Single cell genomics of the brain: focus on neuronal diversity and neuropsychiatric diseases

Abstract

Single cell genomics has made increasingly significant contributions to our understanding of the role that somatic genome variations play in human neuronal diversity and brain diseases. Studying intercellular genome and epigenome variations has provided new clues to the delineation of molecular mechanisms that regulate development, function and plasticity of the human central nervous system (CNS). It has been shown that changes of genomic content and epigenetic profiling at single cell level are involved in the pathogenesis of neuropsychiatric diseases (schizophrenia, mental retardation (intellectual/leaning disability), autism, Alzheimer's disease etc.). Additionally, several brain diseases were found to be associated with genome and chromosome instability (copy number variations, aneuploidy) variably affecting cell populations of the human CNS. The present review focuses on the latest advances of single cell genomics, which have led to a better understanding of molecular mechanisms of neuronal diversity and neuropsychiatric diseases, in the light of dynamically developing fields of systems biology and "omics".

Keywords: Aneuploidy; Brain; Chromosome instability; Disease; Epigenome; Genomic variations; Single cell genomics; Somatic mosaicism..

Fig. (1)

Technological principles of single cell genomics of the brain. The first step of any procedure aimed at studying genome/epigenome (proteome/metabolome) at single cell level is cell isolation. The latter can be performed in a variety of manners (i.e. brain cell suspension preparations, FACS or other flow-cytometry-based approaches; for more details see [28, 29]). The obtained cells can be subjected to procedures allowing microscopic visual analysis (visualization) of macromolecules (nucleic acids, proteins etc.) or macromolecular complexes (i.e. chromatin) through direct staining of cells, FISH, immunocytochemistry or immunohistochemistry. Alternatively, extraction of biomolecules can be performed to perform analysis of nucleic acids (DNA/RNA), proteins and metabolites either through on-chip technologies or through mass spectrometry and nuclear magnetic resonance technologies. Moreover, “lab-on-chip” technologies have been recently become available for analyzing simultaneously nucleic acids, proteins and metabolites of a cell [32]. All the data can be processed by systems biology (bioinformatic/in silico) approaches to create an integrated view of genetic, epigenetic, proteomic and metabolomic profiles.

Fig. (2)

Schematic representation of the hypothesis proposing the contribution of natural somatic variations of neural genome in the developing human brain to neuronal variability and pathogenesis of CIN syndromes (i.e. AT) and non-malignant brain diseases associated with mosaic aneuploidy selectively affecting the brain in postnatal period (for more details see [7, 45, 72, 75]). CIN rates increase during the first trimester (up to 30-35%), then the rates are suggested to decrease, achieving ~10% in the unaffected postnatal brain. In CIN syndromes (AT), the rates remain approximately the same as in the developing brain during the first trimester, whereas CIN rates decreases in cases of neuropsychiatric diseases, but mosaicism levels remain stable causing overall aneuploidy rate to be significantly higher.