Distinct spectra of somatic mutations accumulated with age in mouse heart and small intestine
Distinct spectra of somatic mutations accumulated with age in mouse heart and small intestine
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DOI：
10.1073/pnas.97.15.8403
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发表时间：
2000-07-18
影响因子：
11.1
通讯作者：
Vijg, J
中科院分区：
文献类型：
--
作者：
Dollé, MET;Snyder, WK;Vijg, J
体细胞突变积累被认为是癌症和衰老的主要原因。通过使用带有染色体整合 lacZ 报告基因的转基因小鼠模型，对两个增殖活性差异很大的器官（即心脏和小肠）在年轻和老年时的突变谱进行了表征。在年轻时，光谱几乎相同，主要包括 GC 到 AT 的转换和 l-bp 缺失。然而，到了老年，不同的突变模式就出现了。在小肠中，仅发现点突变累积，包括G.C到T.A、G.C到C.G。以及 A.T 到 C.G 的转换以及 G.C 到 A.T 的转换。相比之下，在心脏中，大约一半累积的突变似乎是大型基因组重排，涉及高达 34 厘摩的染色体 DNA。事实上，心脏中积累的所有其他突变似乎都是 CpG 位点上的 G.C 到 A.T 的转变。这些结果表明，不同的机制导致老年器官特异性基因组退化和功能障碍。
Somatic mutation accumulation has been implicated as a major cause of cancer and aging. By using a transgenic mouse model with a chromosomally integrated lacZ reporter gene, mutational spectra were characterized at young and old age in two organs greatly differing in proliferative activity, i.e., the heart and small intestine. At young age the spectra were nearly identical, mainly consisting of GC to AT transitions and l-bp deletions. At old age, however, distinct patterns of mutations had developed. In small intestine, only point mutations were found to accumulate, including G.C to T.A, G.C to C.G. and A.T to C.G transversions and G.C to A.T transitions. In contrast, in heart about half of the accumulated mutations appeared to be large genome rearrangements, involving up to 34 centimorgans of chromosomal DNA. Virtually all other mutations accumulating in the heart appeared to be G.C to A.T transitions at CpG sites. These results suggest that distinct mechanisms lead to organ-specific genome deterioration and dysfunction at old age.