Germline epimutation: A basis for epigenetic disease in humans
Germline epimutation: A basis for epigenetic disease in humans
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DOI：
10.1196/annals.1345.009
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发表时间：
2005-01-01
期刊：
影响因子：
--
通讯作者：
Suter, CM
中科院分区：
文献类型：
--
作者：
Martin, DIK;Ward, R;Suter, CM
DNA的表观遗传修饰在转录状态上产生可逆的和无性遗传的改变。高等真核生物所拥有的复杂的表观遗传沉默装置中的错误可能导致“异位突变”——基因的异常沉默。据推测，生殖系的突变会产生一种表型，与同一基因中失活的生殖系突变所产生的表型相当。在验证这一假设的过程中，发现了一些个体，其中编码DNA错配修复蛋白MLH1的基因的一个等位基因在整个体细胞中被表观遗传沉默（这意味着种系事件）。这些个体符合遗传性非息肉病性结直肠癌的临床标准，这通常是由MLH1的种系突变产生的。受影响的个体都没有任何基因异常可以解释这种现象。因此，细胞增殖可以表现一种遗传性疾病；这种先天的表观遗传缺陷并不一定是偶然的结果。表观遗传现象具有随机性、可逆性和镶嵌性；变异的发生和遗传可能有完全不同于孟德尔遗传学的规律。讨论了这一原则在地中海贫血中的应用。
Epigenetic modifications of DNA produce reversible and clonally heritable alterations in transcription state. Errors in the elaborate apparatus of epigenetic silencing possessed by higher eukaryotes can lead to "epimutation"' abnormal silencing of a gene. It was supposed that an epimutation in the germline would produce a phenotype equivalent to that resulting from an inactivating germline mutation in the same gene. In testing this hypothesis individuals were identified in whom one allele of the gene encoding the DNA mismatch repair protein MLH1 is epigenetically silenced throughout the soma (implying a germline event). These individuals fit the clinical criteria for hereditary non- polyposis colorectal cancer, which is usually produced by germline mutation of MLH1. None of the affected individuals have any genetic abnormality that would explain the presence of the epimutation. Thus, an epimutation can phenocopy a genetic disease; this innate epigenetic defect is not necessarily the result of anything other than chance. Epigenetic phenomena tend to be stochastic, reversible, and mosaic; the occurrence and inheritance of epimutations are likely to have rules completely different from those of Mendelian genetics. The application of this principle to the thalassemias is discussed.