Interchromosomal core duplicons drive both evolutionary instability and disease susceptibility of the Chromosome 8p23.1 region

Kiana Mohajeri, Stuart Cantsilieris, John Huddleston, Bradley J. Nelson, Bradley P. Coe, Catarina D. Campbell, Carl Baker, Lana Harshman, Katherine M. Munson, Zev N. Kronenberg, Milinn Kremitzki, Archana Raja, Claudia Rita Catacchio, Tina A. Graves, Richard K. Wilson, Mario Ventura, Evan E. Eichler

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

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.

Original languageEnglish
Pages (from-to)1453-1467
Number of pages15
JournalGenome research
Volume26
Issue number11
DOIs
StatePublished - Nov 2016

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