Hominoid lineage specific amplification of low-copy repeats on 22q11.2 (LCR22s) associated with velo-cardio-facial/digeorge syndrome

Melanie Babcock, Svetlana Yatsenko, Janet Hopkins, Matthew Brenton, Qing Cao, Pieter De Jong, Pawel Stankiewicz, James R. Lupski, James M. Sikela, Bernice E. Morrow

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2560-2571
Number of pages12
JournalHuman Molecular Genetics
Volume16
Issue number21
DOIs
StatePublished - Nov 1 2007

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Genomic Segmental Duplications
Gorilla gorilla
DiGeorge Syndrome
Gene Duplication
Pseudogenes
Genetic Recombination
Chromosomes
Congenital, Hereditary, and Neonatal Diseases and Abnormalities
Comparative Genomic Hybridization
Human Genome
Primates
Genes
Libraries
Real-Time Polymerase Chain Reaction
Genome

ASJC Scopus subject areas

  • Genetics

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Hominoid lineage specific amplification of low-copy repeats on 22q11.2 (LCR22s) associated with velo-cardio-facial/digeorge syndrome. / Babcock, Melanie; Yatsenko, Svetlana; Hopkins, Janet; Brenton, Matthew; Cao, Qing; De Jong, Pieter; Stankiewicz, Pawel; Lupski, James R.; Sikela, James M.; Morrow, Bernice E.

In: Human Molecular Genetics, Vol. 16, No. 21, 01.11.2007, p. 2560-2571.

Research output: Contribution to journalArticle

Babcock, M, Yatsenko, S, Hopkins, J, Brenton, M, Cao, Q, De Jong, P, Stankiewicz, P, Lupski, JR, Sikela, JM & Morrow, BE 2007, 'Hominoid lineage specific amplification of low-copy repeats on 22q11.2 (LCR22s) associated with velo-cardio-facial/digeorge syndrome', Human Molecular Genetics, vol. 16, no. 21, pp. 2560-2571. https://doi.org/10.1093/hmg/ddm197
Babcock, Melanie ; Yatsenko, Svetlana ; Hopkins, Janet ; Brenton, Matthew ; Cao, Qing ; De Jong, Pieter ; Stankiewicz, Pawel ; Lupski, James R. ; Sikela, James M. ; Morrow, Bernice E. / Hominoid lineage specific amplification of low-copy repeats on 22q11.2 (LCR22s) associated with velo-cardio-facial/digeorge syndrome. In: Human Molecular Genetics. 2007 ; Vol. 16, No. 21. pp. 2560-2571.
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AU - Hopkins, Janet

AU - Brenton, Matthew

AU - Cao, Qing

AU - De Jong, Pieter

AU - Stankiewicz, Pawel

AU - Lupski, James R.

AU - Sikela, James M.

AU - Morrow, Bernice E.

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AB - 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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