Martin David I K, Ward Robyn, Suter Catherine M
Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia.
Ann N Y Acad Sci. 2005;1054:68-77. doi: 10.1196/annals.1345.009.
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 nonpolyposis 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.
DNA的表观遗传修饰会在转录状态中产生可逆且可克隆遗传的改变。高等真核生物所拥有的精细表观遗传沉默机制中的错误可能会导致“表观突变”，即基因的异常沉默。据推测，生殖系中的表观突变会产生与同一基因中失活性生殖系突变所导致的表型相同的表型。在验证这一假设时，研究人员鉴定出了这样一些个体，其编码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都被表观遗传沉默（这意味着是生殖系事件）。这些个体符合遗传性非息肉病性结直肠癌的临床标准，该病通常由MLH1的生殖系突变引起。所有受影响的个体均没有任何能解释表观突变存在的基因异常。因此，表观突变可以模拟遗传疾病；这种先天性表观遗传缺陷不一定是由偶然因素以外的任何原因导致的。表观遗传现象往往具有随机性、可逆性和嵌合性；表观突变的发生和遗传可能具有与孟德尔遗传学完全不同的规则。本文讨论了这一原理在珠蛋白生成障碍性贫血中的应用。
