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A catalog of homoplasmic and heteroplasmic mitochondrial DNA variants in humans

Alexandre Bolze, Fernando Mendez, Simon White, Francisco Tanudjaja, Magnus Isaksson, Ruomu Jiang, Andrew Dei Rossi, Elizabeth T. Cirulli, Misha Rashkin, William J. Metcalf, Joseph J. Grzymski, William Lee, James T. Lu, Nicole L. Washington
doi: https://doi.org/10.1101/798264
Alexandre Bolze
1Helix, San Mateo, California, USA
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  • For correspondence: alexandre.bolze@helix.com nicole.washington@helix.com
Fernando Mendez
1Helix, San Mateo, California, USA
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Simon White
1Helix, San Mateo, California, USA
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Francisco Tanudjaja
1Helix, San Mateo, California, USA
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Magnus Isaksson
1Helix, San Mateo, California, USA
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Ruomu Jiang
1Helix, San Mateo, California, USA
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Andrew Dei Rossi
1Helix, San Mateo, California, USA
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Elizabeth T. Cirulli
1Helix, San Mateo, California, USA
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Misha Rashkin
1Helix, San Mateo, California, USA
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William J. Metcalf
2Desert Research Institute, Reno, Nevada, USA
3Renown Institute of Health Innovation, Reno, Nevada, USA
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Joseph J. Grzymski
2Desert Research Institute, Reno, Nevada, USA
3Renown Institute of Health Innovation, Reno, Nevada, USA
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William Lee
1Helix, San Mateo, California, USA
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James T. Lu
1Helix, San Mateo, California, USA
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Nicole L. Washington
1Helix, San Mateo, California, USA
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  • For correspondence: alexandre.bolze@helix.com nicole.washington@helix.com
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Summary

High quality population allele frequencies of DNA variants can be used to discover new biology, and study rare disorders. Here, we created a public catalog of mitochondrial DNA variants based on a population of 195,983 individuals. We focused on 3 criteria: (i) the population is not enriched for mitochondrial disorders, or other clinical phenotypes, (ii) all genomes are sequenced and analyzed in the same clinical laboratory, and (iii) both homoplasmic and heteroplasmic variants are reported. We found that 47% of the mitochondrial genome was invariant in this population, including large stretches in the 2 rRNA genes. This information could be used to annotate the mitochondrial genome in future studies. We also showed how to use this resource for the interpretation of pathogenic variants for rare mitochondrial disorders. For example, 42% of variants previously reported to be pathogenic for Leber Hereditary Optic Neuropathy (LHON) should be reclassified.

Competing Interest Statement

AB, FM, SW, FJ, MI, RJ, ADR, EC, MR, WL, JL and NW are employees of Helix.

Footnotes

  • We added more stringent QC threshold for very low levels of contamination. These low levels of contamination were undetectable in the nuclear genome, but could have a small impact on heteroplasmic variants with low levels of heteroplasmy. This resulted in the removal of a couple hundreds samples and a few variants from the database. We provided an updated link to the database and have redone all of the analyses with the new samples and variants. We also added Figure 1 to better characterize the population. Figure 5 is also new.

  • https://s3.amazonaws.com/helix-research-public/mito/HelixMTdb_20200327.tsv

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license.
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Posted June 26, 2020.
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A catalog of homoplasmic and heteroplasmic mitochondrial DNA variants in humans
Alexandre Bolze, Fernando Mendez, Simon White, Francisco Tanudjaja, Magnus Isaksson, Ruomu Jiang, Andrew Dei Rossi, Elizabeth T. Cirulli, Misha Rashkin, William J. Metcalf, Joseph J. Grzymski, William Lee, James T. Lu, Nicole L. Washington
bioRxiv 798264; doi: https://doi.org/10.1101/798264
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A catalog of homoplasmic and heteroplasmic mitochondrial DNA variants in humans
Alexandre Bolze, Fernando Mendez, Simon White, Francisco Tanudjaja, Magnus Isaksson, Ruomu Jiang, Andrew Dei Rossi, Elizabeth T. Cirulli, Misha Rashkin, William J. Metcalf, Joseph J. Grzymski, William Lee, James T. Lu, Nicole L. Washington
bioRxiv 798264; doi: https://doi.org/10.1101/798264

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