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Inverted Low-Copy Repeats and Genome Instability—A Genome-Wide Analysis

Authors

  • Piotr Dittwald,

    1. Institute of Informatics, University of Warsaw, Warsaw, Poland
    2. College of Inter-Faculty Individual Studies in Mathematics and Natural Sciences, University of Warsaw, Warsaw, Poland
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    • Contributed equally to this work and should be considered as co-first authors.

  • Tomasz Gambin,

    Corresponding author
    1. Institute of Computer Science, Warsaw University of Technology, Warsaw, Poland
    • College of Inter-Faculty Individual Studies in Mathematics and Natural Sciences, University of Warsaw, Warsaw, Poland
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    • Contributed equally to this work and should be considered as co-first authors.

  • Claudia Gonzaga-Jauregui,

    1. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas
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    • Contributed equally to this work and should be considered as co-first authors.

  • Claudia M.B. Carvalho,

    1. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas
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  • James R. Lupski,

    1. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas
    2. Pediatrics, Baylor College of Medicine, Houston, Texas
    3. Texas Children's Hospital, Houston, Texas
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  • Paweł Stankiewicz,

    Corresponding author
    1. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas
    • Institute of Informatics, University of Warsaw, Warsaw, Poland
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  • Anna Gambin

    1. Institute of Informatics, University of Warsaw, Warsaw, Poland
    2. Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland
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  • Communicated by David N. Cooper

  • Contract grant sponsors: Polish National Science Center (2011/01/B/NZ2/00864 to A.G. and P.D.); EU through the European Social Fund (UDA-POKL.04.01.01–00-072/09–00 to P.D.); the Polish Ministry of Science and Higher Education (R13–0005-04/2008 to P.S.); and the National Institute of Neurological Disorders and Stroke (R01 NS058529 to J.R.L.).

Correspondence to: Paweł Stankiewicz, Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Room R809, Houston, TX 77030, USA. E-mail: pawels@bcm.edu or Tomasz Gambin, Institute of Computer Science, Warsaw University of Technology, ul. Nowowiejska 15/19, Room 304, 00-665 Warsaw, Poland. Email: tgambin@ii.pw.edu.pl

ABSTRACT

Inverse paralogous low-copy repeats (IP-LCRs) can cause genome instability by nonallelic homologous recombination (NAHR)-mediated balanced inversions. When disrupting a dosage-sensitive gene(s), balanced inversions can lead to abnormal phenotypes. We delineated the genome-wide distribution of IP-LCRs >1 kB in size with >95% sequence identity and mapped the genes, potentially intersected by an inversion, that overlap at least one of the IP-LCRs. Remarkably, our results show that 12.0% of the human genome is potentially susceptible to such inversions and 942 genes, 99 of which are on the X chromosome, are predicted to be disrupted secondary to such an inversion! In addition, IP-LCRs larger than 800 bp with at least 98% sequence identity (duplication/triplication facilitating IP-LCRs, DTIP-LCRs) were recently implicated in the formation of complex genomic rearrangements with a duplication-inverted triplication–duplication (DUP-TRP/INV-DUP) structure by a replication-based mechanism involving a template switch between such inverted repeats. We identified 1,551 DTIP-LCRs that could facilitate DUP-TRP/INV-DUP formation. Remarkably, 1,445 disease-associated genes are at risk of undergoing copy-number gain as they map to genomic intervals susceptible to the formation of DUP-TRP/INV-DUP complex rearrangements. We implicate inverted LCRs as a human genome architectural feature that could potentially be responsible for genomic instability associated with many human disease traits.

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