Mutation order is critical.

<p>(A) Locus A always mutates before locus B. Theoretical asymmetric risk (red) is Eq. (S11) with <i>K</i> = 2, , and <i>H₂</i> defined in Eq. (S49). Theoretical symmetric risk (blue) is Eq. (S55). (B) Either locus may mutate first. Reversing the order in which the loci are mutated reverses the order of the mutation rates since the loci are independent. Theoretical predictions are Eqs. (S66) (red) and (S68) (blue). (C) If the mutation rate of a locus depends on the genomic background then all four mutation rates may be independently chosen. Here, the rate at which B mutates depends on whether A is mutated or not. Theoretical predictions are the same as panel A. In all panels, population size is 10⁴ stem cells and mutation rates are 10⁻⁶ (“slow”) and 10⁻² (“fast”). Panels A and C show the results of simulations under the “Moran” model (Section 3.2 of <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003802#pcbi.1003802.s012" target="_blank">Text S1</a>) whereas panel B corresponds to the “Branching” model (Section 3.1).