Shall genomic correlation structure be considered in copy number variants detection?

ABSTRACT

Copy number variation has been identified as a major source of genomic variation associated with disease susceptibility. With the advent of whole-exome sequencing (WES) technology, massive WES data have been generated, allowing for the identification of copy number variants (CNVs) in the protein-coding regions with direct functional interpretation. We have previously shown evidence of the genomic correlation structure in array data and developed a novel chromosomal breakpoint detection algorithm, LDcnv, which showed significantly improved detection power through integrating the correlation structure in a systematic modeling manner. However, it remains unexplored whether the genomic correlation exists in WES data and how such correlation structure integration can improve the CNV detection accuracy. In this study, we first explored the correlation structure of the WES data using the 1000 Genomes Project data. Both real raw read depth and median-normalized data showed strong evidence of the correlation structure. Motivated by this fact, we proposed a correlation-based method, CORRseq, as a novel release of the LDcnv algorithm in profiling WES data. The performance of CORRseq was evaluated in extensive simulation studies and real data analysis from the 1000 Genomes Project. CORRseq outperformed the existing methods in detecting medium and large CNVs. In conclusion, it would be more advantageous to model genomic correlation structure in detecting relatively long CNVs. This study provides great insights for methodology development of CNV detection with NGS data.