Tandem Repeats and G-Rich Sequences Are Enriched at Human CNV Breakpoints

Promita Bose,Karen E Hermetz,Karen N Conneely,M Katharine Rudd,Brian P Chadwick

doi:10.1371/journal.pone.0101607

Abstract

Chromosome breakage in germline and somatic genomes gives rise to copy number variation (CNV) responsible for genomic disorders and tumorigenesis. DNA sequence is known to play an important role in breakage at chromosome fragile sites; however, the sequences susceptible to double-strand breaks (DSBs) underlying CNV formation are largely unknown. Here we analyze 140 germline CNV breakpoints from 116 individuals to identify DNA sequences enriched at breakpoint loci compared to 2800 simulated control regions. We find that, overall, CNV breakpoints are enriched in tandem repeats and sequences predicted to form G-quadruplexes. G-rich repeats are overrepresented at terminal deletion breakpoints, which may be important for the addition of a new telomere. Interstitial deletions and duplication breakpoints are enriched in Alu repeats that in some cases mediate non-allelic homologous recombination (NAHR) between the two sides of the rearrangement. CNV breakpoints are enriched in certain classes of repeats that may play a role in DNA secondary structure, DSB susceptibility and/or DNA replication errors.

Highlights

Genomic copy number variation (CNV) is a major cause intellectual disability, autism spectrum disorders, epilepsy, and psychiatric disorders
Our analysis of 140 CNV breakpoints revealed an enrichment in tandem repeats and G-quadruplexes
Tandem repeats have been described at other CNV breakpoints and are predicted to form a range of secondary structures [17,18,19]

Summary

Introduction

Genomic CNV is a major cause intellectual disability, autism spectrum disorders, epilepsy, and psychiatric disorders. Though most germline CNVs have different chromosome breakpoints [3,4,5,6], it is possible that breakpoint regions share common DNA features that make them susceptible to double-strand breaks (DSBs). This is true of chromosome rearrangements in leukemia that vary in location, but share repetitive DNA and/or DNAse hypersensitive sites at breakpoint cluster regions (BCRs) [7,8,9]. Though there is no single DNA sequence responsible for fragile sites in the human genome, in general fragile sites are made up of repetitive DNA that may form secondary structures

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