Cellular Systems Genetics in Humans

Many of the DNA sequence variants responsible for disease and complex trait have been hypothesized and partly shown to influence the degree of gene activity. Many of these effects manifest themselves via changes in the biochemistry of the chromatin or the DNA itself. Elucidating the interactions that occur among regions that regulate gene expression and their variability among individuals is fundamental to the understanding of the biology behind human disease and phenotypic variability.

In this project, we aim to disentangle the relationships between genetic, epigenetic and gene expression mechanisms in order to achieve two goals simultaneously:

• to determine the direct molecular functional effects of human genetic variants;
• to unravel the mechanistic relationships and interactions between various molecular effects in regions responsible for gene expression regulation.

To this end, we will perform in depth investigation of the genetic information contained in two cell types, fibroblasts from umbilical cord skin and lymphoblastoid cell lines from blood B-cells, which we obtained from 200 individuals. For each of the cell types in all 200 individuals we will also carry out four epigenetic assays that are known to be relevant to regulatory interactions and gene activation or repression.

Specific goals

The specific aims of our proposal are:

• to obtain a detailed and comprehensive map of key epigenetic effects and gene expression regulators jointly with genetic variation, gene expression and protein abundance of key gene expression regulators;
• to integrate all these data into a meaningful and analysis-friendly framework for the needs of the proposed project but also for the scientific community once these data are published;
• to detect and quantify the impact of genetic variation on gene regulation processes such as epigenetic effects and gene expression, and to provide the raw material for better understanding of their higher order interactions;
• to use genetic variation as perturbations of biological systems in order to determine the mechanistic and synergistic relationships of regulatory components in regional (local) networks and to further validate them.

Updated June 2013