Single-cell variant landscape of the human mitochondrial genome reveals cell type-specific and disease-associated changes

PBMCs and BM share many inherited homoplasmic and highly heteroplasmic SNVs but few somatic SNVs. Somatic SNVs are tissue- and cell type-specific and distributed across the mtDNA genome, suggesting that they arise in a largely random fashion. Although mtDNA replication error is the most likely dominant force shaping homoplasmic variants, oxidative stress may drive a significant portion of heteroplasmic and somatic mutations in the mtDNA genome.

Importantly, we discover cell type-specific and human disease-associated mtDNA SNVs. By coupling mtDNA genotypes with matched single-cell nuclear transcriptomes and structural modeling, we uncover potential molecular mechanisms of how these disease-associated mtDNA SNVs impact cellular function such as inflammation and contribute to disease. Together, these findings define the single-cell variant landscape of the human mitochondrial genome and reveal previously unrecognized lineage- and disease-associated patterns of mtDNA variation in the human hematopoietic system.