Behavioural Genetics in the Postgenomics Era

Abstract

There is growing evidence that the complexity of higher organisms does not correlate with the ‘complexity’ of the genome (the human genome contains fewer protein coding genes than corn, and many genes are preserved across species). Rather, complexity is associated with the complexity of the pathways and processes whereby the cell utilises the deoxyribonucleic acid molecule, and much else, in the process of phenotype formation. These processes include the activity of the epigenome, noncoding ribonucleic acids, alternative splicing and post‐translational modifications. Not accidentally, all of these processes appear to be of particular importance for the human brain, the most complex organ in nature. Because these processes can be highly environmentally reactive, they are a key to understanding behavioural plasticity and highlight the importance of the developmental process in explaining behavioural outcomes.

Key Concepts:

  • Humans possess fewer protein‐coding genes than maize (i.e. corn) and about the same number as a nematode.

  • There is now strong evidence that the complexity of higher organisms correlates with the relative amount of noncoding RNA rather than the number of protein‐coding genes.

  • Epigenetic processes are key to every aspect of human development from cellular differentiation to learning and memory.

  • Epigenetic mechanisms provide an explanation on the molecular level as to how the pre‐ and postnatal environments can impact offspring's behaviour.

  • Alternative splicing is one mechanism that enables the human body to create over 100 000 proteins with a genome that contains only 20 000 protein coding genes.

  • Each gene in the human genome is not ‘encoded’ for the production of a single protein.

  • Isoforms can have very different and even antithetical physiological effects.

  • Alternative splicing patterns are modulated in response to external stimuli, such as depolarisation of neurons, activation of signal transduction cascades and stress.

  • Post‐translational modification supplements alternative splicing as a means of creating protein diversity with a limited number of protein coding genes.

  • DNA is not the sole biological agent of inheritance.

Keywords: epigenetics; methylation; histone modification; micro RNAs; alternative splicing; post‐translational modifications; maternal effects; phenotypic plasticity; perinatal environment; genomic imprinting

Figure 1.

Prenatal stress modulates the brain miRNA expression in male newborn offspring. Expression ratio group averages of miRNAs from brains of newborns born to prenatally stressed dams. All data are presented as mean 6 SEM. Adapted and reprinted with permission from Zucchi et al. (, p. 4) and Nijholt (, p. 177). © PLoS.

Figure 2.

Parental regulation of the hypothalamic–pituitary–adrenal axis. (a) The current working model for the effect of maternal care (specifically, of licking and grooming pups) on the epigenetic regulation of the expression of Nr3c1, the gene that encodes the GR. Licking and grooming of pups activates thyroid hormone‐dependent increases in hippocampal serotonin (5‐hydroxytryptamine or 5‐HT) levels and 5‐HT binding to the 5‐HT7 receptor. Activation of the 5‐HT7 receptor leads to the activation of a cyclic AMP–protein kinase A (PKA) cascade that induces the expression of the transcription factor nerve growth factor‐inducible A (NGFiA) and cyclic AMP response element‐binding (cReB) protein (cBP) expression and their association with the neuron‐specific exon 17 GR gene promoter. (b) In neonates, high levels of licking increases NGFiA and cBP association with the exon 17 promoter by triggering demethylation of a dinucleotide sequence (cpG) that is located within the NGFiA binding region of the exon. This subsequently increases the ability of NGFiA to activate GR gene expression. M, methylation. (c) A schematic of the hypothalamic–pituitary–adrenal axis, the pivot of which are the corticotropin‐releasing factor (cRF) neurons of the paraventricular nucleus of the hypothalamus. cRF is released into the portal system of the anterior pituitary, stimulating the synthesis and release of adrenocorticotropin (AcTH), which then stimulates adrenal glucocorticoid release. Glucocorticoids act on GRs in multiple brain regions, including the hippocampus, to inhibit the synthesis and release of cRF (i.e. glucocorticoid negative feedback takes place). The adult offspring of mothers that exhibit high licking and grooming, by comparison to those of low licking and grooming dams, show increased GR expression, enhanced negative‐feedback sensitivity to glucocorticoids, reduced cRF expression in the hypothalamus and more modest pituitary–adrenal responses to stress. Adapted and reprinted with permission from Hackman et al. (, p. 656). © Nature Publishing Group.

Figure 3.

The human ACHE gene and its alternative messenger RNAs. The core of human AChE is encoded by three exons and parts of additional regions encode the variant‐specific terminal sequences. Transcription begins at E1, and E2 encodes a leader sequence that does not appear in any mature protein. In addition to a proximal promoter (red line adjacent to E1), a distal enhancer region (more distal red line) is rich in potential regulatory sequences, some of which are shown as wedges. Intron 1 (I1) contains an enhancer sequence indicated by a red dot. Nucleotide numbers are those of GeneBank cosmid AF002993. Normally, much more AChE‐S than AChE‐R mRNA is produced, but under stress or inhibition of AChE, AS produces much more of the AChE‐R mRNA. Modified and reprinted with permission from Soreq and Seidman (, p. 299). © Nature Publishing Group.

Figure 4.

Acute immobilisation stress induces AChE‐R upregulation in hippocampal CA1 neurons. Bars represent densitometric analysis (mean 7SEM; both hippocampi of n1/45 per group) of AChE‐R‐positive cells in the stratum pyramidale and stratum radiatum. Statistically significant differences: *p<.05 versus naïves. Adapted and reprinted with permission from Nijholt (, p. 177). © Nature Publishing Group.

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Charney, Evan(Jan 2014) Behavioural Genetics in the Postgenomics Era. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0025250]