title: "Reverse Genomics" Predicts Function of Human Conserved Noncoding Elements.
abstract: Evolutionary changes in cis-regulatory elements are thought to play a key role in morphological and physiological diversity across animals. Many conserved noncoding elements (CNEs) function as cis-regulatory elements, controlling gene expression levels in different biological contexts. However, determining specific associations between CNEs and related phenotypes is a challenging task. Here, we present a computational "reverse genomics" approach that predicts the phenotypic functions of human CNEs. We identify thousands of human CNEs that were lost in at least two independent mammalian lineages (IL-CNEs), and match their evolutionary profiles against a diverse set of phenotypes recently annotated across multiple mammalian species. We identify 2,759 compelling associations between human CNEs and a diverse set of mammalian phenotypes. We discuss multiple CNEs, including a predicted ear element near BMP7, a pelvic CNE in FBN1, a brain morphology element in UBE4B, and an aquatic adaptation forelimb CNE near EGR2, and provide a full list of our predictions. As more genomes are sequenced and more traits are annotated across species, we expect our method to facilitate the interpretation of noncoding mutations in human disease and expedite the discovery of individual CNEs that play key roles in human evolution and development.
authors.affiliation: Department of Developmental Biology, Stanford University.
authors.forename: Amir
authors.initials: A
authors.lastname: Marcovitz
authors.affiliation: Department of Computer Science, Stanford University.
authors.forename: Robin
authors.initials: R
authors.lastname: Jia
authors.affiliation: Department of Developmental Biology, Stanford University Department of Computer Science, Stanford University Department of Pediatrics, Stanford University bejerano@stanford.edu.
authors.forename: Gill
authors.initials: G
authors.lastname: Bejerano
mesh_terms: D000818:Animals; D001483:Base Sequence; D005075:Biological Evolution; D017124:Conserved Sequence; D021901:DNA, Intergenic / Q000235:genetics*; D030561:Databases, Nucleic Acid; D004742:Enhancer Elements, Genetic; D019143:Evolution, Molecular; D005809:Genes, Regulator; D056726:Genetic Association Studies / Q000379:methods; D006801:Humans; D008322:Mammals / Q000235:genetics; D010802:Phylogeny; D022661:RNA, Untranslated / Q000235:genetics / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid; D059386:Reverse Genetics / Q000379:methods*
chemical_list: D021901:DNA, Intergenic; D022661:RNA, Untranslated
keywords: conserved noncoding elements; genotype–phenotype matching; mammals; reverse genomics