Fig. 5: Genetic perturbation in mtDNA can elicit a dosage-dependent decrease in mtDNA copy number.
From: Single-cell mtDNA dynamics in tumors is driven by coregulation of nuclear and mitochondrial genomes
a, Length heteroplasmy composition of m.302 across 126 single cells in HGSC primary tumor sample, SA1047. Each bar represents a cell. b, Effect of length heteroplasmy composition, the reference (n = 148 cells) and the major allele (n = 14 cells), at m.302 on mtDNA copy number. Reported P value from two-sided, two-sample Wilcoxon signed rank test. c, Scatter plot showing heteroplasmy of the reference allele at m.302 and mtDNA copy number (two-sided Pearson correlation, R = 0.17, P < 0.02). Gray-shaded areas represent error bands indicating the 95% confidence interval, and the blue line indicates the regression line. d, Circos plot with lollipop indicating the genomic position of truncating variants identified in DLP+ across both cell lines and PDX models (CI, CIII, CIV, CV, control region, rRNA, tRNA, OLR). e, Concordance between the heteroplasmy level of the truncating, silent and nontruncating variants and the mtDNA copy number across all cell lines and tumors. f, Integrative Genomics Viewer59 of m.6708G>A substitution in DLP+ sequencing data of SPECTRUM-OV-081 Infracolic Omentum sample. The stacked histogram on top reflects the distribution of the reads supporting the reference and the alternate alleles. g, Same as f but for scRNA-seq of the same sample at the matched site. h, Two-sided Pearson correlation between mtDNA copy number and heteroplasmy level of the m.6708 truncating variant in SPECTRUM-OV-081 in DLP+ (R = 0.51, P = 2.9 × 10−48). Gray-shaded areas represent error bands indicating the 95% confidence interval, and the blue line indicates the regression line. i, Two-sided Pearson correlation between MT-ND3 gene expression and heteroplasmy level of the same m.6708G>A truncating variant in SPECTRUM-OV-081 in matched scRNA-seq (R = 0.45, P = 0.00054). Gray-shaded areas represent error bands indicating the 95% confidence interval, and the blue line indicates the regression line. j, Pearson correlation coefficient between the heteroplasmy level of the truncating variant m.6708 and expression of all the genes in the SPECTRUM-OV-081 sample. The mtDNA-encoded genes are colored in red. k, Enrichment of MSigDB hallmarks gene sets for tumors using the rank-sorted gene list based on correlation coefficient, quantified by directional −log10(Q): here >0 denotes upregulation in cells with high heteroplasmy truncating variants and <0 denotes downregulation. CI, mitochondrial complex I; CIII, mitochondrial complex III; CIV, mitochondrial complex IV; CV, mitochondrial complex V; rRNA: ribosomal RNA; tRNA, transfer RNA; OLR, light strand origin of replication.
