Germline epimutation: A basis for epigenetic disease in humans

Area of Science:

• Molecular Biology
• Genetics
• Epigenetics

Background:

• Epigenetic modifications alter gene transcription reversibly and heritably.
• Epimutations, errors in epigenetic silencing, can lead to abnormal gene silencing.
• It was hypothesized that germline epimutations phenocopy genetic mutations.

Purpose of the Study:

• To test the hypothesis that germline epimutations phenocopy genetic mutations.
• To investigate the role of MLH1 epimutation in hereditary nonpolyposis colorectal cancer (HNPCC).

Main Methods:

• Identified individuals with epigenetically silenced MLH1 alleles throughout the soma.
• Assessed individuals for clinical criteria of HNPCC.
• Screened for genetic abnormalities explaining the epimutation.

Main Results:

• Individuals with epigenetically silenced MLH1 fit HNPCC criteria.
• HNPCC in these individuals is phenocopied by epimutation, not genetic mutation.
• No genetic abnormality was found to explain the epimutation in affected individuals.

Conclusions:

• Epimutations can phenocopy genetic diseases, occurring spontaneously.
• Epigenetic inheritance may follow different rules than Mendelian genetics.
• The principles discussed may apply to diseases like thalassemias.