Unlike genetics, epigenomic variations are generally reversible alterations that can be identified by analysis of the state of DNA methylation or histone modifications specific for active and non-active chromatin (Park, 2008
On one hand, the genomic regions which are targets for the epigenomic regulations are under pressure of negative selection. These regions are characterized by a relative deficiency in SNPs (Tolstorukov et al., 2011
). On the other hand, the mutations in these regions, if they occur, may directly affect the chromatin structure or DNA methylation, thereby affecting the capacity of these regions for either epigenomic stress-induced or cell specific (e.g., neuronal) regulations.
I believe it would be reasonable to hypothesize that the genetic–epigenomic interactions (GEI) play a significant role in common human illness, particularly in behavioral diseases, including major psychiatric diseases, such as schizophrenia, affective disorders, autism, or even in age-related dementias. Any SNP or structural genetic variation in cis-position located at a distant regulatory region or nearby gene can alter the constitutive or tissue-specific state of active chromatin and regulation of the gene (Figure ). Certain epigenetic mutations can be silent, but will manifest due to programmed epigenomic transformations during development, the aging process, or triggered under specific conditions, e.g., hypothalamus – axilatory mediated stress conditions, or exposure to infection or chemical compounds. We could speculate that the silent variations affecting the epigenomic state play a role in some psychiatric disorders with reversible clinical manifestation (schizophrenia and bipolar disorder) or stress-induced and age-related diseases.
Figure 1 Epigenomic and genetic interactions in regulation of chromatin and gene activity underlying behavior traits. Genes can be regulated via genomic elements (enhancers, repressors, insulators) in tissue-specific manner. Epigenomic modification of chromatin (more ...)
Despite the fact that the genetic role of schizophrenia is well-established, and that multiple informative schizophrenia families have been available for a long time, there is, as yet, no robust evidence for mutations in genes altering the protein structure in any significant number of schizophrenia cases as observed, e.g., in AD. Classical twin analysis showed that the contribution of non-genetic factors to schizophrenia is at least 50%. The number of autism spectrum disorder (ASD) cases continues to increase. Currently, ASD is diagnosed in 1 of 110 children (Center for Disease Control and Prevention, 2009
). The cause of the rising rate for ASD is unknown. Recent re-evaluation of large cohorts of twins also demonstrated that there is a significant role of non-genetic factors in ASDs, and up to 37–38% of genetic factors in contrast to the previous conception of an ~90% heritability in autism. A surprisingly significant role of shared twin environment, evidenced by high dizygotic twin concordance, was observed (Hallmayer et al., 2011
). The hypothesis of GEI seems to be very relevant to ASD and schizophrenia.
Modified genomic DNA and chromatin complexes can be extracted from neuronal cells separately from glial cell populations from postmortem brain specimens (Matevossian and Akbarian, 2008
). We can attempt to determine whether structural or single-nucleotide variations in individual genomes (genetic variations) correlate with individual variations in DNA methylation or methylation/acetylation histone modifications (epigenomic variations) in the same loci in neuronal cells. Genetic variations can be identified by whole-genome MPS re-sequencing. Epigenomic variations in the same individual genomes can be detected by MPS using rapidly progressing methodologies for analysis of DNA methylation with single-nucleotide resolution, DNAse-I hypersensitive sites, or Chip-seq data for transcriptional start sites or transcriptional regulatory elements. For example, Chip-seq can track transcriptional start sites via detection of sites for histone H3 trimethylated at lysine 4 (H3K4me3) and other transcriptional regulatory elements including enhancers enriched with histone H3 acetylated at lysine 27 (H3K27Ac) and histone H3 monomethylated at lysine 4 (H3K4me1). DNAse-I hypersensitive sites (at least ~1–2% of genome) mark open or active chromatins associated with majority of regulatory and transcriptional start sites.
Beyond neuropsychiatric illnesses, I suggest that GEIs may also underlie changes in non-pathogenic behavioral traits and that the interplay between genetic variations and epigenomic modifications could be identified through the study of non-conventional animal models. Genomic sequencing, coupled with epigenomic studies, provides perspective in the identification of alterations in genome correlated with rapid behavior changes under certain selection process in rodents (e.g., in rats) or, in follow-up artificial selection in domesticated animals. Rapid changes in behavior, from native aggressive defending reaction to tolerant or even to “the man’s best friend” behavior in Canidae species, can be achieved in just a few generations, as demonstrated in the domestication experiments of silver foxes selected for tameability (Spady and Ostrander, 2008
; Trut et al., 2009
; Parker et al., 2010
). The patterns of genetic alterations underlying changes in this behavior paradigm have yet to be identified. Perhaps it is not an exaggeration to speculate that elucidation of such a mechanism may also contribute to understanding the evolution of normal and abnormal social behavior in humans, and even of our own tolerance or intolerance of each other.