and publication are at http://www.genome.org/cgi/doi/10.1101/gr.82802.

    • Received December 18, 2001.
    • Accepted March 15, 2002.
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