Structure and evolution of the Smith-Magenis syndrome repeat gene clusters, SMS-REPs.
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.
Park
Sung-Sup
SS
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, 77030, USA.
Stankiewicz
Paweł
P
Bi
Weimin
W
Shaw
Christine
C
Lehoczky
Jessica
J
Dewar
Ken
K
Birren
Bruce
B
Lupski
James R
JR
D000015:Abnormalities, Multiple / Q000235:genetics*; D001482:Base Composition / Q000235:genetics; D002460:Cell Line; D002461:Cell Line, Transformed; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D003001:Cloning, Molecular / Q000379:methods; D020451:Contig Mapping / Q000379:methods; D016172:DNA Fingerprinting / Q000379:methods; D019143:Evolution, Molecular; D018628:Gene Dosage; D020440:Gene Duplication; D015894:Genome, Human; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D005810:Multigene Family / Q000235:genetics*; D012091:Repetitive Sequences, Nucleic Acid / Q000235:genetics*; D016415:Sequence Alignment / Q000379:methods; D017422:Sequence Analysis, DNA / Q000379:methods; D012689:Sequence Homology, Nucleic Acid; D013577:Syndrome