The UCSC Genome Browser database: 2014 update

Karolchik, Donna; Barber, Galt P.; Casper, Jonathan D.; Clawson, Hiram; Cline, Melissa; Diekhans, Mark; Dreszer, Timothy R.; Fujita, Pauline A.; Guruvadoo, Luvina; Haeussler, Maximilian; Harte, Rachel A.; Heitner, Steven G.; Hinrichs, Angie S.; Learned, Katrina; Lee, Brian T.; Li, Chin H.; Raney, Brian J.; Rhead, Brooke; Rosenbloom, Kate R.; Sloan, Cricket A.; Speir, Matthew L; Zweig, Ann S.; Haussler, David; Kuhn, Robert M.; Kent, W. James

doi:10.1093/nar/gkt1168

Cited by 634 publications

(648 citation statements)

References 34 publications

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“…54 miR-3189 candidates were mapped to mammalian genomes using BLAST 55 or LiftOver. 56 On the basis of the reciprocal BLAST hits and analysis of syntenic regions, we identified 14 orthologous candidates for miR-3189 precursors in different mammalian genomes. Phylogenetic analysis was conducted using MEGA5 and RAxML software.…”

Section: Discussionmentioning

confidence: 99%

Growth differentiation factor-15 encodes a novel microRNA 3189 that functions as a potent regulator of cell death

Jones

Mahadevan

et al. 2015

Cell Death Differ

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According to the latest version of miRBase, approximately 30% of microRNAs (miRNAs) are unique to primates, but the physiological function of the vast majority remains unknown. In this study, we identified miR-3189 as a novel, p53-regulated, primate-specific miRNA embedded in the intron of the p53-target gene GDF15. Antagonizing miR-3189 increased proliferation and sensitized cells to DNA damage-induced apoptosis, suggesting a tumor suppressor function for endogenous miR-3189. Identification of genome-wide miR-3189 targets revealed that miR-3189 directly inhibits the expression of a large number of genes involved in cell cycle control and cell survival. In addition, miR-3189 downregulated the expression of multiple p53 inhibitors resulting in elevated p53 levels and upregulation of several p53 targets including p21 (CDKN1A), GADD45A and the miR-3189 host gene GDF15, suggesting miR-3189 auto-regulation. Surprisingly, miR-3189 overexpression in p53-/-cells upregulated a subset of p53-targets including GDF15, GADD45A, and NOXA, but not CDKN1A. Consistent with these results, overexpression of miR-3189 potently induced apoptosis and inhibited tumorigenicity in vivo in a p53-independent manner. Collectively, our study identified miR-3189 as a novel, primate-specific miRNA whose effects are mediated by both p53-dependent and p53-independent mechanisms. miR-3189 may, therefore, represent a novel tool that can be utilized therapeutically to induce a potent proapoptotic effect even in p53-deficient tumors.

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Section: Discussionmentioning

confidence: 99%

Growth differentiation factor-15 encodes a novel microRNA 3189 that functions as a potent regulator of cell death

Jones

Mahadevan

et al. 2015

Cell Death Differ

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“…The rate of change for each nucleotide flanking branchpoints against reference human sequence was determined using 100-species Vertebrate MULTIZ Alignment (.maf ) from UCSC (Karolchik et al 2014). Background nucleotide substitution rate was determined from the sequence upstream (;25 nt) to each branchpoint.…”

Section: Nucleotide Substitution Ratementioning

confidence: 99%

“…We determined genome coordinates corresponding to instances of motif sequences within the human introns. Motifs coordinates were identified using the findMotif from the Kent source utilities UCSC Tool kit (Karolchik et al 2014) (http://genomewiki.ucsc.edu/index.php/ Kent_source_utilities) that finds exact matches to motif sequence. Identified motifs that overlapped known introns (GENCODE v12 comprehensive assembly) were retained for further analysis.…”

Section: Motif Mappingmentioning

confidence: 99%

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Genome-wide discovery of human splicing branchpoints

et al. 2015

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During the splicing reaction, the 59 intron end is joined to the branchpoint nucleotide, selecting the next exon to incorporate into the mature RNA and forming an intron lariat, which is excised. Despite a critical role in gene splicing, the locations and features of human splicing branchpoints are largely unknown. We use exoribonuclease digestion and targeted RNA-sequencing to enrich for sequences that traverse the lariat junction and, by split and inverted alignment, reveal the branchpoint. We identify 59,359 high-confidence human branchpoints in >10,000 genes, providing a first map of splicing branchpoints in the human genome. Branchpoints are predominantly adenosine, highly conserved, and closely distributed to the 39 splice site. Analysis of human branchpoints reveals numerous novel features, including distinct features of branchpoints for alternatively spliced exons and a family of conserved sequence motifs overlapping branchpoints we term B-boxes, which exhibit maximal nucleotide diversity while maintaining interactions with the keto-rich U2 snRNA. Different B-box motifs exhibit divergent usage in vertebrate lineages and associate with other splicing elements and distinct intron-exon architectures, suggesting integration within a broader regulatory splicing code. Lastly, although branchpoints are refractory to common mutational processes and genetic variation, mutations occurring at branchpoint nucleotides are enriched for disease associations.[Supplemental material is available for this article.]The majority of human genes are spliced, a process whereby introns are removed from the nascent RNA and the remaining exonic sequence joined together into a mature RNA transcript. In addition, alternative splicing generates complex networks of isoforms from human gene loci and plays a major role in shaping the diversity of the transcriptome (Kapranov et al. 2005;Gerstein et al. 2007;Djebali et al. 2012).Splicing occurs in the spliceosome, a large ribonucleoprotein complex that recognizes at least three genetic elements within each intron: the 59 splice site (59SS), the 39 splice site (39SS), and the branchpoint (Will and L€ uhrmann 2011). RNU2-1, the U2 spliceosomal RNA (snRNA) base pairs to the sequence surrounding the unpaired branchpoint nucleotide, which then undergoes transesterification with the 59 end of the intron to form a closed lariat structure. The spliceosome then scans for the downstream 39 splice site, which undergoes a second trans-esterification reaction to join together the two exon ends and excise the intron lariat (Fig.

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“…Annotation was based on several databases provided by annovar such as UCSC known gene, 29 dbSNP (http://www.ncbi.nlm.nih.gov/SNP/), Exome Sequencing Project (http://evs.gs.washington.edu/EVS/) and 1000 Genomes. 30 In addition, we also annotated several functional prediction scores such as SIFT, 31 CADD, 32 PolyPhen2 33 and Mutation Taster.…”

Section: Variant Validationmentioning

confidence: 99%

Systematic analysis of variants related to familial hypercholesterolemia in families with premature myocardial infarction

et al. 2015

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Familial hypercholesterolemia (FH) is an oligogenic disorder characterized by markedly elevated low-density lipoprotein cholesterol (LDLC) levels. Variants in four genes have been reported to cause the classical autosomal-dominant form of the disease. FH is largely under-diagnosed in European countries. As FH increases the risk for coronary artery disease (CAD) and myocardial infarction (MI), it might be specifically overlooked in the large number of such patients. Here, we systematically examined the frequency of potential FH-causing variants by exome sequencing in 255 German patients with premature MI and a positive family history for CAD. We further performed co-segregation analyses in an average of 5.5 family members per MI patient. In total, we identified 11 potential disease-causing variants that co-segregate within the families, that is, 5% of patients with premature MI and positive CAD family history had FH. Eight variants were previously reported as disease-causing and three are novel (LDLR.c.811G4A p.(V271I)), PCSK9.c.610G4A (p. (D204N)) and STAP1.c.139A4G (p. (T47A))). Co-segregation analyses identified multiple additional family members carrying one of these FH variants and the clinical phenotype of either FH (n = 2) or FH and premature CAD (n = 15). However, exome sequencing also revealed that some variants in FH genes, which have been reported to cause FH, do not co-segregate with FH. The data reveal that a large proportion of FH patients escape the diagnosis, even when they have premature MI. Hence, systematic molecular-genetic screening for FH in such patients may reveal a substantial number of cases and thereby allow a timely LDLC-lowering in both FH/MI patients as well as their variantcarrying family members.

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The UCSC Genome Browser database: 2014 update

Cited by 634 publications

References 34 publications

Growth differentiation factor-15 encodes a novel microRNA 3189 that functions as a potent regulator of cell death

Growth differentiation factor-15 encodes a novel microRNA 3189 that functions as a potent regulator of cell death

Genome-wide discovery of human splicing branchpoints

Systematic analysis of variants related to familial hypercholesterolemia in families with premature myocardial infarction

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