title: Mitochondrial heteroplasmy in vertebrates using ChIP-sequencing data.
abstract: Mitochondrial heteroplasmy, the presence of more than one mitochondrial DNA (mtDNA) variant in a cell or individual, is not as uncommon as previously thought. It is mostly due to the high mutation rate of the mtDNA and limited repair mechanisms present in the mitochondrion. Motivated by mitochondrial diseases, much focus has been placed into studying this phenomenon in human samples and in medical contexts. To place these results in an evolutionary context and to explore general principles of heteroplasmy, we describe an integrated cross-species evaluation of heteroplasmy in mammals that exploits previously reported NGS data. Focusing on ChIP-seq experiments, we developed a novel approach to detect heteroplasmy from the concomitant mitochondrial DNA fraction sequenced in these experiments.
  
  
  
  We first demonstrate that the sequencing coverage of mtDNA in ChIP-seq experiments is sufficient for heteroplasmy detection. We then describe a novel detection method for accurate detection of heteroplasmies, which also accounts for the error rate of NGS technology. Applying this method to 79 individuals from 16 species resulted in 107 heteroplasmic positions present in a total of 45 individuals. Further analysis revealed that the majority of detected heteroplasmies occur in intergenic regions.
  
  
  
  In addition to documenting the prevalence of mtDNA in ChIP-seq data, the results of our mitochondrial heteroplasmy detection method suggest that mitochondrial heteroplasmies identified across vertebrates share similar characteristics as found for human heteroplasmies. Although largely consistent with previous studies in individual vertebrates, our integrated cross-species analysis provides valuable insights into the evolutionary dynamics of mitochondrial heteroplasmy.
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SD, UK.
authors.forename: Thomas
authors.initials: T
authors.lastname: Rensch
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Robinson Way, Cambridge, CB2 0RE, UK.
authors.forename: Diego
authors.initials: D
authors.lastname: Villar
authors.affiliation: Biological and Biomedical Sciences, North Carolina Central University, Durham, NC, 27707, USA.|North Carolina Museum of Natural Sciences, Raleigh, NC, 27601, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Horvath
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Robinson Way, Cambridge, CB2 0RE, UK.|Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SA, UK.
authors.forename: Duncan T
authors.initials: DT
authors.lastname: Odom
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SD, UK. flicek@ebi.ac.uk.|Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SA, UK. flicek@ebi.ac.uk.
authors.forename: Paul
authors.initials: P
authors.lastname: Flicek
mesh_terms: D000818:Animals; D047369:Chromatin Immunoprecipitation; D004272:DNA, Mitochondrial / Q000235:genetics*; D019143:Evolution, Molecular; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008928:Mitochondria / Q000235:genetics* / Q000473:pathology; D028361:Mitochondrial Diseases / Q000235:genetics* / Q000473:pathology; D017422:Sequence Analysis, DNA; D014714:Vertebrates / Q000235:genetics
chemical_list: D004272:DNA, Mitochondrial
keywords: Chromatin immunoprecipitation sequencing (ChIP-seq); Heteroplasmy; Mitochondrion; Vertebrates; mitochondrial DNA (mtDNA)