Mitochondrial DNA variation across 56,434 individuals in gnomAD
- Kristen M Laricchia1,
- Nicole J Lake2,
- Nicholas A Watts1,
- Megan Shand3,
- Andrea Haessly3,
- Laura Gauthier3,
- David Benjamin3,
- Eric Banks3,
- Jose Soto3,
- Kiran Garimella3,
- James Emery3,
- Genome Aggregation Database Consortium4,
- Heidi L Rehm1,
- Daniel G MacArthur5,
- Grace Tiao1,
- Monkol V Lek2,
- Vamsi K Mootha6 and
- Sarah E Calvo1,7
Abstract
Genomic databases of allele frequency are extremely helpful for evaluating clinical variants of unknown significance; however, until now, databases such as the Genome Aggregation Database (gnomAD) have focused on nuclear DNA and have ignored the mitochondrial genome (mtDNA). Here we present a pipeline to call mtDNA variants that addresses three technical challenges: (i) detecting homoplasmic and heteroplasmic variants, present respectively in all or a fraction of mtDNA molecules, (ii) circular mtDNA genome, and (iii) misalignment of nuclear sequences of mitochondrial origin (NUMTs). We observed that mtDNA copy number per cell varied across gnomAD cohorts and influenced the fraction of NUMT-derived false-positive variant calls, which can account for the majority of putative heteroplasmies. To avoid false positives, we excluded contaminated samples, cell lines, and samples prone to NUMT misalignment due to few mtDNA copies. Furthermore, we report variants with heteroplasmy greater than 10%. We applied this pipeline to 56,434 whole genome sequences in the gnomAD v3.1 database that includes individuals of European (58%), African (25%), Latino (10%), and Asian (5%) ancestry. Our gnomAD v3.1 release contains population frequencies for 10,850 unique mtDNA variants at more than half of all mtDNA bases. We report frequencies within each nuclear ancestral population and mitochondrial haplogroup. Homoplasmic variants account for most variant calls (98%) and unique variants (85%). We observed that 1/250 individuals carry a pathogenic mtDNA variant with heteroplasmy above 10%. These mtDNA population allele frequencies are freely accessible and will aid in diagnostic interpretation and research studies.
- Received July 23, 2021.
- Accepted January 19, 2022.
- Published by Cold Spring Harbor Laboratory Press
This manuscript is Open Access.
This article, published in Genome Research, is available under a Creative Commons License (Attribution-NonCommercial 4.0 International license), as described at http://creativecommons.org/licenses/by-nc/4.0/.
