Introduction
Mitochondrial DNA (mtDNA) is a small, circular chromosome found in the mitochondria of cells. Unlike nuclear DNA, which is inherited from both parents, mtDNA is inherited solely from the mother. Mitochondrial variant calling refers to the process of identifying genetic variations within the mitochondrial genome. These variations can play a critical role in understanding mitochondrial diseases, population genetics, and other cellular processes.
Mitochondrial heteroplasmy is when an individual has more than one mitochondrial sequence, so that certain variants are only present in a subset of the individual's mitochondria. Such heterogeneity in the mitochondrial DNA present in an individual, means that variants found in only some of the individual's mitochondria are very hard to detect by sequencing as fewer reads will have these variants, leading to variants with a very low allelic balance (the proportion of variant alleles at a given position).
It's important to note that, because mitochondria exist in many copies per cell, detecting low-frequency heteroplasmic variants requires high sequencing depth. If sequencing depth is insufficient, variants present in only a small fraction of mtDNA molecules may be missed.
Does VarSome Clinical call mitochondrial variants?
Yes, all of our pipelines are capable of calling variants in the mitochondrial genome if mtDNA has been sequenced and the target region includes the mitochondrial chromosome. Additionally, the single-sample germline pipeline has been specially adapted to call mitochondrial variants at low allelic balance levels, ensuring more accurate detection of heteroplasmic variants. This pipeline modification is available on-demand. If you wish to turn it on for your group, let us know by contacting us at support@varsome.com.
How to set the filter for mitochondrial variants
VarSome Clinical does not automatically classify mitochondrial variants as "homoplasmic" or "heteroplasmic." Instead, all detected mitochondrial variants are displayed along with their corresponding allelic balance, which reflects the proportion of mutant to normal mitochondrial DNA at each position.
As a user, you can easily customize your own filter based on the allelic balance to target specific heteroplasmy levels. This allows you to retain mitochondrial variants that match your analysis criteria, such as detecting variants at specific thresholds of heteroplasmy.
For instance, if you wish to retain mitochondrial variants with an allelic balance equal to or lower than 0.8, you could use the following filter.
