Multiresolution correction of GC bias and application to identification of copy number alterations

Whole-genome sequencing (WGS) data are affected by various sequencing biases such as GC bias and mappability bias. These biases degrade performance on detection of genetic variations such as copy number alterations. The existing methods use a relation between the GC proportion and depth of coverage (DOC) of markers by means of regression models. Nonetheless, severity of the GC bias varies from sample to sample. We developed a new method for correction of GC bias on the basis of multiresolution analysis. We used a translation-invariant wavelet transform to decompose biased raw signals into high- and low-frequency coefficients. Then, we modeled the relation between GC proportion and DOC of the genomic regions and constructed new control DOC signals that reflect the GC bias. The control DOC signals are used for normalizing genomic sequences by correcting the GC bias.

When we applied our method to simulated sequencing data with various degrees of GC bias, our method showed more robust performance on correcting the GC bias than the other methods did. We also applied our method to real-world cancer sequencing datasets and successfully identified cancer-related focal alterations even when cancer genomes were not normalized to normal control samples. In conclusion, our method can be employed for WGS data with different degrees of GC bias.

The code is available at http://gcancer.org/wabico.

Supplementary data are available at Bioinformatics online.