Causes and consequences of regulatory genetic variation

Project Summary / Abstract
Genetic variation among individuals shapes important phenotypes, including the risk for common human
diseases such as cardiovascular, autoimmune, and neurological disease. In particular, regulatory genetic
variation causes inter-individual differences in gene expression. The resulting gene expression differences
account for a substantial portion of variation in many genetically complex traits.
In spite of the critical importance of regulatory variation, many fundamental questions remain open. First,
most DNA differences in a given genome likely have no effect. The nature of the specific variants that do
have effects remains poorly understood. Second, genetic variation can specifically affect the protein
abundance of a given gene without altering the abundance of the mRNA of the same gene. The
mechanisms that are responsible for these protein-specific effects remain unclear. Third, we only have a
crude understanding of how the differences in gene expression that result from regulatory variation affect
organismal phenotypes.
Over the next five years, research in my laboratory will focus on addressing these critical gaps in
knowledge. Specifically, we seek to identify and characterize causal DNA variants, study the impact of
genetic variation on protein degradation, and examine quantitatively how the precise abundance of a given
gene can shape organismal traits. Our work combines computational biology, quantitative and statistical
genetics with experimental genome-wide approaches. We use the yeast Saccharomyces cerevisiae as a
powerful and tractable model system for regulatory variation, while pursuing related approaches in human
cells.
Our long-term vision is to improve our understanding of regulatory variation to the point at which it becomes
possible to accurately predict the consequences of the DNA variants in an individual’s genome. This ability
will be valuable for fundamental research and personalized approaches for improving human health.

Grant Number: 5R35GM124676-09
NIH Institute/Center: NIH
Principal Investigator: Frank Albert