@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 {38276, title = {Gene expression anti-profiles as a basis for accurate universal cancer signatures}, journal = {BMC bioinformaticsBMC Bioinformatics}, volume = {13}, year = {2012}, note = {http://www.ncbi.nlm.nih.gov/pubmed/23088656?dopt=Abstract}, type = {10.1186/1471-2105-13-272}, abstract = {BACKGROUND: Early screening for cancer is arguably one of the greatest public health advances over the last fifty years. However, many cancer screening tests are invasive (digital rectal exams), expensive (mammograms, imaging) or both (colonoscopies). This has spurred growing interest in developing genomic signatures that can be used for cancer diagnosis and prognosis. However, progress has been slowed by heterogeneity in cancer profiles and the lack of effective computational prediction tools for this type of data. RESULTS: We developed anti-profiles as a first step towards translating experimental findings suggesting that stochastic across-sample hyper-variability in the expression of specific genes is a stable and general property of cancer into predictive and diagnostic signatures. Using single-chip microarray normalization and quality assessment methods, we developed an anti-profile for colon cancer in tissue biopsy samples. To demonstrate the translational potential of our findings, we applied the signature developed in the tissue samples, without any further retraining or normalization, to screen patients for colon cancer based on genomic measurements from peripheral blood in an independent study (AUC of 0.89). This method achieved higher accuracy than the signature underlying commercially available peripheral blood screening tests for colon cancer (AUC of 0.81). We also confirmed the existence of hyper-variable genes across a range of cancer types and found that a significant proportion of tissue-specific genes are hyper-variable in cancer. Based on these observations, we developed a universal cancer anti-profile that accurately distinguishes cancer from normal regardless of tissue type (ten-fold cross-validation AUC > 0.92). CONCLUSIONS: We have introduced anti-profiles as a new approach for developing cancer genomic signatures that specifically takes advantage of gene expression heterogeneity. We have demonstrated that anti-profiles can be successfully applied to develop peripheral-blood based diagnostics for cancer and used anti-profiles to develop a highly accurate universal cancer signature. By using single-chip normalization and quality assessment methods, no further retraining of signatures developed by the anti-profile approach would be required before their application in clinical settings. Our results suggest that anti-profiles may be used to develop inexpensive and non-invasive universal cancer screening tests.}, keywords = {Area Under Curve, Colonic Neoplasms, Gene Expression Profiling, Genetic Variation, Genomics, HUMANS, Oligonucleotide Array Sequence Analysis, Prognosis, Transcriptome, Tumor Markers, Biological}, author = {H{\'e}ctor Corrada Bravo and Pihur, Vasyl and McCall, Matthew and Irizarry, Rafael A. and Leek, Jeffrey T.} } @article {49652, title = {The genome and its implications.}, journal = {Adv Parasitol}, volume = {75}, year = {2011}, month = {2011}, pages = {209-30}, abstract = {

Trypanosoma cruzi has a heterogeneous population composed of a pool of strains that circulate in the domestic and sylvatic cycles. Genome sequencing of the clone CL Brener revealed a highly repetitive genome of about 110Mb containing an estimated 22,570 genes. Because of its hybrid nature, sequences representing the two haplotypes have been generated. In addition, a repeat content close to 50\% made the assembly of the estimated 41 pairs of chromosomes quite challenging. Similar to other trypanosomatids, the organization of T. cruzi chromosomes was found to be very peculiar, with protein-coding genes organized in long polycistronic transcription units encoding 20 or more proteins in one strand separated by strand switch regions. Another remarkable feature of the T. cruzi genome is the massive expansion of surface protein gene families. Because of the high genetic diversity of the T. cruzi population, sequencing of additional strains and comparative genomic and transcriptome analyses are in progress. Five years after its publication, the genome data have proven to be an essential tool for the study of T. cruzi and increasing efforts to translate this knowledge into the development of new modes of intervention to control Chagas disease are underway.

}, keywords = {Animals, Antigens, Protozoan, Chagas Disease, Chromosomes, Comparative Genomic Hybridization, DNA, Protozoan, Gene Expression Regulation, Genetic Variation, Genome, Protozoan, Host-Parasite Interactions, HUMANS, Species Specificity, Synteny, Transcription, Genetic, Transfection, Trypanosoma cruzi}, issn = {0065-308X}, doi = {10.1016/B978-0-12-385863-4.00010-1}, author = {Teixeira, Santuza M and El-Sayed, Najib M and Ara{\'u}jo, Patr{\'\i}cia R} } @article {49640, title = {Trypanosoma cruzi mitochondrial maxicircles display species- and strain-specific variation and a conserved element in the non-coding region.}, journal = {BMC Genomics}, volume = {7}, year = {2006}, month = {2006}, pages = {60}, abstract = {

BACKGROUND: The mitochondrial DNA of kinetoplastid flagellates is distinctive in the eukaryotic world due to its massive size, complex form and large sequence content. Comprised of catenated maxicircles that contain rRNA and protein-coding genes and thousands of heterogeneous minicircles encoding small guide RNAs, the kinetoplast network has evolved along with an extreme form of mRNA processing in the form of uridine insertion and deletion RNA editing. Many maxicircle-encoded mRNAs cannot be translated without this post-transcriptional sequence modification.

RESULTS: We present the complete sequence and annotation of the Trypanosoma cruzi maxicircles for the CL Brener and Esmeraldo strains. Gene order is syntenic with Trypanosoma brucei and Leishmania tarentolae maxicircles. The non-coding components have strain-specific repetitive regions and a variable region that is unique for each strain with the exception of a conserved sequence element that may serve as an origin of replication, but shows no sequence identity with L. tarentolae or T. brucei. Alternative assemblies of the variable region demonstrate intra-strain heterogeneity of the maxicircle population. The extent of mRNA editing required for particular genes approximates that seen in T. brucei. Extensively edited genes were more divergent among the genera than non-edited and rRNA genes. Esmeraldo contains a unique 236-bp deletion that removes the 5{\textquoteright}-ends of ND4 and CR4 and the intergenic region. Esmeraldo shows additional insertions and deletions outside of areas edited in other species in ND5, MURF1, and MURF2, while CL Brener has a distinct insertion in MURF2.

CONCLUSION: The CL Brener and Esmeraldo maxicircles represent two of three previously defined maxicircle clades and promise utility as taxonomic markers. Restoration of the disrupted reading frames might be accomplished by strain-specific RNA editing. Elements in the non-coding region may be important for replication, transcription, and anchoring of the maxicircle within the kinetoplast network.

}, keywords = {Amino Acid Sequence, Animals, Animals, Inbred Strains, Base Composition, Conserved Sequence, DNA, Kinetoplast, Frameshifting, Ribosomal, Gene Deletion, Gene Order, Genetic Variation, Leishmania, Models, Biological, Molecular Sequence Data, Muscle Proteins, NADH Dehydrogenase, Open Reading Frames, Regulatory Elements, Transcriptional, RNA Editing, Sequence Homology, Amino Acid, Species Specificity, Trypanosoma brucei brucei, Trypanosoma cruzi, Ubiquitin-Protein Ligases, Untranslated Regions}, issn = {1471-2164}, doi = {10.1186/1471-2164-7-60}, author = {Westenberger, Scott J and Cerqueira, Gustavo C and El-Sayed, Najib M and Zingales, Bianca and Campbell, David A and Sturm, Nancy R} } @article {38287, title = {Genome analysis of multiple pathogenic isolates of Streptococcus agalactiae: implications for the microbial "pan-genome"}, journal = {Proceedings of the National Academy of Sciences of the United States of AmericaProceedings of the National Academy of Sciences of the United States of America}, volume = {102}, year = {2005}, note = {http://www.ncbi.nlm.nih.gov/pubmed/16172379?dopt=Abstract}, type = {10.1073/pnas.0506758102}, abstract = {The development of efficient and inexpensive genome sequencing methods has revolutionized the study of human bacterial pathogens and improved vaccine design. Unfortunately, the sequence of a single genome does not reflect how genetic variability drives pathogenesis within a bacterial species and also limits genome-wide screens for vaccine candidates or for antimicrobial targets. We have generated the genomic sequence of six strains representing the five major disease-causing serotypes of Streptococcus agalactiae, the main cause of neonatal infection in humans. Analysis of these genomes and those available in databases showed that the S. agalactiae species can be described by a pan-genome consisting of a core genome shared by all isolates, accounting for approximately 80\% of any single genome, plus a dispensable genome consisting of partially shared and strain-specific genes. Mathematical extrapolation of the data suggests that the gene reservoir available for inclusion in the S. agalactiae pan-genome is vast and that unique genes will continue to be identified even after sequencing hundreds of genomes.}, keywords = {Amino Acid Sequence, Bacterial Capsules, Base Sequence, Gene expression, Genes, Bacterial, Genetic Variation, Genome, Bacterial, Molecular Sequence Data, Phylogeny, sequence alignment, Sequence Analysis, DNA, Streptococcus agalactiae, virulence}, author = {Tettelin, Herv{\'e} and Masignani, Vega and Cieslewicz, Michael J. and Donati, Claudio and Medini, Duccio and Ward, Naomi L. and Angiuoli, Samuel V. and Crabtree, Jonathan and Jones, Amanda L. and Durkin, A. Scott and DeBoy, Robert T. and Davidsen, Tanja M. and Mora, Marirosa and Scarselli, Maria and Margarit y Ros, Immaculada and Peterson, Jeremy D. and Hauser, Christopher R. and Sundaram, Jaideep P. and Nelson, William C. and Madupu, Ramana and Brinkac, Lauren M. and Dodson, Robert J. and Rosovitz, Mary J. and Sullivan, Steven A. and Daugherty, Sean C. and Haft, Daniel H. and J. Selengut and Gwinn, Michelle L. and Zhou, Liwei and Zafar, Nikhat and Khouri, Hoda and Radune, Diana and Dimitrov, George and Watkins, Kisha and O{\textquoteright}Connor, Kevin J. B. and Smith, Shannon and Utterback, Teresa R. and White, Owen and Rubens, Craig E. and Grandi, Guido and Madoff, Lawrence C. and Kasper, Dennis L. and Telford, John L. and Wessels, Michael R. and Rappuoli, Rino and Fraser, Claire M.} } @article {49638, title = {What the genome sequence is revealing about trypanosome antigenic variation.}, journal = {Biochem Soc Trans}, volume = {33}, year = {2005}, month = {2005 Nov}, pages = {986-9}, abstract = {

African trypanosomes evade humoral immunity through antigenic variation, whereby they switch expression of the gene encoding their VSG (variant surface glycoprotein) coat. Switching proceeds by duplication of silent VSG genes into a transcriptionally active locus. The genome project has revealed that most of the silent archive consists of hundreds of subtelomeric VSG tandem arrays, and that most of these are not functional genes. Precedent suggests that they can contribute combinatorially to the formation of expressed, functional genes through segmental gene conversion. These findings from the genome project have major implications for evolution of the VSG archive and for transmission of the parasite in the field.

}, keywords = {Animals, Antigens, Protozoan, Evolution, Molecular, Genetic Variation, Genome, Trypanosomatina, Variant Surface Glycoproteins, Trypanosoma}, issn = {0300-5127}, doi = {10.1042/BST20050986}, author = {Barry, J D and Marcello, L and Morrison, L J and Read, A F and Lythgoe, K and Jones, N and Carrington, M and Blandin, G and B{\"o}hme, U and Caler, E and Hertz-Fowler, C and Renauld, H and El-Sayed, N and Berriman, M} } @article {49698, title = {Suppressor U1 snRNAs in Drosophila.}, journal = {Genetics}, volume = {138}, year = {1994}, month = {1994 Oct}, pages = {365-78}, abstract = {

Although the role of U1 small nuclear RNAs (snRNAs) in 5{\textquoteright} splice site recognition is well established, suppressor U1 snRNAs active in intact multicellular animals have been lacking. Here we describe suppression of a 5{\textquoteright} splice site mutation in the Drosophila melanogaster white gene (wDR18) by compensatory changes in U1 snRNA. Mutation of positions -1 and +6 of the 5{\textquoteright} splice site of the second intron (ACG[GTGAGT to ACC]GTGAGC) results in the accumulation of RNA retaining this 74-nucleotide intron in both transfected cells and transgenic flies. U1-3G, a suppressor U1 snRNA which restores base-pairing at position +6 of the mutant intron, increases the ratio of spliced to unspliced wDR18 RNA up to fivefold in transfected Schneider cells and increases eye pigmentation in wDR18 flies. U1-9G, which targets position -1, suppresses wDR18 in transfected cells less well. U1-3G,9G has the same effect as U1-3G although it accumulates to lower levels. Suppression of wDR18 has revealed that the U1b embryonic variant (G134 to U) is active in Schneider cells and pupal eye discs. However, the combination of 9G with 134U leads to reduced accumulation of both U1b-9G and U1b-3G,9G, possibly because nucleotides 9 and 134 both participate in a potential long-range intramolecular base-pairing interaction. High levels of functional U1-3G suppressor reduce both viability and fertility in transformed flies. These results show that, despite the difficulties inherent in stably altering splice site selection in multicellular organisms, it is possible to obtain suppressor U1 snRNAs in flies.

}, keywords = {Alternative Splicing, Animals, Base Sequence, Cell Line, Cell Nucleus, DNA Primers, Drosophila melanogaster, Female, Genes, Suppressor, Genetic Variation, GENOTYPE, Introns, Male, Molecular Sequence Data, Mutagenesis, Site-Directed, Nucleic Acid Conformation, Oligodeoxyribonucleotides, PHENOTYPE, Recombinant Proteins, Ribonucleoprotein, U1 Small Nuclear, RNA, Small Nuclear, Transfection, Transformation, Genetic}, issn = {0016-6731}, author = {Lo, P C and Roy, D and Mount, S M} } @article {49704, title = {Drosophila melanogaster genes for U1 snRNA variants and their expression during development.}, journal = {Nucleic Acids Res}, volume = {18}, year = {1990}, month = {1990 Dec 11}, pages = {6971-9}, abstract = {

We have cloned and characterized a complete set of seven U1-related sequences from Drosophila melanogaster. These sequences are located at the three cytogenetic loci 21D, 82E, and 95C. Three of these sequences have been previously studied: one U1 gene at 21D which encodes the prototype U1 sequence (U1a), one U1 gene at 82E which encodes a U1 variant with a single nucleotide substitution (U1b), and a pseudogene at 82E. The four previously uncharacterized genes are another U1b gene at 82E, two additional U1a genes at 95C, and a U1 gene at 95C which encodes a new variant (U1c) with a distinct single nucleotide change relative to U1a. Three blocks of 5{\textquoteright} flanking sequence similarity are common to all six full length genes. Using specific primer extension assays, we have observed that the U1b RNA is expressed in Drosophila Kc cells and is associated with snRNP proteins, suggesting that the U1b-containing snRNP particles are able to participate in the process of pre-mRNA splicing. We have also examined the expression throughout Drosophila development of the two U1 variants relative to the prototype sequence. The U1c variant is undetectable by our methods, while the U1b variant exhibits a primarily embryonic pattern reminiscent of the expression of certain U1 variants in sea urchin, Xenopus, and mouse.

}, keywords = {Animals, Base Sequence, Blotting, Southern, Cloning, Molecular, Drosophila melanogaster, Gene Expression Regulation, genes, Genetic Variation, Molecular Sequence Data, Nucleic Acid Conformation, Pseudogenes, Restriction Mapping, RNA, Small Nuclear}, issn = {0305-1048}, author = {Lo, P C and Mount, S M} }