Over 98% of our genome is non-coding and is now recognised to have a major role in orchestrating the tissue specific and stimulus inducible gene expression pattern which underpins our wellbeing and mental health. The non-coding genome responds functionally to our environment at all levels, encompassing the span from psychological to physiological challenge. The gene expression pattern, termed the transcriptome, ultimately gives us our neurochemistry. Therefore a major modulator of mental wellbeing is how our genes are regulated in response to life experiences. Superimposed on the aforementioned non-coding DNA framework is a vast body of genetic variation in the elements that control response to challenges. These differences, termed polymorphisms, allow for a differential response from a specific DNA element to the same challenge thus potentially allowing ‘individuality’ in the modulation of our transcriptome. This review will focus on a fundamental mechanism defining our psychological and psychiatric wellbeing, namely how genetic variation can be correlated with differential gene expression in response to specific challenges, thus resulting in altered neurochemistry which consequently may shape behaviour.

Introduction

The human genome has evolved to include a combination of both highly conserved regions of regulatory non-coding DNA (ncDNA) found across many species and humanspecific regulatory DNA elements which together act to regulate expression of mRNA. This combination of DNA elements allows determination of where, when, how much and for how long, genes are expressed in the human brain in response to normal developmental, psychological and physiological cues, Figure 1. Many of these elements exhibit genetic variation which is not only associated with risk for a specific condition, but has also been demonstrated to alter the regulatory properties of the gene. The functional interpretation and analysis of ncDNA variation can be initially addressed in silico by overlaying its position on databases containing characterised and predicted functional elements within the genome, Box 1. The most easily accessible free database is the Encyclopaedia of DNA Elements (ENCODE; https://www.encodeproject.org/) which is a collaboration of research groups funded by the National Human Genome Research Institute [1,2], this can be used in combination with a plethora of other database browsers [3] such as the University of California Santa Cruz (UCSC) Genome Browser (http://genome.ucsc.edu/ )[4]. This review will begin with an introduction to the most conserved regulatory regions in the genome and how these may be functionally modified by the simplest and most extensively studied class of genetic variation, single nucleotide polymorphisms (SNPs). The review will then focus on human regulatory elements that are associated with neuropsychiatric conditions which are larger blocks of DNA variation such as variable number tandem repeats (VNTRs) and nonlong terminal repeat (non-LTR) retrotransposons, Box 2.