Functional genomics and systems biology in human neuroscience

Abstract

Neuroscience research has entered a phase of key discoveries in the realm of neurogenomics owing to strong financial and intellectual support for resource building and tool development. The previous challenge of tissue heterogeneity has been met with the application of techniques that can profile individual cells at scale. Moreover, the ability to perturb genes, gene regulatory elements and neuronal activity in a cell-type-specific manner has been integrated with gene expression studies to uncover the functional underpinnings of the genome at a systems level. Although these insights have necessarily been grounded in model systems, we now have the opportunity to apply these approaches in humans and in human tissue, thanks to advances in human genetics, brain imaging and tissue collection. We acknowledge that there will probably always be limits to the extent to which we can apply the genomic tools developed in model systems to human neuroscience; however, as we describe in this Perspective, the neuroscience field is now primed with an optimal foundation for tackling this ambitious challenge. The application of systems-level network analyses to these datasets will facilitate a deeper appreciation of human neurogenomics that cannot otherwise be achieved from directly observable phenomena.

Figure 1:. Mining human brain single cell datasets to infer regulatory mechanisms.

Human brain tissue can be queried for genomic information at the RNA and chromatin level. However, these datasets require further applied analysis to understand the dynamic nature of the datasets. WGCNA can be used to understand cell type composition and contributions as well as the dynamic nature of cell type development. Gene regulatory networks (GRN) can be applied to infer which transcription factors (TFs) might be important for co-regulation of sets of genes in a given cell type. Since these regulatory mechanisms cannot be directly tested in vivo in human, they can instead be tested in either human brain slice culture or model systems (e.g., rodent or monkey) using CRISPR-based tools.

Figure 2:. Integrative approaches to use human brain tissue to uncover multimodal systems related to genomics.

A) Brain imaging can be combined with peripheral DNA profiling to infer genetic variants that may underlie brain size or function. B) Brain gene expression and chromatin state data from post-mortem tissues can be integrated with functional MRI measures to understand how gene expression patterns may underlie brain activity. C) Human post-mortem tissues can be used to confirm findings from all other approaches. D) Ex vivo brain slice cultures can be acquired from surgical patients and use to integrate physiological and gene expression measures from the same individual.