Whole Genome Duplication

Whole genome duplication (WGD) is a macroevolutionary event in which the entire genome is doubled, producing a tetraploid cell. It is a common event in cancer evolution that precedes extensive subclonal diversification.

Evolutionary Role

WGD creates a buffered genomic state: cells with twice the normal DNA content can tolerate chromosomal losses and gains that would be lethal in a diploid context. Gerstung et al. (2020) demonstrated that WGD typically occurs before extensive subclonal diversification, acting as a permissive event that enables subsequent chromosomal-instability and copy-number-alteration. The tetraploid intermediate provides genetic redundancy — extra copies of essential genes buffer against deleterious losses during the ensuing chromosomal chaos.

Clinical Association

McGranahan & Swanton (2017) identified WGD as associated with worse clinical outcome in non-small cell lung cancer, alongside subclonal copy-number alterations. The link between WGD and poor prognosis is consistent with its role in enabling the genomic plasticity that fuels adaptation and therapy-resistance.

Detection

WGD can be inferred from the variant-allele-fraction distribution of clonal vs. subclonal mutations. Mutations that occurred before WGD are present on two copies, while those after are present on one copy, creating distinct peaks in the VAF distribution. This principle underlies the molecular timing analyses in Gerstung et al. (2020).