Germline mutations are affected by transcription.

<p><i>Panel A</i>, HGMD dataset; <i>y-axis</i>, as in <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003816#pgen-1003816-g001" target="_blank">Figure 1C</a>; <i>x-axis</i>, ratio of mutated NGNN sequences in protein coding genes containing the P2-guanine base on the non-transcribed (<i>NT</i>) <i>vs</i>. transcribed (<i>T</i>) strand; <i>solid circles</i>, HGMD dataset (<i>r</i>² 0.32, P(α)_0.05 0.991, P<0.001); <i>open circles</i>, 1000 Genomes Project dataset. <i>Panel B</i>, inherited splicing mutations dataset; <i>top</i>, cartoon of exon-intron boundaries showing the conserved GT and AG bases at the donor (<i>ds</i>) and acceptor (<i>as</i>) splice sites; <i>bottom</i>, graph of splicing mutations; <i>y-axis</i>, number of SBSs; <i>x-axis</i>, position of SBSs relative to +/−20 nt of splice junctions; <i>Panel C</i>, model for sequence-dependent SBSs in cancer and human inherited disease. In the first step, an electron is lost from within a tetranucleotide sequence, leaving a hole. In the second step, the hole migrates to and from various competing sites, including nearby bases and chromatin-associated amino acids (not shown), eventually being trapped by a guanine base. The resulting guanine radical cation either causes DNA-protein crosslinking or undergoes subsequent chemical modifications. If the modified base is not corrected by DNA repair, it may give rise to a mutation (X-Y base-pair) as a result of error-prone DNA polymerase synthesis during DNA replication (dashed arrow).</p

SBSs and VIPs.

<p><i>Panel A</i>, whisker plot of the fractions of SBSs at G•C bp for the EWS and GWS datasets computed using AgilentV2 and Duke35 mappability counts, respectively; <i>red line</i>, mean; <i>black line</i>, median; <i>green lines</i>, average GC-contents in the mappable AgilentV2 (EWS) and Duke35 (GWS) sets. <i>Panel B</i>, NGRA sequences are enriched in SBSs in melanoma. <i>y-axis</i>, for each 4-member sequence combination with matching P1–P3 bases, the fraction of mutations at P4-A was divided by the average fraction of mutations at P4-(C/T/G); <i>x-axis</i>, P3 base composition; <i>R</i>, purine; <i>Y</i>, pyrimidine; mean ± SD; P-value from two-tailed <i>t</i>-test. <i>Panel C</i>, the <i>ln</i> of normalized fractions of mutated DGNN (D = A/G/T) sequences, <i>F_i</i>, for the seven cancer datasets with −logP ≥3 for DGRN>DGYN (<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003816#pgen-1003816-t001" target="_blank">Table 1</a>) were combined and plotted as a function of the average absolute free energy of base stacking, ΔG(ν), for each of the 48 DGNN sequences. <i>Panel D</i>, three-dimensional model of the (5′-GGG-3′)•(5′-CCC-3′) trinucleotide showing the LUBMO (lowest unoccupied beta molecular orbital) of the ionized sequence. <i>Panel E</i>, plot of the normalized fractions (<i>log f_i</i>×10³) of mutated DGN sequences (Duke35 counts) for the Lung_nsc cancer dataset <i>vs.</i> VIPs; <i>outer circle</i>, 5′D base; <i>inner circle</i>, 3′N base; <i>blue</i>, adenine; <i>green</i>, guanine; <i>red</i>, thymine; <i>yellow</i>, cytosine. <i>Panel F</i>, agglomerative hierarchical clustering of 14 cancer genome datasets obtained from linear correlations with <i>ln</i> VIP values, as obtained from T_hg19 counts; <i>colored boxes</i>, elements found to be clustered at the 90% confidence interval.</p

Vertical ionization potentials (VIPs) of guanine-centered DGN sequences.

<p>VIPs for the centrally (italicized) guanine computed at the M06-2X/6-31G(<i>d</i>) level of theory;</p>a<p>VIP of free unalkylated guanine;</p>b<p>from reference <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003816#pgen.1003816-Zaytseva1" target="_blank">[57]</a>.</p