@article {49734, title = {Genomic variation. Impact of regulatory variation from RNA to protein.}, journal = {Science}, volume = {347}, year = {2015}, month = {2015 Feb 6}, pages = {664-7}, abstract = {

The phenotypic consequences of expression quantitative trait loci (eQTLs) are presumably due to their effects on protein expression levels. Yet the impact of genetic variation, including eQTLs, on protein levels remains poorly understood. To address this, we mapped genetic variants that are associated with eQTLs, ribosome occupancy (rQTLs), or protein abundance (pQTLs). We found that most QTLs are associated with transcript expression levels, with consequent effects on ribosome and protein levels. However, eQTLs tend to have significantly reduced effect sizes on protein levels, which suggests that their potential impact on downstream phenotypes is often attenuated or buffered. Additionally, we identified a class of cis QTLs that affect protein abundance with little or no effect on messenger RNA or ribosome levels, which suggests that they may arise from differences in posttranslational regulation.

}, keywords = {3{\textquoteright} Flanking Region, 5{\textquoteright} Flanking Region, Cell Line, Exons, Gene Expression Regulation, Genetic Variation, HUMANS, PHENOTYPE, Protein Biosynthesis, Quantitative Trait Loci, Ribosomes, RNA, Messenger, Transcription, Genetic}, issn = {1095-9203}, doi = {10.1126/science.1260793}, author = {Battle, Alexis and Khan, Zia and Wang, Sidney H and Mitrano, Amy and Ford, Michael J and Pritchard, Jonathan K and Gilad, Yoav} } @article {49646, title = {The genome of the blood fluke Schistosoma mansoni.}, journal = {Nature}, volume = {460}, year = {2009}, month = {2009 Jul 16}, pages = {352-8}, abstract = {

Schistosoma mansoni is responsible for the neglected tropical disease schistosomiasis that affects 210 million people in 76 countries. Here we present analysis of the 363 megabase nuclear genome of the blood fluke. It encodes at least 11,809 genes, with an unusual intron size distribution, and new families of micro-exon genes that undergo frequent alternative splicing. As the first sequenced flatworm, and a representative of the Lophotrochozoa, it offers insights into early events in the evolution of the animals, including the development of a body pattern with bilateral symmetry, and the development of tissues into organs. Our analysis has been informed by the need to find new drug targets. The deficits in lipid metabolism that make schistosomes dependent on the host are revealed, and the identification of membrane receptors, ion channels and more than 300 proteases provide new insights into the biology of the life cycle and new targets. Bioinformatics approaches have identified metabolic chokepoints, and a chemogenomic screen has pinpointed schistosome proteins for which existing drugs may be active. The information generated provides an invaluable resource for the research community to develop much needed new control tools for the treatment and eradication of this important and neglected disease.

}, keywords = {Animals, Biological Evolution, Exons, Genes, Helminth, Genome, Helminth, Host-Parasite Interactions, Introns, Molecular Sequence Data, Physical Chromosome Mapping, Schistosoma mansoni, Schistosomiasis mansoni}, issn = {1476-4687}, doi = {10.1038/nature08160}, author = {Berriman, Matthew and Haas, Brian J and LoVerde, Philip T and Wilson, R Alan and Dillon, Gary P and Cerqueira, Gustavo C and Mashiyama, Susan T and Al-Lazikani, Bissan and Andrade, Luiza F and Ashton, Peter D and Aslett, Martin A and Bartholomeu, Daniella C and Blandin, Ga{\"e}lle and Caffrey, Conor R and Coghlan, Avril and Coulson, Richard and Day, Tim A and Delcher, Art and DeMarco, Ricardo and Djikeng, Appolinaire and Eyre, Tina and Gamble, John A and Ghedin, Elodie and Gu, Yong and Hertz-Fowler, Christiane and Hirai, Hirohisha and Hirai, Yuriko and Houston, Robin and Ivens, Alasdair and Johnston, David A and Lacerda, Daniela and Macedo, Camila D and McVeigh, Paul and Ning, Zemin and Oliveira, Guilherme and Overington, John P and Parkhill, Julian and Pertea, Mihaela and Pierce, Raymond J and Protasio, Anna V and Quail, Michael A and Rajandream, Marie-Ad{\`e}le and Rogers, Jane and Sajid, Mohammed and Salzberg, Steven L and Stanke, Mario and Tivey, Adrian R and White, Owen and Williams, David L and Wortman, Jennifer and Wu, Wenjie and Zamanian, Mostafa and Zerlotini, Adhemar and Fraser-Liggett, Claire M and Barrell, Barclay G and El-Sayed, Najib M} } @article {49680, title = {A computational survey of candidate exonic splicing enhancer motifs in the model plant Arabidopsis thaliana.}, journal = {BMC Bioinformatics}, volume = {8}, year = {2007}, month = {2007}, pages = {159}, abstract = {

BACKGROUND: Algorithmic approaches to splice site prediction have relied mainly on the consensus patterns found at the boundaries between protein coding and non-coding regions. However exonic splicing enhancers have been shown to enhance the utilization of nearby splice sites.

RESULTS: We have developed a new computational technique to identify significantly conserved motifs involved in splice site regulation. First, 84 putative exonic splicing enhancer hexamers are identified in Arabidopsis thaliana. Then a Gibbs sampling program called ELPH was used to locate conserved motifs represented by these hexamers in exonic regions near splice sites in confirmed genes. Oligomers containing 35 of these motifs have been shown experimentally to induce significant inclusion of A. thaliana exons. Second, integration of our regulatory motifs into two different splice site recognition programs significantly improved the ability of the software to correctly predict splice sites in a large database of confirmed genes. We have released GeneSplicerESE, the improved splice site recognition code, as open source software.

CONCLUSION: Our results show that the use of the ESE motifs consistently improves splice site prediction accuracy.

}, keywords = {Alternative Splicing, Arabidopsis, Computational Biology, Enhancer Elements, Genetic, Exons, Genes, Plant, RNA, Plant}, issn = {1471-2105}, doi = {10.1186/1471-2105-8-159}, author = {Pertea, Mihaela and Mount, Stephen M and Salzberg, Steven L} } @article {49686, title = {Sex-lethal splicing autoregulation in vivo: interactions between SEX-LETHAL, the U1 snRNP and U2AF underlie male exon skipping.}, journal = {Development}, volume = {130}, year = {2003}, month = {2003 Feb}, pages = {463-71}, abstract = {

Alternative splicing of the Sex-lethal pre-mRNA has long served as a model example of a regulated splicing event, yet the mechanism by which the female-specific SEX-LETHAL RNA-binding protein prevents inclusion of the translation-terminating male exon is not understood. Thus far, the only general splicing factor for which there is in vivo evidence for a regulatory role in the pathway leading to male-exon skipping is sans-fille (snf), a protein component of the spliceosomal U1 and U2 snRNPs. Its role, however, has remained enigmatic because of questions about whether SNF acts as part of an intact snRNP or a free protein. We provide evidence that SEX-LETHAL interacts with SANS-FILLE in the context of the U1 snRNP, through the characterization of a point mutation that interferes with both assembly into the U1 snRNP and complex formation with SEX-LETHAL. Moreover, we find that SEX-LETHAL associates with other integral U1 snRNP components, and we provide genetic evidence to support the biological relevance of these physical interactions. Similar genetic and biochemical approaches also link SEX-LETHAL with the heterodimeric splicing factor, U2AF. These studies point specifically to a mechanism by which SEX-LETHAL represses splicing by interacting with these key splicing factors at both ends of the regulated male exon. Moreover, because U2AF and the U1 snRNP are only associated transiently with the pre-mRNA during the course of spliceosome assembly, our studies are difficult to reconcile with the current model that proposes that the SEX-LETHAL blocks splicing at the second catalytic step, and instead argue that the SEX-LETHAL protein acts after splice site recognition, but before catalysis begins.

}, keywords = {Alternative Splicing, Amino Acid Sequence, Animals, Animals, Genetically Modified, Drosophila melanogaster, Drosophila Proteins, Exons, Female, Gene Expression Regulation, Developmental, Genes, Insect, Homeostasis, Male, Models, Genetic, Molecular Sequence Data, Nuclear Proteins, Point Mutation, Ribonucleoprotein, U1 Small Nuclear, Ribonucleoproteins, RNA Splicing, RNA-Binding Proteins, Sequence Homology, Amino Acid, Sex Differentiation}, issn = {0950-1991}, author = {Nagengast, Alexis A and Stitzinger, Shane M and Tseng, Chin-Hsiu and Mount, Stephen M and Salz, Helen K} } @article {49689, title = {Genomic sequence, splicing, and gene annotation.}, journal = {Am J Hum Genet}, volume = {67}, year = {2000}, month = {2000 Oct}, pages = {788-92}, keywords = {Animals, Consensus Sequence, Exons, genes, Genome, Genomics, HUMANS, Nucleotides, Regulatory Sequences, Nucleic Acid, RNA Splice Sites, RNA Splicing, Untranslated Regions}, issn = {0002-9297}, doi = {10.1086/303098}, author = {Mount, S M} }