Figure 3. Replicative strand bias for mtDNA somatic substitutions.
(A) Replicative strand-specific substitution rate (# of observed/# of expected) by 96 trinucleotide context. Substitutions in a specific mtDNA segment (from Ori-b to OH) are not included, because they present a different substitutional signature. (B) Mutational signature across tumor types. Eighteen tumor types, which include at least 25 mtDNA mutations, were shown. (C) Inverted substitution signature in the Ori-b–OH.
Figure 3—figure supplement 1. Replicative strand bias observed in mtDNA substitutions.
(A) Mutational signature of mtDNA somatic substitutions on
the 12 L strand genes by replicative strand (L/H strand). It agrees very
well with the background mutational signature. (Chi-square p = 0.99999).
(B) Mutational signature of mtDNA somatic substitutions
on the H strand gene (MT-ND6) by replicative strand. It
is very close to the background very close to the expected background
signature (Chi-square p = 0.027). If we consider signature by
transcriptional strand, the signature difference is very clear
(Chi-square p = 1 × 10−21). These suggest the strand bias not
to be transcription-coupled, but replication coupled. (C)
Mutational spectrum of mtDNA somatic substitutions on the 22 tRNA genes
by replicative strand. Again, it agrees very well with the background
mutational signature (Chi-square p = 0.71). (D) Mutational
spectrum of mtDNA somatic substitutions on the 22 tRNA genes by
non-transcribed (coding) and transcribed (non-coding) strand. Strand bias
was greatly subsided because somatic substitutions on 14 L strand and 8 H
strand tRNAs neutralize the strand bias (CH > TH
and TL > CL) each other. As a result, this
signature of tRNA mutations by transcriptional strand is significantly
different from the background one (Chi-square p = 3.3 ×
10−12). Taken all together, we concluded that the cause of
strand bias is not transcription-coupled but is replicative.