Interchromosomal core duplicons drive both evolutionary instability and disease susceptibility of the Chromosome 8p23.1 region
- Kiana Mohajeri1,5,
- Stuart Cantsilieris1,5,
- John Huddleston1,2,
- Bradley J. Nelson1,
- Bradley P. Coe1,
- Catarina D. Campbell1,
- Carl Baker1,
- Lana Harshman1,
- Katherine M. Munson1,
- Zev N. Kronenberg1,
- Milinn Kremitzki3,
- Archana Raja1,2,
- Claudia Rita Catacchio4,
- Tina A. Graves3,
- Richard K. Wilson3,
- Mario Ventura4 and
- Evan E. Eichler1,2
- 1Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA;
- 2Howard Hughes Medical Institute, University of Washington, Seattle, Washington 98195, USA;
- 3The McDonnell Genome Institute at Washington University, Washington University School of Medicine, St. Louis, Missouri 63108, USA;
- 4Dipartimento di Biologia, Università degli Studi di Bari Aldo Moro, Bari 70125, Italy
- Corresponding author: eee{at}gs.washington.edu
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↵5 These authors contributed equally to this work.
Abstract
Recurrent rearrangements of Chromosome 8p23.1 are associated with congenital heart defects and developmental delay. The complexity of this region has led to inconsistencies in the current reference assembly, confounding studies of genetic variation. Using comparative sequence-based approaches, we generated a high-quality 6.3-Mbp alternate reference assembly of an inverted Chromosome 8p23.1 haplotype. Comparison with nonhuman primates reveals a 746-kbp duplicative transposition and two separate inversion events that arose in the last million years of human evolution. The breakpoints associated with these rearrangements map to an ape-specific interchromosomal core duplicon that clusters at sites of evolutionary inversion (P = 7.8 × 10−5). Refinement of microdeletion breakpoints identifies a subgroup of patients that map to the same interchromosomal core involved in the evolutionary formation of the duplication blocks. Our results define a higher-order genomic instability element that has shaped the structure of specific chromosomes during primate evolution contributing to rearrangements associated with inversion and disease.
Footnotes
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.211284.116.
- Received June 11, 2016.
- Accepted September 12, 2016.
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