Figure 4

Arrhythmia-associated mutations are unevenly distributed among functionally conserved regions of HERG and KCNQ1 even after accounting for total length and evolutionary conservation of individual sites therein. a) Counts of observed number of AAMs per region (white), counts of expected number of AAMS based on a uniform distribution across each gene (black) and expected number of disease mutations based on an evolutionary distribution within each region (gray). Disease mutations are unevenly distributed among different regions of the channel: HERG_uniform (X²_{(6 df)} = 145.10, p < 0.001), HERG_evolutionary (X²_{(6 df)} = 116.55, p < 0.001), KCNQ1_uniform (X²_{(5 df)} = 81.59, p < 0.001) and KCNQ1_evolutionary (X²_{(5 df)} = 37.39, p < 0.001). b) Scatter plots showing the relationship between channel region conservation (average variability/site within domain) and the average number of observed disease mutations per site (diamonds) or expected number of disease mutations per site based on a uniform (circles) or evolutionary (triangles) distribution. Dotted and dashed lines indicate fits for expected uniform and evolutionary distribution, respectively. Solid lines represent best-fit regression of observed data. The correlation is significant for KCNQ1 but not for HERG, and the best fit of the KCNQ1 data is significantly different from the other two hypotheses.