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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH084703-05
Application #
8538502
Study Section
Genomics, Computational Biology and Technology Study Section (GCAT)
Program Officer
Senthil, Geetha
Project Start
2008-09-25
Project End
2016-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
5
Fiscal Year
2013
Total Cost
$440,461
Indirect Cost
$155,598
Name
University of Chicago
Department
Genetics
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
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Cusanovich, Darren A; Pavlovic, Bryan; Pritchard, Jonathan K et al. (2014) The functional consequences of variation in transcription factor binding. PLoS Genet 10:e1004226
Banovich, Nicholas E; Lan, Xun; McVicker, Graham et al. (2014) Methylation QTLs are associated with coordinated changes in transcription factor binding, histone modifications, and gene expression levels. PLoS Genet 10:e1004663
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Pai, Athma A; Bell, Jordana T; Marioni, John C et al. (2011) A genome-wide study of DNA methylation patterns and gene expression levels in multiple human and chimpanzee tissues. PLoS Genet 7:e1001316
Bell, Jordana T; Pai, Athma A; Pickrell, Joseph K et al. (2011) DNA methylation patterns associate with genetic and gene expression variation in HapMap cell lines. Genome Biol 12:R10
Pickrell, Joseph K; Gaffney, Daniel J; Gilad, Yoav et al. (2011) False positive peaks in ChIP-seq and other sequencing-based functional assays caused by unannotated high copy number regions. Bioinformatics 27:2144-6

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