Monoallelic Gene Expression In Human Neural Stem Cells

Abstract

Monoallelic expression is when only one of a gene’s two copies is transcribed. It has long been recognised in the form of X-chromosome inactivation, genomic imprinting and random monoallelic expression (RME) of a small number of gene families. More recently, studies have reported evidence of widespread autosomal RME in human lymphoblastoid cells (Gimelbrant et al. 2007) and mouse neural stem cells (Wang et al.2010; Li et al. 2012). However, the extent to which RME occurs in human neural tissue is unknown. Using a genome-wide analysis of allele-specific expression in human neural stem cells, I reveal that 1.6 to 2.2% of assayed autosomal genes display monoallelic expression and 0.5 to 1.1% show evidence of RME. This is largely retained after differentiation into neurons and glia. I also present evidence in support of RME altering gene transcript levels and exposing heterozygous functional variation. These results are a first demonstration that autosomal RME is widespread in human neural tissue and
indicate that it is a potential source of phenotypic diversity between genetically identical neural stem cells in vitro. Furthermore, I find the novel RME genes reported in this thesis to be epigenetically distinct from biallelic genes in human foetal and adult brain in a manner consistent with monoallelic expression. Together, these findings support a model in which the human central nervous system is a mosaic of clones of cells, each with different gene expression potentials. Although the presence of widespread RME in the human central nervous system remains to be demonstrated in vivo, if present, this would be predicted to have significant implications for human neural development, function and disease. Finally, I map the genetic variants associated with the monoallelic expression of PM20D1, a gene located in the Parkinson’s disease susceptibility locus PARK16.

Date of Award	1 Apr 2013
Original language	English
Awarding Institution	King's College London
Supervisor	Jack Price (Supervisor) & Sandrine Thuret (Supervisor)