**4. The brain genome - environment interface: – stress as an evolutionary driver**

Following Waddington's early epigenetic concept, biological stress could be stated to represent a dyshomeostatic influence which produces a diversifying biological response following which a novel variant may have a survival advantage, making it an essential driver of evolution. Evolutionary processes are strongly influenced by the competition for available energy, with the required physical or mental skills being passed to offspring of the most able competitors. Diversity is clearly an asset in this process. A broader repertoire of cognitively linked, novelty stress-based learning associated with a complex range of emotions and increased cognitive integration through higher interneuronal density in humans is suggested to have diversified novelty information management. Stress hormones participate in modulation of memory consolidation processes in both the amygdala and the hippocampus (Guterman et al., 2006).

It increasingly appears possible that stress management systems operating within nonpathological parameters are utilised to deal with 'novelty'. The physiological activity of stress hormones has been shown to play an important role in modulation of memory consolidation processes in both the amygdala and the hippocampus (Turner et al., 2008). Severe psychosocial stress in early life crossing the proposed physiological stress management system boundaries, can adversely impact brain development itself, and the literature on stress suggests that these changes also occur largely through the hypothalamic pituitary adrenocortical (HPA) axis (Loman and Gunnar, 2010). Steroid receptors function by binding to specific structural elements in the regulatory regions of target genes by recruitment of cofactors that modify histones and chromatin structure (Trapman & Dubbink, 2007). Global changes in epigenetic markers in response to fear conditioning have been demonstrated

Stress Shaping Brains: Higher Order DNA/Chromosome

Ott, 1996; Savelyeva et al., 2006).

Evolution"(Reprinted in 1982).

Mechanisms Underlying Epigenetic Programming of the Brain Transcriptome 355

assembly process has been adapted from the immune paradigm at the expense of a risk for instability and/or malignant transformation when associated control mechanisms are not in place (such as tumour suppressor genes). It is suggested that the abilities for diverse recognition of externally derived information, a dynamic response of somatic hypermutation followed by genome rearrangement creating a template for memory formation, and entry into a terminally differentiated state are features common to both the brain and immune system. Chromosome breaks and the various resulting structural rearrangements (genetic instability) have mostly been viewed in a pathological context by researchers, but controlled chromosomal breakage and rearrangement leading to altered gene expression without adverse effects may have been necessary for the evolutionary and

Such chromosomal breakage relates to alterations in DNA higher order structures and studies of fragile sites at the level of chromosome organization reveal an unusual chromatin structure associated with fragile sites influencing formation of nucleosomes and the formation of nucleosome arrays (Wang, 2006). The study of epigenetics focuses on the relationship between chromatin structure and gene transcription. DNA is commonly packaged into nucleosomes and wrapped tightly around a core of histone (H) proteins. Modifications that regulate chromatin structure influence transcriptional activity, in part, through effects on transcription factor binding. the environmental regulation of histone methylation states. Chromatin remodeling and gene transcription are linked in that transcriptional activation associates with chromatin states that enhance the probability of subsequent transcriptional activity, providing a feed-forward loop. (Cordero et al., 2006, Murr, 2010; Hayashi et al., 2011). Recent observations reveal that histones are removed and replaced to enable or restrict, respectively, access of the transcription machinery to regulate transcription. The ultimate goal of some epigenetic modifications might well turn out to be the regulation of histone occupancy on the DNA (Williams et al., 2008). CFS-associated duplication and deletion altering AT tract length and DNA flexibility have been linked with variation in nucleosomal architecture (Cosgrove & Walberger, 2005). AT-rich repeats mediate recombination events in non-homologous chromosomes during meiosis (Jackson et al., 2003) and due to a modification of binding factor characteristics, CFS have been proposed to contribute to epigenetic sensitive phenotypes (Woynarowski, 2004), a phenomenon which has been suggested to include neurobehavioral effects (Garofalo et al.,1993; Gericke et al., 1995, Gericke 1998, 2006, 2010; Simonic & Gericke 1996; Simonic &

neurodevelopmental flexibility required by the human brain (Gericke, 2010).

**4.2 Developmental cytogenetic instability in the mammalian brain** 

"As many of the examples of epigenetic inheritance are mediated by position effects, the possibility exists that chromosome rearrangements may be one of the driving forces behind evolutionary change by exerting position effect alterations in gene activity, an idea first articulated by Richard Goldschmidt in 1940 in his book "The Material Basis of

The emerging evidence suggests that Goldschmidt's controversial hypothesis deserves a serious reevaluation" (Varmuza, 2003). Recent findings of rearranged and aneuploid chromosomes in brain cells suggest an unexpected link between developmental chromosomal instability and brain genome diversity (Yurov et al., 2007), (Yang et al., 2003). In humans, previously unrecognized large-scale double-stranded DNA breaks are now known to occur under normal circumstances in early postmitotic and differentiating

(Lubin & Sweatt, 2007), and RNA-mediated chromatin-level silencing is increasingly implicated in development, stress responses, and natural epigenetic variation that may promote phenotypic diversity, physiological plasticity, and evolutionary change (Madlung & Comai, 2004). Epigenetic markers on the promoter regions of the Bdnf gene have been the most extensively studied, including alterations in histone acetylation, phosphorylation, methylation, and DNA methylation associated with memory behaviour (Gupta et al., 2010), as well as activity-dependent changes in DNA methylation (Nelson et al., 2008).
