Human Molecular Genetics Advance Access published online on August 3, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm197
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Hominoid lineage specific amplification of low-copy repeats on 22q11.2 (LCR22s) associated with velo-cardio-facial/DiGeorge syndrome
1 Department of Molecular Genetics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461 2 Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030 3 Department of Pharmacology and Human Medical Genetics Program, University of Colorado Health Sciences Center, Campus Box 8303, Denver, CO 80217 4 Children's Hospital of Oakland Research Institute, 747 52nd Street, Oakland, CA 94609
* To whom correspondence should be addressed: Bernice E. Morrow, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY 10461, Phone: 1-718-430-4274, Fax: 1-718-430-8778, Email: morrow{at}aecom.yu.edi
Received April 6, 2007; Revised July 16, 2007; Accepted July 16, 2007
Segmental duplications or low copy repeats (LCRs) constitute 
5% of the sequenced portion of the human genome and are associated with many human congenital anomaly disorders. The low-copy repeats on chromosome 22q11.2 (LCR22s) mediate chromosomal rearrangements resulting in deletions, duplications, and translocations. The evolutionary mechanisms leading to LCR22 formation is unknown. Four genes, USP18, BCR, GGTLA and GGT, map adjacent to the LCR22s and pseudogene copies are located within them. It has been hypothesized that gene duplication occurred during primate evolution, followed by recombination events, forming pseudogene copies. We investigated whether gene duplication could be detected in non-human hominoid species. FISH mapping was performed using probes to the four functional gene loci. There was evidence for a single copy in humans but additional copies in hominoid species. We then compared LCR22 copy number using LCR22 FISH probes. Lineage specific LCR22 variation was detected in the hominoid species supporting the hypothesis. To independently validate initial findings, real time PCR, and screening of gorilla BAC library filters were performed. This was compared to array comparative genome hybridization data available. The most striking finding was a dramatic amplification of LCR22s in the gorilla. The LCR22s localized to the telomeric or subtelomeric bands of gorilla chromosomes. The most parsimonious explanation is that the LCR22s became amplified by inter-chromosomal recombination between telomeric bands. In summary, our results are consistent with a lineage specific coupling between gene and LCR22 duplication events. The LCR22s thus serve as an important model for evolution of genome variation.
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