The Value of Whole-Genome Sequencing for Mitochondrial DNA Population Studies: Strategies and Criteria for Extracting High-Quality Mitogenome Haplotypes

Int J Mol Sci. 2022 Feb 17;23(4):2244. doi: 10.3390/ijms23042244.


Whole-genome sequencing (WGS) data present a readily available resource for mitochondrial genome (mitogenome) haplotypes that can be utilized for genetics research including population studies. However, the reconstruction of the mitogenome is complicated by nuclear mitochondrial DNA (mtDNA) segments (NUMTs) that co-align with the mtDNA sequences and mimic authentic heteroplasmy. Two minimum variant detection thresholds, 5% and 10%, were assessed for the ability to produce authentic mitogenome haplotypes from a previously generated WGS dataset. Variants associated with NUMTs were detected in the mtDNA alignments for 91 of 917 (~8%) Swedish samples when the 5% frequency threshold was applied. The 413 observed NUMT variants were predominantly detected in two regions (nps 12,612-13,105 and 16,390-16,527), which were consistent with previously documented NUMTs. The number of NUMT variants was reduced by ~97% (400) using a 10% frequency threshold. Furthermore, the 5% frequency data were inconsistent with a platinum-quality mitogenome dataset with respect to observed heteroplasmy. These analyses illustrate that a 10% variant detection threshold may be necessary to ensure the generation of reliable mitogenome haplotypes from WGS data resources.

Keywords: NUMTs; heteroplasmy; massively parallel sequencing; mitochondrial DNA; next-generation sequencing; nuclear elements of mtDNA; whole-genome sequencing.

MeSH terms

  • Cell Nucleus / genetics
  • DNA, Mitochondrial / genetics*
  • Genome, Mitochondrial / genetics*
  • Haplotypes / genetics*
  • Humans
  • Mitochondria / genetics*
  • Whole Genome Sequencing / methods


  • DNA, Mitochondrial