Germline epimutation: A basis for epigenetic disease in humans.

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.