Recurrent horizontal transfer identifies mitochondrial positive selection in a transmissible cancer

Andrea Strakova ,Katherine Polak ,Mohammed Fazil ,Sophie Ae Widdowson ,Alan G Sherlock ,Janice L Allen ,Jocelyn Bisson ,Artemio Castillo Domracheva ,Cathy King ,Eleni Fotopoulou ,Joaquim Henriques ,Mayra F Martínez-López ,Mirjam G Van Der Wel ,Edward J Migneco ,R.s Horta ,Leontine Bansse-Issa ,Francisco Pedraza-Ordóñez ,Bedan M Masuruli ,Stephen M Cutter ,Juan C Ramírez-Ante ,Maria C Peleteiro ,Adriana M Lopez Quintana ,Marta Lanza-Perea ,Jinhong Wang ,Jane T Crawford ,Ada Krupa ,Alex Sampson ,Hugh R Cran ,Maria Falkenberg ,John F Reece ,Antonio Ortega‐Pacheco ,Cristóbal Briceño ,Thibault Losfelt ,Anne M Corrigan ,Adela R Espinoza Huerta ,Fanny Gallardo-Arrieta ,Olga Shamanova ,Irina Zvarich ,Alla Svitich ,Kevin Gori ,Claes M Gustafsson ,Kelli Blank ,Andrigo B De Nardi ,Steven J Kruzeniski ,Winifred Neunzig ,Michael J Meyer ,Yaghouba Kane ,Olga Glebova ,Karter B Neal ,Isobelle A G Bolton ,Thinlay N Bhutia ,Gabriele Marino ,Sally J Nixon ,Haleema Sadia ,Mihran Lazyan ,Patrick F Chinnery ,Karen M Allum ,Thomas J Nicholls ,Rodrigo F Häfelin Manrique ,Cristian G Torres ,P.g Gouletsou ,Berna Nakanwagi ,Bogdan Alexandru Vițălaru ,Anna P De Vos ,Simón Martínez Castañeda ,Adrian Baez‐Ortega ,Jose Rojas Gutierrez ,Ibikunle A Faramade ,Oliver Walkinton ,Debbie Koenig ,Ismail Thoya Ngoka ,Natalia A Ignatenko ,Máire Ní Leathlobhair ,Katherine Hughes ,Laura Keenan ,Alvaro Wehrle-Martinez ,Elizabeth Tudor ,Sheila K Schmeling ,Ruth J Pye ,Sevil Atalay Vural ,Eric S Davis ,Audrey E Steenland-Smit ,Skye N Fruean ,Karina Ferreira De Castro ,Clara L Arnold ,Edward M Donelan ,Lester J Tapia Martínez ,Ilona Airikkala-Otter ,Elizabeth P Murchison

doi:10.1038/s41467-020-16765-w

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.

Highlights

Autonomous replication and segregation of mitochondrial DNA creates the potential for evolutionary conflict driven by emergence of haplotypes under positive selection for ‘selfish’ traits, such as replicative advantage
A survey of canine transmissible venereal tumour (CTVT) mitochondrial DNA (mtDNA) diversity revealed that a single canine mtDNA haplotype, A1d1a, has repeatedly and recently colonised CTVT cells via horizontal transfer
We cannot rule out the possibilities that A1d1a has an increased propensity for horizontal transfer, or that it offers an adaptive advantage to CTVT cells, our data most strongly support a model whereby A1d1a replaces other mtDNA haplotypes via selfish selection

Summary

Introduction

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. Selection acts on genetic variation arising in mtDNA at two levels It can act on cellular or organismal phenotypes produced by altered mitochondrial function (adaptive selection), and, second, it can drive changes in the frequency of haplotypes with altered replicative or segregation potential (selfish selection)[1]. We identify repeated recent capture of a single canine mtDNA haplotype, A1d1a, by CTVT This haplotype likely confers a selfish selective advantage via a regulatory polymorphism that may influence mtDNA transcription and replication. Assuming a CTVT mtDNA somatic mutation rate of 0.0201 mutations per year (0.0127–0.0393, 95% highest posterior density interval[12,13], Methods), this implies that all A1d1a horizontal transfers occurred recently, probably within the last few decades (Fig. 1d, Supplementary Data 4)

Methods

Results

Conclusion