title: Evidence for deep regulatory similarities in early developmental programs across highly diverged insects.
abstract: Many genes familiar from Drosophila development, such as the so-called gap, pair-rule, and segment polarity genes, play important roles in the development of other insects and in many cases appear to be deployed in a similar fashion, despite the fact that Drosophila-like "long germband" development is highly derived and confined to a subset of insect families. Whether or not these similarities extend to the regulatory level is unknown. Identification of regulatory regions beyond the well-studied Drosophila has been challenging as even within the Diptera (flies, including mosquitoes) regulatory sequences have diverged past the point of recognition by standard alignment methods. Here, we demonstrate that methods we previously developed for computational cis-regulatory module (CRM) discovery in Drosophila can be used effectively in highly diverged (250-350 Myr) insect species including Anopheles gambiae, Tribolium castaneum, Apis mellifera, and Nasonia vitripennis. In Drosophila, we have successfully used small sets of known CRMs as "training data" to guide the search for other CRMs with related function. We show here that although species-specific CRM training data do not exist, training sets from Drosophila can facilitate CRM discovery in diverged insects. We validate in vivo over a dozen new CRMs, roughly doubling the number of known CRMs in the four non-Drosophila species. Given the growing wealth of Drosophila CRM annotation, these results suggest that extensive regulatory sequence annotation will be possible in newly sequenced insects without recourse to costly and labor-intensive genome-scale experiments. We develop a new method, Regulus, which computes a probabilistic score of similarity based on binding site composition (despite the absence of nucleotide-level sequence alignment), and demonstrate similarity between functionally related CRMs from orthologous loci. Our work represents an important step toward being able to trace the evolutionary history of gene regulatory networks and defining the mechanisms underlying insect evolution.
authors.affiliation: Department of Computer Science, University of Illinois at Urbana-Champaign Laboratory of Molecular Immunology, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland mshalfon@buffalo.edu sinhas@illinois.edu.
authors.forename: Majid
authors.initials: M
authors.lastname: Kazemian
authors.affiliation: Department of Biochemistry, University at Buffalo-State University of New York NY State Center of Excellence in Bioinformatics and Life Sciences, Buffalo, New York mshalfon@buffalo.edu sinhas@illinois.edu.
authors.forename: Kushal
authors.initials: K
authors.lastname: Suryamohan
authors.affiliation: Department of Computer Science, University of Illinois at Urbana-Champaign mshalfon@buffalo.edu sinhas@illinois.edu.
authors.forename: Jia-Yu
authors.initials: JY
authors.lastname: Chen
authors.affiliation: Department of Computer Science, University of Illinois at Urbana-Champaign.
authors.forename: Yinan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Computer Science, University of Illinois at Urbana-Champaign.
authors.forename: Md Abul Hassan
authors.initials: MA
authors.lastname: Samee
authors.affiliation: Department of Biochemistry, University at Buffalo-State University of New York NY State Center of Excellence in Bioinformatics and Life Sciences, Buffalo, New York Department of Biological Sciences, University at Buffalo-State University of New York Molecular and Cellular Biology Department and Program in Cancer Genetics, Roswell Park Cancer Institute, Buffalo, New York mshalfon@buffalo.edu sinhas@illinois.edu.
authors.forename: Marc S
authors.initials: MS
authors.lastname: Halfon
authors.affiliation: Department of Computer Science, University of Illinois at Urbana-Champaign Institute of Genomic Biology, University of Illinois at Urbana-Champaign mshalfon@buffalo.edu sinhas@illinois.edu.
authors.forename: Saurabh
authors.initials: S
authors.lastname: Sinha
mesh_terms: D000818:Animals; D001483:Base Sequence; D004330:Drosophila / Q000737:chemistry / Q000145:classification / Q000235:genetics / Q000254:growth & development; D018507:Gene Expression Regulation, Developmental; D019476:Insect Proteins / Q000737:chemistry / Q000235:genetics*; D007313:Insecta / Q000737:chemistry / Q000145:classification / Q000235:genetics* / Q000254:growth & development; D010802:Phylogeny; D017385:Sequence Homology; D013045:Species Specificity
chemical_list: D019476:Insect Proteins
keywords: alignment free enhancer prediction; cross species enhancer discovery; regulatory modules in diverged insects