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Nat Genet. 2014 Dec;46(12):1293-302. doi: 10.1038/ng.3120. Epub 2014 Oct 19.

Palindromic GOLGA8 core duplicons promote chromosome 15q13.3 microdeletion and evolutionary instability.

Author information

1
Dipartimento di Biologia, Università degli Studi di Bari Aldo Moro, Bari, Italy.
2
Department of Genome Sciences, University of Washington, Seattle, Washington, USA.
3
1] Department of Genome Sciences, University of Washington, Seattle, Washington, USA. [2] Howard Hughes Medical Institute, University of Washington, Seattle, Washington, USA.
4
Genome Institute at Washington University, Washington University School of Medicine, St. Louis, Missouri, USA.
5
Signature Genomic Laboratories, LLC, Spokane, Washington, USA.
6
Benaroya Research Institute at Virginia Mason, Seattle, Washington, USA.
7
1] Signature Genomic Laboratories, LLC, Spokane, Washington, USA. [2] Genetic Veterinary Sciences, Inc., Paw Print Genetics, Spokane, Washington, USA.

Abstract

Recurrent deletions of chromosome 15q13.3 associate with intellectual disability, schizophrenia, autism and epilepsy. To gain insight into the instability of this region, we sequenced it in affected individuals, normal individuals and nonhuman primates. We discovered five structural configurations of the human chromosome 15q13.3 region ranging in size from 2 to 3 Mb. These configurations arose recently (∼0.5-0.9 million years ago) as a result of human-specific expansions of segmental duplications and two independent inversion events. All inversion breakpoints map near GOLGA8 core duplicons-a ∼14-kb primate-specific chromosome 15 repeat that became organized into larger palindromic structures. GOLGA8-flanked palindromes also demarcate the breakpoints of recurrent 15q13.3 microdeletions, the expansion of chromosome 15 segmental duplications in the human lineage and independent structural changes in apes. The significant clustering (P = 0.002) of breakpoints provides mechanistic evidence for the role of this core duplicon and its palindromic architecture in promoting the evolutionary and disease-related instability of chromosome 15.

PMID:
25326701
PMCID:
PMC4244265
DOI:
10.1038/ng.3120
[Indexed for MEDLINE]
Free PMC Article

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