Donor-specific assemblies enhance somatic structural variant detection in complex genomic regions.

Area of Science:

• Genomics
• Cancer Genomics
• Bioinformatics

Background:

• Somatic structural variants (sSVs) are crucial in genomic variation and disease.
• Detecting sSVs is challenging due to reference bias, mosaicism, and repetitive regions.
• Linear reference genomes (e.g., GRCh38, CHM13) have limitations in capturing individual genomic structures.

Purpose of the Study:

• To systematically assess the performance of donor-specific assemblies (DSAs) for sSV detection.
• To benchmark DSA utility against linear references using multiple sSV callers and long-read platforms.
• To evaluate sSV discovery in the COLO829 melanoma cell line using a matched DSA.

Main Methods:

• Compared sSV detection using GRCh38, CHM13, and the COLO829BL_DSA.
• Employed three sSV callers (Delly, Severus, Sniffles2) with long-read sequencing data.
• Benchmarked performance on the COLO829 melanoma cell line with a matched normal sample.

Main Results:

• The COLO829BL_DSA identified 1.8-fold more manually validated sSVs than linear references.
• DSAs detected sSVs in both shared and unique regions, including difficult-to-resolve repeat-rich areas.
• DSA-specific sSVs were found in genes, some associated with cancer.

Conclusions:

• Donor-specific assemblies significantly enhance sSV detection capabilities.
• DSAs are valuable tools for resolving complex structural variations, particularly in repetitive genomic regions.
• Utilizing DSAs improves the discovery of disease-associated sSVs.