Its easy to obsess over little details, and want to understand every nuance of a subject that you’re passionate about, but sometimes it’s helpful to step back and get a broader perspective on what you’re working on. This review article from Richard Meagher and Kristofer Müssar at the University of Georgia does just that by gathering all the available epigenetic evidence to date about how DNA sequence (genotype) influences chromatin structure (epitype), which sometimes contributes to disease.

Meagher and Müssar begin by summarizing the data around the transgenerational transmission of aberrant and disease phenotypes. There is much evidence linking genotype and disease, but relatively few that tie epitype, aka as chromatin structure, to various pathologies. Epigenetics research still hasn’t quite worked out how epitypes are passed on as populations evolve, and yet epigenetics is thought to be a critical factor in evolution and disease susceptibility.

The authors explore the hypothesis that, “for transgenerationally inherited chromatin structures, genotype predisposes epitype”, or in other words; that DNA sequences lead to specific epitypes that then modulate gene expression. The evidence of a causal relationship between genotype, inherited epitypes and epigenetic risk comes from studies that fall into one of two buckets:

Direct methods of research delve into the transgenerational inheritance of epitypes and the passing of a phenotype among genetically related individuals.

A second more indirect approach involves epitypes that are duplicated, as part of DNA replication, and become evolutionarily conserved within the genome.

Most of the evidence discussed suggests that indeed, genotypes predispose epitypes for chromatin structures that are transgenerationally inherited, and that this mechanism influences epigenetically controlled diseases. The Georgia scientists observed that genotypes controlling inherited epigenetic risk are often well camouflaged within DNA sequences and small RNAs. They also noticed that remethylation of DNA cytosines only occurs at specific developmental times and in specific tissues, meaning that extra effort may be needed when studying those mechanisms.

Meagher and Müssar propose that so far, we’ve only scratched the surface in our understanding of inherited epigenome-induced disorders. Once we can properly ID which genotype predisposes epitype for a particular disease, it will make the job of creating therapeutics and lowering epigenetic risk of disease much easier.

Get a bigger picture of genotype, epitype and disease risk at Epigenetics & Chromatin, July 2012.