Early/late-life adversities and behavioural phenotypes: insight into metabolomics, genomics and connectomics.

03Original abstract

The 19th International Research Symposium of the Society for the Study of Behavioral Phenotypes (SSBP) will be held in Siena, Italy, and the main theme will be the new biochemical, genetic and neuroimaging techniques now available to investigate brain function in typical development and in different pathological conditions. “The factors which confer upon us our predispositions to and immunities from the various mishaps which are spoken of as diseases, are inherent in our very chemical structure; and even in the molecular groupings which confer upon us our individualities, and which went to the making of the chromosomes from which we sprang.” Garrod's work more than one hundred years ago opened the way for description of the metabolic basis of human diseases and for the concept that an enzyme deficiency, reflecting metabolic changes of the brain, may be the basis of the different phenotypic manifestation related to different vulnerabilities of the central nervous system cells. In 2005, METLIN, the first metabolomics web database to characterize human metabolites, was developed. It contained more than 10,000 metabolites and tandem mass spectral data. As of September 2015, METLIN contained over 240,000 metabolites as well as the largest repository of tandem mass spectrometry data in metabolomics (Smith et al. 2005). Two years later In 2007, the Human Metabolome Project, completed the first draft of the human metabolome (approximately 2500 metabolites, 1200 drugs and 3500 food components) (Wishart et al. 2007). Alongside these developments in metabolomics there have been parallel advances in genomics. Genomics applies recombinant DNA, DNA sequencing methods, and bioinformatics to sequence, assemble and analyse the function and structure of genomes - the complete set of DNA within a single cell of an organism. Advances in genomics have the potential to make particular contributions to understanding the genetic basis of the most complex biological systems such as the brain (Kadakkuzha & Puthanveettil 2013). The field includes efforts to determine the entire DNA sequence of organisms and fine-scale genetic mapping, including studies on intragenomic changes and interactions between the genetic loci and allele. Epigenomics is the study of the complete set of epigenetic modifications on the genetic material of a cell, known as the epigenome (Francis 2011). Epigenetic changes are reversible modifications on a cell's DNA or histones that affect gene expression without altering the DNA sequence. Two of the most well-characterised epigenetic modifications are DNA methylation and histone modification, the first playing an important role in gene expression and regulation, and both are involved in numerous cellular processes, such as in differentiation/development and tumorigenesis. The study of epigenetics on a global level has been made possible only recently through the adaptation of genomic high-throughput assays (Laird 2010). Connectomics is considered a branch of biotechnology that uses automated, high-speed imaging systems to construct detailed maps of neural circuits. As the human genome project sought to map and identify all of the genes in human DNA, connectomics seeks to identify and map all neural connections in the brain (connectomes). There is now evidence that network organisation is altered in different brain diseases, and a connectomic approach may therefore be important to generate predictive models of the spread and functional consequences of brain disease (Fornito et al. 2015). The Human Connectome Project has been developed recently, with the aim of mapping the neural pathways that underlie human brain function with a tentative explanation for accumulating results in normal and pathological human disorders. Other aspects of the symposium will cover autism and related neurodevelopmental disorders, from genetics to epigenetics, behavioural phenotypes in genetic neurometabolic diseases as a model for understanding the role of different metabolic alterations in brain functions and dysfunctions, Down syndrome and Alzheimer's disease, sex chromosomal aneuploidies and fragile X syndrome. As always, the SSBP symposia will have submitted abstract on the full range of syndromes associated with behavioural phenotypes. The integration of the results of modern genetic, biochemical and neuroimaging techniques may open new developments and enhance our knowledge of the complexity of the central nervous system functions and dysfunctions. The use of all these techniques in the human models of pathology may illuminate the metabolic and structural network organisation abnormalities derived from a primary genetic change. Our hope is that the exciting advances in all the ‘omics’ as outlined above, may soon directly lead to improved insights into the causes of and treatments for children, adolescents and adults who live with genetic syndromes.

Journal of intellectual disability research : JIDR, 2016 · doi:10.1111/jir.12326