Tumorigenesis as the Paradigm of Quasi-neutral Molecular Evolution

In the absence of both positive and negative selections, coding sequences evolve at a neutral rate (R = 1). Such a high genomic rate is generally not achievable due to the prevalence of negative selection against codon substitutions. Remarkably, somatic evolution exhibits the seemingly neutral rate R ∼ 1 across normal and cancerous tissues. Nevertheless, R ∼ 1 may also mean that positive and negative selections are both strong, but equal in intensity. We refer to this regime as quasi-neutral. Indeed, individual genes in cancer cells often evolve at a much higher, or lower, rate than R ∼ 1. Here, we show that 1) quasi-neutrality is much more likely when populations are small (N < 50); 2) stem-cell populations in single normal tissue niches, from which tumors likely emerge, have a small N (usually <50) but selection at this stage is measurable and strong; 3) when N dips below 50, selection efficacy decreases precipitously; and 4) notably, N is smaller in the stem-cell niche of the small intestine than in the colon. Hence, the ∼70-fold higher rate of phenotypic evolution (observed as cancer risk) in the latter can be explained by the greater efficacy of selection, which then leads to the fixation of more advantageous and fewer deleterious mutations in colon cancers. In conclusion, quasi-neutral evolution sheds a new light on a general evolutionary principle that helps to explain aspects of cancer evolution.