Frank Steven A
Department of Ecology and Evolutionary Biology, University of California, Irvine, CA 92697-2525, USA.
Curr Biol. 2014 Jun 16;24(12):R577-R581. doi: 10.1016/j.cub.2014.05.021.
The large number of cell divisions required to make a human body inevitably leads to the accumulation of somatic mutations. Such mutations cause individuals to be somatic mosaics. Recent advances in genomic technology now allow measurement of somatic diversity. Initial studies confirmed the expected high levels of somatic mutations within individuals. Going forward, the big questions concern the degree to which those somatic mutations influence disease. Theory predicts that the frequency of mutant cells should vary greatly between individuals. Such somatic mutational variability between individuals could explain much of the diversity in the risk of disease. But how variable is mosaicism between individuals in reality? What is the relation between the fraction of cells carrying a predisposing mutation and the risk of disease? What kinds of heritable somatic change lead to disease besides classical DNA mutations? What molecular processes connect a predisposing somatic change to disease? We know that predisposing somatic mutations strongly influence the onset of cancer. Likewise, neurodegenerative diseases may often begin from somatically mutated cells. If so, both neurodegeneration and cancer may be diseases of later life for which much of the risk may be set by early life somatic mutations.
构成人体所需的大量细胞分裂不可避免地导致体细胞突变的积累。此类突变使个体成为体细胞嵌合体。基因组技术的最新进展如今使得对体细胞多样性的测量成为可能。初步研究证实了个体内体细胞突变的预期高水平。展望未来，重大问题在于这些体细胞突变对疾病影响的程度。理论预测，突变细胞的频率在个体间应存在很大差异。个体间这种体细胞突变变异性可能解释了疾病风险的大部分多样性。但实际上个体间的嵌合现象有多可变呢？携带易患突变的细胞比例与疾病风险之间有何关系？除了经典的DNA突变外，还有哪些可遗传的体细胞变化会导致疾病？哪些分子过程将易患体细胞变化与疾病联系起来？我们知道，易患体细胞突变会强烈影响癌症的发病。同样，神经退行性疾病可能常常始于体细胞突变的细胞。如果是这样，神经退行性变和癌症可能都是晚年疾病，其大部分风险可能由早年的体细胞突变所决定。
