Correction of Read Biases Induced by Complex Reference Genome Regions for Improving Copy Number Variation Detection Using a Gaussian Mixture Model

Copy number variations are crucial in cancer research, but their detection through next-generation sequencing is often hindered by read biases, particularly in complex genomic regions. Existing bias-correction methods address common issues like GC content but often fail in regions with repetitive sequences or segmental duplications, leading to false-positive CNVs. We propose refMask, a hybrid Gaussian model-based method that dynamically identifies low-confidence regions in the reference genome, correcting read biases and improving CNV detection accuracy. By integrating features from hg38 and T2T genomes, refMask tailors a custom blacklist for each sequencing sample, enhancing the reliability of CNV detection across diverse conditions. Our method provides a more accurate and flexible solution compared to current fixed blacklists, offering improved performance in challenging genomic regions.