4.7 Article

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

Journal

GENOME RESEARCH
Volume 12, Issue 5, Pages 729-738

Publisher

COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gr.82802

Keywords

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Funding

  1. NHGRI NIH HHS [U54 HG02045] Funding Source: Medline
  2. NICHD NIH HHS [P01 HD39420, P01 HD039420] Funding Source: Medline
  3. NINDS NIH HHS [R01 NS27042, R01 NS027042] Funding Source: Medline

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An similar to4-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 bacteria] artificial chromosome/Pl 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 (similar to256 kb) and the distal copy (similar to176 kb) are located in the same orientation and derived from a progenitor copy, whereas the middle SMS-REP (similar to241 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 similar to40-65 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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