Direct measurements of human colon crypt stem cell niche genetic fidelity: the role of chance in non-darwinian mutation selection

Abstract

Perfect human stem cell genetic fidelity would prevent aging and cancer. However, perfection would be difficult to achieve, and aging is universal and cancers common. A hypothesis is that because mutations are inevitable over a human lifetime, downstream mechanisms have evolved to manage the deleterious effects of beneficial and lethal mutations. In the colon, a crypt stem cell architecture reduces the number of mitotic cells at risk for mutation accumulation, and multiple niche stem cells ensure that a lethal mutation within any single stem cell does not lead to crypt death. In addition, the architecture of the colon crypt stem cell niche may harness probability or chance to randomly discard many beneficial mutations that might lead to cancer. An analysis of somatic chromosome copy number alterations (CNAs) reveals a lack of perfect fidelity in individual normal human crypts, with age-related increases and higher frequencies in ulcerative colitis, a proliferative, inflammatory disease. The age-related increase in somatic CNAs appears consistent with relatively normal replication error and cell division rates. Surprisingly, and similar to point mutations in cancer genomes, the types of crypt mutations were more consistent with random fixation rather than selection. In theory, a simple "non-Darwinian" way to nullify selection is to reduce the size of the reproducing population. Fates are more determined by chance rather than selection in very small populations, and therefore selection may be minimized within small crypt niches. The desired effect is that many beneficial mutations that might lead to cancer are randomly lost by drift rather than fixed by selection. The subdivision of the colon into multiple very small stem cell niches may trade Darwinian evolution for non-Darwinian somatic cell evolution, capitulating to aging but reducing cancer risks.

Keywords: Muller’s ratchet; aging; human; neutral drift; non-Darwinian; replication errors; stem cell niche.

Figure 1

Diagram of a colon crypt stem cell niche, illustrating niche stem cell turnover. With multiple niche stem cells, a mutation will become detectable if its stem cell eventually dominates its niche.

Figure 2

Crypt chromosome copy number alterations (CNAs) across all non-UC and UC crypts. (A) Locations of chromosome CNAs. Arrows indicate loss of heterozygosity, red bars indicate gene conversion, black bar is a duplication. (B) Increase in mutant non-UC crypts with age. (C) Relative proportions of chromosome CNA types in normal colon crypts and normal UC crypts.

Figure 3

Percent of crypts with any chromosome copy number alteration versus age. Circles are averaged experimental data and the dotted lines indicate calculated mutation frequencies with different combinations of mutation and stem cell division rates. A regression analysis indicates that the experimental increase in CNA frequency with age is significant (p = 0.01). The calculated mutation frequencies do not account for the lag between a mutation in a stem cell and the time needed to become detectable by niche succession.

Figure 4

Relative locations of crypt LOH chromosome copy number alterations and common CRC LOH copy number alterations [from Ref. (26)]. The locations of the crypt CNAs did not preferentially fall within common CRC CNA intervals, but appeared randomly scattered by chance (see Table 3). Triangles indicate chromosome ends.

Figure 5

Darwinian versus non-Darwinian stem cell niche evolution. Mutations may increase or decrease cell fitness. With multiple stem cells subject to selection, progeny with the highest fitness should reliably dominate the niche, paradoxically increasing fitness with age and predisposing to cancer. With the non-Darwinian evolution favored by very small niche populations, chance or drift more determines niche succession, and almost any stem cell may become fixed, even stem cells with lower relative fitness. The result is the random loss of many driver mutations, and more consistent with aging, a stochastic tendency for decreased crypt fitness.