Timing: before and after a gain
Timing asks which mutational processes acted before a copy-number gain (a whole-genome doubling, or one chromosome's gain) and which after. Give it one tumor's PURPLE-annotated VCF.
Inputs, read from the VCF
PURPLE writes what timing needs on every variant: the tumor's read counts (AD), the copy number around the variant (PURPLE_CN) and its minor allele (PURPLE_MACN), and the purity-adjusted allele frequency (PURPLE_AF). The studio builds Tau's two tables from them in the page:
- SNVs with the tumor's reference and alternate read counts;
- copy-number segments: runs of variants on one chromosome with the same rounded major and minor copy number, from the first to the last variant of the run (not PURPLE's own breakpoints);
- purity, solved per variant from the raw and the adjusted allele frequency and the median taken. On two PCAWG breast genomes: 0.59 and 0.77.
Tau on the runner, the epochs here
Run Tau uploads the two tables and runs Tau with that purity; Tau times each gained segment and groups the timings into events (BR001: a genome doubling at 0.47 of molecular time over 43% of the genome, and a gain of chromosome 21 at 0.60). The run is kept and chosen like any other runner step.
Each mutation then gets a posterior over its multiplicity: Tau's fitted share of mutations at each multiplicity in its segment, times a binomial on its read counts at the allele frequency that multiplicity implies (sigscape-core's multiplicity_posteriors). In a timed segment with a gained allele (major copy number 2 or more):
- on two or more copies: the mutation arose before the gain;
- on one copy: after the gain, or on the other allele at any time.
Mutations in segments without a gain, or that Tau left untimed, are not timed.
The comparison
The two epochs' spectra are refitted with the refit confidence report (COSMIC v3.2, whole genome). The table gives each signature's share before and after with its 90% interval. A process changed between epochs only where the intervals separate. "After" is a mixture by construction, which damps any change.