Direct measurements of human colon crypt stem cell niche genetic fidelity: the role of chance in non-darwinian mutation selection.
Direct measurements of human colon crypt stem cell niche genetic fidelity: the role of chance in non-darwinian mutation selection.
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DOI：
10.3389/fonc.2013.00264
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发表时间：
2013-10-14
影响因子：
4.7
通讯作者：
Shibata D
中科院分区：
文献类型：
--
作者：
Kang H;Shibata D
完美的人类干细胞遗传保真度将防止衰老和癌症。然而，完美是很难实现的，衰老是普遍的，癌症是常见的。有一种假说认为，由于突变在人的一生中是不可避免的，因此下游机制已经进化到管理有益和致命突变的有害影响。在结肠中，隐窝干细胞结构减少了突变积累风险的有丝分裂细胞的数量，多个小生境干细胞确保任何单个干细胞内的致命突变不会导致隐窝死亡。此外，结肠隐窝干细胞小生境的结构可能利用概率或机会随机丢弃许多可能导致癌症的有益突变。对体细胞染色体拷贝数改变（CNA）的分析揭示了个体正常人隐窝缺乏完美的保真度，溃疡性结肠炎（一种增殖性炎症性疾病）的年龄相关性增加和频率较高。体细胞CNA的年龄相关性增加似乎与相对正常的复制错误和细胞分裂率一致。令人惊讶的是，与癌症基因组中的点突变相似，隐窝突变的类型更符合随机固定而不是选择。从理论上讲，一个简单的“非达尔文”的方法来抵消选择是减少繁殖人口的规模。在非常小的种群中，命运更多的是由偶然而不是选择决定的，因此在小的隐窝生态位中，选择可能会被最小化。预期的效果是，许多可能导致癌症的有益突变会因漂移而随机丢失，而不是通过选择而固定。将结肠细分为多个非常小的干细胞小生境可能会将达尔文进化论转化为非达尔文体细胞进化论，从而向衰老投降，但降低癌症风险。
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.