Extended Data Fig. 9: Relationship between the mtDNA local constraint (MLC) score and genomic annotations.
From: Quantifying constraint in the human mitochondrial genome
(a) The proportion of benign (n = 884) and pathogenic (n = 205) variants in each score quartile. (b) Density plot showing the score distribution of disease-associated variants; numbers per (a). (c) Density plot showing the score distribution of 184 pathogenic variants with disease plasmy status in MITOMAP, colored by association with disease at heteroplasmy only, or at homoplasmy. (d) Density plot showing the score distribution of 88 ‘confirmed’ pathogenic variants from MITOMAP, colored by whether reported in individuals at heteroplasmy only or at homoplasmy, per a manual literature review. Plots (a-d) include missense and RNA variants only, and for (c-d) ‘at homplasmy’ includes observed at both homoplasmy and heteroplasmy. (e) Boxplot showing the score distribution for base positions where indels are observed in gnomAD (n = 416), HelixMTdb (n = 697), and MITOMAP (n = 667) databases. (f) The distribution of PhyloP base conservation scores for bases within each score quartile (0.0-0.25, n = 4142; 0.25-0.50, n = 4142; 0.50-0.75, n = 4141; 0.75-1.0, n = 4143); a dashed line is shown at score = 0. (g) The MLC score across every base position in the human mtDNA; bases that are conserved in chimpanzees are denoted by black pipe symbols, while those non-conserved and encoding base or amino acid substitutions are shown as white pipe symbols. (h-j) The MLC variant score distribution for SNVs across population frequency categories in gnomAD (homoplasmy AF ≥ 0.002%, n = 7363; homoplasmy AF < 0.002%, n = 1846 and heteroplasmy only, n = 1641) (h), HelixMTdb (homoplasmy AF ≥ 0.002%, n = 8049; homoplasmy AF < 0.002%, n = 3442 and heteroplasmy only, n = 2613) (i) and MITOMAP (AF ≥ 0.002%, n = 8617 and AF < 0.002%, n = 10,343) (j) databases. Note that allele frequency <0.002% is recommended as evidence of pathogenicity in ACMG/AMP mtDNA guidelines12, and that heteroplasmy data is not available for MITOMAP. For (e-f, h-j), boxplot elements include: center line, median; box limits, 25th and 75th percentiles; minima and maxima, 1.5x interquartile range; points, outliers.
