title: Predicting gene expression in massively parallel reporter assays: A comparative study.
abstract: In many human diseases, associated genetic changes tend to occur within noncoding regions, whose effect might be related to transcriptional control. A central goal in human genetics is to understand the function of such noncoding regions: given a region that is statistically associated with changes in gene expression (expression quantitative trait locus [eQTL]), does it in fact play a regulatory role? And if so, how is this role "coded" in its sequence? These questions were the subject of the Critical Assessment of Genome Interpretation eQTL challenge. Participants were given a set of sequences that flank eQTLs in humans and were asked to predict whether these are capable of regulating transcription (as evaluated by massively parallel reporter assays), and whether this capability changes between alternative alleles. Here, we report lessons learned from this community effort. By inspecting predictive properties in isolation, and conducting meta-analysis over the competing methods, we find that using chromatin accessibility and transcription factor binding as features in an ensemble of classifiers or regression models leads to the most accurate results. We then characterize the loci that are harder to predict, putting the spotlight on areas of weakness, which we expect to be the subject of future studies.
authors.affiliation: Department of Electrical Engineering and Computer Science and Center for Computational Biology, University of California, Berkeley, Berkeley, California.|Department of Bioengineering and Therapeutic Sciences, Institute for Human Genetics, University of California, San Francisco, California.
authors.forename: Anat
authors.initials: A
authors.lastname: Kreimer
authors.affiliation: Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, Massachusetts.
authors.forename: Haoyang
authors.initials: H
authors.lastname: Zeng
authors.affiliation: Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, Massachusetts.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Edwards
authors.affiliation: Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, Massachusetts.
authors.forename: Yuchun
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, Massachusetts.
authors.forename: Kevin
authors.initials: K
authors.lastname: Tian
authors.affiliation: Department of Statistics, Department of Biostatistics and Medical Informatics University of Wisconsin-Madison, Madison, Wisconsin.
authors.forename: Sunyoung
authors.initials: S
authors.lastname: Shin
authors.affiliation: Department of Statistics, Department of Biostatistics and Medical Informatics University of Wisconsin-Madison, Madison, Wisconsin.
authors.forename: Rene
authors.initials: R
authors.lastname: Welch
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Department of Computer Science, Stanford, California.
authors.forename: Michael
authors.initials: M
authors.lastname: Wainberg
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Department of Computer Science, Stanford, California.
authors.forename: Rahul
authors.initials: R
authors.lastname: Mohan
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Department of Computer Science, Stanford, California.
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Sinnott-Armstrong
authors.affiliation: Computer Science and Artificial Intelligence Lab, Massachusetts Institute of Technology, Cambridge, Massachusetts.
authors.forename: Yue
authors.initials: Y
authors.lastname: Li
authors.affiliation: Computational Cell Maps, Institute of Computational Biology, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Gökcen
authors.initials: G
authors.lastname: Eraslan
authors.affiliation: Computational and Systems Biology, Genome Institute of Singapore, Singapore, 138672, Singapore.
authors.forename: Talal Bin
authors.initials: TB
authors.lastname: Amin
authors.affiliation: Center for Systems Biology, Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, Massachusetts.|Broad Institute, Cambridge, Massachusetts.
authors.forename: Ryan
authors.initials: R
authors.lastname: Tewhey
authors.affiliation: Center for Systems Biology, Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, Massachusetts.|Broad Institute, Cambridge, Massachusetts.
authors.forename: Pardis C
authors.initials: PC
authors.lastname: Sabeti
authors.affiliation: Computational and Systems Biology, Genome Institute of Singapore, Singapore, 138672, Singapore.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Goke
authors.affiliation: Computational Cell Maps, Institute of Computational Biology, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Nikola S
authors.initials: NS
authors.lastname: Mueller
authors.affiliation: Computer Science and Artificial Intelligence Lab, Massachusetts Institute of Technology, Cambridge, Massachusetts.
authors.forename: Manolis
authors.initials: M
authors.lastname: Kellis
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Department of Computer Science, Stanford, California.
authors.forename: Anshul
authors.initials: A
authors.lastname: Kundaje
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Beer
authors.affiliation: Department of Statistics, Department of Biostatistics and Medical Informatics University of Wisconsin-Madison, Madison, Wisconsin.
authors.forename: Sunduz
authors.initials: S
authors.lastname: Keles
authors.affiliation: Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, Massachusetts.
authors.forename: David K
authors.initials: DK
authors.lastname: Gifford
authors.affiliation: Department of Electrical Engineering and Computer Science and Center for Computational Biology, University of California, Berkeley, Berkeley, California.|Ragon Institute of Massachusetts General Hospital, MIT and Harvard, Cambridge, Massachusetts.
authors.forename: Nir
authors.initials: N
authors.lastname: Yosef
mesh_terms: D019295:Computational Biology / Q000379:methods*; D015870:Gene Expression; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D006801:Humans; D040641:Quantitative Trait Loci
keywords: eQTLs; functional genomics; gene regulation; massively parallel reporter assays