MtDNA sequence features associated with 'selfish genomes' predict tissue-specific segregation and reversion.

Ellen C Røyrvik,Iain G Johnston

doi:10.1093/nar/gkaa622

Abstract

Mitochondrial DNA (mtDNA) encodes cellular machinery vital for cell and organism survival. Mutations, genetic manipulation, and gene therapies may produce cells where different types of mtDNA coexist in admixed populations. In these admixtures, one mtDNA type is often observed to proliferate over another, with different types dominating in different tissues. This ‘segregation bias’ is a long-standing biological mystery that may pose challenges to modern mtDNA disease therapies, leading to substantial recent attention in biological and medical circles. Here, we show how an mtDNA sequence’s balance between replication and transcription, corresponding to molecular ‘selfishness’, in conjunction with cellular selection, can potentially modulate segregation bias. We combine a new replication-transcription-selection (RTS) model with a meta-analysis of existing data to show that this simple theory predicts complex tissue-specific patterns of segregation in mouse experiments, and reversion in human stem cells. We propose the stability of G-quadruplexes in the mtDNA control region, influencing the balance between transcription and replication primer formation, as a potential molecular mechanism governing this balance. Linking mtDNA sequence features, through this molecular mechanism, to cellular population dynamics, we use sequence data to obtain and verify the sequence-specific predictions from this hypothesis on segregation behaviour in mouse and human mtDNA.

Highlights

Mitochondria are metabolically central organelles contained in almost all eukaryotic cells
Synthesising published in vitro biochemical data, we identify specific sequence features, related to Gquadruplex formation, that predict the behaviour of an individual Mitochondrial DNA (mtDNA) haplotype under this model and show that these features predict both tissue-specific mtDNA behaviour in mice and haplotype-specific reversion in human stem cells
Our results suggest that the stabilities of G-quadruplex forming sections of the mtDNA control region determine sequence ‘selfishness’ and are important contributors to tissue-specific mtDNA segregation bias

Summary

Introduction

Mitochondria are metabolically central organelles contained in almost all eukaryotic cells. As a result of mutation, experimental manipulation, or gene therapies, mtDNA populations within cells may consist of a mixture of different mtDNA sequences co-existing. This situation is known as heteroplasmy [2,3]. A cell starting with a mixture of 50% haplotype A and 50% haplotype B may after one year retain 80% haplotype B and only 20% haplotype A This segregation is of pronounced medical importance as it can lead to the amplification of a disease-causing mutation if present on the proliferating haplotype [4]. The causes of segregation bias remain largely unknown, challenging our basic biological understanding and our ability to optimally plan gene therapies

Methods

Results

Conclusion