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Cell. 2019 Mar 7;176(6):1310-1324.e10. doi: 10.1016/j.cell.2019.01.045. Epub 2019 Feb 28.

Megabase Length Hypermutation Accompanies Human Structural Variation at 17p11.2.

Author information

1
Department of Molecular and Human Genetics, BCM, Houston, TX 77030, USA.
2
Human Genome Sequencing Center, BCM, Houston, TX 77030, USA.
3
Department of Genetics and the Informatics Institute, the University of Alabama at Birmingham, Birmingham, AL 35294, USA.
4
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
5
Department of Molecular and Human Genetics, BCM, Houston, TX 77030, USA; Human Genome Sequencing Center, BCM, Houston, TX 77030, USA.
6
Department of Molecular and Human Genetics, BCM, Houston, TX 77030, USA; Dan L. Duncan Comprehensive Cancer Center, BCM, Houston, TX 77030, USA. Electronic address: hastings@bcm.edu.
7
Department of Molecular and Human Genetics, BCM, Houston, TX 77030, USA; Human Genome Sequencing Center, BCM, Houston, TX 77030, USA; Department of Pediatrics, BCM, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA; Dan L. Duncan Comprehensive Cancer Center, BCM, Houston, TX 77030, USA. Electronic address: jlupski@bcm.edu.

Abstract

DNA rearrangements resulting in human genome structural variants (SVs) are caused by diverse mutational mechanisms. We used long- and short-read sequencing technologies to investigate end products of de novo chromosome 17p11.2 rearrangements and query the molecular mechanisms underlying both recurrent and non-recurrent events. Evidence for an increased rate of clustered single-nucleotide variant (SNV) mutation in cis with non-recurrent rearrangements was found. Indel and SNV formation are associated with both copy-number gains and losses of 17p11.2, occur up to ∼1 Mb away from the breakpoint junctions, and favor C > G transversion substitutions; results suggest that single-stranded DNA is formed during the genesis of the SV and provide compelling support for a microhomology-mediated break-induced replication (MMBIR) mechanism for SV formation. Our data show an additional mutational burden of MMBIR consisting of hypermutation confined to the locus and manifesting as SNVs and indels predominantly within genes.

KEYWORDS:

CNVs; DNA repair; complex rearrangements; genomic characterization; genomic disorders; long-read sequencing; phasing

PMID:
30827684
PMCID:
PMC6438178
[Available on 2020-03-07]
DOI:
10.1016/j.cell.2019.01.045

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