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. 2017 Oct 16;18(Suppl 12):407.
doi: 10.1186/s12859-017-1821-7.

Detection and quantification of mitochondrial DNA deletions from next-generation sequence data

Colleen M Bosworth  1 , Sneha Grandhi  1 , Meetha P Gould  1 , Thomas LaFramboise  2
Affiliations

Detection and quantification of mitochondrial DNA deletions from next-generation sequence data

Colleen M Bosworth et al. BMC Bioinformatics. .

Abstract

Background: Chromosomal deletions represent an important class of human genetic variation. Various methods have been developed to mine "next-generation" sequencing (NGS) data to detect deletions and quantify their clonal abundances. These methods have focused almost exclusively on the nuclear genome, ignoring the mitochondrial chromosome (mtDNA). Detecting mtDNA deletions requires special care. First, the chromosome's relatively small size (16,569 bp) necessitates the ability to detect extremely focal events. Second, the chromosome can be present at thousands of copies in a single cell (in contrast to two copies of nuclear chromosomes), and mtDNA deletions may be present on only a very small percentage of chromosomes. Here we present a method, termed MitoDel, to detect mtDNA deletions from NGS data.

Results: We validate the method on simulated and real data, and show that MitoDel can detect novel and previously-reported mtDNA deletions. We establish that MitoDel can find deletions such as the "common deletion" at heteroplasmy levels well below 1%.

Conclusions: MitoDel is a tool for detecting large mitochondrial deletions at low heteroplasmy levels. The tool can be downloaded at http://mendel.gene.cwru.edu/laframboiselab/ .

Keywords: Chromosomal deletions; Human genome; Mitochondria DNA; Next-generation sequencing.

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Competing interests

The authors declare no competing interests.

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Figures

Fig. 1
Fig. 1
Depiction of a hypothetical mitochondrial genome deletion (top). The intact genome is shown at left with deleted segment indicated in green and a copy harboring the deletion at right. In the cell (bottom), both intact and deletion copies are present within the mitochondrial organelles, with per-cell abundance of the deletion at a low percentage
Fig. 2
Fig. 2
Standard mitochondrial reference genome numbering shown in interior of the circular genome, with the deleted segment, from base position s + 1 to base position e – 1, indicated in green, and the copy harboring the deletion shown at right. The position x i in a single hypothetical read i (black arc) shown in circle exterior. This read may be unaligned by BWA [17], but BLAT [20] will be able to align its two segments as a split read
Fig. 3
Fig. 3
An overview of MitoDel, from aligned sequence files to mtDNA deletion fusion point and abundance inferences. A sample output table from the software is shown at bottom, where each row is a putative deletion with read support, deleted segment coordinates, and indication of whether it passes quality filtering
Fig. 4
Fig. 4
False positive rates and sensitivity of MitoDel. Vertical axis (log scale) indicates the average number of deletions called with a least n reads supporting the deletion, where n is indicated on horizontal axis. Each experiment simulates one actual deletion, so average positives greater than 1.0 are false positives, while average positives less than one indicate specificity. Average positives exactly 1.0 indicate perfect sensitivity and specificity
Fig. 5
Fig. 5
BLAT output showing the split alignment of a read harboring a putative 27 bp deletion in 1000 Genomes individual HG02332
See this image and copyright information in PMC

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