Statistical models to investigate long-distance QTL transcription regulation

Summary

Principal Investigator: BARBARA ELIZABETH ENGELHARDT
Abstract: Project Summary/Abstract Thousands of genome-wide association studies link speci c diseases or complex phenotypes to single mutations in the human genome. But translating these results to medical treatments requires a precise understanding of how that mutation contributes to the mechanism of disease. Currently, the regulatory role of single nucleotide polymorphisms (SNPs) is, for the most part, con ned to local, or cis-, expression quantitative trait loci (eQTLs) in a small number of human tissues. But not all diseases or complex phenotypes are mediated by cis-eQTLs. Very few long-distance, or trans-, eQTLs have been identi ed and validated in human tissues, although trans-eQTLs play an important role in some complex phenotypes. Alternative splicing has also been shown to modulate certain phenotypes;however, little is known about SNPs that regulate alternative splicing. The proposed K99/R00 research seeks to design statistical methods that build gene and transcript networks to identify SNPs that regulate gene and mRNA isoform tran- scription, both locally and over long distances, and to validate those ndings, for the purpose of providing insight into mechanisms for complex phenotypes and disease. We propose to leverage cis-eQTLs and gene expression data in humans identi ed in our current work to build precise, directed gene networks on a genome-scale. We will build these networks using Bayesian statistical models to compute the probability of a particular network with respect to each gene in the network jointly, with associated eQTLs providing information about whether regulated genes are upstream or downstream of other network genes. We will use Markov chain Monte Carlo and linear programming relaxation methods that have been shown to nd near-optimal solutions to this type of problem. We will use these networks to identify trans-eQTLs, and quantify the e ect of each trans-eQTL in a particular process using Bayesian statistical tests developed in our lab. Subsequently, we propose to exploit the opportunities of novel RNA sequencing techniques and nonparametric statistical models to identify transcript isoforms for each transcribed gene and, simultaneously, individual-speci c transcript levels by extending sparse factor analysis models. This will enable us to identify QTLs that regulate the transcription of speci c transcript isoforms (tQTLs) via alternative splicing events by extending the methods we have for eQTL identi cation. We will use the methodology we developed for eQTLs to build networks for transcript isoforms (transcript networks ). Finally, we will use transcript networks to identify and quantify tQTLs that regulate individual-speci c levels of transcript isoforms both locally and over long genetic distances, as with eQTLs. We will make all of our methods and results publicly available.
Funding Period: 2011-09-06 - 2015-06-30
more information: NIH RePORT

Top Publications

  1. pmc Molecular function prediction for a family exhibiting evolutionary tendencies toward substrate specificity swapping: recurrence of tyrosine aminotransferase activity in the Iα subfamily
    Kathryn E Muratore
    Department of Molecular and Cell Biology, University of California, Berkeley, California
    Proteins 81:1593-609. 2013
  2. pmc Genetic variation associated with euphorigenic effects of d-amphetamine is associated with diminished risk for schizophrenia and attention deficit hyperactivity disorder
    Amy B Hart
    Departments of Human Genetics, Medicine, and Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL 60637
    Proc Natl Acad Sci U S A 111:5968-73. 2014

Detail Information

Publications2

  1. pmc Molecular function prediction for a family exhibiting evolutionary tendencies toward substrate specificity swapping: recurrence of tyrosine aminotransferase activity in the Iα subfamily
    Kathryn E Muratore
    Department of Molecular and Cell Biology, University of California, Berkeley, California
    Proteins 81:1593-609. 2013
    ..The additional functional characterizations described in this article, alongside a detailed sequence and phylogenetic analysis, provide some novel clues to understanding the evolutionary mechanisms at work in this family...
  2. pmc Genetic variation associated with euphorigenic effects of d-amphetamine is associated with diminished risk for schizophrenia and attention deficit hyperactivity disorder
    Amy B Hart
    Departments of Human Genetics, Medicine, and Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL 60637
    Proc Natl Acad Sci U S A 111:5968-73. 2014
    ....

Research Grants30

  1. Genetic &Functional Analyses of Hypertension Susceptibility Genes
    YEN PEI CHRISTY CHANG; Fiscal Year: 2013
    ..To accomplish these goals, we have brought together investigators who are experts in hypertension genetics, transcriptional regulation, bioinformatics, molecular biology, biochemistry, and renal physiology. ..
  2. Genomics for Transplantation: Discovery and Biomarkers
    Daniel R Salomon; Fiscal Year: 2013
    ..Ultimately, we hope to create the genomic tools that will allow physicians to optimize and personalize the safety and efficacy of immunosuppression. ..
  3. Intellectual and Development Disabilities Research Center
    Marc Yudkoff; Fiscal Year: 2013
    ..5 million from NICHD). The Center includes an excess of 70 Penn faculty at 15 departments at the Schools of Medicine, Veterinary Medicine, Nursing, the Wistar Institute, and the College of Arts and Sciences. ..
  4. Molecular Pathogenesis of Basal-like Breast Cancer
    Richard J Baer; Fiscal Year: 2013
    ..e., metastasis, and develop strategies for therapy. ..
  5. The Virtual Physiological Rat Project
    Daniel A Beard; Fiscal Year: 2013
    ..This proposal targets the grand challenge of understanding complex multi-faceted disease phenotypes through experiments and simulations that capture the complex genotype-environment-phenotype relationship. ..
  6. Mapping Expression Quantitative Trait Loci with Next Generation Sequencing in SLE
    Min Chen; Fiscal Year: 2013
    ....
  7. Informatics platform for mammalian gene regulation at isoform-level
    Ramana V Davuluri; Fiscal Year: 2013
    ..The novel bioinformatics methods developed by this project will help in silico discovery and research for accelerating the linkage of phenotypic and genomic information, at gene-isoform level. ..
  8. Molecular and Cellular Therapies for Muscular Dystrophy
    Stanley C Froehner; Fiscal Year: 2013
    ..The mechanism of NPC1 phenotype amelioration and its applicability to LGMDs will be studied. Two core facilities will serve the participating laboratories. ..
  9. Protein homeostasis mechanisms underlying enterovirus replication and evolution
    Raul Andino; Fiscal Year: 2013
    ..Core A: Administrative Core;and Core B: "High-throughput functional genomics and proteomics core. ..
  10. Elucidation of Tissue-Specific Transcriptomic Profiles in Cardiometabolic Disease
    Muredach P Reilly; Fiscal Year: 2013
    ....
  11. Annotation and interpretation of loss-of-function polymorphisms in human genomes
    Daniel G MacArthur; Fiscal Year: 2013
    ..This study will provide powerful tools for discovering and characterizing natural loss-of-function variants, and for exploring their potential association with human disease risk. ..
  12. New Methods to Uncover Global Transcriptional Programs for Disease Risk Variants
    Yousin Suh; Fiscal Year: 2013
    ..abstract_text> ..
  13. DIABETES AND ENDOCRINOLOGY RESEARCH CENTER
    Domenico Accili; Fiscal Year: 2013
    ....
  14. T cell effector and regulatory mechanisms in asthma and food allergy
    Andrew D Luster; Fiscal Year: 2013
    ..This would pave the way for new therapeutic approaches to treat these and other allergic diseases. ..
  15. Mapping QTLs Associated with Variation in RNA Decay Rates
    Yoav Gilad; Fiscal Year: 2013
    ....
  16. Alignment Software for Second-Generation Sequencing
    Steven L Salzberg; Fiscal Year: 2013
    ....
  17. Inflammatory responses of vascular cells
    Paul L Fox; Fiscal Year: 2013
    ..abstract_text> ..
  18. JCIMPT-Complexes
    Raymond C Stevens; Fiscal Year: 2013
    ..These proteins (e.g. human G-protein coupled receptors) are the target of the majority of therapeutic drug targets. There is a critical need to develop breakthrough technologies to enable better characterization of this protein family. ..
  19. Functional Genomics of Atrial Fibrillation in Human Atria
    David R Van Wagoner; Fiscal Year: 2013
    ....