Understanding the epigenome using system genetics

Abstract

Genetics has been successful in associating DNA sequence variants to both dichotomous and continuous traits in a variety of organisms, from plant and farm animal studies to human disease. With the advent of high-throughput genotyping, there has been an almost routine gen- eration of genome-wide association studies (GWAS) between human disease traits and genomic regions. Despite this success, a particular frustration is that the majority of associated loci are in non-coding regions of the genome and thus interpretation is hard. To improve characterisation of non-coding regions, molecular as- says can be used as a phenotype, and subsequently be used to explain how genetics alter molecular mechanisms. In this thesis, the inter- play of three molecular assays that are involved in regulating gene expression is studied. On 60 individuals, several assays are performed: FAIRE-chip, CTCF- seq, RNA-seq and DNA-seq. In the first part, the discovery and characteristics of FAIRE-QTLs is presented. The identified FAIRE-QTLs show strong overlap with other molecular QTLs, histone modifications, and transcription factors. The second part consists of the integration of genome-wide molecu- lar assays in a human population to reconstruct the human epigenome. Each of the molecular assays is associated with each of the other assays to discover phenotype-to-phenotype correlations. Furthermore, QTL data are used to dissect the causality for these phenotype-to-phenotype correlations in a system genetic manner. The third part presents a comprehensive view of CTCF binding on the X chromosome, and its implications for X-chromosome inactivation. A novel X chromosome-wide CTCF effect is observed. Using the gender of each of the cell lines, observations are made about which CTCF sites are dosage-compensated, active on both chromosomes, or are only bound in females.