Figure 1.

Principle behind timing amplifications. (A) A schematic representation of a single copy gain. Symbols represent point mutations occurring both before and after the depicted chromosomal gain. $t_0$ represents tumour initiation, $t_1$ or $t_{G1}$ represents the time of the first gain, and $t_S$ represents the time of tumour sampling. Mutations occurring before $t_1$ are duplicated, and thus present on two chromosome copies. Mutations occurring after $t_1$, or on the unaffected chromosome, are present on one chromosome copy. (B) A schematic representations of three scenarios ($S_1$, $S_2$, and $S_3$) leading to a copy number state of $4+2$ in a whole genome duplicated sample. W and G are used to refer to whole genome duplication (WGD) and gain, respectively. In $S_1$ a WGD event is followed by two sequential gains of the same chromosome, in which case mutations are expected to occur in all multiplicity states in the set $\{1,2,3,4\}$. However, if no mutations of multiplicity three are observed, this suggests that the order of events may be a single gain followed by a whole genome duplication ($S_3$), which can be timed, or a whole genome duplication followed by gains of two separate chromosomes ($S_2$), which cannot be timed. Red lines indicate gain or WGD events. Image created with BioRender.com.