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.

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Acknowledgements

We thank M. Ventura, C. Campbell and H.C. Mefford for useful discussions and T. Brown for critical review of the manuscript. We also thank S. Diede, H. Tanaka, B. Brewer, C. Payen, L. Harshman and K. Penewit for experimental advice and support for the palindromic snapback assay. We are grateful to all of the families at the participating Simons Simplex Collection (SSC) sites, as well as the principal investigators (A. Beaudet, R. Bernier, J. Constantino, E. Cook, E. Fombonne, D. Geschwind, R. Goin-Kochel, E. Hanson, D. Grice, A. Klin, D. Ledbetter, C. Lord, C. Martin, D. Martin, R. Maxim, J. Miles, O. Ousley, K. Pelphrey, B. Peterson, J. Piggot, C. Saulnier, M. State, W. Stone, J. Sutcliffe, C. Walsh, Z. Warren and E. Wijsman). We appreciate obtaining access to phenotypic data on SFARI Base. This work was supported, in part, by US National Institutes of Health grants HG002385 and HG004120 to E.E.E. M.Y.D. is supported by the National Institute of Neurological Disorder and Stroke of the US National Institutes of Health (award K99NS083627). E.E.E. is an investigator of the Howard Hughes Medical Institute.

Author information

Author notes

    • Francesca Antonacci
    •  & Megan Y Dennis

    These authors contributed equally to this work.

Affiliations

  1. Dipartimento di Biologia, Università degli Studi di Bari Aldo Moro, Bari, Italy.

    • Francesca Antonacci
    •  & Mattia Miroballo
  2. Department of Genome Sciences, University of Washington, Seattle, Washington, USA.

    • Megan Y Dennis
    • , John Huddleston
    • , Peter H Sudmant
    • , Laura Vives
    • , Maika Malig
    • , Laura Denman
    • , Archana Raja
    • , Brenton Munson
    •  & Evan E Eichler
  3. Howard Hughes Medical Institute, University of Washington, Seattle, Washington, USA.

    • John Huddleston
    • , Laura Vives
    • , Archana Raja
    •  & Evan E Eichler
  4. Genome Institute at Washington University, Washington University School of Medicine, St. Louis, Missouri, USA.

    • Karyn Meltz Steinberg
    • , Tina A Graves
    •  & Richard K Wilson
  5. Signature Genomic Laboratories, LLC, Spokane, Washington, USA.

    • Jill A Rosenfeld
    •  & Lisa G Shaffer
  6. Benaroya Research Institute at Virginia Mason, Seattle, Washington, USA.

    • Andrew Stuart
    • , Joyce Tang
    •  & Chris T Amemiya
  7. Genetic Veterinary Sciences, Inc., Paw Print Genetics, Spokane, Washington, USA.

    • Lisa G Shaffer

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Contributions

F.A., M.Y.D. and E.E.E. designed the study. F.A. performed FISH experiments, library construction for Illumina sequencing, array CGH experiments and sequence analysis. M.Y.D. performed MIP experiments, library construction for Illumina sequencing, array CGH experiments and sequence analysis. J.H. performed SMRT sequence analysis and haplotype reconstruction. P.H.S. and K.M.S. performed sequencing data analysis. T.A.G. and R.K.W. performed capillary sequencing and analysis of CH17 and nonhuman primate BAC clones. L.V. and M. Malig performed FISH experiments. M. Miroballo performed array CGH experiments. B.M. performed library construction for SMRT sequencing. L.D. performed MIP experiments and library construction for SMRT sequencing. A.R. performed SMRT sequence analysis. C.T.A., A.S. and J.T. performed library construction for the VMRC53, VMRC54 and VMRC57 BACs. J.A.R. and L.G.S. contributed to 15q13.3 microdeletion data collection. F.A., M.Y.D. and E.E.E. contributed to data interpretation. F.A., M.Y.D. and E.E.E. wrote the manuscript.

Competing interests

E.E.E. is on the scientific advisory board (SAB) of DNAnexus, Inc., and was an SAB member of Pacific Biosciences, Inc. (2009–2013) and SynapDx Corp. (2011–2013). J.A.R. is an employee of Signature Genomic Laboratories, a subsidiary of PerkinElmer, Inc. L.G.S. was an employee of Signature Genomic Laboratories and is now an employee of Genetic Veterinary Sciences, Inc.

Corresponding author

Correspondence to Evan E Eichler.

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https://doi.org/10.1038/ng.3120

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