Recent technological advances in genome sequencing have enabled numerous large-scale association studies aimed at discovering genetic variants underlying a wide array of complex diseases. It has become increasingly evident that the majority of these associations stem from a perturbation of regulatory function. While the ENCODE project and related efforts have strengthened our ability to comprehensively identify regulatory elements, our ability to decipher the impact of individual variants within these elements has not kept step. To address this gap, I aim to develop and apply the massively parallel reporter assay (MPRA) to empirically test the regulatory potential of thousands of individual variant sites for a wide range of roles.
My specific aims are to: (1) Demonstrate the utility of MPRA by applying the method to loci in the human genome with evidence of recent positive selection and those identified in published genome wide association studies; (2) Modify MPRA to capture a more comprehensive array of regulatory mechanisms; and (3) Transition the current MPRA episomal vector to a viral delivery platform, allowing for chromosomal integration. I anticipate that these methods will provide the broader research community with a catalog of biologically meaningful regulatory variants and a valuable toolkit for understanding the role that regulatory variation plays in human health and disease.

Public Health Relevance

We are entering an era of personalized medicine where our ability to decipher a patient's genome has the potential to transform clinical care. Critical to ths transformation will be our ability to understand the role of the genetic variation within the vast majority of the genome that does not directly code for proteins. My work aims to develop high-throughput experimental systems to empirically test the function of this variation in influencing human health and disease.

Agency
National Institute of Health (NIH)
Institute
National Human Genome Research Institute (NHGRI)
Type
Research Transition Award (R00)
Project #
5R00HG008179-04
Application #
9623356
Study Section
Special Emphasis Panel (NSS)
Program Officer
Pazin, Michael J
Project Start
2014-12-01
Project End
2020-11-30
Budget Start
2018-12-01
Budget End
2019-11-30
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Jackson Laboratory
Department
Type
DUNS #
042140483
City
Bar Harbor
State
ME
Country
United States
Zip Code
04609