Abstract

One of the central problems in modern human genetics is to understand the functional impact of genetic variation. Of the millions of DNA positions that vary among humans, which sites actually impact human phenotypes and disease? It is becoming increasingly clear that noncoding variants that impact gene regulation play central roles in the genetics of disease. Yet we have limited understanding of the precise pathways by which these variants act, and it remains extremely difficult to predict which variants in the genome have regulatory effects. In this projec we propose to use detailed functional characterization of a variety of aspects of gene regulation, using 70 human lymphoblastoid cell lines as a model system, along with new computational methods, to dissect in detail the mechanisms by which genetic variation impacts gene expression levels.

Public Health Relevance

The purpose of this project is to improve our understanding of the mechanistic links between genetic variation and differences in gene regulation across individuals. This work will be valuable for interpreting disease association studies using resequencing and GWAS approaches.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
2R01MH084703-04
Application #
8439146
Study Section
Genomics, Computational Biology and Technology Study Section (GCAT)
Program Officer
Addington, Anjene M
Project Start
2008-09-25
Project End
2016-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
4
Fiscal Year
2012
Total Cost
$509,792
Indirect Cost
$180,091

  Institution

Name
University of Chicago
Department
Genetics
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637

  Publications

Blake, Lauren E; Thomas, Samantha M; Blischak, John D et al. (2018) A comparative study of endoderm differentiation in humans and chimpanzees. Genome Biol 19:162
Banovich, Nicholas E; Li, Yang I; Raj, Anil et al. (2018) Impact of regulatory variation across human iPSCs and differentiated cells. Genome Res 28:122-131
Gymrek, Melissa; Willems, Thomas; Guilmatre, Audrey et al. (2016) Abundant contribution of short tandem repeats to gene expression variation in humans. Nat Genet 48:22-9
Raj, Anil; Wang, Sidney H; Shim, Heejung et al. (2016) Thousands of novel translated open reading frames in humans inferred by ribosome footprint profiling. Elife 5:
Li, Yang I; van de Geijn, Bryce; Raj, Anil et al. (2016) RNA splicing is a primary link between genetic variation and disease. Science 352:600-4
Field, Yair; Boyle, Evan A; Telis, Natalie et al. (2016) Detection of human adaptation during the past 2000 years. Science 354:760-764
Burrows, Courtney K; Banovich, Nicholas E; Pavlovic, Bryan J et al. (2016) Genetic Variation, Not Cell Type of Origin, Underlies the Majority of Identifiable Regulatory Differences in iPSCs. PLoS Genet 12:e1005793
Raj, Anil; Shim, Heejung; Gilad, Yoav et al. (2015) msCentipede: Modeling Heterogeneity across Genomic Sites and Replicates Improves Accuracy in the Inference of Transcription Factor Binding. PLoS One 10:e0138030
Battle, Alexis; Khan, Zia; Wang, Sidney H et al. (2015) Genomic variation. Impact of regulatory variation from RNA to protein. Science 347:664-7
Thomas, Samantha M; Kagan, Courtney; Pavlovic, Bryan J et al. (2015) Reprogramming LCLs to iPSCs Results in Recovery of Donor-Specific Gene Expression Signature. PLoS Genet 11:e1005216

Showing the most recent 10 out of 32 publications