Heteroplasmic mitochondrial DNA mutations in normal and tumour cells

With the help of massively parallel sequencing-by-synthesis of mitochondrial DNA (mtDNA) genomes, He et al. uncover widespread heterogeneity (heteroplasmy) in the mtDNA of normal human cells and homoplasmic and heteroplasmic mutations in cancer cells. The frequency of heteroplasmy is shown to vary among tissues of the same individual. Together, these findings provide new insights into the nature and variability of mtDNA sequences and have implications for cancer biomarker development and forensic analysis. Each human cell contains hundreds of copies of mitochondrial DNA (mtDNA), making it difficult to characterize mtDNA completely. Here, massively parallel sequencing-by-synthesis of mtDNA reveals widespread heterogeneity (heteroplasmy) in the mtDNA of normal human cells, and homoplasmic and heteroplasmic mutations in cancer cells. The findings provide new insight into the nature and variability of mtDNA sequences, with implications for forensic analysis and the development of biomarkers for cancer. The presence of hundreds of copies of mitochondrial DNA (mtDNA) in each human cell poses a challenge for the complete characterization of mtDNA genomes by conventional sequencing technologies1. Here we describe digital sequencing of mtDNA genomes with the use of massively parallel sequencing-by-synthesis approaches. Although the mtDNA of human cells is considered to be homogeneous, we found widespread heterogeneity (heteroplasmy) in the mtDNA of normal human cells. Moreover, the frequency of heteroplasmic variants varied considerably between different tissues in the same individual. In addition to the variants identified in normal tissues, cancer cells harboured further homoplasmic and heteroplasmic mutations that could also be detected in patient plasma. These studies provide insights into the nature and variability of mtDNA sequences and have implications for mitochondrial processes during embryogenesis, cancer biomarker development and forensic analysis. In particular, they demonstrate that individual humans are characterized by a complex mixture of related mitochondrial genotypes rather than a single genotype.