TY  - JOUR
A1  - Laricchia, Kristen M.
A1  - Lake, Nicole J.
A1  - Watts, Nicholas A.
A1  - Shand, Megan
A1  - Haessly, Andrea
A1  - Gauthier, Laura
A1  - Benjamin, David
A1  - Banks, Eric
A1  - Soto, Jose
A1  - Garimella, Kiran
A1  - Emery, James
A1  - Genome Aggregation Database Consortium
A1  - Rehm, Heidi L.
A1  - MacArthur, Daniel G.
A1  - Tiao, Grace
A1  - Lek, Monkol
A1  - Mootha, Vamsi K.
A1  - Calvo, Sarah E.
T1  - Mitochondrial DNA variation across 56,434 individuals in gnomAD
Y1  - 2022/03/01 
JF  - Genome Research 
JO  - Genome Research 
SP  - 569 
EP  - 582 
DO  - 10.1101/gr.276013.121 
VL  - 32 
IS  - 3 
UR  - http://genome.cshlp.org/content/32/3/569.abstract 
N2  - 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: (1) detecting homoplasmic and heteroplasmic variants, present, respectively, in all or a fraction of mtDNA molecules; (2) circular mtDNA genome; and (3) 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 ≥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. Importantly, 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. 
ER  -