Mitochondrial genomics in the cancer cell line encyclopedia and a scoring method to effectively pair cell lines for cytoplasmic hybridization

Abstract

Mitochondrial sequence variants have been associated with many human diseases, including cancer. A well-established experimental strategy to assess the impact of mitochondrial sequence variants is to generate cytoplasmic hybrids (cybrids). Cybridization facilitates the study of mitochondrial DNA (mtDNA) mutations under a controlled nuclear genetic background. However, in generating cybrids, it is important to select most suitable mtDNA donor and recipient cells so that any change in recipient's cellular phenotype may be attributed to the introduction, through the donor, of mutations in the gene of interest. Here we catalog mitochondrial sequence variants, gene expression, and haplogroups across 937 publicly available cancer cell lines curated by the Cancer Cell Line Encyclopedia (CCLE). We then present DoReMi (Donor, Recipient Mitochondrial DNA matching) as a method to score candidate donor and recipient cell lines based on their mtDNA mutational profiles, including their heteroplasmy levels. DoReMi will allow researchers to design successful cybrid experiments for querying the role of mutations in their mitochondrial-encoded gene of interest. Researchers may also apply DoReMi to study their own cell lines. DoReMi and the other resources provided by this study help optimize cybridization experiments. This software is available for use at http://mendel.gene.cwru.edu/laframboiselab/software.php.