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Recurrent horizontal transfer identifies mitochondrial positive selection in a transmissible cancer.

ABSTRACT: Autonomous replication and segregation of mitochondrial DNA (mtDNA) creates the potential for evolutionary conflict driven by emergence of haplotypes under positive selection for 'selfish' traits, such as replicative advantage. However, few cases of this phenomenon arising within natural populations have been described. Here, we survey the frequency of mtDNA horizontal transfer within the canine transmissible venereal tumour (CTVT), a contagious cancer clone that occasionally acquires mtDNA from its hosts. Remarkably, one canine mtDNA haplotype, A1d1a, has repeatedly and recently colonised CTVT cells, recurrently replacing incumbent CTVT haplotypes. An A1d1a control region polymorphism predicted to influence transcription is fixed in the products of an A1d1a recombination event and occurs somatically on other CTVT mtDNA backgrounds. We present a model whereby 'selfish' positive selection acting on a regulatory variant drives repeated fixation of A1d1a within CTVT cells.

SUBMITTER: Strakova A

PROVIDER: S-EPMC7297733 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Recurrent horizontal transfer identifies mitochondrial positive selection in a transmissible cancer.

Strakova Andrea A Nicholls Thomas J TJ Baez-Ortega Adrian A Ní Leathlobhair Máire M Sampson Alexander T AT Hughes Katherine K Bolton Isobelle A G IAG Gori Kevin K Wang Jinhong J Airikkala-Otter Ilona I Allen Janice L JL Allum Karen M KM Arnold Clara L CL Bansse-Issa Leontine L Bhutia Thinlay N TN Bisson Jocelyn L JL Blank Kelli K Briceño Cristóbal C Castillo Domracheva Artemio A Corrigan Anne M AM Cran Hugh R HR Crawford Jane T JT Cutter Stephen M SM Davis Eric E de Castro Karina F KF De Nardi Andrigo B AB de Vos Anna P AP Delgadillo Keenan Laura L Donelan Edward M EM Espinoza Huerta Adela R AR Faramade Ibikunle A IA Fazil Mohammed M Fotopoulou Eleni E Fruean Skye N SN Gallardo-Arrieta Fanny F Glebova Olga O Gouletsou Pagona G PG Häfelin Manrique Rodrigo F RF Henriques Joaquim J G P JJGP Horta Rodrigo S RS Ignatenko Natalia N Kane Yaghouba Y King Cathy C Koenig Debbie D Krupa Ada A Kruzeniski Steven J SJ Lanza-Perea Marta M Lazyan Mihran M Lopez Quintana Adriana M AM Losfelt Thibault T Marino Gabriele G Martínez Castañeda Simón S Martínez-López Mayra F MF Masuruli Bedan M BM Meyer Michael M Migneco Edward J EJ Nakanwagi Berna B Neal Karter B KB Neunzig Winifred W Nixon Sally J SJ Ortega-Pacheco Antonio A Pedraza-Ordoñez Francisco F Peleteiro Maria C MC Polak Katherine K Pye Ruth J RJ Ramirez-Ante Juan C JC Reece John F JF Rojas Gutierrez Jose J Sadia Haleema H Schmeling Sheila K SK Shamanova Olga O Sherlock Alan G AG Steenland-Smit Audrey E AE Svitich Alla A Tapia Martínez Lester J LJ Thoya Ngoka Ismail I Torres Cristian G CG Tudor Elizabeth M EM van der Wel Mirjam G MG Vițălaru Bogdan A BA Vural Sevil A SA Walkinton Oliver O Wehrle-Martinez Alvaro S AS Widdowson Sophie A E SAE Zvarich Irina I Chinnery Patrick F PF Falkenberg Maria M Gustafsson Claes M CM Murchison Elizabeth P EP

Nature communications 20200616 1

Autonomous replication and segregation of mitochondrial DNA (mtDNA) creates the potential for evolutionary conflict driven by emergence of haplotypes under positive selection for 'selfish' traits, such as replicative advantage. However, few cases of this phenomenon arising within natural populations have been described. Here, we survey the frequency of mtDNA horizontal transfer within the canine transmissible venereal tumour (CTVT), a contagious cancer clone that occasionally acquires mtDNA from ...[more]

PMID: 32546718

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Project description:BackgroundBreast cancer is, despite screening, not always detected early enough and is together with other tumor types known to shed genetic information in circulation. Unlike single-copy nuclear DNA, mitochondrial DNA (mtDNA) copies range from 100s to 10,000s per cell, thus providing a potentially alternative to identify potential missing cancer information in circulation at an early stage.MethodsTo characterize mitochondrial mutation landscapes in breast cancer, whole mtDNA sequencing and bioinformatics analyses were performed on 86 breast cancer biopsies and 50 available matched baseline cancer-free whole blood samples from the same individuals, selected from a cohort of middle-aged women in Sweden. To determine whether the mutations can be detected in blood plasma prior to cancer diagnosis, we further designed a nested case-control study (n = 663) and validated the shortlisted mutations using droplet digital PCR.ResultsWe detected different mutation landscapes between biopsies and matched whole blood samples. Compared to whole blood samples, mtDNA from biopsies had higher heteroplasmic mutations in the D-loop region (P = 0.02), RNR2 (P = 0.005), COX1 (P = 0.037) and CYTB (P = 0.006). Furthermore, the germline mtDNA mutations had higher heteroplasmy level than the lost (P = 0.002) and de novo mutations (P = 0.04). The nonsynonymous to synonymous substitution ratio (dN/dS) was higher for the heteroplasmic mutations (P = 7.25 × 10-12) than that for the homoplasmic mutations, but the de novo (P = 0.06) and lost mutations (P = 0.03) had lower dN/dS than the germline mutations. Interestingly, we found that the critical regions for mitochondrial transcription: MT-HSP1 (odds ratio [OR]: 21.41), MT-TFH (OR: 7.70) and MT-TAS2 (OR: 3.62), had significantly higher heteroplasmic mutations than the rest of the D-loop sub-regions. Finally, we found that the presence of mt.16093T > C mutation increases 67% risk of developing breast cancer.ConclusionsOur findings show that mitochondrial genetic landscape changes during cancer pathogenesis and positive selection of mtDNA heteroplasmic mutations in breast cancer. Most importantly, the mitochondrial mutations identified in biopsies can be traced back in matched plasma samples and could potentially be used as early breast cancer diagnostic biomarkers.

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Recurrent horizontal transfer identifies mitochondrial positive selection in a transmissible cancer.

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Recurrent horizontal transfer identifies mitochondrial positive selection in a transmissible cancer.

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