EGAGenomicsMultiomicsJohn Hardyhttps://ega-archive.org/dacs/EGAC00001000314EGAEGA DAC EGAC00001000314EGAj.hardy@ucl.ac.ukIt is generally believed that splicing removes introns as single units from precursor messenger RNA transcripts. However, some long Drosophila melanogaster introns contain a cryptic site, known as a recursive splice site (RS-site), that enables a multi-step process of intron removal termed recursive splicing. The extent to which recursive splicing occurs in other species and its mechanistic basis have not been examined. Here we identify highly conserved RS-sites in genes expressed in the mammalian brain that encode proteins functioning in neuronal development. Moreover, the RS-sites are found in some of the longest introns across vertebrates. We find that vertebrate recursive splicing requires initial definition of an 'RS-exon' that follows the RS-site. The RS-exon is then excluded from the dominant mRNA isoform owing to competition with a reconstituted 5' splice site formed at the RS-site after the first splicing step. Conversely, the RS-exon is included when preceded by cryptic promoters or exons that fail to reconstitute an efficient 5' splice site. Most RS-exons contain a premature stop codon such that their inclusion can decrease mRNA stability. Thus, by establishing a binary splicing switch, RS-sites demarcate different mRNA isoforms emerging from long genes by coupling cryptic elements with inclusion of RS-exons.Germ-line genetic control of gene expression occurs via expression quantitative trait loci (eQTLs). We present a large, exon-specific eQTL data set covering ten human brain regions. We found that cis-eQTL signals (within 1 Mb of their target gene) were numerous, and many acted heterogeneously among regions and exons. Co-regulation analysis of shared eQTL signals produced well-defined modules of region-specific co-regulated genes, in contrast to standard coexpression analysis of the same samples. We report cis-eQTL signals for 23.1% of catalogued genome-wide association study hits for adult-onset neurological disorders. The data set is publicly available via public data repositories and via http://www.braineac.org/. Our study increases our understanding of the regulation of gene expression in the human brain and will be of value to others pursuing functional follow-up of disease-associated variants.Genetic variability in the regulation of gene expression in ten regions of the human brain.Recursive splicing in long vertebrate genes.Ramasamy Adaikalavan A, Trabzuni Daniah D, Guelfi Sebastian S, Varghese Vibin V, Smith Colin C, Walker Robert R, De Tisham T, Coin Lachlan L, de Silva Rohan R, Cookson Mark R MR, Singleton Andrew B AB, Hardy John J, Ryten Mina M, Weale Michael E MESibley Christopher R CR, Emmett Warren W, Blazquez Lorea L, Faro Ana A, Haberman Nejc N, Briese Michael M, Trabzuni Daniah D, Ryten Mina M, Weale Michael E ME, Hardy John J, Modic Miha M, Curk Tomaž T, Wilson Stephen W SW, Plagnol Vincent V, Ule Jernej Jfbwd4, l(2)04454, DmelCG1772, dac, CIB1, shsf3, Person., shfm3, E(Sev-CycE)2B, p21[dacapo], Fbw4, FBW4, dactylin, E130112M23Rik, Dach, CDKN2B, cdi4, SHFM3, Dac, DAC, p27[Dap], dactylyn, dacapo/cyclin-dependent kinase interactor 4, AI182278, p21, CG1772, FBWD4, Dap, Cdi4, CDI4, CES5A1, p27, P15, fbw4, SHSF3, Decapothe brain, suprasegmental structures, human being, Man (Taxonomy), Modern, Regulation of Gene Expression, familial, Gene, suprasegmental levels of nervous system, encephalon, human, Encephalon., regulation of protein expression, regulation of gene product expression, genetic, Gene Action, Human, Gene Action Regulation, Gene Expression, Expression Regulation, Homo sapiens, Modern Man, inherited genetic, synganglion, gene regulation, constitutitional genetic, hereditary, Regulation, Manextent, the brain, fruit fly, nuclear mRNA cis splicing, Materials, GRP1/cytohesin 1, single-organism developmental process, postnatal development, Degradation, mRNA Stability, Gene, Mini Exon, growth and development, Sophophora melanogaster, precursor, melanogaster, element, protrusion, CG11633, cytohesin/GRP1, Stability, STOP, Sense Codon, Stable tubule-only polypeptide, Messenger, Drosophila melangaster, GRP1, Grp1, Mini-Exon, Gene Products, synganglion, mRNA Transcript, Non Polyadenylated, Genetic, STOP145, Polyadenylated Messenger, long, PTPSTEP, Sense, l(2)SH2 0323, messenger RNA, suprasegmental levels of nervous system, via U2-type spliceosome, template RNA, cryptic, Neural-specific protein-tyrosine phosphatase, l(2)k08110, site, mRNA Transcript Degradation, Intron, b2b970Clo, species, Decay, elements, atom, GPH, Mini-Exon., RNA Degradation, RNA, 2810411E12Rik, suprasegmental structures, anatomical protrusion, Polyadenylated, completeness, Intervening Sequences, Map-6, Proteins, Messenger RNA, AV265756, stepk, Cistrons, D. melanogaster, encephalon, CFC1B, Sequences, development, Intervening Sequence, INSDC_feature:intron, macromolecular stability of mRNA, Sequence, Poly(A)+ mRNA, Protein, 3.1.3.48, vertebrates, INSDC_feature:mRNA, mRNA Instability, Genetic Materials, Vertebrata, Mtap6, 145-kDa STOP, Sense Codons, atomo, atomus, Polyadenylated RNA, Vertebrate, mRNA Decay, atome, l(2)SH0323, RNA Decay, RNA Instability, region, Genetic Material, Codons, MAP-6, parent ion, Polyadenylated Messenger RNA, CYH1, HTX2, Poly(A)+ RNA, Non Polyadenylated mRNA, Element, protein_coding_transcript, mRNA, Poly(A) Tail, Step, CG11628, exonic region, Mini-Exons, Encephalon, atoms, postnatal growth, Non-Polyadenylated, CRYPTIC, Exon, Codon, Striatum-enriched protein-tyrosine phosphatase, mRNA Degradation, Transcript Degradation, Intervening, Non-Polyadenylated mRNA, DmelCG11628, Protein Gene Products, Gene Proteins, Drosophila, precursor ion, STEP, spine, Material, Drosophila melanogasters, DTGA2, Cistron, Polyadenylated mRNA, Instability, growth, Poly(A) RNAfalseThis DAC is the list of persons that, on behalf of the UKBEC consortium, manage the access to the UKBEC data.Data Access Committee EGAC00001000314EGAC0000100031496062597024625174004EGAS00001002113EGAS00001001170EGAD00001001274EGAD00001003100