DNA damage is a pervasive cause of sequencing errors, directly confounding variant identification

Area of Science:

• Genomics
• Molecular Biology
• Bioinformatics

Background:

• Somatic mutations in cells contribute to diverse pathologies, including cancer.
• Advances in DNA sequencing reveal cell-specific variants influencing various phenotypes.
• Accurate identification of somatic variants is crucial for understanding disease mechanisms.

Purpose of the Study:

• To investigate the impact of mutagenic damage on the accurate identification of low-frequency somatic variants.
• To determine the prevalence of mutagenic damage signatures in large-scale sequencing datasets.
• To assess how DNA damage confounds somatic variant detection.

Main Methods:

• Analysis of DNA sequencing data from public resources.
• Identification and characterization of mutagenic damage signatures.
• Quantification of sequencing errors attributed to DNA damage.
• Comparison of variant calls in damaged versus undamaged samples (implied).

Main Results:

• Mutagenic damage is the primary cause of erroneously identified low-to-moderate frequency variants (1-5%).
• Signatures of DNA damage were prevalent across major sequencing datasets, including the 1000 Genomes Project and The Cancer Genome Atlas.
• The extent of DNA damage significantly confounds the accurate determination of somatic variants.

Conclusions:

• DNA damage is a pervasive source of sequencing errors, not just in cancer but across various genomic studies.
• Relying solely on current sequencing data may lead to misinterpretation of somatic variant landscapes.
• Future genomic analyses must account for mutagenic damage to ensure variant accuracy and reliable biological conclusions.