Genetic load and mutational meltdown in cancer cell populations

ABSRACT Large and non-recombining genomes are prone to accumulating deleterious mutations faster than natural selection can purge (Muller’s ratchet). A possible consequence would then be the extinction of small populations. Relative to most single-cell organisms, cancer cells, with large and non-recombining genomes, could be particularly susceptible to such “mutational meltdown”. Curiously, deleterious mutations in cancer cells are rarely noticed despite the strong signals in cancer genome sequences. Here, by monitoring single-cell clones from HeLa cell lines, we characterize deleterious mutations that retard cell proliferation. The main mutational events are copy number variations (CNVs), which happen at an extraordinarily high rate of 0.29 events per cell division. The average fitness reduction, estimated to be 18% per mutation, is also very high. HeLa cell populations therefore have very substantial genetic load and, at this level, natural population would likely experience mutational meltdown. We suspect that HeLa cell populations may avoid extinction only after the population size becomes large. Because CNVs are common in most cell lines and cancer tissues, the observations hint at cancer cells’ vulnerability, which could be exploited by therapeutic strategies.