Motivation:
Annotations are a key feature of many biological databases, used to convey our knowledge of a sequence to the reader. Ideally, annotations are curated manually, however manual curation is costly, time consuming and requires expert knowledge and training. Given these issues and the exponential increase of data, many databases implement automated annotation pipelines in an attempt to avoid un-annotated entries. Both manual and automated annotations vary in quality between databases and annotators, making assessment of annotation reliability problematic for users. The community lacks a generic measure for determining annotation quality and correctness, which we look at addressing within this work. Specifically we investigate word reuse within bulk textual annotations and relate this to Zipf's Principle of Least Effort. We use UniProt Knowledge Base (UniProtKB) as a case study to demonstrate this approach since it allows us to compare annotation change, both over time and between automated and manually curated annotations.
Results:
By applying power-law distributions to word reuse in annotation, we show clear trends in UniProtKB over time, which are consistent with existing studies of quality on free text English. Further, we show a clear distinction between manual and automated analysis and investigate cohorts of protein records as they mature. These results suggest that this approach holds distinct promise as a mechanism for judging annotation quality.
For more information available at the authors website: www.michaeljbell.co.uk
Biomarkers For Neural Differentiation With Ion AmpliSeq | ESHG 2015 Poster PS...Thermo Fisher Scientific
Neural stem cells (NSCs) are pluripotent cells that give rise to neurons, astrocytes and oligodendrocytes in the nervous system. They hold promise for treatment of brain and spinal injuries and diseases. However, very little is known about their regulatory mechanisms. Here we used Next-Generation Sequencing (NGS) to define the temporal transcriptome signatures of NSCs. Cultured human embryonic stem cells (H9) were compared to induced NSCs at days 0, 7 and 14. Total RNAs were extracted and Ion AmpliSeq™ Transcriptome libraries were created for sequencing. The expression profiles of the same dataset were also evaluated by Whole transcriptome (WT) RNA-Seq and Affymetrix Gene 2.0 ST arrays. The transcriptome profiles of H9 cells differed little between days 0, 7, and 14 while NSCs induced from H9 cells showed remarkable differences from day 0 to days 7 and 14 during differentiation. Hierarchical clustering results also showed more robust sample classification for NSCs than H9 cells. Comparing the expression profiles of NSCs versus H9 cells, a total of 4001 and 4768 were differentially expressed at day 7 and day 14 respectively (p-value < 0.01, fold change > 2) . We further clustered their expressions into 24 groups by Self-organizing map. A total of ~250 genes showed similar expression patterns to known NSC markers including SOX1 and PAX6. These genes are enriched for neural differentiation related pathways and are potential candidates for novel NSC markers. Their expressions will be further verified by TaqMan® gene expression assays. In summary, we used NGS to construct a temporal transcriptome database of H9 cells and NSCs. We also developed an analysis pipeline to systematically identify potential novel NSC markers.
1. Reconstitution of RNA interference (RNAi) in Saccharomyces cerevisiae by expressing RNAi components from other species. RNAi was successfully reconstituted using S. castellii Ago1 and Dcr1, but not human Ago2 and S. castellii Dcr1.
2. Inhibition of Hsp90 using geldanamycin did not reduce RNAi in the reconstituted S. cerevisiae strains, indicating Hsp90 is not required for RNAi in this system.
3. S. castellii Ago1 localized to P-bodies in S. cerevisiae independent of Dcr1, but the origin of small RNAs
This study examines the relationship between the splicing factor SR45 and the antioxidant enzyme GPX7 in Arabidopsis thaliana. Previous research has indicated that SR45 upregulates GPX7 expression. The researchers extracted RNA from wild type and SR45 mutant plants and used qPCR to analyze GPX7 expression levels. They found no significant difference in GPX7 expression between genotypes. H2O2 levels were also observed in seedlings using DAB staining but no visible differences were detected between genotypes except in damaged SR45 mutant plants. Future work will analyze GPX7 protein levels and use endpoint PCR to further study GPX7 expression trends in SR45 and overexpression mutants.
Large hexanucleotide repeats in the C9ORF72 gene are associated with Amyotrophic Lateral Sclerosis-Frontotemporal Dementia (ALS-FTD). Zebrafish models with C9ORF72 knockout show motor neuron defects but have limitations in representing human disease. This study aims to generate human ALS-FTD induced pluripotent stem cells (iPSCs) and use them to model the disease. The TALEN system will be used to alter hexanucleotide repeat numbers in iPSCs to examine the relationship between repeat expansions and RNA expression changes in human neurons in order to better understand ALS-FTD pathogenesis.
The document summarizes research into how mutations affecting the nucleotide state of the E. coli replication initiator protein DnaA alter its function as a transcription factor. Experiments showed that expressing a DnaA mutant (DnaAR334A) that preferentially binds ATP leads to overinitiation of replication, DNA damage, and differential expression of genes involved in DNA replication and the SOS response. In contrast, a DnaA mutant (DnaAT174P) that preferentially binds ADP showed underinitiation and different gene expression patterns. ChIP-seq and RNA-seq were used to identify direct transcriptional targets of DnaA and new genes regulated by its nucleotide state.
Transcription Initiation Factor II H (TFIIH) and its Effects on the Recruitment of Rad50 to Double Strand Breaks in Yeast
This study investigated the role of Transcription Initiation Factor II H (TFIIH) in the recruitment of repair proteins Rad50 and Rad52 to double strand breaks (DSBs) in yeast. The study found that in a mutant lacking the TFIIH subunit Rad3, recruitment of both Rad50 and Rad52 to DSBs was reduced. However, recruitment of the TFIIH subunit TFB1 still occurred in a mutant lacking Rad50. This suggests that TFIIH is involved in recruiting Rad50 to DSBs, rather than Rad50
Los días 20 y 21 de octubre de 2016, la Fundacion Ramón Areces organizó un simposio internacional para analizar las 'Enfermedades raras de la piel: de la clínica al gen y viceversa'. El doctor Fernando Larcher Laguzzi, del CIEMAT-Universidad Carlos III de Madrid-IIS Fundación Jiménez Díaz, ejerció de coordinador.
Sequencing cannabis sativa and cannabis indica, Courtagen Life Sciences, Inc,...Copenhagenomics
1. Medicinal Genomics Corporation sequenced the genomes of several cannabis cultivars including Chemdawg and LA Confidential.
2. Analysis of the genome sequences revealed high levels of polymorphisms and identified several copies of THCA synthase genes with single nucleotide variants.
3. RNA sequencing of different tissues showed tissue-specific expression of potential cannabinoid synthase genes, including a novel root-expressed synthase with a different N-terminal domain.
4. A family tree analysis grouped the potential synthase genes into families across the different cultivars.
Biomarkers For Neural Differentiation With Ion AmpliSeq | ESHG 2015 Poster PS...Thermo Fisher Scientific
Neural stem cells (NSCs) are pluripotent cells that give rise to neurons, astrocytes and oligodendrocytes in the nervous system. They hold promise for treatment of brain and spinal injuries and diseases. However, very little is known about their regulatory mechanisms. Here we used Next-Generation Sequencing (NGS) to define the temporal transcriptome signatures of NSCs. Cultured human embryonic stem cells (H9) were compared to induced NSCs at days 0, 7 and 14. Total RNAs were extracted and Ion AmpliSeq™ Transcriptome libraries were created for sequencing. The expression profiles of the same dataset were also evaluated by Whole transcriptome (WT) RNA-Seq and Affymetrix Gene 2.0 ST arrays. The transcriptome profiles of H9 cells differed little between days 0, 7, and 14 while NSCs induced from H9 cells showed remarkable differences from day 0 to days 7 and 14 during differentiation. Hierarchical clustering results also showed more robust sample classification for NSCs than H9 cells. Comparing the expression profiles of NSCs versus H9 cells, a total of 4001 and 4768 were differentially expressed at day 7 and day 14 respectively (p-value < 0.01, fold change > 2) . We further clustered their expressions into 24 groups by Self-organizing map. A total of ~250 genes showed similar expression patterns to known NSC markers including SOX1 and PAX6. These genes are enriched for neural differentiation related pathways and are potential candidates for novel NSC markers. Their expressions will be further verified by TaqMan® gene expression assays. In summary, we used NGS to construct a temporal transcriptome database of H9 cells and NSCs. We also developed an analysis pipeline to systematically identify potential novel NSC markers.
1. Reconstitution of RNA interference (RNAi) in Saccharomyces cerevisiae by expressing RNAi components from other species. RNAi was successfully reconstituted using S. castellii Ago1 and Dcr1, but not human Ago2 and S. castellii Dcr1.
2. Inhibition of Hsp90 using geldanamycin did not reduce RNAi in the reconstituted S. cerevisiae strains, indicating Hsp90 is not required for RNAi in this system.
3. S. castellii Ago1 localized to P-bodies in S. cerevisiae independent of Dcr1, but the origin of small RNAs
This study examines the relationship between the splicing factor SR45 and the antioxidant enzyme GPX7 in Arabidopsis thaliana. Previous research has indicated that SR45 upregulates GPX7 expression. The researchers extracted RNA from wild type and SR45 mutant plants and used qPCR to analyze GPX7 expression levels. They found no significant difference in GPX7 expression between genotypes. H2O2 levels were also observed in seedlings using DAB staining but no visible differences were detected between genotypes except in damaged SR45 mutant plants. Future work will analyze GPX7 protein levels and use endpoint PCR to further study GPX7 expression trends in SR45 and overexpression mutants.
Large hexanucleotide repeats in the C9ORF72 gene are associated with Amyotrophic Lateral Sclerosis-Frontotemporal Dementia (ALS-FTD). Zebrafish models with C9ORF72 knockout show motor neuron defects but have limitations in representing human disease. This study aims to generate human ALS-FTD induced pluripotent stem cells (iPSCs) and use them to model the disease. The TALEN system will be used to alter hexanucleotide repeat numbers in iPSCs to examine the relationship between repeat expansions and RNA expression changes in human neurons in order to better understand ALS-FTD pathogenesis.
The document summarizes research into how mutations affecting the nucleotide state of the E. coli replication initiator protein DnaA alter its function as a transcription factor. Experiments showed that expressing a DnaA mutant (DnaAR334A) that preferentially binds ATP leads to overinitiation of replication, DNA damage, and differential expression of genes involved in DNA replication and the SOS response. In contrast, a DnaA mutant (DnaAT174P) that preferentially binds ADP showed underinitiation and different gene expression patterns. ChIP-seq and RNA-seq were used to identify direct transcriptional targets of DnaA and new genes regulated by its nucleotide state.
Transcription Initiation Factor II H (TFIIH) and its Effects on the Recruitment of Rad50 to Double Strand Breaks in Yeast
This study investigated the role of Transcription Initiation Factor II H (TFIIH) in the recruitment of repair proteins Rad50 and Rad52 to double strand breaks (DSBs) in yeast. The study found that in a mutant lacking the TFIIH subunit Rad3, recruitment of both Rad50 and Rad52 to DSBs was reduced. However, recruitment of the TFIIH subunit TFB1 still occurred in a mutant lacking Rad50. This suggests that TFIIH is involved in recruiting Rad50 to DSBs, rather than Rad50
Los días 20 y 21 de octubre de 2016, la Fundacion Ramón Areces organizó un simposio internacional para analizar las 'Enfermedades raras de la piel: de la clínica al gen y viceversa'. El doctor Fernando Larcher Laguzzi, del CIEMAT-Universidad Carlos III de Madrid-IIS Fundación Jiménez Díaz, ejerció de coordinador.
Sequencing cannabis sativa and cannabis indica, Courtagen Life Sciences, Inc,...Copenhagenomics
1. Medicinal Genomics Corporation sequenced the genomes of several cannabis cultivars including Chemdawg and LA Confidential.
2. Analysis of the genome sequences revealed high levels of polymorphisms and identified several copies of THCA synthase genes with single nucleotide variants.
3. RNA sequencing of different tissues showed tissue-specific expression of potential cannabinoid synthase genes, including a novel root-expressed synthase with a different N-terminal domain.
4. A family tree analysis grouped the potential synthase genes into families across the different cultivars.
This document discusses characterization of the NADH dehydrogenase subunit 1 protein of Fasciola gigantica, a parasitic flatworm, through computational analysis. Key findings include:
- The protein sequence was analyzed using tools like MotifScan to identify functional motifs, with the NADH dehydrogenase motif found.
- Pairwise comparison to F. hepatica showed 91.5% identity, indicating the proteins are orthologs performing the same function.
- Secondary structure prediction identified helices and coils. A 3D model was built from different protein family folds due to the lack of a matching template.
- The model depicted coiled regions that may play roles in protein complex formation and proton translocation in
In Vitro Characterization of a Novel Cis-acting Element (NCE) in the Cd4 Locus Yordan Penev
We have characterized a novel cis-acting regulatory element (NCE) in the Cd4 locus that exhibits developmental stage specificity in murine T cell lines. NCE functions as an enhancer in cell lines representing the intermediate and single positive developmental stages, but not in double positive stage cell lines. Transcription factor expression levels in the cell lines match expected developmental profiles, except for ThPok in one cell line. Initial experiments found no correlation between T cell receptor stimulation and NCE function. We are working to define the minimum functional sequence of NCE and identify transcription factors that bind it to understand how it regulates increasing Cd4 expression as thymocytes mature.
1. The document discusses a gene therapy trial for X-linked severe combined immunodeficiency (X-SCID) where a retrovirus was used to insert the gamma chain gene into patients' cells.
2. However, in subsequent years some patients developed leukemia due to insertional mutagenesis of the retrovirus activating the LMO2 oncogene, which blocks T-cell differentiation and promotes proliferation.
3. The success of gene therapy depends on transduced cells gaining a growth advantage, but the PEG-ADA therapy for ADA-SCID succeeded because extra ADA expression did not provide an advantage.
Targeted T-cell receptor beta immune repertoire sequencing in several FFPE ti...Thermo Fisher Scientific
T-cell receptor beta (TCRβ) immune repertoire analysis by next-generation sequencing is a valuable tool for studies of the tumor microenvironment and potential immune responses to cancer immunotherapy. Here we describe a TCRβ sequencing assay that leverages the low sample input requirements of AmpliSeq library preparation technology to extend the capability of targeted immune repertoire sequencing to include FFPE samples which can often be degraded and in short supply
1. Protein misfolding in the endoplasmic reticulum (ER) activates the unfolded protein response (UPR) signaling pathway, which involves the activation of ER stress sensors IRE1α, PERK, and ATF6.
2. This leads to the activation of the kinase HIPK2, which phosphorylates downstream targets like ASK1 and JNK, ultimately resulting in neuronal cell death.
3. Studies in ALS mouse models and human patient samples indicate HIPK2 activation through the ER stress pathway contributes to neurodegeneration in different forms of ALS caused by mutations in SOD1, TDP-43, FUS, and C9orf72.
1) The document summarizes research into genetic interactors of the BRCA2 tumor suppressor gene, which is linked to hereditary breast cancer. A retroviral screening identified BRE as a genetic interactor that rescues lethality in BRCA2-deficient cells.
2) Further experiments showed that BRE overexpression in BRCA2-deficient cells leads to increased levels of the Cdc25A cell cycle regulator after DNA damage, preventing cell cycle arrest.
3) BRE was found to interact with the transcription factor ATF3 and induce transcription of Cdc25A. Reporter assays aim to identify the role of ATF3 binding sites on the Cdc25A promoter in regulating its transcription
Remdesivir is a direct-acting antiviral that inhibits RNA-dependent RNA polymerase from severe acute respiratory syndrome coronavirus 2 with high potency
The slide shows the cellular stress response leading to growth arrest as explained by the induction of the universal cell cycle inhibitor p21(WAF1) by the tumor suppressor p53.
This document summarizes work done on culturing crocodile cell lines and cloning the parc gene from Pseudomonas keratitis. Primary crocodile cell lines were established from various organs and immortalized using hTERT. The parc gene was cloned from mutant and wild-type Pseudomonas strains and will be expressed and crystallized to study its role in quinolone antibiotic resistance.
1. A study found that the bacterial infection Citrobacter rodentium releases extracellular proteinases like trypsin and granzyme A during infectious colitis in mice.
2. These proteinases activate proteinase-activated receptor 2 (PAR2) and induce acute inflammation in the colon through G protein activation and calcium mobilization.
3. Inhibiting the proteinase activity or removing PAR2 reduced colon inflammation, demonstrating the important role of PAR2 activation in the host inflammatory response during enteric bacterial infection.
This document summarizes a study investigating the minimum requirements for reconstituting an RNA interference (RNAi) pathway in yeast. The key findings are:
1) RNAi can be reconstituted in yeast by introducing the Dicer and Argonaute proteins from another yeast species, Saccharomyces castellii, but not with human Dicer.
2) Both S. castellii and human Argonaute proteins require regulation by the heat shock protein Hsp90 to function in the yeast RNAi pathway, suggesting this regulatory mechanism has been conserved.
3) Unlike previous reports, the study found that human Dicer, TRBP2 and Argonaute2 were not sufficient to reconstit
1. DNA contains the genetic instructions that determine traits and is found in the cells of living organisms.
2. DNA is made up of nucleotides, which consist of phosphate, sugar, and one of four nitrogenous bases (adenine, guanine, cytosine, thymine).
3. Watson and Crick discovered that DNA takes the shape of a double helix with the bases on the inside pairing up in specific ways (A pairs with T, C pairs with G) to form the rungs of the DNA ladder.
Approach for limited cell ChIP-Seq on a semiconductor-based sequencing platformThermo Fisher Scientific
Dendritic cell (DC) lineages coordinate immune system activity
through functional specialization.
• Irf4, a transcription factor(TF), is required for CD11b+ DC
lineage development from bone marrow stem cells and has
been implicated in multiple inflammatory diseases, eg. asthma.
• The epigenetic consequences of immune specialization in
CD11b+ DCs and relation to inflammatory diseases remain
largely unexplored partly due to the difficulty of using highly
purified, and typically, limited populations of cells in ChIP-seq
(chromatin immunoprecipitation then sequencing) assays.
• A robust, multiplexed ChIP-seq protocol – using an input
control, TF (CTCF) and histone modification marks (H3K9me3-
methylation, H3K27ac-acetylation) - was developed using
limited amounts of K562 cells, for the Ion ProtonTM system.
• Peak-calling analysis was performed using using MACS2.
• Significant data correlations were observed with ENCODE.
• The Ion ProtonTM results are based on chromatin derived from
1 million(M) cells, making it viable for generating data from a
limited number of primary cells. This is in contrast to the 10M
cells recommended by ENCODE.
• The developed methodology was used to compare Irf4 genomic
binding sites generated from flow-sorted populations of 1, 3, 5,
and 20M CD11b+ lineage murine DCs.
• Comparable Irf4 ChIP-seq results were obtained from 5M
versus 20M cells, indicating that as low as 5M flow-sorted cells
can be used to acquire high quality(FDR: 10-19) data.
• We identified genomic Irf4 binding sites proximal to genes,
whose activity is consistent with CD11b+ DC lineage activity
and/or known to contribute to inflammatory disease.
• We examined Irf4 functional regulation of the identified gene
targets via RNA-seq analysis with CD11b+ DCs and a related
lineage, CD103+ DCs. Integrating expression analysis with
ChIP-seq indicates a unique CD11b+ DC gene expression
program concordant with Irf4 loci association in comparison to
CD103+ DC (data not shown).
TransVax, a therapeutic DNA vaccine targeting cytomegalovirus (CMV), showed promising results in a Phase 2 trial involving 80 hematopoietic cell transplant recipients. The vaccine significantly reduced CMV reactivation rates, increased the time to initial viral reactivation, and decreased the duration of viremia compared to placebo. No significant safety concerns were observed. The trial provides evidence that TransVax can control CMV reactivation in high-risk transplant patients in a manner superior to preemptive antiviral therapy alone.
CRISPR-Cas9 is a powerful tool for genome engineering. The document provides guidance on using CRISPR-Cas9 to modify genomes. It describes: 1) Designing single guide RNAs (sgRNAs) to target specific gene loci using online tools; 2) Constructing plasmids expressing Cas9 and sgRNAs; 3) Validating plasmid function using assays like Surveyor nuclease; and 4) Transfecting cells, isolating clones, and further validating genome edits through sequencing. The goal is to use this method to precisely modify genomes for research applications.
This proposal aims to develop an assay to screen for inhibitors of West Nile virus (WNV) protease. The assay will utilize a Gal4 fusion system where the WNV protease is inserted between the Gal4 DNA binding and activation domains. Protease cleavage of the fusion would prevent GFP expression, while inhibition would allow GFP expression. Preliminary data shows the mutated, non-cleavable fusion induces GFP, while the wild type fusion does not, demonstrating proof of concept. Stable cell lines will be generated expressing all assay components to enable high-throughput screening for WNV protease inhibitors.
We previously reported a CRISPR-mediated knock-in strategy into introns of Drosophila genes, generating an attP-FRT-SA T2A-GAL4-polyA-3XP3-EGFP-FRT-attP transgenic library for multiple uses (Lee et al., 2018a). The method relied on double stranded DNA (dsDNA) homology donors with ~1 kb homology arms. Here, we describe three new simpler ways to edit genes in flies. We create single stranded DNA (ssDNA) donors using PCR and add 100 nt of homology on each side of an integration cassette, followed by enzymatic removal of one strand. Using this method, we generated GFP-tagged proteins that mark organelles in S2 cells. We then describe two dsDNA methods using cheap synthesized donors flanked by 100 nt homology arms and gRNA target sites cloned into a plasmid. Upon injection, donor DNA (1 to 5 kb) is released from the plasmid by Cas9. The cassette integrates efficiently and precisely in vivo. The approach is fast, cheap, and scalable.
This study developed a new genetic assay to detect transcription errors in vivo using Saccharomyces cerevisiae. The assay uses a mutant form of the Cre recombinase gene with a missense mutation in the active site tyrosine. Rare transcription errors that restore the wild-type tyrosine codon can be detected by Cre-dependent rearrangement of reporter genes. Using this assay, the researchers screened for mutations in the largest subunit of RNA polymerase II, Rpb1, that increase the rate of transcription errors. They identified mutations in three domains of Rpb1 - the trigger loop, bridge helix, and TFIIS binding sites - that lead to higher misincorporation rates or defects in error correction. Biochemical characterization confirmed
A sequence is a database object that generates unique integer values and can be shared across users and tables. It is created using the CREATE SEQUENCE statement which specifies properties like the name, increment amount, starting value, minimum, maximum and caching settings. The NEXTVAL pseudocolumn is used to retrieve the next value from a sequence and CURRVAL returns the last value retrieved in the current session.
Lecture delivered by T. Ashok Kumar, Head, Department of Bioinformatics, Noorul Islam College of Arts and Science, Kumaracoil, Thuckalay, INDIA. UGC Sponsored National Workshop on BIOINFORMATICS AND GENOME ANALYSIS for College Teachers on August 11 & 12, 2014. Organized by Centre for Bioinformatics, Department of Zoology, NMCC.
This document discusses characterization of the NADH dehydrogenase subunit 1 protein of Fasciola gigantica, a parasitic flatworm, through computational analysis. Key findings include:
- The protein sequence was analyzed using tools like MotifScan to identify functional motifs, with the NADH dehydrogenase motif found.
- Pairwise comparison to F. hepatica showed 91.5% identity, indicating the proteins are orthologs performing the same function.
- Secondary structure prediction identified helices and coils. A 3D model was built from different protein family folds due to the lack of a matching template.
- The model depicted coiled regions that may play roles in protein complex formation and proton translocation in
In Vitro Characterization of a Novel Cis-acting Element (NCE) in the Cd4 Locus Yordan Penev
We have characterized a novel cis-acting regulatory element (NCE) in the Cd4 locus that exhibits developmental stage specificity in murine T cell lines. NCE functions as an enhancer in cell lines representing the intermediate and single positive developmental stages, but not in double positive stage cell lines. Transcription factor expression levels in the cell lines match expected developmental profiles, except for ThPok in one cell line. Initial experiments found no correlation between T cell receptor stimulation and NCE function. We are working to define the minimum functional sequence of NCE and identify transcription factors that bind it to understand how it regulates increasing Cd4 expression as thymocytes mature.
1. The document discusses a gene therapy trial for X-linked severe combined immunodeficiency (X-SCID) where a retrovirus was used to insert the gamma chain gene into patients' cells.
2. However, in subsequent years some patients developed leukemia due to insertional mutagenesis of the retrovirus activating the LMO2 oncogene, which blocks T-cell differentiation and promotes proliferation.
3. The success of gene therapy depends on transduced cells gaining a growth advantage, but the PEG-ADA therapy for ADA-SCID succeeded because extra ADA expression did not provide an advantage.
Targeted T-cell receptor beta immune repertoire sequencing in several FFPE ti...Thermo Fisher Scientific
T-cell receptor beta (TCRβ) immune repertoire analysis by next-generation sequencing is a valuable tool for studies of the tumor microenvironment and potential immune responses to cancer immunotherapy. Here we describe a TCRβ sequencing assay that leverages the low sample input requirements of AmpliSeq library preparation technology to extend the capability of targeted immune repertoire sequencing to include FFPE samples which can often be degraded and in short supply
1. Protein misfolding in the endoplasmic reticulum (ER) activates the unfolded protein response (UPR) signaling pathway, which involves the activation of ER stress sensors IRE1α, PERK, and ATF6.
2. This leads to the activation of the kinase HIPK2, which phosphorylates downstream targets like ASK1 and JNK, ultimately resulting in neuronal cell death.
3. Studies in ALS mouse models and human patient samples indicate HIPK2 activation through the ER stress pathway contributes to neurodegeneration in different forms of ALS caused by mutations in SOD1, TDP-43, FUS, and C9orf72.
1) The document summarizes research into genetic interactors of the BRCA2 tumor suppressor gene, which is linked to hereditary breast cancer. A retroviral screening identified BRE as a genetic interactor that rescues lethality in BRCA2-deficient cells.
2) Further experiments showed that BRE overexpression in BRCA2-deficient cells leads to increased levels of the Cdc25A cell cycle regulator after DNA damage, preventing cell cycle arrest.
3) BRE was found to interact with the transcription factor ATF3 and induce transcription of Cdc25A. Reporter assays aim to identify the role of ATF3 binding sites on the Cdc25A promoter in regulating its transcription
Remdesivir is a direct-acting antiviral that inhibits RNA-dependent RNA polymerase from severe acute respiratory syndrome coronavirus 2 with high potency
The slide shows the cellular stress response leading to growth arrest as explained by the induction of the universal cell cycle inhibitor p21(WAF1) by the tumor suppressor p53.
This document summarizes work done on culturing crocodile cell lines and cloning the parc gene from Pseudomonas keratitis. Primary crocodile cell lines were established from various organs and immortalized using hTERT. The parc gene was cloned from mutant and wild-type Pseudomonas strains and will be expressed and crystallized to study its role in quinolone antibiotic resistance.
1. A study found that the bacterial infection Citrobacter rodentium releases extracellular proteinases like trypsin and granzyme A during infectious colitis in mice.
2. These proteinases activate proteinase-activated receptor 2 (PAR2) and induce acute inflammation in the colon through G protein activation and calcium mobilization.
3. Inhibiting the proteinase activity or removing PAR2 reduced colon inflammation, demonstrating the important role of PAR2 activation in the host inflammatory response during enteric bacterial infection.
This document summarizes a study investigating the minimum requirements for reconstituting an RNA interference (RNAi) pathway in yeast. The key findings are:
1) RNAi can be reconstituted in yeast by introducing the Dicer and Argonaute proteins from another yeast species, Saccharomyces castellii, but not with human Dicer.
2) Both S. castellii and human Argonaute proteins require regulation by the heat shock protein Hsp90 to function in the yeast RNAi pathway, suggesting this regulatory mechanism has been conserved.
3) Unlike previous reports, the study found that human Dicer, TRBP2 and Argonaute2 were not sufficient to reconstit
1. DNA contains the genetic instructions that determine traits and is found in the cells of living organisms.
2. DNA is made up of nucleotides, which consist of phosphate, sugar, and one of four nitrogenous bases (adenine, guanine, cytosine, thymine).
3. Watson and Crick discovered that DNA takes the shape of a double helix with the bases on the inside pairing up in specific ways (A pairs with T, C pairs with G) to form the rungs of the DNA ladder.
Approach for limited cell ChIP-Seq on a semiconductor-based sequencing platformThermo Fisher Scientific
Dendritic cell (DC) lineages coordinate immune system activity
through functional specialization.
• Irf4, a transcription factor(TF), is required for CD11b+ DC
lineage development from bone marrow stem cells and has
been implicated in multiple inflammatory diseases, eg. asthma.
• The epigenetic consequences of immune specialization in
CD11b+ DCs and relation to inflammatory diseases remain
largely unexplored partly due to the difficulty of using highly
purified, and typically, limited populations of cells in ChIP-seq
(chromatin immunoprecipitation then sequencing) assays.
• A robust, multiplexed ChIP-seq protocol – using an input
control, TF (CTCF) and histone modification marks (H3K9me3-
methylation, H3K27ac-acetylation) - was developed using
limited amounts of K562 cells, for the Ion ProtonTM system.
• Peak-calling analysis was performed using using MACS2.
• Significant data correlations were observed with ENCODE.
• The Ion ProtonTM results are based on chromatin derived from
1 million(M) cells, making it viable for generating data from a
limited number of primary cells. This is in contrast to the 10M
cells recommended by ENCODE.
• The developed methodology was used to compare Irf4 genomic
binding sites generated from flow-sorted populations of 1, 3, 5,
and 20M CD11b+ lineage murine DCs.
• Comparable Irf4 ChIP-seq results were obtained from 5M
versus 20M cells, indicating that as low as 5M flow-sorted cells
can be used to acquire high quality(FDR: 10-19) data.
• We identified genomic Irf4 binding sites proximal to genes,
whose activity is consistent with CD11b+ DC lineage activity
and/or known to contribute to inflammatory disease.
• We examined Irf4 functional regulation of the identified gene
targets via RNA-seq analysis with CD11b+ DCs and a related
lineage, CD103+ DCs. Integrating expression analysis with
ChIP-seq indicates a unique CD11b+ DC gene expression
program concordant with Irf4 loci association in comparison to
CD103+ DC (data not shown).
TransVax, a therapeutic DNA vaccine targeting cytomegalovirus (CMV), showed promising results in a Phase 2 trial involving 80 hematopoietic cell transplant recipients. The vaccine significantly reduced CMV reactivation rates, increased the time to initial viral reactivation, and decreased the duration of viremia compared to placebo. No significant safety concerns were observed. The trial provides evidence that TransVax can control CMV reactivation in high-risk transplant patients in a manner superior to preemptive antiviral therapy alone.
CRISPR-Cas9 is a powerful tool for genome engineering. The document provides guidance on using CRISPR-Cas9 to modify genomes. It describes: 1) Designing single guide RNAs (sgRNAs) to target specific gene loci using online tools; 2) Constructing plasmids expressing Cas9 and sgRNAs; 3) Validating plasmid function using assays like Surveyor nuclease; and 4) Transfecting cells, isolating clones, and further validating genome edits through sequencing. The goal is to use this method to precisely modify genomes for research applications.
This proposal aims to develop an assay to screen for inhibitors of West Nile virus (WNV) protease. The assay will utilize a Gal4 fusion system where the WNV protease is inserted between the Gal4 DNA binding and activation domains. Protease cleavage of the fusion would prevent GFP expression, while inhibition would allow GFP expression. Preliminary data shows the mutated, non-cleavable fusion induces GFP, while the wild type fusion does not, demonstrating proof of concept. Stable cell lines will be generated expressing all assay components to enable high-throughput screening for WNV protease inhibitors.
We previously reported a CRISPR-mediated knock-in strategy into introns of Drosophila genes, generating an attP-FRT-SA T2A-GAL4-polyA-3XP3-EGFP-FRT-attP transgenic library for multiple uses (Lee et al., 2018a). The method relied on double stranded DNA (dsDNA) homology donors with ~1 kb homology arms. Here, we describe three new simpler ways to edit genes in flies. We create single stranded DNA (ssDNA) donors using PCR and add 100 nt of homology on each side of an integration cassette, followed by enzymatic removal of one strand. Using this method, we generated GFP-tagged proteins that mark organelles in S2 cells. We then describe two dsDNA methods using cheap synthesized donors flanked by 100 nt homology arms and gRNA target sites cloned into a plasmid. Upon injection, donor DNA (1 to 5 kb) is released from the plasmid by Cas9. The cassette integrates efficiently and precisely in vivo. The approach is fast, cheap, and scalable.
This study developed a new genetic assay to detect transcription errors in vivo using Saccharomyces cerevisiae. The assay uses a mutant form of the Cre recombinase gene with a missense mutation in the active site tyrosine. Rare transcription errors that restore the wild-type tyrosine codon can be detected by Cre-dependent rearrangement of reporter genes. Using this assay, the researchers screened for mutations in the largest subunit of RNA polymerase II, Rpb1, that increase the rate of transcription errors. They identified mutations in three domains of Rpb1 - the trigger loop, bridge helix, and TFIIS binding sites - that lead to higher misincorporation rates or defects in error correction. Biochemical characterization confirmed
A sequence is a database object that generates unique integer values and can be shared across users and tables. It is created using the CREATE SEQUENCE statement which specifies properties like the name, increment amount, starting value, minimum, maximum and caching settings. The NEXTVAL pseudocolumn is used to retrieve the next value from a sequence and CURRVAL returns the last value retrieved in the current session.
Lecture delivered by T. Ashok Kumar, Head, Department of Bioinformatics, Noorul Islam College of Arts and Science, Kumaracoil, Thuckalay, INDIA. UGC Sponsored National Workshop on BIOINFORMATICS AND GENOME ANALYSIS for College Teachers on August 11 & 12, 2014. Organized by Centre for Bioinformatics, Department of Zoology, NMCC.
This document outlines the course content for a bioinformatics course covering 4 units:
Unit 1 introduces basic concepts of bioinformatics including proteins, DNA, RNA, and sequence, structure, and function.
Unit 2 covers major bioinformatics databases including those for nucleotide sequences, protein sequences, sequence motifs, protein structures, and other relevant databases.
Unit 3 discusses topics like single and pairwise sequence alignment, scoring matrices, and multiple sequence alignments.
Unit 4 covers the human genome project, gene and genomic databases, genomic data mining, and microarray techniques.
Protein databases can contain either sequence or structure information. Some key protein sequence databases include PIR, Swiss-Prot, and TrEMBL. PIR classifies entries by annotation level, Swiss-Prot aims to provide high annotation levels and interlink information, and TrEMBL contains all coding sequences with some entries eventually incorporated into Swiss-Prot. Important structure databases are PDB, which contains 3D protein structures, and SCOP and CATH, which classify evolutionary and structural relationships between protein domains.
This document discusses databases in bioinformatics. It begins by noting the rapid increase in biological data from sources like gene sequences, protein sequences, structural data, and gene expression data. It then defines biological databases as structured, searchable collections of data that are periodically updated and cross-referenced. The major purposes of databases are to make biological data available, systematize the data, and allow analysis of computed biological data. The document provides a brief history of biological databases and sequencing efforts. It also classifies biological databases based on data type, maintenance status, data access, data sources, database design, and organism. Specific databases discussed include DDBJ, EMBL, GenBank, Swiss-Prot, and NCB
The document describes three problems involving determining the optimal sequence of jobs through multiple machines to minimize the total elapsed time.
For the first problem involving two machines, the optimal sequence is job 2, 1, 6, 5, 4, 3 with a total elapsed time of 85 hours.
The second problem involving three machines is converted to two virtual machines, and the optimal sequence is job 3, 4, 2, 1, 5 with a total elapsed time of 51 hours.
The third problem involving four machines is also converted to two virtual machines, and the optimal sequence is job C, A, B, D with a total elapsed time of 82 hours.
This document discusses the roles of O-linked β-N-acetylglucosamine (O-GlcNAc) in physiology and the analytical challenges of studying it. O-GlcNAc is a post-translational modification found on nuclear and cytosolic proteins that is involved in nutrient sensing and the regulation of many cellular processes. It has extensive crosstalk with phosphorylation and over 3000 protein sites have been mapped to date. Increased global O-GlcNAcylation, even over just 2.5 hours, affects the occupancy of nearly every phosphorylated site that is actively cycling. Many kinases are also regulated by O-GlcNAcylation, with over 40 synaptic kinases identified as being O-
RNA-Seq To Identify Novel Markers For Research on Neural Tissue DifferentiationThermo Fisher Scientific
Neural tissue differentiated and cultured from derived stem cells is expected to revolutionize the treatment of brain and spinal injuries and diseases. Critical for these cellular therapies is accurate control and monitoring of differentiation but current methods for such cell typing are limited to qPCR and immunocytochemisty (ICC) which is not sufficient to discriminate between the numerous (likely >100,000) possible neural cell-types. Research using RNA sequencing (RNA-Seq) permits the characterization and discovery of much-needed novel markers. To define the temporal transcriptional signature of neural stem cells, cultured human embryonic stem cells (H9) were compared to induced neural stem cells (NSCs) at d0, d7 and d14. Total RNA was isolated over the time course from the undifferentiated and differentiated cells. Ion Torrent™ libraries were created to profile expression of miRNAs and whole transcriptomes for each cell population. Multiplexed Ion Proton™ sequencing and Torrent Suite™ Software analysis yielded ≥2.5 million small RNA reads and ≥29 million whole transcriptome reads per sample. Cluster analysis of the RNA-Seq profiles indicates that the cell populations have characteristic molecular signatures. Among genes that are decreased in induced cells are OCT4 (POU5F1), JARID2, NANOG, consistent with the differentiation of iPSCs into neurons. Among genes that showed increased expressions are NTRK2, POU3F2, and a number of HOX family genes. Recently, Ion AmpliSeq™ Transcriptome Human Gene Expression Kit has been launched, and the results from this analysis corroborated with whole transcriptome RNA-Seq results.
Introduction to Genetic Variation in GPCR
G-Protein couple Receptor
Genetic variation in GPCRs
V2 Vasopressin Receptor, Thrombroxane Receptor, P2Y 12ADP Receptor, Chemokine Receptor, Biogenic amine receptors
Presented by
R. REKHA
Department of Pharmacology
The document discusses prion diseases and the protein-only hypothesis of pathogenesis. It summarizes the structures of cellular and scrapie prion protein and describes techniques used to study prion protein aggregates, including EPR spectroscopy. The document outlines research showing recombinant prion protein forms amyloid fibrils with a parallel in-register beta-sheet structure between residues 160-220. Both denaturing and native conditions produce similar amyloid fibrils, but buffer conditions can lead to structurally distinct fibrils. Substitution of single residues is also shown to produce different amyloid structures.
The document summarizes the structure and function of the p53 tumor suppressor protein. It describes the various domains of p53 including the N-terminal domain, proline-rich domain, central DNA-binding domain, tetramerization domain, and C-terminal regulatory domain. It discusses how each domain contributes to p53's role in regulating genes involved in cell cycle arrest and apoptosis in response to cellular stress. The document also provides information on the location of the TP53 gene and includes figures depicting the structure and domains of the p53 protein.
Multiple mouse reference genomes and strain specific gene annotationsThomas Keane
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2) Gene predictions are being developed using a combination of annotation lifting from C57BL/6J, local refinement with strain-specific RNA-seq data, and de novo prediction.
3) Resources have been created for viewing and accessing these new reference genomes and annotations.
An aminopeptidase P (PepP)-encoding gene has been cloned from Streptomyces lividans 66. The gene, pepP, was localized by deletion mapping and its nucleotide sequence was determined. The deduced amino acid sequence was found to display significant similarity to Escherichia coli PepP. The partially purified S. lividans enzyme had a 50-kDa subunit and was present as a homodimer, confirming that pepP encodes the observed intracellular PepP.
Sima lev: Lipid Transfer Proteins and Membrane Contact Sites in Human CancerSima Lev
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Modulation of MMP and ADAM gene expression in human chondrocytes by IL-1 and OSMpjtkoshy
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GenBank format and FASTA format as homo sapiens pepsin as an example bioinformatics practical 1st experiment ; sequence retrival from nucleotide sequence from NCBI
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1. Be familiar with next generation molecular diagnostic techniques that can provide guidance in clinical decision making
2. Identify the utility of these diagnostic approaches with some examples
3. Be aware of the challenges that exist in implementing these tools as part of the routine clinical decision making process, especially in resource limited settings
KDM5 epigenetic modifiers as a focus for drug discoveryChristopher Wynder
A summary presentation of my scientific work.
My laboratory focused on an enzyme KDM5b (aka PLU-1, JARID1b) that was widely expressed during development and played a key role in progression of breast cancer through HER-2.
My lab focused on understanding the key biochemical activity of the enzyme through dissecting the proteomic and genomic interactors.
Our results were confirmed through the use of ES cells, adult stem cells and mouse models.
Much of this work remains unpublished, please contact me for more information and/or access to any reagents that I still have as part of this work.
crwynder@gmail.com
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The document discusses several studies on the p53 tumor suppressor protein and its role in cancer development. It summarizes that p53 is stabilized in response to DNA damage, activating kinases and the ARF protein. Stabilized p53 can then act as a transcription factor to block angiogenesis and tumor growth. The document also reviews how viral oncogenes can inactivate p53 through binding proteins like MDM2, contributing to cancer development.
1. The document summarizes research on genetic causes and pathogenic mechanisms underlying various forms of Charcot-Marie-Tooth (CMT) disease and distal hereditary motor neuropathies (dHMN). It describes mutations found in genes involved in protein folding, axonal transport, cytoskeletal stability and other pathways.
2. Research shows that mutations in small heat shock proteins HSPB1 and HSPB8, which are implicated in CMT and dHMN, cause motor neuron dysfunction and protein aggregation. Studies using cell and animal models demonstrate disease-relevant gain of toxic function from these mutations.
3. The small heat shock proteins HSPB1 and HSPB8 are normally involved in
DNA microarrays contain small spots of DNA, with each spot representing a different gene. The intensity of each spot indicates the expression level of that gene's mRNA. Microarrays allow clustering of genes and experiments based on similar expression profiles, linking related pathway components. Post-translational modifications of histone tails, such as acetylation, provide binding sites that regulate chromatin structure and transcription.
A new effector pathway links ATM kinase with the DNA damage responseCostas Demonacos
The related kinases ATM (ataxia-telangiectasia mutated) and ATR (ataxia-telangiectasia and Rad3-related) phosphorylate a limited number of downstream protein targets in response to DNA damage. Here we report a new pathway in which ATM kinase signals the DNA damage response by targeting the transcriptional cofactor Strap. ATM phosphorylates Strap at a serine residue, stabilizing nuclear Strap and facilitating formation of a stress-responsive co-activator complex. Strap activity enhances p53 acetylation, and augments the response to DNA damage. Strap remains localized in the cytoplasm in cells derived from ataxia telangiectasia individuals with defective ATM, as well as in cells expressing a Strap mutant that cannot be phosphorylated by ATM. Targeting Strap to the nucleus reinstates protein stabilization and activates the DNA damage response. These results indicate that the nuclear accumulation of Strap is a critical regulator in the damage response, and argue that this function can be assigned to ATM through the DNA damage-dependent phosphorylation of Strap.
1) The Dlx5 homeodomain is a transcription factor linked to several human diseases. Mutations in the DLX5 gene have been associated with split hand and foot malformation syndrome 1 (SHFM1).
2) NMR spectroscopy was used to study the interaction between the Dlx5 homeodomain and DNA, identifying a 14 base pair DNA sequence (CGACTAATTAGTCG) that formed a stable complex.
3) The crystal structure of the Dlx5-DNA complex was determined at 1.85 angstrom resolution, revealing that residues associated with SHFM1 are involved in key interactions for DNA recognition and binding.
1) DksA is a transcription factor in E. coli that plays an important role in stress response. It binds directly to RNA polymerase, not DNA.
2) The dksA gene has three temporal promoters that are expressed at different growth phases. One promoter, P3, is located within another gene, sfsA, and is followed by a putative open reading frame (ORF) of unknown function.
3) The goal was to determine if this ORF encodes a polypeptide co-expressed with DksA during stationary phase. However, experiments failed to detect expression of the putative ORF polypeptide, even with various techniques. This suggests the ORF is not translated into a
The document summarizes experiments conducted to isolate and analyze a gene called mrfA involved in aerial hyphae development in Monascus ruber. Key findings include:
1. M. ruber mutants with disrupted mrfA showed abnormal hyphae growth compared to the original strain.
2. TAIL-PCR and other techniques were used to isolate the mrfA gene sequence.
3. A knock-out vector was constructed and transformed into M. ruber, resulting in transformants that exhibited autolytic aerial hyphae.
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An approach to describing and analysing bulk biological annotation quality: a case study using UniProtKB
1. An approach to describe and analyse bulk annotation
quality
Michael J Bell*, Colin Gillespie, Daniel Swan and Phillip Lord
*m.j.bell1@ncl.ac.uk
www.michaeljbell.co.uk
2. Talk Outline
• Annotation Quality? Why UniProtKB?
• Data extraction
• Applying power laws
• Analysing Swiss-Prot and TrEMBL annotation
• Discussion and Conclusion
• Questions
Michael J Bell @mj_bell
Newcastle University 2
m.j.bell1@ncl.ac.uk
3. Annotation Quality in UniProtKB
Michael J Bell @mj_bell
Newcastle University 3
m.j.bell1@ncl.ac.uk
4. ID PAX6_RAT Reviewed; 422 AA. CC -!- FUNCTION: Transcription factor with important functions in the DR GO; GO:0000790; C:nuclear chromatin; IDA:BHF-UCL.
AC P63016; A1A5N7; P32117; P70601; Q62222; Q64037; Q6QHS5; Q701Q8; CC development of the eye, nose, central nervous system and pancreas. DR GO; GO:0003680; F:AT DNA binding; IDA:RGD.
DT 31-AUG-2004, integrated into UniProtKB/Swiss-Prot. CC Required for the differentiation of pancreatic islet alpha cells. DR GO; GO:0003690; F:double-stranded DNA binding; IDA:RGD.
DT 31-AUG-2004, sequence version 1. CC Competes with PAX4 in binding to a common element in the glucagon, DR GO; GO:0000979; F:RNA polymerase II core promoter sequence-specific DNA binding; IC:BHF-UCL.
DT 11-JUL-2012, entry version 74. CC insulin and somatostatin promoters (By similarity). Regulates DR GO; GO:0000981; F:sequence-specific DNA binding RNA polymerase II transcription factor activity; IC:BHF-U
DE RecName: Full=Paired box protein Pax-6; CC specification of the ventral neuron subtypes by establishing the DR GO; GO:0004842; F:ubiquitin-protein ligase activity; ISS:UniProtKB.
DE AltName: Full=Oculorhombin; CC correct progenitor domains. DR GO; GO:0030902; P:hindbrain development; IDA:RGD.
GN Name=Pax6; Synonyms=Pax-6, Sey; CC -!- SUBUNIT: Interacts with MAF and MAFB (By similarity). Interacts DR GO; GO:0050768; P:negative regulation of neurogenesis; ISS:UniProtKB.
OS Rattus norvegicus (Rat). CC with TRIM11; this interaction leads to ubiquitination and DR GO; GO:0001764; P:neuron migration; IMP:RGD.
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; CC proteasomal degradation, as well as inhibition of transactivation, DR GO; GO:0003322; P:pancreatic A cell development; IMP:BHF-UCL.
OC Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Sciurognathi; CC possibly in part by preventing PAX6 binding to consensus DNA DR GO; GO:0042660; P:positive regulation of cell fate specification; IMP:RGD.
OC Muroidea; Muridae; Murinae; Rattus. CC sequences (By similarity). DR GO; GO:0045893; P:positive regulation of transcription, DNA-dependent; IC:BHF-UCL.
OX NCBI_TaxID=10116; CC -!- SUBCELLULAR LOCATION: Nucleus (By similarity). DR GO; GO:0050678; P:regulation of epithelial cell proliferation; IMP:RGD.
RN [1] CC -!- ALTERNATIVE PRODUCTS: DR GO; GO:0045664; P:regulation of neuron differentiation; IDA:RGD.
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). CC Event=Alternative splicing; Named isoforms=2; DR Gene3D; G3DSA:1.10.10.60; Homeodomain-rel; 1.
RA Gimlich R., Arnold G.S., Wawersik S., Maas R., Wong G.; CC Name=1; DR Gene3D; G3DSA:1.10.10.10; Wing_hlx_DNA_bd; 2.
RT "Pax-6 is required for pancreatic islet development."; CC IsoId=P63016-1; Sequence=Displayed; DR InterPro; IPR017970; Homeobox_CS.
RL Submitted (SEP-1996) to the EMBL/GenBank/DDBJ databases. CC Name=5a; Synonyms=Pax6-5a; DR InterPro; IPR001356; Homeodomain.
RN [2] CC IsoId=P63016-2; Sequence=VSP_011531; DR InterPro; IPR009057; Homeodomain-like.
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 5A). CC -!- PTM: Ubiquitinated by TRIM11, leading to ubiquitination and DR InterPro; IPR001523; Paired_box_N.
RC STRAIN=New England Deaconess Hospital, and Sprague-Dawley; CC proteasomal degradation (By similarity). DR InterPro; IPR011991; WHTH_trsnscrt_rep_DNA-bd.
RA Karkour A., Wolf G.M., Walther R.; CC -!- DISEASE: Note=Defects in Pax6 are the cause of a condition known DR Pfam; PF00046; Homeobox; 1.
RL Submitted (FEB-2004) to the EMBL/GenBank/DDBJ databases. CC as small eye (Sey) which results in the complete lack of eyes and DR Pfam; PF00292; PAX; 1.
RN [3] CC nasal primordia. DR PRINTS; PR00027; PAIREDBOX.
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 5A). CC -!- SIMILARITY: Belongs to the paired homeobox family. DR SMART; SM00389; HOX; 1.
RC STRAIN=Sprague-Dawley; TISSUE=Brain; CC -!- SIMILARITY: Contains 1 homeobox DNA-binding domain. DR SMART; SM00351; PAX; 1.
RA Wei F.; CC -!- SIMILARITY: Contains 1 paired domain. DR SUPFAM; SSF46689; Homeodomain_like; 2.
RT "Cloning the homologic isoform gene pax6 5a in the rat."; CC ----------------------------------------------------------------------- DR PROSITE; PS00027; HOMEOBOX_1; 1.
RL Submitted (FEB-2004) to the EMBL/GenBank/DDBJ databases. CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms DR PROSITE; PS50071; HOMEOBOX_2; 1.
RN [4] CC Distributed under the Creative Commons Attribution-NoDerivs License DR PROSITE; PS00034; PAIRED_1; 1.
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). CC ----------------------------------------------------------------------- DR PROSITE; PS51057; PAIRED_2; 1.
RC TISSUE=Heart; DR EMBL; U69644; AAB09042.1; -; mRNA. PE 2: Evidence at transcript level;
RX PubMed=15489334; DOI=10.1101/gr.2596504; DR EMBL; AY540905; AAS48919.1; -; mRNA. KW Alternative splicing; Complete proteome; Developmental protein;
RG The MGC Project Team; DR EMBL; AY540906; AAS48920.1; -; mRNA. KW Differentiation; DNA-binding; Homeobox; Nucleus; Paired box;
RT "The status, quality, and expansion of the NIH full-length cDNA DR EMBL; AJ627631; CAF29075.1; -; mRNA. KW Reference proteome; Transcription; Transcription regulation;
RT project: the Mammalian Gene Collection (MGC)."; DR EMBL; BC128741; AAI28742.1; -; mRNA. KW Ubl conjugation.
RL Genome Res. 14:2121-2127(2004). DR EMBL; S74393; AAB32671.1; ALT_TERM; mRNA. FT CHAIN 1 422 Paired box protein Pax-6.
RN [5] DR IPI; IPI00231698; -. FT /FTId=PRO_0000050187.
RP PARTIAL NUCLEOTIDE SEQUENCE [MRNA], AND INVOLVEMENT IN SEY. DR IPI; IPI00464480; -. FT DOMAIN 4 130 Paired.
RC STRAIN=Sprague-Dawley; TISSUE=Embryo; DR PIR; S36166; S36166. FT DNA_BIND 210 269 Homeobox.
RX MEDLINE=95072652; PubMed=7981749; DOI=10.1038/ng0493-299; DR RefSeq; NP_037133.1; NM_013001.2. FT COMPBIAS 131 209 Gln/Gly-rich.
RA Matsuo T., Osumi-Yamashita N., Noji S., Ohuchi H., Koyama E., DR UniGene; Rn.89724; -. FT COMPBIAS 279 422 Pro/Ser/Thr-rich.
RA Myokai F., Matsuo N., Taniguchi S., Doi H., Iseki S., Ninomiya Y., DR ProteinModelPortal; P63016; -. FT VAR_SEQ 47 47 Q -> QTHADAKVQVLDSEN (in isoform 5a).
RA Fujiwara M., Wantanabe T., Eto K.; DR SMR; P63016; 4-136, 211-278. FT /FTId=VSP_011531.
RT "A mutation in the Pax-6 gene in rat small eye is associated with DR STRING; P63016; -. FT CONFLICT 159 159 R -> C (in Ref. 3; CAF29075).
RT impaired migration of midbrain crest cells."; DR Ensembl; ENSRNOT00000005882; ENSRNOP00000005882; ENSRNOG00000004410. FT CONFLICT 183 183 Q -> G (in Ref. 5; AAB32671).
RL Nat. Genet. 3:299-304(1993). DR Ensembl; ENSRNOT00000006302; ENSRNOP00000006302; ENSRNOG00000004410. SQ SEQUENCE 422 AA; 46754 MW; B0B2E5C176A518FE CRC64;
RN [6] DR GeneID; 25509; -. MQNSHSGVNQ LGGVFVNGRP LPDSTRQKIV ELAHSGARPC DISRILQVSN GCVSKILGRY
RP FUNCTION. DR KEGG; rno:25509; -. YETGSIRPRA IGGSKPRVAT PEVVSKIAQY KRECPSIFAW EIRDRLLSEG VCTNDNIPSV
RX MEDLINE=21869997; PubMed=11880342; DR UCSC; RGD:3258; rat. SSINRVLRNL ASEKQQMGAD GMYDKLRMLN GQTGSWGTRP GWYPGTSVPG QPTQDGCQQQ
RA Takahashi M., Osumi N.; DR CTD; 5080; -. EGQGENTNSI SSNGEDSDEA QMRLQLKRKL QRNRTSFTQE QIEALEKEFE RTHYPDVFAR
RT "Pax6 regulates specification of ventral neurone subtypes in the DR RGD; 3258; Pax6. ERLAAKIDLP EARIQVWFSN RRAKWRREEK LRNQRRQASN TPSHIPISSS FSTSVYQPIP
RT hindbrain by establishing progenitor domains."; DR eggNOG; NOG326044; -. QPTTPVSSFT SGSMLGRTDT ALTNTYSALP PMPSFTMANN LPMQPPVPSQ TSSYSCMLPT
RL Development 129:1327-1338(2002). DR GeneTree; ENSGT00650000093130; -. SPSVNGRSYD TYTPPHMQTH MNSQPMGTSG TTSTGLISPG VSVPVQVPGS EPDMSQYWPR
DR HOVERGEN; HBG009115; -. LQ
DR KO; K08031; -. //
5. ID PAX6_RAT Reviewed; 422 AA. CC -!- FUNCTION: Transcription factor with important functions in the DR GO; GO:0000790; C:nuclear chromatin; IDA:BHF-UCL.
AC P63016; A1A5N7; P32117; P70601; Q62222; Q64037; Q6QHS5; Q701Q8; CC development of the eye, nose, central nervous system and pancreas. DR GO; GO:0003680; F:AT DNA binding; IDA:RGD.
DT 31-AUG-2004, integrated into UniProtKB/Swiss-Prot. CC Required for the differentiation of pancreatic islet alpha cells. DR GO; GO:0003690; F:double-stranded DNA binding; IDA:RGD.
DT 31-AUG-2004, sequence version 1. CC Competes with PAX4 in binding to a common element in the glucagon, DR GO; GO:0000979; F:RNA polymerase II core promoter sequence-specific DNA binding; IC:BHF-UCL.
DT 11-JUL-2012, entry version 74. CC insulin and somatostatin promoters (By similarity). Regulates DR GO; GO:0000981; F:sequence-specific DNA binding RNA polymerase II transcription factor activity; IC:BHF-U
DE RecName: Full=Paired box protein Pax-6; CC specification of the ventral neuron subtypes by establishing the DR GO; GO:0004842; F:ubiquitin-protein ligase activity; ISS:UniProtKB.
DE AltName: Full=Oculorhombin; CC correct progenitor domains. DR GO; GO:0030902; P:hindbrain development; IDA:RGD.
GN Name=Pax6; Synonyms=Pax-6, Sey; CC -!- SUBUNIT: Interacts with MAF and MAFB (By similarity). Interacts DR GO; GO:0050768; P:negative regulation of neurogenesis; ISS:UniProtKB.
OS Rattus norvegicus (Rat). CC with TRIM11; this interaction leads to ubiquitination and DR GO; GO:0001764; P:neuron migration; IMP:RGD.
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; CC proteasomal degradation, as well as inhibition of transactivation, DR GO; GO:0003322; P:pancreatic A cell development; IMP:BHF-UCL.
OC Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Sciurognathi; CC possibly in part by preventing PAX6 binding to consensus DNA DR GO; GO:0042660; P:positive regulation of cell fate specification; IMP:RGD.
OC Muroidea; Muridae; Murinae; Rattus. CC sequences (By similarity). DR GO; GO:0045893; P:positive regulation of transcription, DNA-dependent; IC:BHF-UCL.
OX NCBI_TaxID=10116; CC -!- SUBCELLULAR LOCATION: Nucleus (By similarity). DR GO; GO:0050678; P:regulation of epithelial cell proliferation; IMP:RGD.
RN [1] CC -!- ALTERNATIVE PRODUCTS: DR GO; GO:0045664; P:regulation of neuron differentiation; IDA:RGD.
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). CC Event=Alternative splicing; Named isoforms=2; DR Gene3D; G3DSA:1.10.10.60; Homeodomain-rel; 1.
RA Gimlich R., Arnold G.S., Wawersik S., Maas R., Wong G.; CC Name=1; DR Gene3D; G3DSA:1.10.10.10; Wing_hlx_DNA_bd; 2.
RT "Pax-6 is required for pancreatic islet development."; CC IsoId=P63016-1; Sequence=Displayed; DR InterPro; IPR017970; Homeobox_CS.
RL Submitted (SEP-1996) to the EMBL/GenBank/DDBJ databases. CC Name=5a; Synonyms=Pax6-5a; DR InterPro; IPR001356; Homeodomain.
RN [2] CC IsoId=P63016-2; Sequence=VSP_011531; DR InterPro; IPR009057; Homeodomain-like.
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 5A). CC -!- PTM: Ubiquitinated by TRIM11, leading to ubiquitination and DR InterPro; IPR001523; Paired_box_N.
RC STRAIN=New England Deaconess Hospital, and Sprague-Dawley; CC proteasomal degradation (By similarity). DR InterPro; IPR011991; WHTH_trsnscrt_rep_DNA-bd.
RA Karkour A., Wolf G.M., Walther R.; CC -!- DISEASE: Note=Defects in Pax6 are the cause of a condition known DR Pfam; PF00046; Homeobox; 1.
RL Submitted (FEB-2004) to the EMBL/GenBank/DDBJ databases. CC as small eye (Sey) which results in the complete lack of eyes and DR Pfam; PF00292; PAX; 1.
RN [3] CC nasal primordia. DR PRINTS; PR00027; PAIREDBOX.
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 5A). CC -!- SIMILARITY: Belongs to the paired homeobox family. DR SMART; SM00389; HOX; 1.
RC STRAIN=Sprague-Dawley; TISSUE=Brain; CC -!- SIMILARITY: Contains 1 homeobox DNA-binding domain. DR SMART; SM00351; PAX; 1.
RA Wei F.; CC -!- SIMILARITY: Contains 1 paired domain. DR SUPFAM; SSF46689; Homeodomain_like; 2.
RT "Cloning the homologic isoform gene pax6 5a in the rat."; CC ----------------------------------------------------------------------- DR PROSITE; PS00027; HOMEOBOX_1; 1.
RL Submitted (FEB-2004) to the EMBL/GenBank/DDBJ databases. CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms DR PROSITE; PS50071; HOMEOBOX_2; 1.
RN [4] CC Distributed under the Creative Commons Attribution-NoDerivs License DR PROSITE; PS00034; PAIRED_1; 1.
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). CC ----------------------------------------------------------------------- DR PROSITE; PS51057; PAIRED_2; 1.
RC TISSUE=Heart; DR EMBL; U69644; AAB09042.1; -; mRNA. PE 2: Evidence at transcript level;
RX PubMed=15489334; DOI=10.1101/gr.2596504; DR EMBL; AY540905; AAS48919.1; -; mRNA. KW Alternative splicing; Complete proteome; Developmental protein;
RG The MGC Project Team; DR EMBL; AY540906; AAS48920.1; -; mRNA. KW Differentiation; DNA-binding; Homeobox; Nucleus; Paired box;
RT "The status, quality, and expansion of the NIH full-length cDNA DR EMBL; AJ627631; CAF29075.1; -; mRNA. KW Reference proteome; Transcription; Transcription regulation;
RT project: the Mammalian Gene Collection (MGC)."; DR EMBL; BC128741; AAI28742.1; -; mRNA. KW Ubl conjugation.
RL Genome Res. 14:2121-2127(2004). DR EMBL; S74393; AAB32671.1; ALT_TERM; mRNA. FT CHAIN 1 422 Paired box protein Pax-6.
RN [5] DR IPI; IPI00231698; -. FT /FTId=PRO_0000050187.
RP PARTIAL NUCLEOTIDE SEQUENCE [MRNA], AND INVOLVEMENT IN SEY. DR IPI; IPI00464480; -. FT DOMAIN 4 130 Paired.
RC STRAIN=Sprague-Dawley; TISSUE=Embryo; DR PIR; S36166; S36166. FT DNA_BIND 210 269 Homeobox.
RX MEDLINE=95072652; PubMed=7981749; DOI=10.1038/ng0493-299; DR RefSeq; NP_037133.1; NM_013001.2. FT COMPBIAS 131 209 Gln/Gly-rich.
RA Matsuo T., Osumi-Yamashita N., Noji S., Ohuchi H., Koyama E., DR UniGene; Rn.89724; -. FT COMPBIAS 279 422 Pro/Ser/Thr-rich.
RA Myokai F., Matsuo N., Taniguchi S., Doi H., Iseki S., Ninomiya Y., DR ProteinModelPortal; P63016; -. FT VAR_SEQ 47 47 Q -> QTHADAKVQVLDSEN (in isoform 5a).
RA Fujiwara M., Wantanabe T., Eto K.; DR SMR; P63016; 4-136, 211-278. FT /FTId=VSP_011531.
RT "A mutation in the Pax-6 gene in rat small eye is associated with DR STRING; P63016; -. FT CONFLICT 159 159 R -> C (in Ref. 3; CAF29075).
RT impaired migration of midbrain crest cells."; DR Ensembl; ENSRNOT00000005882; ENSRNOP00000005882; ENSRNOG00000004410. FT CONFLICT 183 183 Q -> G (in Ref. 5; AAB32671).
RL Nat. Genet. 3:299-304(1993). DR Ensembl; ENSRNOT00000006302; ENSRNOP00000006302; ENSRNOG00000004410. SQ SEQUENCE 422 AA; 46754 MW; B0B2E5C176A518FE CRC64;
RN [6] DR GeneID; 25509; -. MQNSHSGVNQ LGGVFVNGRP LPDSTRQKIV ELAHSGARPC DISRILQVSN GCVSKILGRY
RP FUNCTION. DR KEGG; rno:25509; -. YETGSIRPRA IGGSKPRVAT PEVVSKIAQY KRECPSIFAW EIRDRLLSEG VCTNDNIPSV
RX MEDLINE=21869997; PubMed=11880342; DR UCSC; RGD:3258; rat. SSINRVLRNL ASEKQQMGAD GMYDKLRMLN GQTGSWGTRP GWYPGTSVPG QPTQDGCQQQ
RA Takahashi M., Osumi N.; DR CTD; 5080; -. EGQGENTNSI SSNGEDSDEA QMRLQLKRKL QRNRTSFTQE QIEALEKEFE RTHYPDVFAR
RT "Pax6 regulates specification of ventral neurone subtypes in the DR RGD; 3258; Pax6. ERLAAKIDLP EARIQVWFSN RRAKWRREEK LRNQRRQASN TPSHIPISSS FSTSVYQPIP
RT hindbrain by establishing progenitor domains."; DR eggNOG; NOG326044; -. QPTTPVSSFT SGSMLGRTDT ALTNTYSALP PMPSFTMANN LPMQPPVPSQ TSSYSCMLPT
RL Development 129:1327-1338(2002). DR GeneTree; ENSGT00650000093130; -. SPSVNGRSYD TYTPPHMQTH MNSQPMGTSG TTSTGLISPG VSVPVQVPGS EPDMSQYWPR
DR HOVERGEN; HBG009115; -. LQ
DR KO; K08031; -. //
6. ID PAX6_RAT Reviewed; 422 AA. CC -!- FUNCTION: Transcription factor with important functions in the DR GO; GO:0000790; C:nuclear chromatin; IDA:BHF-UCL.
AC P63016; A1A5N7; P32117; P70601; Q62222; Q64037; Q6QHS5; Q701Q8; CC development of the eye, nose, central nervous system and pancreas. DR GO; GO:0003680; F:AT DNA binding; IDA:RGD.
DT 31-AUG-2004, integrated into UniProtKB/Swiss-Prot. CC Required for the differentiation of pancreatic islet alpha cells. DR GO; GO:0003690; F:double-stranded DNA binding; IDA:RGD.
DT 31-AUG-2004, sequence version 1. CC Competes with PAX4 in binding to a common element in the glucagon, DR GO; GO:0000979; F:RNA polymerase II core promoter sequence-specific DNA binding; IC:BHF-UCL.
DT 11-JUL-2012, entry version 74. CC insulin and somatostatin promoters (By similarity). Regulates DR GO; GO:0000981; F:sequence-specific DNA binding RNA polymerase II transcription factor activity; IC:BHF-U
DE RecName: Full=Paired box protein Pax-6; CC specification of the ventral neuron subtypes by establishing the DR GO; GO:0004842; F:ubiquitin-protein ligase activity; ISS:UniProtKB.
DE AltName: Full=Oculorhombin; CC correct progenitor domains. DR GO; GO:0030902; P:hindbrain development; IDA:RGD.
GN Name=Pax6; Synonyms=Pax-6, Sey; CC -!- SUBUNIT: Interacts with MAF and MAFB (By similarity). Interacts DR GO; GO:0050768; P:negative regulation of neurogenesis; ISS:UniProtKB.
OS Rattus norvegicus (Rat). CC with TRIM11; this interaction leads to ubiquitination and DR GO; GO:0001764; P:neuron migration; IMP:RGD.
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; CC proteasomal degradation, as well as inhibition of transactivation, DR GO; GO:0003322; P:pancreatic A cell development; IMP:BHF-UCL.
OC Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Sciurognathi; CC possibly in part by preventing PAX6 binding to consensus DNA DR GO; GO:0042660; P:positive regulation of cell fate specification; IMP:RGD.
OC Muroidea; Muridae; Murinae; Rattus. CC sequences (By similarity). DR GO; GO:0045893; P:positive regulation of transcription, DNA-dependent; IC:BHF-UCL.
OX NCBI_TaxID=10116; CC -!- SUBCELLULAR LOCATION: Nucleus (By similarity). DR GO; GO:0050678; P:regulation of epithelial cell proliferation; IMP:RGD.
RN [1] CC -!- ALTERNATIVE PRODUCTS: DR GO; GO:0045664; P:regulation of neuron differentiation; IDA:RGD.
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). CC Event=Alternative splicing; Named isoforms=2; DR Gene3D; G3DSA:1.10.10.60; Homeodomain-rel; 1.
RA Gimlich R., Arnold G.S., Wawersik S., Maas R., Wong G.; CC Name=1; DR Gene3D; G3DSA:1.10.10.10; Wing_hlx_DNA_bd; 2.
RT "Pax-6 is required for pancreatic islet development."; CC IsoId=P63016-1; Sequence=Displayed; DR InterPro; IPR017970; Homeobox_CS.
RL Submitted (SEP-1996) to the EMBL/GenBank/DDBJ databases. CC Name=5a; Synonyms=Pax6-5a; DR InterPro; IPR001356; Homeodomain.
RN [2] CC IsoId=P63016-2; Sequence=VSP_011531; DR InterPro; IPR009057; Homeodomain-like.
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 5A). CC -!- PTM: Ubiquitinated by TRIM11, leading to ubiquitination and DR InterPro; IPR001523; Paired_box_N.
RC STRAIN=New England Deaconess Hospital, and Sprague-Dawley; CC proteasomal degradation (By similarity). DR InterPro; IPR011991; WHTH_trsnscrt_rep_DNA-bd.
RA Karkour A., Wolf G.M., Walther R.; CC -!- DISEASE: Note=Defects in Pax6 are the cause of a condition known DR Pfam; PF00046; Homeobox; 1.
RL Submitted (FEB-2004) to the EMBL/GenBank/DDBJ databases. CC as small eye (Sey) which results in the complete lack of eyes and DR Pfam; PF00292; PAX; 1.
RN [3] CC nasal primordia. DR PRINTS; PR00027; PAIREDBOX.
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 5A). CC -!- SIMILARITY: Belongs to the paired homeobox family. DR SMART; SM00389; HOX; 1.
RC STRAIN=Sprague-Dawley; TISSUE=Brain; CC -!- SIMILARITY: Contains 1 homeobox DNA-binding domain. DR SMART; SM00351; PAX; 1.
RA Wei F.; CC -!- SIMILARITY: Contains 1 paired domain. DR SUPFAM; SSF46689; Homeodomain_like; 2.
RT "Cloning the homologic isoform gene pax6 5a in the rat."; CC ----------------------------------------------------------------------- DR PROSITE; PS00027; HOMEOBOX_1; 1.
RL Submitted (FEB-2004) to the EMBL/GenBank/DDBJ databases. CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms DR PROSITE; PS50071; HOMEOBOX_2; 1.
RN [4] CC Distributed under the Creative Commons Attribution-NoDerivs License DR PROSITE; PS00034; PAIRED_1; 1.
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). CC ----------------------------------------------------------------------- DR PROSITE; PS51057; PAIRED_2; 1.
RC TISSUE=Heart; DR EMBL; U69644; AAB09042.1; -; mRNA. PE 2: Evidence at transcript level;
RX PubMed=15489334; DOI=10.1101/gr.2596504; DR EMBL; AY540905; AAS48919.1; -; mRNA. KW Alternative splicing; Complete proteome; Developmental protein;
RG The MGC Project Team; DR EMBL; AY540906; AAS48920.1; -; mRNA. KW Differentiation; DNA-binding; Homeobox; Nucleus; Paired box;
RT "The status, quality, and expansion of the NIH full-length cDNA DR EMBL; AJ627631; CAF29075.1; -; mRNA. KW Reference proteome; Transcription; Transcription regulation;
RT project: the Mammalian Gene Collection (MGC)."; DR EMBL; BC128741; AAI28742.1; -; mRNA. KW Ubl conjugation.
RL Genome Res. 14:2121-2127(2004). DR EMBL; S74393; AAB32671.1; ALT_TERM; mRNA. FT CHAIN 1 422 Paired box protein Pax-6.
RN [5] DR IPI; IPI00231698; -. FT /FTId=PRO_0000050187.
RP PARTIAL NUCLEOTIDE SEQUENCE [MRNA], AND INVOLVEMENT IN SEY. DR IPI; IPI00464480; -. FT DOMAIN 4 130 Paired.
RC STRAIN=Sprague-Dawley; TISSUE=Embryo; DR PIR; S36166; S36166. FT DNA_BIND 210 269 Homeobox.
RX MEDLINE=95072652; PubMed=7981749; DOI=10.1038/ng0493-299; DR RefSeq; NP_037133.1; NM_013001.2. FT COMPBIAS 131 209 Gln/Gly-rich.
RA Matsuo T., Osumi-Yamashita N., Noji S., Ohuchi H., Koyama E., DR UniGene; Rn.89724; -. FT COMPBIAS 279 422 Pro/Ser/Thr-rich.
RA Myokai F., Matsuo N., Taniguchi S., Doi H., Iseki S., Ninomiya Y., DR ProteinModelPortal; P63016; -. FT VAR_SEQ 47 47 Q -> QTHADAKVQVLDSEN (in isoform 5a).
RA Fujiwara M., Wantanabe T., Eto K.; DR SMR; P63016; 4-136, 211-278. FT /FTId=VSP_011531.
RT "A mutation in the Pax-6 gene in rat small eye is associated with DR STRING; P63016; -. FT CONFLICT 159 159 R -> C (in Ref. 3; CAF29075).
RT impaired migration of midbrain crest cells."; DR Ensembl; ENSRNOT00000005882; ENSRNOP00000005882; ENSRNOG00000004410. FT CONFLICT 183 183 Q -> G (in Ref. 5; AAB32671).
RL Nat. Genet. 3:299-304(1993). DR Ensembl; ENSRNOT00000006302; ENSRNOP00000006302; ENSRNOG00000004410. SQ SEQUENCE 422 AA; 46754 MW; B0B2E5C176A518FE CRC64;
RN [6] DR GeneID; 25509; -. MQNSHSGVNQ LGGVFVNGRP LPDSTRQKIV ELAHSGARPC DISRILQVSN GCVSKILGRY
RP FUNCTION. DR KEGG; rno:25509; -. YETGSIRPRA IGGSKPRVAT PEVVSKIAQY KRECPSIFAW EIRDRLLSEG VCTNDNIPSV
RX MEDLINE=21869997; PubMed=11880342; DR UCSC; RGD:3258; rat. SSINRVLRNL ASEKQQMGAD GMYDKLRMLN GQTGSWGTRP GWYPGTSVPG QPTQDGCQQQ
RA Takahashi M., Osumi N.; DR CTD; 5080; -. EGQGENTNSI SSNGEDSDEA QMRLQLKRKL QRNRTSFTQE QIEALEKEFE RTHYPDVFAR
RT "Pax6 regulates specification of ventral neurone subtypes in the DR RGD; 3258; Pax6. ERLAAKIDLP EARIQVWFSN RRAKWRREEK LRNQRRQASN TPSHIPISSS FSTSVYQPIP
RT hindbrain by establishing progenitor domains."; DR eggNOG; NOG326044; -. QPTTPVSSFT SGSMLGRTDT ALTNTYSALP PMPSFTMANN LPMQPPVPSQ TSSYSCMLPT
RL Development 129:1327-1338(2002). DR GeneTree; ENSGT00650000093130; -. SPSVNGRSYD TYTPPHMQTH MNSQPMGTSG TTSTGLISPG VSVPVQVPGS EPDMSQYWPR
DR HOVERGEN; HBG009115; -. LQ
DR KO; K08031; -. //
7. Functional Annotation
• Annotation is overloaded:
– Here we mean “high level”
• Knowledge associated with the data
• Aimed at the human reader
Michael J Bell @mj_bell
Newcastle University 7
m.j.bell1@ncl.ac.uk
8. Michael J Bell @mj_bell
Newcastle University 8
m.j.bell1@ncl.ac.uk
9. Swiss-Prot Entry
P26367 – PAX6_HUMAN
(Homo sapiens)
43 Sentences
Michael J Bell @mj_bell
Newcastle University 9
m.j.bell1@ncl.ac.uk
10. Michael J Bell @mj_bell
Newcastle University 10
m.j.bell1@ncl.ac.uk
11. TrEMBL Entry
A4PBK5 – A4PBK5_9METZ
(Ephydatia fluviatilis)
1 Sentence
Michael J Bell @mj_bell
Newcastle University 11
m.j.bell1@ncl.ac.uk
12. Annotation Quality
• Annotation is highly variable
– E.g. Automated Vs. Manual
• Current approaches rely upon specific
database structure/features
– Ontology
– Evidence Codes
• Can we develop a metric based on free text?
Michael J Bell @mj_bell
Newcastle University 12
m.j.bell1@ncl.ac.uk
13. Why UniProtKB?
• UniProtKB is well known and established
• Number of technical reasons:
– UniProtKB composed of TrEMBL and Swiss-Prot
– Historical version
– Cross species
• Lack of gold standard
Michael J Bell @mj_bell
Newcastle University 13
m.j.bell1@ncl.ac.uk
15. Investigating Word Occurrences
• Extract word occurrence from all annotation
Michael J Bell @mj_bell
Newcastle University 15
m.j.bell1@ncl.ac.uk
16. Investigating Word Occurrences
• Extract word occurrence from all annotation
1. Protein
2. Proteins
3. Chains
4. Chain
5. Sequence
6. Enzyme
7. Complex
Michael J Bell @mj_bell
Newcastle University 16
m.j.bell1@ncl.ac.uk
17. Word Occurrences in Wikipedia
Taken from: http://en.wikipedia.org/wiki/File:Wikipedia-n-zipf.png
Michael J Bell @mj_bell
Newcastle University 17
m.j.bell1@ncl.ac.uk
18. Zipf’s Principle of Least Effort
• Take word occurrences and apply to Zipf’s
Principle of Least Effort
• Human nature to take path of least effort
when achieving a goal
α Value Examples in literature Least effort for
α < 1.6 Advanced Schizophrenia, Young children -
1.6 < α < 2 Military Combat Texts, Wikipedia, Web pages listed on the open Annotator
directory project
α=2 Single author texts Equal
2 < α < 2.4 Multi author texts Audience
α > 2.4 Fragmented discourse schizophrenia -
Michael J Bell @mj_bell
Newcastle University 18
m.j.bell1@ncl.ac.uk
20. The Model & Resulting Graphs
• Power Law Distribution
• Logarithmic scales
• X-axis – Size
• Y-Axis – Probability
• A point represents
probability a word will
occur X or more times
• E.g. upper left most point:
– Probability word occurs once = 10^0
Michael J Bell @mj_bell
Newcastle University 20
m.j.bell1@ncl.ac.uk
21. Does UniProtKB obey a power-law?
• Broadly, yes. However, distinct structure?
Michael J Bell @mj_bell
Newcastle University 21
m.j.bell1@ncl.ac.uk
22. The removal of copyright
• Development of two slopes
– As seen in mature resources
Michael J Bell @mj_bell
Newcastle University 22
m.j.bell1@ncl.ac.uk
23. Quality of Biological Knowledge?
• How does automated annotation compare to
manual annotation?
– i.e. TrEMBL Vs. Swiss-Prot
• Assume Swiss-Prot acts as a more mature
resource than TrEMBL
• Analyse this by comparing annotations at
equivalent points in time
Michael J Bell @mj_bell
Newcastle University 23
m.j.bell1@ncl.ac.uk
25. Viewing over time
• Show just alpha
values
• Appears to be
becoming
optimised (least
effort) for
annotator
Michael J Bell @mj_bell
Newcastle University 25
m.j.bell1@ncl.ac.uk
26. Annotation Maturity
• Does this decrease happen because entries
are, on average, getting older?
Michael J Bell @mj_bell
Newcastle University 26
m.j.bell1@ncl.ac.uk
27. Annotation Maturity
• Want to abstract from size and analyse how
individual records are maturing
• Need essentially a set of records which relate
to a defined set of proteins
• Therefore extract entries common in both
Swiss-Prot V9 and UniProtKB V15
Michael J Bell @mj_bell
Newcastle University 27
m.j.bell1@ncl.ac.uk
29. Analysing new annotations
• Mature entries are decreasing
• How are new annotations impacted?
• Take annotations from entries that appear for
the first time in a given database version
Michael J Bell @mj_bell
Newcastle University 29
m.j.bell1@ncl.ac.uk
30. The impact of new annotations
Michael J Bell @mj_bell
Newcastle University 30
m.j.bell1@ncl.ac.uk
31. Explanation for the decrease?
• Annotation curation involves identifying
similar entries
• Annotations between these entries are
standardised
• Is this standardisation changing the way
entries are annotated?
– Subsequently placing the least effort onto the
annotator?
Michael J Bell @mj_bell
Newcastle University 31
m.j.bell1@ncl.ac.uk
32. Conclusions
• Approach acting as a quality measure
– Detection of artefacts
– Distinction between TrEMBL and Swiss-Prot
• Annotations in UniProtKB are becoming
optimised for the annotator rather than the
reader
– Constant increase of data & pressure on curators
– Also true for existing and new annotations
Michael J Bell @mj_bell
Newcastle University 32
m.j.bell1@ncl.ac.uk
33. Summary
• The biological community lacks a generic quality
metric that allows biological annotation to be
quantitatively assessed and compared.
• Here we investigated word reuse within bulk
textual annotation and related it to Zipf's
Principle of Least Effort.
• Straight forward approach once data extracted
• Holds promise of being useful for curators and
end users
Michael J Bell @mj_bell
Newcastle University 33
m.j.bell1@ncl.ac.uk
34. Colin Gillespie, Daniel Swan
Thank You! and Phillip Lord
Many thanks go to:
Allyson Lister1
Daniel Barrell2
Michael Bell
UniProt Helpdesk
1 Newcastle
m.j.bell1@ncl.ac.uk
University, UK
2 EBIMichael J Bell @mj_bell
m.j.bell1@ncl.ac.uk
Newcastle University www.michaeljbell.co.uk
34
Editor's Notes
For example this is an analysis over Wikipedia. And we find that word occurrence size ranked by the word broadly obeys a power law. Taken from - http://en.wikipedia.org/wiki/File:Wikipedia-n-zipf.png
We can relate these power laws to Zipf's principle of least effort. This states that... Point about reader and author. Different texts resolve this in different ways. By taking the exponenet of the regression line – alpha – we can see that Wikipedia has is least effort is placed on the curator.
The first step of our approach is to extract the necessary data from UniProtKB. Our extraction process consists of 4 key steps. Firstly we obtain each version of Swiss-Prot and TrEMBL and then extract just those lines that hold comments. We then extract all the words from this data, and remove topic and block headings. We can then count how frequently each word occurs, with the output being a list of all words and their occurrence.
We can then apply a power law distribution to this data. The result of which is a graph, as shown here. The graph is actually represented as a cumulative distribution function, and is shown on logarithmic scales. Along the X axis we have the size of a word – that is how frequently it occurs, whilst along the Y axis we have the probability of a word occurring X or more times. This graph isn’t straight forward – so as an example, the top left point represents that the probability a word occurs once is 1, as only words that occur within the corpus are used. Conversely, the point at the bottom right shows that the probability of a word occuring over 100,000 times is very small. Using this approach we can now initially apply it to Swiss-Prot
The first question to ask is – does Swiss-Prot obey a power law? And it does boradly appear to, yes. However, there is a distinct structure or kink in the tail of the graph in a number of versions. So the question here is, what is this kink?
Copyright statement added to every entry in a version. Therefore we see these statements here.Sort out graphsIt turns out to be copyright statements. This shows that using this approach we can detect the introduction of data with no biological significance. It also shows that our approach is acting as a measure of quality, albeit for detecting artifacts.
Although Swiss-Prot obeys a power-law, does it relate to the quality of biological knowledge? One way we can address this quesiton is to compare automated and manual annotation.As shown previously, we can make the assumption that swiss-prot acts as a more mature resource than trembl. So by analysing annotations at similar points in time between the two resources, we would expect swiss-prot to act as a more mature resource.
By overlaying the graphs for TrEMBL and Swiss-Prot we can more clearly see how they mature over time. It is clear from this slide that they appear to diverge over time, with TrEMBL showing higher levels or re-use and swiss-prot showing a richer use of vocabulary. So it does indeed suggest our approach is acting as a measure of quality. However, the main analytical value from these graphs from the alpha value
So we can show the alpha value over time for both swiss-prot and trembl. This also provides a clearer image of effort over time.We can see how both databases show a decrease over time – that is they appear to be becoming least effort for the annotator – although this progression is much more irregular in TrEMBL.This view shows two major disjuncts in TrEMBL – which appears to coincide with changes to the underlying annotation process in TrEMBL. One possible explanation for this decrease is due to the age of entries.
So one possibility for this decrease is that entries, on average, getting older as the database is getting older. This isn’t the case however, entries are getting younger. This is mainly due to new records being added exponentially – outnumbering the old records.So we ask if the decrease happens because entries are, on average, getting older? However this isn't true as actually average age isn't getting older and is decreasing over time.
So here we want to abstract form the size of the database and ask how are individual records maturing?This isn’t straight forward – essentially we need a set of records which relate to a defined set of proteinsTherefore, we extract those entries that are common in SWP 9 and UPSP 15, providing a span of over 20 years.
Again, highlight slope of graph we are looking at – and that we are looking at the subsets.Like with the database as a whole, we again see a decrease. However, this isn’t as low as the remainder of the database.
Re-iterate earlier question – and that this is another way to look at it. All annotations are approx of same age, as they are new.
As we see a decrease in the mature entries – how do the new entries fare?Similarly they decrease over time, which is the same pattern as all other graphsWhy do we see all of these decreases...?
The protocol was recently published (2011) and again shows advantage of using UniProtKB, as well documented.Need to be careful we don't say “standardisation == poor quality”, it is just something that can explain it, rather than a definitive answer. Rather, it is more likely that trying to be consistent has lost some of the more “personal” annotations to entries, and thus become more generic.TOO WORDY
Try finish on a high here. Give a very quick and brief recap of the main idea and points, and how it is “easy” and could be useful for both curators and end users alike.
Word Cloud is from UniProtKB/Swiss-Prot Version 15
Number of competing models were considered. However, Power Law distribution gives a good balance between model parsimony and fit.Only deal with discrete power law distribution here – which has the probability mass function described.To fit the power-law distribution we followed a Bayesian paradigm.Xmin, determined using the BIC criteria, was set to 50 throughout.