title: Fast, scalable prediction of deleterious noncoding variants from functional and population genomic data.
abstract: Many genetic variants that influence phenotypes of interest are located outside of protein-coding genes, yet existing methods for identifying such variants have poor predictive power. Here we introduce a new computational method, called LINSIGHT, that substantially improves the prediction of noncoding nucleotide sites at which mutations are likely to have deleterious fitness consequences, and which, therefore, are likely to be phenotypically important. LINSIGHT combines a generalized linear model for functional genomic data with a probabilistic model of molecular evolution. The method is fast and highly scalable, enabling it to exploit the 'big data' available in modern genomics. We show that LINSIGHT outperforms the best available methods in identifying human noncoding variants associated with inherited diseases. In addition, we apply LINSIGHT to an atlas of human enhancers and show that the fitness consequences at enhancers depend on cell type, tissue specificity, and constraints at associated promoters.
authors.affiliation: Simons Center for Quantitative Biology, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA.
authors.forename: Yi-Fei
authors.initials: YF
authors.lastname: Huang
authors.affiliation: Simons Center for Quantitative Biology, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA.|Graduate Field of Computer Science, Cornell University, Ithaca, New York, USA.
authors.forename: Brad
authors.identifier: http://orcid.org/0000-0001-8366-589X
authors.initials: B
authors.lastname: Gulko
authors.affiliation: Simons Center for Quantitative Biology, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Siepel
mesh_terms: D000818:Animals; D001483:Base Sequence / Q000235:genetics; D019295:Computational Biology / Q000379:methods; D019143:Evolution, Molecular; D014644:Genetic Variation / Q000235:genetics*; D016678:Genome / Q000235:genetics*; D006801:Humans; D008322:Mammals; D056186:Metagenomics / Q000379:methods; D010641:Phenotype; D011323:Primates; D014714:Vertebrates