Research Square · Oct 19, 2026
Barcode, Passenger, or Driver? Mitochondrial Heteroplasmy in the Somatic Evolution of Human Haematopoiesis
By Biswas B
Human haematopoiesis is increasingly understood as a lifelong evolutionary process in which somatic variation, clonal competition and changing cellular environments reshape the contribution of individual haematopoietic stem cells. Most models of this process remain centred on the nuclear genome. Mitochondrial DNA introduces a second, genetically distinct substrate of somatic variation whose evolutionary role is less settled. Naturally occurring mitochondrial DNA variants can provide lineage information because they are abundant, clonally inherited and recoverable alongside single cell transcriptional or chromatin states. Large population genetic studies further suggest that many age associated mitochondrial heteroplasmies in blood behave predominantly as neutral passengers exposed by haematopoietic clonal expansion. Yet neutrality is not universal. Pathogenic mitochondrial variants undergo lineage dependent purifying selection, heteroplasmy associates with high risk clonal haematopoiesis and myeloid neoplasia, nuclear genetic variation regulates mitochondrial copy number and heteroplasmy, and DNMT3A R882 mutant haematopoietic stem and progenitor cells show genotype specific dependence on mitochondrial metabolism. This Review proposes a framework distinguishing mitochondrial variants acting as barcodes, passengers, fitness modifiers or, under a deliberately stringent evidentiary threshold, drivers. A fifth possibility, mitonuclear epistasis, considers clonal fitness as an emergent property of nuclear genotype, mitochondrial genotype, heteroplasmy, lineage and cellular context. Distinguishing these states will require longitudinal, lineage resolved and experimentally perturbable models. Mitochondrial heteroplasmy may therefore be more than an instrument for observing somatic evolution: in defined contexts, it may form part of the evolutionary system itself.