Mitochondrial Genomics

We contribute to advance our understanding of mitochondrial genomes and their role in human health and disease. Besides developing and providing tools for mtDNA analysis to the research community, we also investigate mtDNA changes on various levels in different disease/phenotypes.

Lead

Sebastian Schönherr, Dr.techn.
Professor of Computational Genomics

+43 512 9003 70579
sebastian.schoenherr@i-med.ac.at
Hansi Weissensteiner, Dr.techn.
Senior Scientist

+43 512 9003 70564
hansi.weissensteiner@i-med.ac.at

Co-Lead

Lukas Forer, PhD
Assistant Professor of Genome Informatics

+43 512 9003 70562
lukas.forer@i-med.ac.at
Florian Kronenberg, MD, MAE
Full Professor

+43 512 9003 70560
florian.kronenberg@i-med.ac.at

Team

Adriana Koller, MSc.
PhD Student

+43 512 9003 70582
adriana.koller@i-med.ac.at

About

We are working on a variety of projects related to mitochondrial genomes (mtDNA). We are developing software for the analysis of mitochondrial genomes, tools for quality control, perform benchmarking for second and third generation sequencing mtDNA variant calling tools and investigate abundance changes of mtDNA content in different cohorts. We further investigate the role of mtDNA variants in diseases, such as Prostate cancer or Parkinson’s disease. Additional we take advantage of the mitochondrial phylogeny to address questions of population genetics.

Software and Web-services for mtDNA analysis

Over the last decade, our group developed several tools for the analyisis of mtDNA data for different sequencing platforms. We implemented eCOMPAGT for the analysis of mtDNA data from Sanger-based Sequencing, followed by the web-service Haplogrep, which can be used for haplogroup classification for different types of mtDNA data, from sequenced data from NGS, long-read sequencing, to genotyped data from different platforms. In the subsequent years we improved Haplogrep 2, to manage additional file formats, improved the algorithm and changed the user interface in the latest Haplogrep 3 version, besides several new features like improved annotation of variants (see documentation for more: https://haplogrep.readthedocs.io/en/latest/). Subsequently we developed mtDNA-Server, which is an NGS variant caller specifically designed for mtDNA. Combining the variant caller used in the mtDNA-Server mutserve with haplogrep, we developed haplocheck, a tool for contamination detection in sequencing studies.

Weissensteiner H, Schönherr S, Specht G, Kronenberg F, Brandstätter A: eCOMPAGT integrates mtDNA: import, validation and export of mitochondrial DNA profiles for population genetics, tumour dynamics and genotype-phenotype association studies. BMC Bioinformatics 11:122, 2010. PMID: 20214782   Journal Article

Kloss-Brandstätter A, Pacher D, Schönherr S, Weissensteiner H, Binna R, Specht G, Kronenberg F: HaploGrep: a fast and reliable algorithm for automatic classification of mitochondrial DNA haplogroups. Hum. Mutat. 32:25-32, 2011. PMID: 20960467   Journal Article

Weissensteiner H, Pacher D, Kloss-Brandstätter A, Forer L, Specht G, Bandelt HJ, Kronenberg F, Salas A, Schönherr S: HaploGrep 2: mitochondrial haplogroup classification in the era of high-throughput sequencing. Nucleic Acids Res. 44:W58-63, 2016. PMID: 27084951   Journal Article

Schönherr S, Weissensteiner H, Kronenberg F, Forer L: Haplogrep 3 - an interactive haplogroup classification and analysis platform. Nucleic Acids Res. 51:W263-W268, 2023. PMID: 37070190   Journal Article

Weissensteiner H, Forer L, Fuchsberger C, Schöpf B, Kloss-Brandstätter A, Specht G, Kronenberg F, Schönherr S: mtDNA-Server: next-generation sequencing data analysis of human mitochondrial DNA in the cloud. Nucleic Acids Res. 44:W64-9, 2016. PMID: 27084948   Journal Article

Weissensteiner H, Forer L, Fendt L, Kheirkhah A, Salas A, Kronenberg F, Schoenherr S: Contamination detection in sequencing studies using the mitochondrial phylogeny. Genome Res. 31:309-316, 2021. PMID: 33452015   Journal Article

Benchmarking mtDNA analysis

As our group develops software for our own sequencing projects, we strongly rely on accurate validations for the newly developed tools. Over the last years we performed various comparisons for mtDNA variant calling, which helped improve our software. Thereby we assessed the accuracy of Illumina HiSeq and MiSeq, IonTorrent PGM and S5, as well as long-read sequencing from Oxford Nanopore by taking advantate of our tools and the mitochondrial phylogeny.

Kloss-Brandstätter A, Weissensteiner H, Erhart G, Schäfer G, Forer L, Schönherr S, Pacher D, Seifarth C, Stöckl A, Fendt L, Sottsas I, Klocker H, Huck CW, Rasse M, Kronenberg F, Kloss FR: Validation of next-generation sequencing of entire mitochondrial genomes and the diversity of mitochondrial DNA mutations in oral squamous cell carcinoma. PLoS One 10:e0135643, 2015. PMID: 26262956   Journal Article

Fazzini F, Fendt L, Schönherr S, Forer L, Schöpf B, Streiter G, Losso JL, Kloss-Brandstätter A, Kronenberg F, Weissensteiner H: Analyzing low-level mtDNA heteroplasmy-pitfalls and challenges from bench to benchmarking. Int. J. Mol. Sci. 22:935, 2021. PMID: 33477827   Journal Article

Cortes-Figueiredo F, Carvalho FS, Fonseca AC, Paul F, Ferro JM, Schönherr S, Weissensteiner H, Morais VA: From forensics to clinical research: Expanding the variant calling pipeline for the Precision ID mtDNA Whole Genome Panel. Int. J. Mol. Sci. 22:12031, 2021. PMID: 34769461   Journal Article

Lüth T, Schaake S, Grünewald A, May P, Trinh J, Weissensteiner H: Benchmarking low-frequency variant calling with long-read data on mitochondrial DNA. Front. Genet. 13:887644, 2022. PMID: 35664331   Journal Article

mtDNA copy number in diseases

Mitochondria, containing their own DNA, are multifunctional and essential to life. Estimating the number of mitochondria in a tissue based on their mtDNA molecules, can be applied as a biomarker for mitochondrial function. Thereby the mtDNA abundance can be affected by several factors, including age, gender, genetics as well as environmental factors (e.g. oxidative stress due to smoking, pollutants, nutrition, sleep duration…). After implementing and setting up a plasmid-normalized protocol for measuring the mtDNA copy number (mt-CN), our group investigated mt-CN in patients with diabetes and metabolic syndrome, in a large cohort of patients with chronic kidney disease and all-cause mortality in patients with peripheral arterial disease.

Fazzini F, Lamina C, Raftopoulou A, Koller A, Fuchsberger C, Pattaro C, Del Greco FM, Döttelmayer P, Fendt L, Fritz J, Meiselbach H, Schönherr S, Forer L, Weissensteiner H, Pramstaller PP, Eckardt KU, Hicks AA, Kronenberg F, GCKD Investigators: Association of mitochondrial DNA copy number with metabolic syndrome and type 2 diabetes in 14 176 individuals. J. Intern. Med. 290:190-202, 2021. PMID: 33453124   Journal Article

Fazzini F, Schöpf B, Blatzer M, Coassin S, Hicks AA, Kronenberg F, Fendt L: Plasmid-normalized quantification of relative mitochondrial DNA copy number. Sci. Rep. 8:15347, 2018. PMID: 30337569   Journal Article

Koller A, Fazzini F, Lamina C, Rantner B, Kollerits B, Stadler M, Klein-Weigel P, Fraedrich G, Kronenberg F: Mitochondrial DNA copy number is associated with all-cause mortality and cardiovascular events in patients with peripheral arterial disease. J. Intern. Med. 287:569-579, 2020. PMID: 32037598   Journal Article

mtDNA variants in diseases

Our group not only is interested in the number of mitochondria in different tissues, we are also interested in the genetic architecture of mitochondrial genomes, the evolution of somatic variants in form of heteroplasmy and its impact on various diseases. So far we investigated heteroplasmic variants in Oral Squamous Cell Carcinoma, Prostate Cancer as well as Parkinson’s disease:

Schöpf B, Weissensteiner H, Schäfer G, Fazzini F, Charoentong P, Naschberger A, Rupp B, Fendt L, Bukur V, Giese I, Sorn P, Sant’Anna-Silva AC, Iglesias-Gonzalez J, Sahin U, Kronenberg F, Gnaiger E, Klocker H: OXPHOS remodeling in high-grade prostate cancer involves mtDNA mutations and increased succinate oxidation. Nat. Commun. 11:1487, 2020. PMID: 32198407   Journal Article

Trinh J, Hicks AA, König IR, Delcambre S, Lüth T, Schaake S, Wasner K, Ghelfi J, Borsche M, Vilariño-Güell C, Hentati F, Germer EL, Bauer P, Takanashi M, Kostić V, Lang AE, Brüggemann N, Pramstaller PP, Pichler I, Rajput A, Hattori N, Farrer MJ, Lohmann K, Weissensteiner H, May P, Klein C, Grünewald A: Mitochondrial DNA heteroplasmy distinguishes disease manifestation in PINK1/PRKN-linked Parkinson’s disease. Brain 146:2753-2765, 2023. PMID: 36478228   Journal Article

Latzko L, Schöpf B, Weissensteiner H, Fazzini F, Fendt L, Steiner E, Bruckmoser E, Schäfer G, Moncayo RC, Klocker H, Laimer J: Implications of standardized uptake values of oral squamous cell carcinoma in PET-CT on prognosis, tumor characteristics and mitochondrial DNA heteroplasmy. Cancers (Basel) 13:2273, 2021. PMID: 34068489   Journal Article

Fendt L, Fazzini F, Weissensteiner H, Bruckmoser E, Schönherr S, Schäfer G, Losso JL, Streiter GA, Lamina C, Rasse M, Klocker H, Kofler B, Kloss-Brandstätter A, Huck CW, Kronenberg F, Laimer J: Profiling of mitochondrial DNA heteroplasmy in a prospective oral squamous cell carcinoma study. Cancers (Basel) 12:1933, 2020. PMID: 32708892   Journal Article

Kloss-Brandstätter A, Weissensteiner H, Erhart G, Schäfer G, Forer L, Schönherr S, Pacher D, Seifarth C, Stöckl A, Fendt L, Sottsas I, Klocker H, Huck CW, Rasse M, Kronenberg F, Kloss FR: Validation of next-generation sequencing of entire mitochondrial genomes and the diversity of mitochondrial DNA mutations in oral squamous cell carcinoma. PLoS One 10:e0135643, 2015. PMID: 26262956   Journal Article

mtDNA in population genetics

Mitochondria, being a uniparental marker, inherited exclusively along the maternal line, has several advantages which render it a helpful tool for studying human populations genetics. It has a higher mutation rate than nuclear DNA, is present in higher copies than nuclear DNA and can be further detected in ancient DNA samples, which helps tracking maternal lineages through time and space. With the help of our tools we could investigate the genetic diversity in Myanmar, Cambodia and Brazil from the maternal perspective.

Salas A, Schönherr S, Bandelt HJ, Gómez-Carballa A, Weissensteiner H: Extraordinary claims require extraordinary evidence in asserted mtDNA biparental inheritance. Forensic Sci. Int. Genet. 47:102274, 2020. PMID: 32330850   Commentary

Kehdy FS, Gouveia MH, Machado M, Magalhães WC, Horimoto AR, Horta BL, Moreira RG, Leal TP, Scliar MO, Soares-Souza GB, Rodrigues-Soares F, Araújo GS, Zamudio R, Sant Anna HP, Santos HC, Duarte NE, Fiaccone RL, Figueiredo CA, Silva TM, Costa GN, Beleza S, Berg DE, Cabrera L, Debortoli G, Duarte D, Ghirotto S, Gilman RH, Gonçalves VF, Marrero AR, Muniz YC, Weissensteiner H, Yeager M, Rodrigues LC, Barreto ML, Lima-Costa MF, Pereira AC, Rodrigues MR, Tarazona-Santos E, Brazilian EPIGEN Project Consortium: Origin and dynamics of admixture in Brazilians and its effect on the pattern of deleterious mutations. Proc. Natl. Acad. Sci. U. S. A. 112:8696-8701, 2015. PMID: 26124090   Journal Article

Summerer M, Horst J, Erhart G, Weißensteiner H, Schönherr S, Pacher D, Forer L, Horst D, Manhart A, Horst B, Sanguansermsri T, Kloss-Brandstätter A: Large-scale mitochondrial DNA analysis in Southeast Asia reveals evolutionary effects of cultural isolation in the multi-ethnic population of Myanmar. BMC Evol. Biol. 14:17, 2014. PMID: 24467713   Journal Article

Kloss-Brandstätter A, Summerer M, Horst D, Horst B, Streiter G, Raschenberger J, Kronenberg F, Sanguansermsri T, Horst J, Weissensteiner H: An in-depth analysis of the mitochondrial phylogenetic landscape of Cambodia. Sci. Rep. 11:10816, 2021. PMID: 34031453   Journal Article

Other GenEpi investigators involved

Earlier Team Members and Students