title: Genetic variants regulating expression levels and isoform diversity during embryogenesis.
abstract: Embryonic development is driven by tightly regulated patterns of gene expression, despite extensive genetic variation among individuals. Studies of expression quantitative trait loci (eQTL) indicate that genetic variation frequently alters gene expression in cell-culture models and differentiated tissues. However, the extent and types of genetic variation impacting embryonic gene expression, and their interactions with developmental programs, remain largely unknown. Here we assessed the effect of genetic variation on transcriptional (expression levels) and post-transcriptional (3' RNA processing) regulation across multiple stages of metazoan development, using 80 inbred Drosophila wild isolates, identifying thousands of developmental-stage-specific and shared QTL. Given the small blocks of linkage disequilibrium in Drosophila, we obtain near base-pair resolution, resolving causal mutations in developmental enhancers, validated transcription-factor-binding sites and RNA motifs. This fine-grain mapping uncovered extensive allelic interactions within enhancers that have opposite effects, thereby buffering their impact on enhancer activity. QTL affecting 3' RNA processing identify new functional motifs leading to transcript isoform diversity and changes in the lengths of 3' untranslated regions. These results highlight how developmental stage influences the effects of genetic variation and uncover multiple mechanisms that regulate and buffer expression variation during embryogenesis.
authors.affiliation: European Molecular Biology Laboratory (EMBL), Genome Biology Unit, D-69117 Heidelberg, Germany.
authors.forename: Enrico
authors.initials: E
authors.lastname: Cannavò
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Hinxton CB10 1SD, UK.
authors.forename: Nils
authors.initials: N
authors.lastname: Koelling
authors.affiliation: European Molecular Biology Laboratory (EMBL), Genome Biology Unit, D-69117 Heidelberg, Germany.
authors.forename: Dermot
authors.initials: D
authors.lastname: Harnett
authors.affiliation: European Molecular Biology Laboratory (EMBL), Genome Biology Unit, D-69117 Heidelberg, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Garfield
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Hinxton CB10 1SD, UK.
authors.forename: Francesco P
authors.initials: FP
authors.lastname: Casale
authors.affiliation: European Molecular Biology Laboratory (EMBL), Genome Biology Unit, D-69117 Heidelberg, Germany.
authors.forename: Lucia
authors.initials: L
authors.lastname: Ciglar
authors.affiliation: European Molecular Biology Laboratory (EMBL), Genome Biology Unit, D-69117 Heidelberg, Germany.
authors.forename: Hilary E
authors.initials: HE
authors.lastname: Gustafson
authors.affiliation: European Molecular Biology Laboratory (EMBL), Genome Biology Unit, D-69117 Heidelberg, Germany.
authors.forename: Rebecca R
authors.initials: RR
authors.lastname: Viales
authors.affiliation: European Molecular Biology Laboratory (EMBL), Genome Biology Unit, D-69117 Heidelberg, Germany.
authors.forename: Raquel
authors.initials: R
authors.lastname: Marco-Ferreres
authors.affiliation: European Molecular Biology Laboratory (EMBL), Genome Biology Unit, D-69117 Heidelberg, Germany.
authors.forename: Jacob F
authors.initials: JF
authors.lastname: Degner
authors.affiliation: European Molecular Biology Laboratory (EMBL), Genome Biology Unit, D-69117 Heidelberg, Germany.
authors.forename: Bingqing
authors.initials: B
authors.lastname: Zhao
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Hinxton CB10 1SD, UK.
authors.forename: Oliver
authors.initials: O
authors.lastname: Stegle
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Hinxton CB10 1SD, UK.
authors.forename: Ewan
authors.initials: E
authors.lastname: Birney
authors.affiliation: European Molecular Biology Laboratory (EMBL), Genome Biology Unit, D-69117 Heidelberg, Germany.
authors.forename: Eileen E M
authors.initials: EE
authors.lastname: Furlong
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000483:Alleles; D000818:Animals; D001665:Binding Sites; D004331:Drosophila melanogaster / Q000196:embryology* / Q000235:genetics*; D047108:Embryonic Development / Q000235:genetics*; D004742:Enhancer Elements, Genetic; D018507:Gene Expression Regulation, Developmental; D014644:Genetic Variation; D015810:Linkage Disequilibrium; D009154:Mutation; D040641:Quantitative Trait Loci; D026721:RNA 3' End Processing; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D020413:3' Untranslated Regions; D014157:Transcription Factors