Figure 1

Statistic construction. In this example, we consider r∈{3,9} and up to 3 potential mutational hotspots in the protein. First, μ and σ are calculated over each column. Next, we normalize each entry in the column by calculating $Z_{i,s,r}=\frac{X_{i,s,r}-{\mu }_{s,r}}{{\sigma }_{s,r}}$. We then take the maximum over each row to get Z₀,…,Z₁₀₀₀. The percentage of times Z₀≥Z _i , where i∈{1,…,1000}, is the p-value of our observed statistic Z₀. Note that if Z₀ is greater than Z _i for all 1000 simulations, we report a p-value of <1.00 E-03.