Tissue-specific time courses of spontaneous mutation frequency and deviations in mutation pattern are observed in middle to late adulthood in Big Blue mice
Tissue-specific time courses of spontaneous mutation frequency and deviations in mutation pattern are observed in middle to late adulthood in Big Blue mice
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DOI：
10.1002/em.20119
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发表时间：
2005-06-01
影响因子：
2.8
通讯作者：
Sommer, SS
中科院分区：
文献类型：
--
作者：
Hill, KA;Halangoda, A;Sommer, SS
为了更好地确定小鼠成年中后期自发突变频率的时间过程，在10、14、17、23、25和30个月时对脂肪组织、肝脏、小脑（90%的神经元）和雄性生殖系（95%的生殖细胞）的样本进行了测量。在六个时间点共筛选了4600万个斑块形成单位（pus），收集了1450个圆形蓝色斑块并对其进行了测序。这些数据提高了分辨率，并证实了先前观察到的至少两种自发突变频率的组织特异性谱的发生（脂肪组织和肝脏随年龄升高，神经元和男性生殖细胞随年龄不变），男性生殖系的低突变频率，以及组织内随年龄不变的突变模式。这些发现似乎延伸到非常大的年龄（30个月）。其他发现包括动物间自发突变频率的差异在脂肪组织和肝脏中比在神经元和雄性生殖细胞中更大，组织间突变模式的细微但显著差异，与组织特异性代谢的微小影响相一致。在男性生殖系中，DNA损伤和修复随年龄增长而保持不变的假定平衡具有进化后果。考虑到随着父亲年龄增加的生殖系突变频率是否与某些类型遗传疾病的高发病率相关的报告存在争议，这一点尤其令人感兴趣。这些迄今为止最详细的关于个体组织中自发突变频率和模式的时间过程的测量有助于限制关于突变机制在DNA修复和衰老中的作用的假设。(c) 2005 Wiley-Liss, Inc。
To better define the time course of spontaneous mutation frequency in middle to late adulthood of the mouse, measurements were made at 10, 14, 17, 23, 25, and 30 months of age in samples of adipose tissue, liver, cerebellum (90% neurons), and the male germline (95% germ cells). A total of 46 million plaque-forming units (pfus) were screened at the six time points and 1,450 circular blue plaques were harvested and sequenced. These data improve resolution and confirm the previously observed occurrence of at least two tissue-specific profiles of spontaneous mutation frequency (elevation with age in adipose tissue and liver, and constancy with age in neurons and male germ cells), a low mutation frequency in the male germline, and a mutation pattern unchanged with age within a tissue. These findings appear to extend to very old age (30 months). Additional findings include interanimal variation in spontaneous mutation frequency is larger in adipose tissues and liver compared with neurons and male germ cells, and subtle but significant differences in the mutation pattern among tissues, consistent with a minor effect of tissue-specific metabolism. The presumptive unaltered balance of DNA damage and repair with age in the male germline has evolutionary consequences. It is of particular interest given the controversy over whether or not increasing germline mutation frequency with paternal age underlies the reports associating older males with a higher incidence of some types of genetic disease. These most detailed measurements available to date regarding the time course of spontaneous mutation frequency and pattern in individual tissues help to constrain hypotheses regarding the role of mutational mechanisms in DNA repair and aging. (c) 2005 Wiley-Liss, Inc.