TRGT-denovo

TRGT-denovo identifies de novo tandem repeat mutations within family trios using PacBio HiFi sequencing data to improve precision and reduce false positives in mutation detection.

Key Features:

• Direct read evidence interrogation: TRGT-denovo directly interrogates read evidence rather than relying solely on variant call format (VCF) files, enabling detection of subtle variations often overlooked in standard genotype-based approaches.
• Comprehensive mutation type detection: The method identifies all types of de novo tandem repeat mutations, including expansions, contractions, and compositional changes.
• False positive reduction: TRGT-denovo reduces the number of de novo candidates by an order of magnitude compared to genotype-based approaches while maintaining high sensitivity for true discoveries.
• Experimental validation support: In experiments with eight rare disease trios, TRGT-denovo correctly reclassified all false positive de novo mutation candidates as true negatives, and 95% (19/20) of new candidates identified using an expanded repeat catalog were experimentally validated.

Scientific Applications:

• Rare disease research: TRGT-denovo enables accurate genome-wide identification of de novo tandem repeat mutations to understand genetic variability and its implications in rare diseases.
• Expanded repeat catalog analysis: The method supports identification of novel de novo mutation candidates from expanded tandem repeat catalogs with high experimental validation rates.

Methodology:

TRGT-denovo is built in Rust and directly interrogates PacBio HiFi sequencing read evidence to identify de novo tandem repeat mutations within family trios.