MitoScope: a comprehensive mitochondrial genome analysis workflow for long-read sequencing data

Abstract

The mitochondrial genome (mtDNA), rich in repeats and prone to nuclear mitochondrial DNA segments (NUMTs), is implicated in cancer, metabolic syndromes, and neurodegeneration, yet short-read sequencing yields incomplete catalogs, mapping artifacts, and false heteroplasmies. We introduce MitoScope, a scalable end-to-end long-read mitochondrial analysis workflow that integrates mtDNA-read selection, heteroplasmic variant detection, assembly, copy number estimation, read-level haplotyping, and NUMT profiling. Applied to benchmarking data from the Somatic Mosaicism Across Human Tissues (SMaHT) Network, we reveal high sensitivity and precision compared to existing methods and successfully uncover known mitochondrial biology relevant for variant interpretation, aging, and human disease.