Research Papers:

Analysis of the 9p21.3 sequence associated with coronary artery disease reveals a tendency for duplication in a CAD patient

Natalay Kouprina _, Mikhail Liskovykh, Nicholas C.O. Lee, Vladimir N. Noskov, Joshua J. Waterfall, Robert L. Walker, Paul S. Meltzer, Eric J. Topol and Vladimir Larionov

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Oncotarget. 2018; 9:15275-15291. https://doi.org/10.18632/oncotarget.24567

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Natalay Kouprina1, Mikhail Liskovykh1,*, Nicholas C.O. Lee1,*, Vladimir N. Noskov1, Joshua J. Waterfall2, Robert L. Walker2, Paul S. Meltzer2, Eric J. Topol3 and Vladimir Larionov1

1Developmental Therapeutics Branch, National Cancer Institute, Bethesda, MD 20892, USA

2Genetics Branch, National Cancer Institute, Bethesda, MD 20892, USA

3The Scripps Translational Science Institute, The Scripps Research Institute and Scripps Health, La Jolla, CA 92037, USA

*These authors have contributed equally to this work

Correspondence to:

Natalay Kouprina, email: kouprinn@mail.nih.gov

Keywords: TAR-cloning; segmental duplication; genome alterations; 9p21; CAD interval

Received: November 29, 2017     Accepted: February 10, 2018     Epub: February 26, 2018     Published: March 16, 2018


Tandem segmental duplications (SDs) greater than 10 kb are widespread in complex genomes. They provide material for gene divergence and evolutionary adaptation, while formation of specific de novo SDs is a hallmark of cancer and some human diseases. Most SDs map to distinct genomic regions termed ‘duplication blocks’. SDs organization within these blocks is often poorly characterized as they are mosaics of ancestral duplicons juxtaposed with younger duplicons arising from more recent duplication events. Structural and functional analysis of SDs is further hampered as long repetitive DNA structures are underrepresented in existing BAC and YAC libraries. We applied Transformation-Associated Recombination (TAR) cloning, a versatile technique for large DNA manipulation, to selectively isolate the coronary artery disease (CAD) interval sequence within the 9p21.3 chromosome locus from a patient with coronary artery disease and normal individuals. Four tandem head-to-tail duplicons, each ~50 kb long, were recovered in the patient but not in normal individuals. Sequence analysis revealed that the repeats varied by 10-15 SNPs between each other and by 82 SNPs between the human genome sequence (version hg19). SNPs polymorphism within the junctions between repeats allowed two junction types to be distinguished, Type 1 and Type 2, which were found at a 2:1 ratio. The junction sequences contained an Alu element, a sequence previously shown to play a role in duplication. Knowledge of structural variation in the CAD interval from more patients could help link this locus to cardiovascular diseases susceptibility, and maybe relevant to other cases of regional amplification, including cancer.

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