Genome, epigenome, mutations, epimutations... rethinking inheritance

I just learned a new word: epimutation. Genetic mutations occur in the DNA, while epimutations describe the transcriptional silencing of a gene that is normally active.

What's intriguing about epimutations is that even though they do not change the DNA, these changes can be transmitted from one cell to its daughter cells, a process called epigenetic somatic inheritance. There's another level of inheritance, which happens when such epigenetic changes are passed on from one generation of individuals to the next. This is a very intriguing concept because, since epigenetic changes don't affect the DNA, it is a non-Mendelian type of inheritance. Also, this type of inheritance is non-obvious because of a caveat called epigenetic reprogramming: all epigenetic marks are generally erased during gametogenesis and early embryogenesis so that the cells that will make a new individual can start afresh. If you think about it, it makes perfect sense: embryonic stem cells have the "potential" to become any kind of cell line and hence they have to start from an epigenetic "clean slate." So, in order for epigenetic inheritance to occur, an epimutation must escape epigenetic reprogramming.

"If the entire genome were reprogrammed in the germline it would be impossible for epigenetic modifications to be inherited. However there are epigenetic markers that can escape both incidences of reprogramming resulting in epigenetic modifications that persist in the somatic cells of the individual [1]."

In [1], Migicovsky and Kovalchuk review the different mechanisms by which epigenetic inheritance could arise: for example, you know how in all cells DNA is wound around proteins called histones? Well, it turns out that in sperm chromatin the majority of DNA is actually bound by "protamines," another kind of proteins that replace histones during spermatogenesis. However, a small percentage of histones are still retained in mature sperm and these histones could be responsible for epigenetic inheritance. In addition, there is methylation- and histone-mediated inheritance, which alter the gene expression patterns, and, finally, certain RNAs could be inherited through the germlines, again, making non-DNA changes inheritable.

Epigenetic inheritance has been documented in the case of MLH1, a gene located on chromosome 3. Individuals carrying a germline epimutation in this gene only have one functional copy of the gene and are at a higher risk of developing non-polyposis colorectal cancer:

"Studies have indicated that such inheritance is possible, with one family showing maternal transmission of the epimutation to the son, although the mutation was erased in his spermatozoa. In this case, the MLH1 epimutation that caused a predisposition to HNPCC in the mother was also present in the son, indicating he also had an increased risk of cancer. However, in her other children the epimutation was shown to revert to its normal state, indicating that the mutation was erased during reprogramming. These results indicated that germline transmission of an epigenetic state that confers disease susceptibility such as in the case of hypermethylation of MLH1 is possible. Overall, studies thus far have indicated that although epimutations are usually erased in the germline, they may be retained at a low frequency."

[1] Migicovsky, Z., & Kovalchuk, I. (2011). Epigenetic Memory in Mammals Frontiers in Genetics, 2 DOI: 10.3389/fgene.2011.00028