1,399 results
Search Results
2. Modeling Chromosomes: Building paper chromosomes to help understand five key terms in genetics
- Author
-
Robertson, Carol
- Published
- 2016
3. Three Early Papers on Efficient Parametric Estimation
- Author
-
Edwards, A. W. F.
- Published
- 1997
4. The Genetics Society of America. [Papers Read at the Chicago Meeting]
- Published
- 1934
5. Papers Read at the Pittsburgh Meeting of the Genetics Society of America
- Published
- 1935
6. A. Biometrics Invited Paper. Survey of Histocompatibility Testing: Biological Backgrounds, Probabilistic and Statistical Models and Problems
- Author
-
Elandt-Johnson, Regina C.
- Published
- 1969
- Full Text
- View/download PDF
7. A Biometrics Invited Paper. Genetic Equilibrium under Selection
- Author
-
Li, C. C.
- Published
- 1967
- Full Text
- View/download PDF
8. Development of microsatellite loci and optimization of a multiplex assay for Latibulus argiolus (Hymenoptera: Ichneumonidae), the specialized parasitoid of paper wasps
- Author
-
Anna Siekiera, Magdalena Czajkowska, Jan J. Pomorski, Agata Kostro-Ambroziak, and Hanna Panagiotopoulou
- Subjects
0106 biological sciences ,0301 basic medicine ,Genetic Markers ,Population ,Genome, Insect ,Wasps ,lcsh:Medicine ,Locus (genetics) ,Ectoparasitic Infestations ,Biology ,010603 evolutionary biology ,01 natural sciences ,03 medical and health sciences ,Animals ,Multiplex ,Genetic variability ,Allele ,education ,lcsh:Science ,Alleles ,education.field_of_study ,Multidisciplinary ,Polymorphism, Genetic ,lcsh:R ,biology.organism_classification ,Null allele ,Ichneumonidae ,030104 developmental biology ,Genetics, Population ,Evolutionary biology ,Genetic Loci ,Microsatellite ,lcsh:Q ,Multiplex Polymerase Chain Reaction ,Microsatellite Repeats - Abstract
Microsatellite loci are commonly used markers in population genetic studies. In this study, we present 40 novel and polymorphic microsatellite loci elaborated for the ichneumonid parasitoid Latibulus argiolus (Rossi, 1790). Reaction condition optimisation procedures allowed 14 of these loci to be co-amplified in two PCRs and loaded in two multiplex panels onto a genetic analyser. The assay was tested on 197 individuals of L. argiolus originating from ten natural populations obtained from the host nests of paper wasps. The validated loci were polymorphic with high allele numbers ranging from eight to 27 (average 17.6 alleles per locus). Both observed and expected heterozygosity values were high, ranging between 0.75 and 0.92 for HO (mean 0.83) and from 0.70 to 0.90 for HE (mean 0.85). The optimized assay showed low genotyping error rate and negligible null allele frequency. The designed multiplex panels could be successfully applied in relatedness analyses and genetic variability studies of L. argiolus populations, which would be particularly interesting considering the coevolutionary context of this species with its social host.
- Published
- 2020
9. Abstracts of papers presented in Collegiate Academy Paper Sessions
- Published
- 1982
10. Comments on the Paper by Wickliffe et al. (Radiat. Res. 159, 458-464, 2003)
- Author
-
Dubrova, Yuri E.
- Published
- 2003
11. Abstracts of Papers Presented at the Meeting of the Collegiate Academy of the North Carolina Academy of Science, Inc., April 3-4, 1981, at the University of North Carolina, Charlotte, NC
- Published
- 1982
12. Assessing false paternity risk in simulated motherless cases from more than 20 000 real exclusion trios.
- Author
-
Aguiar VRC, de Castro AM, Pinto LM, Ferreira ACS, Dos Santos EVW, and Louro ID
- Subjects
- Alleles, Computer Simulation, Female, Genotype, Humans, Male, Mothers, Mutation, Paternity, Probability, Genetic Loci, Microsatellite Repeats
- Abstract
Background: When the mother's DNA profile is not available for paternity testing, there is a smaller probability that a locus will exclude an alleged father. This study aims to evaluate the risk of potential false paternity inclusions in motherless cases., Study Design and Methods: More than 20 000 duos were generated by removing the maternal genotypes from exclusion trios. After recalculating paternity in these duos, any found inclusions would be false., Results: The use of an appropriate number of loci, mutation model, and mutation rates to analyze motherless paternity cases was robust against false inclusions. A single potential false inclusion was observed in a case wherein kinship plays a role. This result highlights the importance of testing the mother when available and of obtaining information on family circumstances for the proper handling of cases involving related individuals., Conclusion: The guidelines we used here were sufficient to avoid false inclusions in a data set of more than 20 000 motherless cases., (© 2020 AABB.)
- Published
- 2021
- Full Text
- View/download PDF
13. Population Differences in Quantitative Characters and Gene Frequencies: A Comment on Papers by Lewontin and Rogers
- Author
-
Felsenstein, Joseph
- Published
- 1986
14. Mating system and population structure in the natural distribution of Toona ciliata (Meliaceae) in South China.
- Author
-
Zhou W, Zhang XX, Ren Y, Li P, Chen XY, and Hu XS
- Subjects
- China, Crosses, Genetic, Endangered Species, Inbreeding, Meliaceae, Pollination genetics, Reproduction genetics, Genetic Loci genetics, Microsatellite Repeats genetics, Toona physiology
- Abstract
Most initially perfect flowers of Toona ciliata Roem subsequently develop into functionally unisexual flowers and their relative positions in the same inflorescence could enhance the outcrossing system in this species. Here we investigated the mating system of this species. We used eight nuclear microsatellite markers and investigated the progeny of 125 mother trees from six populations naturally distributed in South China, with sample sizes ranging from 64 to 300 seeds. The multilocus outcrossing rate was 0.970 ± 0.063, and the single locus outcrossing rate was 0.859 ± 0.106, indicating the pattern of predominant outcrossing. Selfing was present in one population, but biparental inbreeding occurred in five populations. Inbreeding was absent in maternal parents, and correlations of selfing among families or among loci were generally insignificant. Positive correlation of paternity at multiple loci was significant in four populations, but was not consistent with the results at single loci. Population substructure occurred in male similarity between outcrosses only in one population. Population genetic differentaitaion was significant (F
st = 34.5%) and the effects of isolation-by-distance at the eight loci were significant among the six populations. These results provide evidence that self-comptability and inbreeding naturally occur in T. ciliata and indicate that inbreeding avoidance is necessary during genetic improvement and breeding of this endangered tree species.- Published
- 2020
- Full Text
- View/download PDF
15. The μ Opiate Receptor as a Candidate Gene for Pain: Polymorphisms, Variations in Expression, Nociception, and Opiate Responses
- Author
-
Uhl, George R., Sora, Ichiro, and Wang, Zaijie
- Published
- 1999
16. Statistical correction of the Winner’s Curse explains replication variability in quantitative trait genome-wide association studies.
- Author
-
Palmer, Cameron and Pe’er, Itsik
- Subjects
GENOMES ,DATABASES ,REGRESSION analysis ,ANALYSIS of covariance ,DIFFERENTIAL psychology - Abstract
Genome-wide association studies (GWAS) have identified hundreds of SNPs responsible for variation in human quantitative traits. However, genome-wide-significant associations often fail to replicate across independent cohorts, in apparent inconsistency with their apparent strong effects in discovery cohorts. This limited success of replication raises pervasive questions about the utility of the GWAS field. We identify all 332 studies of quantitative traits from the NHGRI-EBI GWAS Database with attempted replication. We find that the majority of studies provide insufficient data to evaluate replication rates. The remaining papers replicate significantly worse than expected (p < 10
−14 ), even when adjusting for regression-to-the-mean of effect size between discovery- and replication-cohorts termed the Winner’s Curse (p < 10−16 ). We show this is due in part to misreporting replication cohort-size as a maximum number, rather than per-locus one. In 39 studies accurately reporting per-locus cohort-size for attempted replication of 707 loci in samples with similar ancestry, replication rate matched expectation (predicted 458, observed 457, p = 0.94). In contrast, ancestry differences between replication and discovery (13 studies, 385 loci) cause the most highly-powered decile of loci to replicate worse than expected, due to difference in linkage disequilibrium. [ABSTRACT FROM AUTHOR]- Published
- 2017
- Full Text
- View/download PDF
17. Genome-wide association meta-analysis of individuals of European ancestry identifies new loci explaining a substantial fraction of hair color variation and heritability.
- Author
-
Hysi PG, Valdes AM, Liu F, Furlotte NA, Evans DM, Bataille V, Visconti A, Hemani G, McMahon G, Ring SM, Smith GD, Duffy DL, Zhu G, Gordon SD, Medland SE, Lin BD, Willemsen G, Jan Hottenga J, Vuckovic D, Girotto G, Gandin I, Sala C, Concas MP, Brumat M, Gasparini P, Toniolo D, Cocca M, Robino A, Yazar S, Hewitt AW, Chen Y, Zeng C, Uitterlinden AG, Ikram MA, Hamer MA, van Duijn CM, Nijsten T, Mackey DA, Falchi M, Boomsma DI, Martin NG, Hinds DA, Kayser M, and Spector TD
- Subjects
- Aged, Chromosomes, Human, X, Female, Genome-Wide Association Study methods, Humans, Male, Middle Aged, Phenotype, Genetic Loci, Hair Color genetics, Multifactorial Inheritance, Polymorphism, Single Nucleotide genetics, White People genetics
- Abstract
Hair color is one of the most recognizable visual traits in European populations and is under strong genetic control. Here we report the results of a genome-wide association study meta-analysis of almost 300,000 participants of European descent. We identified 123 autosomal and one X-chromosome loci significantly associated with hair color; all but 13 are novel. Collectively, single-nucleotide polymorphisms associated with hair color within these loci explain 34.6% of red hair, 24.8% of blond hair, and 26.1% of black hair heritability in the study populations. These results confirm the polygenic nature of complex phenotypes and improve our understanding of melanin pigment metabolism in humans.
- Published
- 2018
- Full Text
- View/download PDF
18. Evolutionary games, climate and the generation of diversity.
- Author
-
Friedman, Daniel, Magnani, Jacopo, Paranjpe, Dhanashree, and Sinervo, Barry
- Subjects
BIODIVERSITY ,GAME theory in biology ,HEALTH outcome assessment ,MAXIMUM likelihood statistics ,ROCK-paper-scissors (Game) ,OSCILLATIONS - Abstract
Environmental stochasticity and climate affect outcomes in evolutionary games, which can thereby affect biological diversity. Our maximum likelihood (ML) estimates of replicator dynamics for morph frequency data from control (25 years) and three experimentally perturbed populations (14 years) of side-blotched lizards yield a 3 × 3 payoff matrix in the generalized Rock-Paper-Scissors family; it has intransitive best replies, and each strategy is its own worst reply. ML estimates indicate significant interactive effects of density and temperature on morph frequency. Implied dynamics feature a powerful interior attractor and recover (for the first time) observed 4-5 year oscillations. Our evolutionary experiment on morph frequency confirms that oscillations are driven by frequency dependent selection, but climate entrains the cycles across the perturbed and control populations within 10 generations. Applying the model across the species range, we find that climate also accounts for morph fixation and mating system diversity, suggesting climate may similarly impact ecosystem diversity. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
19. Frequency-Dependent Selection Can Lead to Evolution of High Mutation Rates
- Author
-
Rosenbloom, Daniel I. S. and Allen, Benjamin
- Published
- 2014
- Full Text
- View/download PDF
20. How Flowering Plants Discriminate between Self and Non-Self Pollen to Prevent Inbreeding
- Author
-
Kao, Teh-Hui and McCubbin, Andrew G.
- Published
- 1996
21. Many chronological aging clocks can be found throughout the epigenome: Implications for quantifying biological aging
- Author
-
Chase A. Brown, Xiavan Roopnarinesingh, Jonathan D. Wren, Willard M. Freeman, Hunter Porter, Constantin Georgescu, and Cory B. Giles
- Subjects
Adult ,Epigenomics ,Male ,Aging ,Age prediction ,Longevity ,Context (language use) ,Disease ,Computational biology ,epigenetic clocks ,Biology ,Epigenesis, Genetic ,Epigenome ,Basic research ,Biological Clocks ,Databases, Genetic ,Humans ,Epigenetics ,Aged ,Aged, 80 and over ,Original Paper ,epigenetics ,Brain ,Cell Biology ,bioinformatics ,DNA Methylation ,Middle Aged ,Original Papers ,Genetic Loci ,DNA methylation ,Weak association ,Female ,Biomarkers - Abstract
Epigenetic alterations are a hallmark of aging and age‐related diseases. Computational models using DNA methylation data can create “epigenetic clocks” which are proposed to reflect “biological” aging. Thus, it is important to understand the relationship between predictive clock sites and aging biology. To do this, we examined over 450,000 methylation sites from 9,699 samples. We found ~20% of the measured genomic cytosines can be used to make many different epigenetic clocks whose age prediction performance surpasses that of telomere length. Of these predictive sites, the average methylation change over a lifetime was small (~1.5%) and these sites were under‐represented in canonical regions of epigenetic regulation. There was only a weak association between “accelerated” epigenetic aging and disease. We also compare tissue‐specific and pan‐tissue clock performance. This is critical to applying clocks both to new sample sets in basic research, as well as understanding if clinically available tissues will be feasible samples to evaluate “epigenetic aging” in unavailable tissues (e.g., brain). Despite the reproducible and accurate age predictions from DNA methylation data, these findings suggest they may have limited utility as currently designed in understanding the molecular biology of aging and may not be suitable as surrogate endpoints in studies of anti‐aging interventions. Purpose‐built clocks for specific tissues age ranges or phenotypes may perform better for their specific purpose. However, if purpose‐built clocks are necessary for meaningful predictions, then the utility of clocks and their application in the field needs to be considered in that context., Epigenetic clocks show promise as a biomarker of aging. Our study identifies components of epigenetic clocks critical to understanding their uses and where improvements are still needed. We identified a parabolic trajectory of methylation aging and the extent to which epigenetic clocks are robust to removing the most age‐predictive loci. These data shape our understanding of epigenetic age acceleration and what epigenetic clocks can tell us about the biology of aging.
- Published
- 2021
22. Congruent species delineation of Tulasnella using multiple loci and methods.
- Author
-
Linde CC, Phillips RD, Crisp MD, and Peakall R
- Subjects
- Species Specificity, Basidiomycota genetics, DNA, Fungal, DNA, Ribosomal Spacer, Genetic Loci, Phylogeny
- Published
- 2014
- Full Text
- View/download PDF
23. Discovering the mechanism and involvement of the methylation of cyclin-dependent kinase inhibitor 2A (CDKN2A) gene and its special locus region in gastric cancer
- Author
-
Ning Li, Wenying Deng, Jiye Xu, and Suxia Luo
- Subjects
0301 basic medicine ,Adult ,Male ,cdkn2a ,Bioengineering ,Locus (genetics) ,Biology ,medicine.disease_cause ,Applied Microbiology and Biotechnology ,Cyclin-Dependent Kinase Inhibitor 2A ,03 medical and health sciences ,0302 clinical medicine ,gsea ,CDKN2A ,Stomach Neoplasms ,hemic and lymphatic diseases ,medicine ,Humans ,tcga ,Gene ,neoplasms ,Cyclin-Dependent Kinase Inhibitor p16 ,Aged ,Aged, 80 and over ,gastric cancer ,General Medicine ,Methylation ,DNA Methylation ,Middle Aged ,Prognosis ,Phenotype ,digestive system diseases ,Gene Expression Regulation, Neoplastic ,Survival Rate ,stomatognathic diseases ,030104 developmental biology ,Genetic Loci ,030220 oncology & carcinogenesis ,DNA methylation ,Cancer research ,Female ,KRAS ,methylation ,TP248.13-248.65 ,Research Article ,Research Paper ,Biotechnology - Abstract
Cyclin-dependent kinase inhibitor 2A (CDKN2A) gene methylation has been paramount in the development of malignant masses. The purpose of the conducted research was to evaluate the mechanism and involvement of methylation in regards to the CDKN2A gene and the specific locus region in gastric cancer (GC) with comprehensive statistical analysis utilizing statistics acquired from The Cancer Genome Atlas (TCGA) database. Gene Set Enrichment Analysis (GSEA) revealed that the level of CDKN2A gene methylation and its locus in GC tissues was increased compared to para-cancerous tissues. In multivariate analysis, low methylation of CDKN2A gene, cg03079681, cg04026675, cg07562918, and cg13601799 locus were independently linked to better OS. In addition, the methylation of CDKN2A gene, cg00718440, cg03079681, cg04026675, cg07562918, cg10848754, cg14069088 and cg14430974 locus were negative correlated with CDKN2A gene expression. Meanwhile, the methylation of cg12840719 locus was positively correlated with CDKN2A gene expression. GSEA showed that hallmark_kras_signaling_dn, hallmark_myogenesis, and hallmark_epithelial_mesenchymal_transition pathways were enriched in the CDKN2A gene hypermethylation phenotype. Taken together, the low methylation of CDKN2A gene, cg03079681, cg04026675, cg07562918, and cg13601799 locus indicated a better prognosis in GC. The methylation levels of cg14069088 were most negatively correlated with CDKN2A gene expression. Hallmark_kras_signaling_dn, Hallmark_myogenesis, and hallmark_epithelial_mesenchymal_transition pathways might be important in the regulation of CDKN2A gene hypermethylation., Graphical abstract
- Published
- 2021
24. Comparative Biochemical Studies of Allelic Inositolles Mutants in Neurospora crassa
- Author
-
Partridge, C. W. H. and Giles, Norman H.
- Published
- 1953
25. DNA methylation in the promoters of PD-L1, MMP9, ARG1, galectin-9, TIM-3, VISTA and TGF-β genes in HLA-DR– myeloid cells, compared with HLA-DR+ antigen-presenting cells
- Author
-
Saleh, Reem, Toor, Salman M., Taha, Rowaida Z., Al-Ali, Dana, Sasidharan Nair, Varun, and Elkord, Eyad
- Subjects
DNA methylation ,immunosuppression ,B7 Antigens ,epigenetics ,Arginase ,MDSC ,Sialic Acid Binding Ig-like Lectin 3 ,Antigen-Presenting Cells ,HLA-DR Antigens ,B7-H1 Antigen ,Epigenesis, Genetic ,Matrix Metalloproteinase 9 ,Genetic Loci ,Transforming Growth Factor beta ,Humans ,Myeloid Cells ,Promoter Regions, Genetic ,Hepatitis A Virus Cellular Receptor 2 ,Research Article ,Research Paper - Abstract
Myeloid cells, including antigen-presenting cells (APCs) and myeloid-derived suppressor cells (MDSCs) play opposing roles to orchestrate innate and adaptive immune responses during physiological and pathological conditions. We investigated the role of DNA methylation in regulating the transcription of inhibitory/suppressive molecules in myeloid suppressive cells (identified as CD33+HLA-DR–) in comparison to APCs. We selected a number of immune checkpoints (ICs), IC ligands, and immunosuppressive molecules that have been implicated in MDSC function, including PD-L1, TIM-3, VISTA, galectin-9, TGF-β, ARG1 and MMP9. We examined their mRNA expression levels, and investigated whether DNA methylation regulates their transcription in sorted myeloid cell subpopulations. We found that mRNA levels of PD-L1, TIM-3, TGF-β, ARG1 and MMP9 in CD33+HLA-DR– cells were higher than APCs. However, VISTA and galectin-9 mRNA levels were relatively similar in both myeloid subpopulations. CpG islands in the promoter regions of TGF-β1, TIM-3 and ARG1 were highly unmethylated in CD33+HLA-DR–cells, compared with APCs, suggesting that DNA methylation is one of the key mechanisms, which regulate their expression. However, we did not find differences in the methylation status of PD-L1 and MMP9 between CD33+HLA-DR– and APCs, suggesting that their transcription could be regulated via other genetic and epigenetic mechanisms. The promoter methylation status of VISTA was relatively similar in both myeloid subpopulations. This study provides novel insights into the epigenetic mechanisms, which control the expression of inhibitory/suppressive molecules in circulating CD33+HLA-DR– cells in a steady-state condition, possibly to maintain immune tolerance and haemostasis.
- Published
- 2020
26. Genome-wide characterization of cytosine-specific 5-hydroxymethylation in normal breast tissue
- Author
-
Owen M. Wilkins, E. Andres Houseman, Kevin C. Johnson, Brock C. Christensen, Jessica E. King, and Carmen J. Marsit
- Subjects
0301 basic medicine ,Adult ,Cancer Research ,Adolescent ,Biology ,Epigenesis, Genetic ,03 medical and health sciences ,chemistry.chemical_compound ,Epigenome ,0302 clinical medicine ,Lactate oxidation ,Breast cancer ,medicine ,Humans ,Epigenetics ,5-hydroxymethylcytosine ,Mammary Glands, Human ,Molecular Biology ,Aged ,5-Hydroxymethylcytosine ,Transcriptionally active chromatin ,Regulation of gene expression ,Aged, 80 and over ,DNA methylation ,Middle Aged ,medicine.disease ,Cell biology ,030104 developmental biology ,chemistry ,CpG site ,Genetic Loci ,030220 oncology & carcinogenesis ,5-Methylcytosine ,CpG Islands ,Female ,Transcriptome ,Research Paper - Abstract
Despite recent evidence that 5-hydroxymethylcytosine (5hmC) possesses roles in gene regulation distinct from 5-methylcytosine (5mC), relatively little is known regarding the functions of 5hmC in mammalian tissues. To address this issue, we utilized an approach combining both paired bisulfite (BS) and oxidative bisulfite (oxBS) DNA treatment, to resolve genome-wide patterns of 5hmC and 5mC in normal breast tissue from disease-free women. Although less abundant than 5mC, 5hmC was differentially distributed, and consistently enriched among breast-specific enhancers and transcriptionally active chromatin. In contrast, regulatory regions associated with transcriptional inactivity, such as heterochromatin and repressed Polycomb regions, were relatively depleted of 5hmC. Gene regions containing abundant 5hmC were significantly associated with lactate oxidation, immune cell function, and prolactin signaling pathways. Furthermore, genes containing abundant 5hmC were enriched among those actively transcribed in normal breast tissue. Finally, in independent data sets, normal breast tissue 5hmC was significantly enriched among CpG loci demonstrated to have altered methylation in pre-invasive breast cancer and invasive breast tumors. Primarily, our findings identify genomic loci containing abundant 5hmC in breast tissues and provide a genome-wide map of nucleotide-level 5hmC in normal breast tissue. Additionally, these data suggest 5hmC may participate in gene regulatory programs that are dysregulated during breast-related carcinogenesis.
- Published
- 2019
27. Sex and Space Destabilize Intransitive Competition within and between Species
- Author
-
Vellend, Mark and Litrico, Isabelle
- Published
- 2008
- Full Text
- View/download PDF
28. Functional validation of the albinism-associated tyrosinase T373K SNP by CRISPR/Cas9-mediated homology-directed repair (HDR) in rabbits
- Author
-
Mao Chen, Liangxue Lai, Jichao Deng, Tingting Sui, Zhanjun Li, Yuxin Zhang, and Yuning Song
- Subjects
0301 basic medicine ,Research paper ,Tyrosinase ,Mutant ,Rabbit ,Biology ,medicine.disease_cause ,Polymorphism, Single Nucleotide ,General Biochemistry, Genetics and Molecular Biology ,Melanin ,Homology directed repair ,03 medical and health sciences ,medicine ,Animals ,Genetic Predisposition to Disease ,Gene ,CRISPR/Cas9 ,Cells, Cultured ,Genetic Association Studies ,Genetics ,OCA ,Gene Editing ,Melanins ,Mutation ,T373K ,Point mutation ,Monophenol Monooxygenase ,Recombinational DNA Repair ,General Medicine ,medicine.disease ,Oculocutaneous albinism ,Enzyme Activation ,Disease Models, Animal ,030104 developmental biology ,Amino Acid Substitution ,Albinism, Oculocutaneous ,Genetic Loci ,Albinism ,Female ,sense organs ,Rabbits ,CRISPR-Cas Systems - Abstract
Background Oculocutaneous albinism (OCA) is a group of autosomal recessive disorders characterized by reduced melanin that are caused by mutations in the gene encoding tyrosinase (TYR), which is the rate-limiting enzyme in the production of the pigment melanin. Many studies or meta-analyses have suggested an association between the TYR T373K SNP and OCA1, but there is limited biochemical and genetic evidence to support this association. Methods We overexpressed TYR-WT and TYR-T373K mutants on HK293T cells and tested the changes of melanin production and tyrosinase activity. Then we generated TYR-K373T knock-in (KI) rabbits by microinjection of ssDNA and synthesized RNAs targeting C1118A using CRISPR/Cas9-HDR to observe the formation of melanin. Findings We demonstrated that the T373K mutation in TYR can reduce tyrosinase activity, leading to an absence of melanin synthesis at the cell-level. The gene-edited TYR-K373T rabbits exhibited rescued melanin production in hair follicles and irises, as inferred from the evident decrease in pigmentation in TYR-T373K rabbits, thus providing functional validation of the albinism-associated T373K SNP at the animal level. Interpretation Our study provides the first animal-level functional validation of the albinism-associated TYR K373T SNP in rabbits, and these results will facilitate gene therapy of OCA1 in pre-clinical settings in the future. Fund The National Key Research and Development Program of China Stem Cell and Translational Research, the Strategic Priority Research Program of the Chinese Academy of Sciences, the Guangdong Province Science and Technology Plan Project, and the Program for JLU Science and Technology Innovative Research Team.
- Published
- 2018
29. Contrasting Complexity of Two Rust Resistance Loci in Flax
- Author
-
Ellis, J. G., Lawrence, G. J., Finnegan, E. J., and Anderson, P. A.
- Published
- 1995
30. The Disease-Resistance Gene Pto and the Fenthion-Sensitivity Gene Fen Encode Closely Related Functional Protein Kinases
- Author
-
Loh, Ying-Tsu and Martin, Gregory B.
- Published
- 1995
31. How Can the Low Levels of DNA Sequence Variation in Regions of the Drosophila Genome with Low Recombination Rates be Explained?
- Author
-
Hudson, Richard R.
- Published
- 1994
32. Molecular Genetics of Speciation and Human Origins
- Author
-
Ayala, Francisco J., Escalante, Ananias, O'hUigin, Colm, and Klein, Jan
- Published
- 1994
33. A Comparison of the Tryptic Peptides Obtained from Immobilization Antigens of Paramecium aurelia
- Author
-
Steers, Edward
- Published
- 1962
34. AvrPm2 encodes an RNase‐like avirulence effector which is conserved in the two different specialized forms of wheat and rye powdery mildew fungus
- Author
-
Francis Parlange, Luisa K. Schäfer, Dazhao Yu, Kaitlin E. McNally, Yang Lijun, Javier Sánchez-Martín, Rainer Boni, Xue Minfeng, Salim Bourras, Simone Oberhaensli, Coraline R. Praz, Roi Ben-David, Fabrizio Menardo, Gerard Herren, Stefan Roffler, Beat Keller, Zeng Fansong, Simon Flückiger, Thomas Wicker, University of Zurich, and Yu, Dazhao
- Subjects
Models, Molecular ,0301 basic medicine ,Secale ,Physiology ,Blumeria graminis ,Plant Science ,580 Plants (Botany) ,Conserved sequence ,Fungal Proteins ,03 medical and health sciences ,Ribonucleases ,Ascomycota ,10126 Department of Plant and Microbial Biology ,Gene Expression Regulation, Plant ,wheat ,Tobacco ,1110 Plant Science ,Gene family ,Amino Acid Sequence ,Gene ,Conserved Sequence ,Phylogeny ,Triticum ,Plant Diseases ,Plant Proteins ,Genetics ,Mildew ,Virulence ,biology ,Full Paper ,Research ,food and beverages ,Pm2 ,1314 Physiology ,Full Papers ,RNAse‐like ,Physical Chromosome Mapping ,biology.organism_classification ,030104 developmental biology ,avirulence gene ,Genetic Loci ,powdery mildew ,Gene pool ,Corrigendum ,Powdery mildew ,Genome-Wide Association Study - Abstract
Summary There is a large diversity of genetically defined resistance genes in bread wheat against the powdery mildew pathogen Blumeria graminis (B. g.) f. sp. tritici. Many confer race‐specific resistance to this pathogen, but until now only the mildew avirulence gene AvrPm3 a2/f2 that is recognized by Pm3a/f was known molecularly.We performed map‐based cloning and genome‐wide association studies to isolate a candidate for the mildew avirulence gene AvrPm2. We then used transient expression assays in Nicotiana benthamiana to demonstrate specific and strong recognition of AvrPm2 by Pm2.The virulent AvrPm2 allele arose from a conserved 12 kb deletion, while there is no protein sequence diversity in the gene pool of avirulent B. g. tritici isolates. We found one polymorphic AvrPm2 allele in B. g. triticale and one orthologue in B. g. secalis and both are recognized by Pm2. AvrPm2 belongs to a small gene family encoding structurally conserved RNase‐like effectors, including Avr a13 from B. g. hordei, the cognate Avr of the barley resistance gene Mla13.These results demonstrate the conservation of functional avirulence genes in two cereal powdery mildews specialized on different hosts, thus providing a possible explanation for successful introgression of resistance genes from rye or other grass relatives to wheat., See also the Commentary on this article by Spanu, 213: 969–971.
- Published
- 2016
35. Dominant inhibition of awn development by a putative zinc‐finger transcriptional repressor expressed at the B1 locus in wheat
- Author
-
Nikolai M. Adamski, Catherine Chinoy, Paul Nicholson, Curt A. McCartney, Yasmina Bekkaoui, Sateesh Kagale, Qian Zheng, Frank M. You, Tancey Melchkart, J. Allan Feurtado, Martha Clarke, David Konkin, Daiqing Huang, Adrian J. Cutler, Martial Martucci, and A. Steed
- Subjects
0106 biological sciences ,0301 basic medicine ,Physiology ,Mutant ,Amino Acid Motifs ,Plant Science ,01 natural sciences ,Gene Expression Regulation, Plant ,Chromosome Segregation ,wheat ,Coding region ,B1 Locus ,Triticum ,Genes, Dominant ,Plant Proteins ,Zinc finger ,Genetics ,education.field_of_study ,C2H2 Zinc Finger ,Full Paper ,Chromosome Mapping ,food and beverages ,Genetic Pleiotropy ,Zinc Fingers ,Bread ,Full Papers ,awnletted ,Multigene Family ,Population ,Plant Development ,Locus (genetics) ,Biology ,03 medical and health sciences ,Open Reading Frames ,transcriptional repression ,Deletion mapping ,education ,Gene ,Cell Proliferation ,Polymorphism, Genetic ,Indoleacetic Acids ,zinc finger ,Research ,awn ,transcription repression ,Repressor Proteins ,030104 developmental biology ,Haplotypes ,C2H2 ,Genetic Loci ,Mutation ,EAR motif ,010606 plant biology & botany - Abstract
Summary Awns, bristle‐like structures extending from grass lemmas, provide protection against predators, contribute to photosynthesis and aid in grain dispersal. In wheat, selection of awns with minimal extension, termed awnletted, has occurred during domestication by way of loci that dominantly inhibit awn development, such as Tipped1 (B1), Tipped2 (B2), and Hooded (Hd). Here we identify and characterize the B1 gene. B1 was identified using bulked segregant RNA‐sequencing of an F2 durum wheat population and through deletion mapping of awned bread wheat mutants. Functional characterization was accomplished by gene overexpression while haplotype analyses assessed B1 polymorphisms and genetic variation.Located on chromosome 5A, B1 is a C2H2 zinc finger encoding gene with ethylene‐responsive element binding factor‐associated amphiphilic repression (EAR) motifs. Constitutive overexpression of B1 in awned wheat produced an awnletted phenotype with pleiotropic effects on plant height and fertility. Transcriptome analysis of B1 overexpression plants suggests a role as transcriptional repressor, putatively targeting pathways involved in cell proliferation. Haplotype analysis revealed a conserved B1 coding region with proximal polymorphisms and supported the contention that B1 is mainly responsible for awnletted wheats globally. B1, predominantly responsible for awn inhibition in wheat, encodes a C2H2 zinc finger protein with EAR motifs which putatively functions as a transcriptional repressor.
- Published
- 2019
36. Chromatin structure regulates cancer-specific alternative splicing events in primary HPV-related oropharyngeal squamous cell carcinoma
- Author
-
Eli Winkler, Elana J. Fertig, Michael Considine, Alexander V. Favorov, Hildegard A. Wulf, Kristina Diana A. Zambo, Christopher Hopkins, Fernando T. Zamuner, Rossin Erbe, Daria A. Gaykalova, David Sidransky, Liliana Florea, Theresa Guo, Ludmila Danilova, Dylan Z. Kelley, and Tingting Ou
- Subjects
0301 basic medicine ,Cancer Research ,animal structures ,In silico ,Biology ,Alphapapillomavirus ,medicine.disease_cause ,Epigenesis, Genetic ,Histones ,03 medical and health sciences ,0302 clinical medicine ,Cell Line, Tumor ,medicine ,Humans ,Epigenetics ,Molecular Biology ,Head and neck cancer ,Alternative splicing ,Cancer ,medicine.disease ,Chromatin Assembly and Disassembly ,Chromatin ,Gene Expression Regulation, Neoplastic ,Histone Code ,Alternative Splicing ,Oropharyngeal Neoplasms ,030104 developmental biology ,Histone ,Genetic Loci ,030220 oncology & carcinogenesis ,Cancer research ,biology.protein ,Carcinoma, Squamous Cell ,Carcinogenesis ,Research Paper - Abstract
Human papillomavirus-related oropharyngeal squamous cell carcinoma (HPV+ OPSCC) represents a unique disease entity within head and neck cancer with rising incidence. Previous work has shown that alternative splicing events (ASEs) are prevalent in HPV+ OPSCC, but further validation is needed to understand the regulation of this process and its role in these tumours. In this study, eleven ASEs (GIT2, CTNNB1, MKNK2, MRPL33, SIPA1L3, SNHG6, SYCP2, TPRG1, ZHX2, ZNF331, and ELOVL1) were selected for validation from 109 previously published candidate ASEs to elucidate the post-transcriptional mechanisms of oncogenesis in HPV+ disease. In vitro qRT-PCR confirmed differential expression of 9 of 11 ASE candidates, and in silico analysis within the TCGA cohort confirmed 8 of 11 candidates. Six ASEs (MRPL33, SIPA1L3, SNHG6, TPRG1, ZHX2, and ELOVL1) showed significant differential expression across both methods. Further evaluation of chromatin modification revealed that ASEs strongly correlated with cancer-specific distribution of acetylated lysine 27 of histone 3 (H3K27ac). Subsequent epigenetic treatment of HPV+ HNSCC cell lines (UM-SCC-047 and UPCI-SCC-090) with JQ1 not only induced downregulation of cancer-specific ASE isoforms, but also growth inhibition in both cell lines. The UPCI-SCC-090 cell line, with greater ASE expression, also showed more significant growth inhibition after JQ1 treatment. This study confirms several novel cancer-specific ASEs in HPV+OPSCC and provides evidence for the role of chromatin modifications in regulation of alternative splicing in HPV+OPSCC. This highlights the role of epigenetic changes in the oncogenesis of HPV+OPSCC, which represents a unique, unexplored target for therapeutics that can alter the global post-transcriptional landscape.
- Published
- 2020
37. Population and evolutionary genetics of the PAH locus to uncover overdominance and adaptive mechanisms in phenylketonuria: Results from a multiethnic study
- Author
-
Oussalah, Abderrahim, Jeannesson-Thivisol, Elise, Chery, Céline, Perrin, Pascal, Rouyer, Pierre, Josse, Thomas, Cano, Aline, Barth, Magalie, Fouilhoux, Alain, Mention, Karine, Labarthe, François, Arnoux, Jean-Baptiste, Maillot, François, Lenaerts, Catherine, Dumesnil, Cécile, Wagner, Kathy, Terral, Daniel, Broue, Pierre, de Parscau, Loïc, Gay, Claire, Kuster, Alice, Bedu, Antoine, Besson, Gérard, Lamireau, Delphine, Odent, Sylvie, Masurel, Alice, Rodriguez-Guéant, Rosa-Maria, Feillet, François, Guéant, Jean-Louis, Namour, Fares, Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Centre de référence des maladies héréditaires du métabolisme (MaMEA Nancy-Brabois), Hôpital de la Timone [CHU - APHM] (TIMONE), Service de génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Hôpital Jeanne de Flandres, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Amiens-Picardie, CHU Rouen, Normandie Université (NU), Hôpitaux Pédiatriques de Nice Lenval (CHU-Lenval), Centre Hospitalier Universitaire de Nice (CHU Nice), Service de Pédiatrie Générale [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Hôpital des Enfants, CHU Toulouse [Toulouse], CHRU de Brest - Département de Pédiatrie (CHU BREST Pédiatrie), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Centre hospitalier universitaire de Nantes (CHU Nantes), Service de Pédiatrie médicale - réanimation et néonatologie [CHU Limoges], CHU Limoges, Centre Hospitalier Universitaire [Grenoble] (CHU), Hôpital Pellegrin, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, CHU Pontchaillou [Rennes], Service de génétique, CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), IMPACT GEENAGE, ANR-15-IDEX-0004,LUE,Isite LUE(2015), Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), DE CARVALHO, Philippe, ISITE - Isite LUE - - LUE2015 - ANR-15-IDEX-0004 - IDEX - VALID, and Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)
- Subjects
Male ,Research paper ,[SDV]Life Sciences [q-bio] ,lcsh:Medicine ,Metabolic adaptation ,Gene Frequency ,Phenylketonurias ,Overdominance ,[SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Ethnicity ,Humans ,Phenylketonuria ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Exome ,Genetic Association Studies ,Phylogeny ,Principal Component Analysis ,lcsh:R5-920 ,Geography ,lcsh:R ,Phenylalanine Hydroxylase ,Biological Evolution ,[SDV] Life Sciences [q-bio] ,Balancing selection ,Genetics, Population ,Haplotypes ,Genetic Loci ,Population divergence ,Female ,France ,lcsh:Medicine (General) - Abstract
Background: Phenylketonuria (PKU) is the most common inborn error of amino acid metabolism in Europe. The reasons underlying the high prevalence of heterozygous carriers are not clearly understood. We aimed to look for pathogenic PAH variant enrichment according to geographical areas and patients’ ethnicity using a multiethnic nationwide cohort of patients with PKU in France. We subsequently appraised the population differentiation, balancing selection and the molecular evolutionary history of the PAH locus. Methods: The French nationwide PKU study included patients who have been referred at the national level to the University Hospital of Nancy, and for whom a molecular diagnosis of phenylketonuria was made by Sanger sequencing. We performed enrichment analyses by comparing alternative allele frequencies using Fisher's exact test with Bonferroni adjustment. We estimated the amount of genetic differentiation among populations using Wright's fixation index (Fst). To estimate the molecular evolutionary history of the PAH gene, we performed phylogenetic and evolutionary analyses using whole-genome and exome-sequencing data from healthy individuals and non-PKU patients, respectively. Finally, we used exome-wide association study to decipher potential genetic loci associated with population divergence on PAH. Findings: The study included 696 patients and revealed 132 pathogenic PAH variants. Three geographical areas showed significant enrichment for a pathogenic PAH variant: North of France (p.Arg243Leu), North-West of France (p.Leu348Val), and Mediterranean coast (p.Ala403Val). One PAH variant (p.Glu280Gln) was significantly enriched among North-Africans (OR = 23·23; 95% CI: 9·75–55·38). PAH variants exhibiting a strong genetic differentiation were significantly enriched in the ‘Biopterin_H’ domain (OR = 6·45; 95% CI: 1·99–20·84), suggesting a balancing selection pressure on the biopterin function of PAH. Phylogenetic and timetree analyses were consistent with population differentiation events on European-, African-, and Asian-ancestry populations. The five PAH variants most strongly associated with a high selection pressure were phylogenetically close and were located within the biopterin domain coding region of PAH or in its vicinity. Among the non-PAH loci potentially associated with population divergence, two reached exome-wide significance: SSPO (SCO-spondin) and DBH (dopamine beta-hydroxylase), involved in neuroprotection and metabolic adaptation, respectively. Interpretation: Our data provide evidence on the combination of evolutionary and adaptive events in populations with distinct ancestries, which may explain the overdominance of some genetic variants on PAH. Funding: French National Institute of Health and Medical Research (INSERM) UMR_S 1256. Keywords: Phenylketonuria, Balancing selection, Population divergence, Overdominance, Metabolic adaptation
- Published
- 2020
38. Seed dormancy release accelerated by elevated partial pressure of oxygen is associated with DOG loci
- Author
-
Jan Kodde, Leónie Bentsink, Gonda Buijs, and Steven P.C. Groot
- Subjects
0106 biological sciences ,0301 basic medicine ,EPPO ,Arabidopsis thaliana ,Physiology ,Partial Pressure ,Quantitative Trait Loci ,Arabidopsis ,Germination ,Plant Science ,Common method ,elevated partial pressure of oxygen ,Quantitative trait locus ,Biology ,01 natural sciences ,03 medical and health sciences ,DOG ,BIOS Plant Development Systems ,Laboratorium voor Plantenfysiologie ,Arabidopsis Proteins ,Seed dormancy ,seed dormancy ,food and beverages ,Chromosome Mapping ,Partial pressure ,Delay of Germination ,Plant Dormancy ,Research Papers ,Oxygen ,Horticulture ,030104 developmental biology ,Stratification (seeds) ,Ageing ,Genetic Loci ,quantitative trait loci ,Seeds ,Dormancy ,After-ripening ,Growth and Development ,EPS ,Laboratory of Plant Physiology ,010606 plant biology & botany - Abstract
Storage of seeds under elevated partial pressure of oxygen mimics dry after-ripening at the genetic level, as indicated by identification of DELAY OF GERMINATION quantitative trait loci., Seed dormancy determines the timing of seed germination and may be released by dry storage, also referred to as after-ripening. Studies on dormancy-release mechanisms are often hampered by the long after-ripening requirements of seeds. After-ripening is thought to be mainly caused by oxidative processes during seed dry storage. These processes are also the main cause of seed ageing. Increasing partial oxygen pressure through the elevated partial pressure of oxygen (EPPO) system has been shown to mimic and accelerate dry seed ageing. In this study, we investigated whether the EPPO system may also release primary seed dormancy in Arabidopsis thaliana. EPPO mimics dry after-ripening at the genetic level, as quantitative trait locus (QTL) analysis after EPPO treatment identified the DELAY OF GERMINATION loci DOG1, DOG2, and DOG6 that were first described in a study using dry after-ripening to release seed dormancy. QTL analysis also showed that dormancy release by cold stratification (another common method to break seed dormancy) partly overlaps with release by after-ripening and EPPO treatment. We conclude that EPPO is an appropriate method to mimic and accelerate dormancy release and, as such, may have applications in both research and industry.
- Published
- 2018
39. PhenotypeSimulator: A comprehensive framework for simulating multi-trait, multi-locus genotype to phenotype relationships
- Author
-
Ewan Birney, Rakesh Choorikkadu, and Meyer Hannah
- Subjects
0301 basic medicine ,Statistics and Probability ,Genotype ,Computer science ,Locus (genetics) ,Machine learning ,computer.software_genre ,Biochemistry ,Genetic analysis ,03 medical and health sciences ,Multi trait ,Molecular Biology ,business.industry ,Genetics and Population Analysis ,Phenotype ,Original Papers ,Computer Science Applications ,Computational Mathematics ,030104 developmental biology ,Computational Theory and Mathematics ,Genetic Loci ,Artificial intelligence ,Genotype to phenotype ,business ,computer ,Software - Abstract
Motivation Simulation is a critical part of method development and assessment. With the increasing sophistication of multi-trait and multi-locus genetic analysis techniques, it is important that the community has flexible simulation tools to challenge and explore the properties of these methods. Results We have developed PhenotypeSimulator, a comprehensive phenotype simulation scheme that can model multiple traits with multiple underlying genetic loci as well as complex covariate and observational noise structure. This package has been designed to work with many common genetic tools both for input and output. We describe the underlying components of this simulation tool and illustrate its use on an example dataset. Availability and implementation PhenotypeSimulator is available as a well documented R/CRAN package and the code is available on github: https://github.com/HannahVMeyer/PhenotypeSimulator. Supplementary information Supplementary data are available at Bioinformatics online.
- Published
- 2018
40. A Genome-Wide Association Study Finds Genetic Associations with Broadly-Defined Headache in UK Biobank (N = 223,773)
- Author
-
Ian J. Deary, Weihua Meng, Harry L. Hébert, Mark Adams, Blair H. Smith, and Andrew M. McIntosh
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Genome-wide association study ,LRP1 ,lcsh:Medicine ,Single-nucleotide polymorphism ,Polymorphism, Single Nucleotide ,Linkage Disequilibrium ,General Biochemistry, Genetics and Molecular Biology ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Single entity ,Statistical significance ,Internal medicine ,Tissue expression ,Humans ,Medicine ,Genetic Predisposition to Disease ,Biological Specimen Banks ,lcsh:R5-920 ,business.industry ,Gene Expression Profiling ,lcsh:R ,Case-control study ,Headache ,General Medicine ,UK biobank ,Biobank ,United Kingdom ,3. Good health ,030104 developmental biology ,Genetic Loci ,Case-Control Studies ,Cohort ,business ,lcsh:Medicine (General) ,030217 neurology & neurosurgery ,Research Paper ,Cohort study - Abstract
Background Headache is the most common neurological symptom and a leading cause of years lived with disability. We sought to identify the genetic variants associated with a broadly-defined headache phenotype in 223,773 subjects from the UK Biobank cohort. Methods We defined headache based on a specific question answered by the UK Biobank participants. We performed a genome-wide association study of headache as a single entity, using 74,461 cases and 149,312 controls. Results We identified 3343 SNPs which reached the genome-wide significance level of P, Highlights • This genome-wide association study identified 28 genomic loci for broadly-defined headache, among which, 14 are new. • Through tissue expression analysis, brain tissues showed significant relationships to broadly-defined headache. • Broadly-defined headache shared common genetic components with many psychological traits such as neuroticism. This genetic study using the UK Biobank resource has identified 28 genomic loci for broadly-defined headache, among which, 14 are new loci. In addition, it has provided extra evidence that the functions of brain tissues are closely related to headache. Moreover, it has suggested that headache and many psychological disorders share common genetic factors. These findings will not only contribute to the understanding of the causes of headache (and its subtypes) and its relationships with psychological disorders, it might also bring potential genetic targets for drug treatment for patients with headache and psychological disorders.
- Published
- 2018
41. Natural antisense transcripts drive a regulatory cascade controlling c-MYC transcription
- Author
-
Sara Napoli, Giuseppina Pisignano, Sarah N. Mapelli, Carlo V. Catapano, and Valentina Piccinelli
- Subjects
0301 basic medicine ,Ribonuclease III ,endocrine system ,RNA, Untranslated ,Transcription, Genetic ,Genes, myc ,natural antisense transcripts ,Models, Biological ,Epigenesis, Genetic ,Histones ,03 medical and health sciences ,Transcription (biology) ,small RNAs ,Cell Line, Tumor ,Transcriptional regulation ,Humans ,transcriptional regulation ,RNA, Antisense ,Small nucleolar RNA ,Cloning, Molecular ,Molecular Biology ,Gene ,3' Untranslated Regions ,Regulation of gene expression ,Genetics ,biology ,epigenetics ,fungi ,Acetylation ,Cell Biology ,Long non-coding RNA ,030104 developmental biology ,c-MYC ,Sense strand ,Gene Expression Regulation ,Genetic Loci ,long non coding RNA ,biology.protein ,Nucleic Acid Conformation ,Transcription Initiation Site ,Dicer ,Research Paper - Abstract
Cis-natural antisense transcripts (cis-NATs) are long noncoding RNAs transcribed from the opposite strand and overlapping coding and noncoding genes on the sense strand. cis-NATs are widely present in the human genome and can be involved in multiple mechanisms of gene regulation. Here, we describe the presence of cis-NATs in the 3′ distal region of the c-MYC locus and investigate their impact on transcriptional regulation of this key oncogene in human cancers. We found that cis-NATs are produced as consequence of the activation of cryptic transcription initiation sites in the 3′ distal region downstream of the c-MYC 3′UTR. The process is tightly regulated and leads to the formation of two main transcripts, NAT6531 and NAT6558, which differ in their ability to fold into stem-loop secondary structures. NAT6531 acts as a substrate for DICER and as a source of small RNAs capable of modulating c-MYC transcription. This complex system, based on the interplay between cis-NATs and NAT-derived small RNAs, may represent an important layer of epigenetic regulation of the expression of c-MYC and other genes in human cells.
- Published
- 2017
42. Fbxw7 haploinsufficiency loses its protection against DNA damage and accelerates MNU-induced gastric carcinogenesis
- Author
-
Jin Ren, Zhenggang Zhu, Xinming Qi, Jun Ji, Yannan Jiang, Xinyu Liu, Yingyan Yu, and Jun Zhang
- Subjects
0301 basic medicine ,F-Box-WD Repeat-Containing Protein 7 ,DNA Repair ,Genes, myc ,Apoptosis ,Haploinsufficiency ,Gene Knockout Techniques ,Mice ,0302 clinical medicine ,Gene Order ,Mice, Knockout ,biology ,Fbxw7 ,Methylnitrosourea ,Ubiquitin ligase ,Gene Expression Regulation, Neoplastic ,medicine.anatomical_structure ,Cell Transformation, Neoplastic ,Oncology ,030220 oncology & carcinogenesis ,Knockout mouse ,N-Methyl-N-nitrosourea ,Gene Targeting ,Research Paper ,Genotype ,DNA damage ,DNA repair ,Models, Biological ,03 medical and health sciences ,Stomach Neoplasms ,Cell Line, Tumor ,Gastric mucosa ,medicine ,Animals ,Genetic Predisposition to Disease ,business.industry ,gastric cancer ,Cancer ,medicine.disease ,Comet assay ,Disease Models, Animal ,030104 developmental biology ,Gastric Mucosa ,Genetic Loci ,biology.protein ,Cancer research ,business ,knockout mouse - Abstract
// Yannan Jiang 1 , Xinming Qi 2 , Xinyu Liu 1 , Jun Zhang 1 , Jun Ji 1 , Zhenggang Zhu 1 , Jin Ren 2 , Yingyan Yu 1 1 Department of Surgery of Shanghai Ruijin Hospital, Shanghai Institute of Digestive Surgery, Shanghai Key Laboratory for Gastric Neoplasms, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China 2 Center for Drug Safety Evaluation and Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China Correspondence to: Yingyan Yu, email: yingyan3y@sjtu.edu.cn Keywords: Fbxw7, knockout mouse, N-Methyl-N-nitrosourea, gastric cancer, DNA damage Received: January 17, 2017 Accepted: March 22, 2017 Published: April 03, 2017 ABSTRACT Fbxw7, a subunit of the SCF E3 ubiquitin ligase, recognizes oncoprotein substrates and leads to their proteasomal degradation. Fbxw7 acts as a tumor suppressor via inducing apoptosis and growth arrest in various kinds of tumors. To clarify the initiating role in gastric carcinogenesis as well as the histologic characterization of tumor in Fbxw7 allele haploinsufficient mice, we generated Fbxw7 heterozygous knockout mice (Fbxw7 +/− ) and treated them with chemical carcinogen N-methyl-N-nitrosourea (MNU) at 5–6 weeks of age. We also treated mouse embryo fibroblasts (MEFs) from Fbxw7 +/− and Fbxw7 +/+ mice with MNU and examined cell DNA damage via comet assay. The protein expression of Fbxw7 and its substrate c-Myc from mouse tumors, as well as human tumors sampled from six patients, were detected by Western blot. As results, the tumor incidence was obviously higher in Fbxw7 +/− mice (13/20) than in Fbxw7 +/+ mice (6/20) after 35-week observation. Intestinal metaplasia ( P = 0.013) and dysplasia ( P = 0.036) were more severe in Fbxw7 +/− mice than in Fbxw7 +/+ mice. The repair potential of DNA damage was suppressed in MEFs from Fbxw7 +/− mice after MNU exposure. Increased c-Myc expression was accompanied by decreased Fbxw7 protein expression in tumor tissues from mouse and patients. In conclusion, Fbxw7 haploinsufficiency increased the risk of gastric carcinogenesis induced by MNU, which is associated with the accumulation of DNA damage as well as c-Myc oncoprotein.
- Published
- 2017
43. Myostatin-deficiency in mice increases global gene expression at the Dlk1-Dio3 locus in the skeletal muscle
- Author
-
Keisuke Hitachi and Kunihiro Tsuchida
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Locus (genetics) ,Myostatin ,Muscle Development ,Iodide Peroxidase ,Cell Line ,Epigenesis, Genetic ,03 medical and health sciences ,Mice ,Internal medicine ,Gene expression ,medicine ,Animals ,Epigenetics ,skeletal muscle ,IG-DMR ncRNA ,Muscle, Skeletal ,miRNA ,Mice, Knockout ,biology ,Calcium-Binding Proteins ,Skeletal muscle ,musculoskeletal system ,callipyge ,Molecular biology ,Chromosomes, Mammalian ,Up-Regulation ,MicroRNAs ,030104 developmental biology ,Endocrinology ,DLK1 ,medicine.anatomical_structure ,Oncology ,Genetic Loci ,GDF11 ,Knockout mouse ,biology.protein ,Intercellular Signaling Peptides and Proteins ,Research Paper - Abstract
// Keisuke Hitachi 1 , Kunihiro Tsuchida 1 1 Division for Therapies Against Intractable Diseases, Institute for Comprehensive Medical Science (ICMS), Fujita Health University, Toyoake, Aichi 470-1192, Japan Correspondence to: Kunihiro Tsuchida, email: tsuchida@fujita-hu.ac.jp Keywords: myostatin, miRNA, callipyge, IG-DMR ncRNA, skeletal muscle Received: July 20, 2016 Accepted: December 08, 2016 Published: December 15, 2016 ABSTRACT Myostatin, a member of the transforming growth factor-beta superfamily, is a negative regulator of skeletal muscle growth and development. Myostatin inhibition leads to increased skeletal muscle mass in mammals; hence, myostatin is considered a potential therapeutic target for skeletal muscle wasting. However, downstream molecules of myostatin in the skeletal muscle have not been fully elucidated. Here, we identified the Dlk1-Dio3 locus at the mouse chromosome 12qF1, also called as the callipyge locus in sheep, as a novel downstream target of myostatin. In skeletal muscle of myostatin knockout mice, the expression of mature miRNAs at the Dlk1-Dio3 locus was significantly increased. The increased miRNA levels are caused by the transcriptional activation of the Dlk1-Dio3 locus, because a significant increase in the primary miRNA transcript was observed in myostatin knockout mice. In addition, we found increased expression of coding and non-coding genes ( Dlk1 , Gtl2 , Rtl1/Rtl1as , and Rian ) at the Dlk1-Dio3 locus in myostatin-deficient skeletal muscle. Moreover, epigenetic changes, associated with the regulation of the Dlk1-Dio3 locus, were observed in myostatin knockout mice. Taken together, this is the first report demonstrating the role of myostatin in regulating the Dlk1-Dio3 (the callipyge ) locus in the skeletal muscle.
- Published
- 2016
44. The VEGF-A exon 8 splicing-sensitive fluorescent reporter mouse is a novel tool to assess the effects of splicing regulatory compounds in vivo
- Author
-
Eleanor Star, Matthew Lee, Elizabeth Bowler, Megan Stevens, E. Innes, Ling Li, Sebastian Oltean, David O. Bates, and Steven J. Harper
- Subjects
Genetically modified mouse ,Vascular Endothelial Growth Factor A ,mouse model ,Green Fluorescent Proteins ,SRPK1 ,Biology ,Protein Serine-Threonine Kinases ,Eye ,Kidney ,Green fluorescent protein ,Animals, Genetically Modified ,03 medical and health sciences ,Exon ,chemistry.chemical_compound ,Mice ,angiogenesis ,0302 clinical medicine ,Genes, Reporter ,Animals ,Protein Isoforms ,vascular endothelial growth factor-A ,Muscle, Skeletal ,Molecular Biology ,Pancreas ,Protein Kinase Inhibitors ,030304 developmental biology ,0303 health sciences ,Messenger RNA ,Myocardium ,Alternative splicing ,Cell Biology ,Exons ,Introns ,3. Good health ,Cell biology ,Vascular endothelial growth factor ,Alternative Splicing ,Luminescent Proteins ,chemistry ,splicing-sensitive fluorescent reporter ,Genetic Loci ,030220 oncology & carcinogenesis ,RNA splicing ,Research Paper - Abstract
Vascular endothelial growth factor (VEGF)-A is differentially spliced to give two functionally different isoform families; pro-angiogenic, pro-permeability VEGF-Axxx and anti-angiogenic, anti-permeability VEGF-Axxxb. VEGF-A splicing is dysregulated in several pathologies, including cancer, diabetes, and peripheral arterial disease. The bichromatic VEGF-A splicing-sensitive fluorescent reporter harboured in a transgenic mouse is a novel approach to investigate the splicing patterns of VEGF-A in vivo. We generated a transgenic mouse harbouring a splicing-sensitive fluorescent reporter designed to mimic VEGF-A terminal exon splicing (VEGF8ab) by insertion into the ROSA26 genomic locus. dsRED expression denotes proximal splice site selection (VEGF-Axxx) and eGFP expression denotes distal splice site selection (VEGF-Axxxb). We investigated the tissue-specific expression patterns in the eye, skeletal muscle, cardiac muscle, kidney, and pancreas, and determined whether the splicing pattern could be manipulated in the same manner as endogenous VEGF-A by treatment with the SRPK1 inhibitor SPHINX 31. We confirmed expression of both dsRED and eGFP in the eye, skeletal muscle, cardiac muscle, kidney, and pancreas, with the highest expression of both fluorescent proteins observed in the exocrine pancreas. The ratio of dsRED and eGFP matched that of endogenous VEGF-Axxx and VEGF-Axxxb. Treatment of the VEGF8ab mice with SPHINX 31 increased the mRNA and protein eGFP/dsRED ratio in the exocrine pancreas, mimicking endogenous VEGF-A splicing. The VEGF-A exon 8 splicing-sensitive fluorescent reporter mouse is a novel tool to assess splicing regulation in the individual cell-types and tissues, which provides a useful screening process for potentially therapeutic splicing regulatory compounds in vivo.
- Published
- 2019
45. Associations between placental CpG methylation of metastable epialleles and childhood body mass index across ages one, two and ten in the Extremely Low Gestational Age Newborns (ELGAN) cohort
- Author
-
Jeliyah Clark, Catherine M. Bulka, Lisa Smeester, Elizabeth M. Martin, Hudson P. Santos, T. Michael O'Shea, and Rebecca C. Fry
- Subjects
0301 basic medicine ,Adult ,Male ,Cancer Research ,Placenta ,Biology ,Childhood obesity ,Body Mass Index ,Epigenesis, Genetic ,Andrology ,03 medical and health sciences ,0302 clinical medicine ,Pregnancy ,medicine ,Humans ,Infant, Very Low Birth Weight ,Epigenetics ,Molecular Biology ,Alleles ,Infant, Newborn ,Gestational age ,Methylation ,DNA Methylation ,medicine.disease ,030104 developmental biology ,In utero ,Genetic Loci ,030220 oncology & carcinogenesis ,DNA methylation ,CpG Islands ,Female ,Genomic imprinting ,Body mass index ,Research Paper - Abstract
The Developmental Origins of Health and Disease (DOHaD) hypothesis posits that in utero and early life conditions can disrupt normal fetal development and program susceptibility to later-life disease. Metastable epialleles are genomic loci in which CpG methylation patterning is responsive to maternal diet and conserved across time and tissues. Thus, these sites could serve as 'signatures' of gestational environment conditions. Here, we sought to determine if methylation of metastable epialleles was associated with changes in childhood body mass index (BMI) z-scores across ages one, two and ten in the Extremely Low Gestational Age Newborns (ELGAN) cohort. CpG methylation of 250 probes (corresponding to 111 genes) within metastable epiallele regions was measured in placental tissue. Linear mixed effects models were fit to evaluate the overall and sex-stratified associations between methylation and changes in BMI z-score over time. In total, 26 probes were associated (p < 0.05) with changes in BMI z-score overall, including probes within Mesoderm Specific Transcript (MEST) and Histone Deacetylase 4 (HDAC4), which have previously been associated with childhood obesity and adipogenesis. Sex-stratified analyses revealed a significant association, after adjusting for multiple comparisons (q < 0.05), within female placentas for one probe annotated to the imprinted gene PLAG1 Like Zinc Finger 1 (PLAGL1). These findings suggest epigenetic marks may be involved in programming susceptibility to obesity in utero and highlight the potential to use placental tissues in predicting growth rate trajectories among premature infants.
- Published
- 2019
46. Powerful testing via hierarchical linkage disequilibrium in haplotype association studies
- Author
-
Jeanine J. Houwing-Duistermaat, Stefan Böhringer, Brunilda Balliu, Balliu B., Houwing-Duistermaat J.J., and Bohringer S.
- Subjects
Statistics and Probability ,Linkage disequilibrium ,Biometry ,Computer science ,Degrees of freedom (statistics) ,Genome-wide association study ,computer.software_genre ,Polymorphism, Single Nucleotide ,haplotype association study ,Arthritis, Rheumatoid ,03 medical and health sciences ,Humans ,030304 developmental biology ,Genetic association ,genome‐wide association study ,General Biometry ,0303 health sciences ,genome-wide association study ,Liver Cirrhosis, Biliary ,030305 genetics & heredity ,Haplotype ,Statistics ,General Medicine ,cis interaction ,Other Topics ,Nominal level ,Haplotypes ,cis interactions ,Genetic Loci ,Multinomial distribution ,Probability and Uncertainty ,Data mining ,Statistics, Probability and Uncertainty ,computer ,linkage disequilibrium ,Type I and type II errors ,Research Paper - Abstract
Marginal tests based on individual SNPs are routinely used in genetic association studies. Studies have shown that haplotype‐based methods may provide more power in disease mapping than methods based on single markers when, for example, multiple disease‐susceptibility variants occur within the same gene. A limitation of haplotype‐based methods is that the number of parameters increases exponentially with the number of SNPs, inducing a commensurate increase in the degrees of freedom and weakening the power to detect associations. To address this limitation, we introduce a hierarchical linkage disequilibrium model for disease mapping, based on a reparametrization of the multinomial haplotype distribution, where every parameter corresponds to the cumulant of each possible subset of a set of loci. This hierarchy present in the parameters enables us to employ flexible testing strategies over a range of parameter sets: from standard single SNP analyses through the full haplotype distribution tests, reducing degrees of freedom and increasing the power to detect associations. We show via extensive simulations that our approach maintains the type I error at nominal level and has increased power under many realistic scenarios, as compared to single SNP and standard haplotype‐based studies. To evaluate the performance of our proposed methodology in real data, we analyze genome‐wide data from the Wellcome Trust Case‐Control Consortium.
- Published
- 2019
47. Novel DNA methylation sites associated with cigarette smoking among African Americans
- Author
-
Sharon L.R. Kardia, Yunfeng Huang, Jiaxuan Liu, Jennifer A. Smith, Yan V. Sun, Veronica Barcelona, Miao Yu, Kristen M. Brown, Jacquelyn Y. Taylor, and Wei Zhao
- Subjects
0301 basic medicine ,Adult ,Male ,Cancer Research ,Lung Neoplasms ,Heart disease ,Biology ,Health outcomes ,Affect (psychology) ,Cigarette Smoking ,Epigenesis, Genetic ,03 medical and health sciences ,0302 clinical medicine ,Cigarette smoking ,Environmental health ,medicine ,Humans ,Genetic Predisposition to Disease ,Child ,Molecular Biology ,Epigenomics ,DNA Methylation ,medicine.disease ,Obesity ,Black or African American ,030104 developmental biology ,Cardiovascular Diseases ,Genetic Loci ,030220 oncology & carcinogenesis ,Child, Preschool ,DNA methylation ,Female ,Research Paper - Abstract
Introduction: Cigarette smoking has been associated with adverse health outcomes for mothers and children and is a major contributor to heart disease. Although cigarette smoking is known to affect the epigenome, few studies have been done in African American populations. In this study, we investigated the association between cigarette smoking and DNA methylation (DNAm) among African Americans from the Intergenerational Impact of Genetic and Psychological Factors on Blood Pressure Study (InterGEN), and the Genetic Epidemiology Network of Arteriopathy (GENOA). Methods: The InterGEN study aims to examine the effects of genetic and psychological factors on blood pressure among African American women and their children. Current cigarette smoking was assessed at baseline. DNAm of saliva was assessed using the 850K EPIC Illumina BeadChip for Epigenome-Wide Association analyses. A replication study was conducted among 1100 participants in the GENOA study using the same BeadChip. Results: After controlling for age, body mass index, population structure and cell composition, 26 epigenome-wide significant sites (FDR q
- Published
- 2019
48. NOXA1-dependent NADPH oxidase regulates redox signaling and phenotype of vascular smooth muscle cell during atherogenesis
- Author
-
Andrey Lozhkin, Nageswara R. Madamanchi, Chandrika Canugovi, Arihiro Sumida, Takayuki Hayami, Aleksandr E. Vendrov, and Marschall S. Runge
- Subjects
NOXA1 ,0301 basic medicine ,Vascular smooth muscle ,Clinical Biochemistry ,MMP2, matrix metalloproteinase 2 ,medicine.disease_cause ,Biochemistry ,Muscle, Smooth, Vascular ,Pathogenesis ,Mice ,0302 clinical medicine ,lcsh:QH301-705.5 ,Mice, Knockout ,chemistry.chemical_classification ,Neointimal hyperplasia ,lcsh:R5-920 ,NADPH oxidase ,biology ,CCL2, CC chemokine ligand 2 ,NOX, NADPH oxidase ,KLF4 ,Cell biology ,VSMC, vascular smooth muscle cells ,Phenotype ,VCAM1, vascular cell adhesion molecule 1 ,Smooth muscle cells ,Organ Specificity ,POVPC, 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphatidylcholine ,cardiovascular system ,medicine.symptom ,lcsh:Medicine (General) ,Oxidation-Reduction ,Research Paper ,NOXA1, Nox activator 1 ,Signal Transduction ,Myocytes, Smooth Muscle ,Mice, Transgenic ,Inflammation ,Lesion ,Kruppel-Like Factor 4 ,03 medical and health sciences ,ROS, reactive oxygen species ,Apolipoproteins E ,KLF4, Krüppel-like factor 4 ,medicine ,Animals ,Adaptor Proteins, Signal Transducing ,Reactive oxygen species ,Tumor Necrosis Factor-alpha ,Organic Chemistry ,NADPH Oxidases ,Proteins ,Macrophage-like cells ,Atherosclerosis ,medicine.disease ,Enzyme Activation ,030104 developmental biology ,Receptors, LDL ,chemistry ,lcsh:Biology (General) ,Oxidative stress ,Genetic Loci ,biology.protein ,APOE, apolipoprotein E ,Reactive Oxygen Species ,Biomarkers ,Gene Deletion ,030217 neurology & neurosurgery - Abstract
Increased reactive oxygen species (ROS) production and inflammation are key factors in the pathogenesis of atherosclerosis. We previously reported that NOX activator 1 (NOXA1) is the critical functional homolog of p67phox for NADPH oxidase activation in mouse vascular smooth muscle cells (VSMC). Here we investigated the effects of systemic and SMC-specific deletion of Noxa1 on VSMC phenotype during atherogenesis in mice. Neointimal hyperplasia following endovascular injury was lower in Noxa1-deficient mice versus the wild-type following endovascular injury. Noxa1 deletion in Apoe-/- or Ldlr-/- mice fed a Western diet showed 50% reduction in vascular ROS and 30% reduction in aortic atherosclerotic lesion area and aortic sinus lesion volume (P, Graphical abstract fx1, Highlights • NOXA1 is a VSMC-specific regulator of NADPH oxidase 1 activity and downstream cell signaling. • NOX1 NADPH oxidase-dependent ROS generation is required for VSMC proliferation and migration after endovascular injury. • NOXA1-dependent NOX1 activation of KLF4 in atherosclerotic lesions induces SMC phenotypic switch to macrophage-like cells. • Atherosclerotic lesion macrophage-like cells promote plaque inflammation, matrix remodeling and increase volume expansion.
- Published
- 2019
49. Integration of genetic and physical maps of the Primula vulgaris S locus and localization by chromosome in situ hybridization
- Author
-
Matthew C. Smith, Jinhong Li, Pat Heslop-Harrison, Philip M. Gilmartin, Farah Badakshi, Margaret A. Webster, Jonathan M. Wright, and Jonathan M. Cocker
- Subjects
0106 biological sciences ,Genetic Markers ,Chromosomes, Artificial, Bacterial ,Primula vulgaris ,DNA, Plant ,Physiology ,Genetic Linkage ,Plant Development ,Locus (genetics) ,Plant Science ,Flowers ,Biology ,Genes, Plant ,01 natural sciences ,DNA sequencing ,Chromosomes, Plant ,S locus ,Evolution, Molecular ,03 medical and health sciences ,Contig Mapping ,Gene mapping ,chromosome in situ ,Centromere ,genetic map ,Gene ,In Situ Hybridization ,030304 developmental biology ,Genetics ,0303 health sciences ,Contig ,Gene map ,Full Paper ,Base Sequence ,Research ,Chromosome ,food and beverages ,Chromosome Mapping ,Full Papers ,Phenotype ,Primula ,Genetic Loci ,Mutation ,heterostyly ,Genome, Plant ,010606 plant biology & botany - Abstract
Summary Heteromorphic flower development in Primula is controlled by the S locus. The S locus genes, which control anther position, pistil length and pollen size in pin and thrum flowers, have not yet been characterized. We have integrated S‐linked genes, marker sequences and mutant phenotypes to create a map of the P. vulgaris S locus region that will facilitate the identification of key S locus genes. We have generated, sequenced and annotated BAC sequences spanning the S locus, and identified its chromosomal location.We have employed a combination of classical genetics and three‐point crosses with molecular genetic analysis of recombinants to generate the map. We have characterized this region by Illumina sequencing and bioinformatic analysis, together with chromosome in situ hybridization.We present an integrated genetic and physical map across the P. vulgaris S locus flanked by phenotypic and DNA sequence markers. BAC contigs encompass a 1.5‐Mb genomic region with 1 Mb of sequence containing 82 S‐linked genes anchored to overlapping BACs. The S locus is located close to the centromere of the largest metacentric chromosome pair.These data will facilitate the identification of the genes that orchestrate heterostyly in Primula and enable evolutionary analyses of the S locus.
- Published
- 2015
50. CRISPRstrand: predicting repeat orientations to determine the crRNA-encoding strand at CRISPR loci
- Author
-
Fabrizio Costa, Roger A. Garrett, Omer S. Alkhnbashi, Shiraz A. Shah, Sita J. Saunders, and Rolf Backofen
- Subjects
Statistics and Probability ,Sequence analysis ,Computational biology ,Biology ,Biochemistry ,Conserved sequence ,CRISPR ,Clustered Regularly Interspaced Short Palindromic Repeats ,Repeated sequence ,Molecular Biology ,Conserved Sequence ,Genetics ,Trans-activating crRNA ,Base Sequence ,Molecular Sequence Annotation ,Sequence Analysis, DNA ,Original Papers ,Structural Bioinformatics ,Archaea ,Computer Science Applications ,Computational Mathematics ,Computational Theory and Mathematics ,Genetic Loci ,Mutation (genetic algorithm) ,CRISPR Loci ,RNA ,CRISPR-Cas Systems ,Eccb 2014 Proceedings Papers Committee ,Software - Abstract
Motivation: The discovery of CRISPR-Cas systems almost 20 years ago rapidly changed our perception of the bacterial and archaeal immune systems. CRISPR loci consist of several repetitive DNA sequences called repeats, inter-spaced by stretches of variable length sequences called spacers. This CRISPR array is transcribed and processed into multiple mature RNA species (crRNAs). A single crRNA is integrated into an interference complex, together with CRISPR-associated (Cas) proteins, to bind and degrade invading nucleic acids. Although existing bioinformatics tools can recognize CRISPR loci by their characteristic repeat-spacer architecture, they generally output CRISPR arrays of ambiguous orientation and thus do not determine the strand from which crRNAs are processed. Knowledge of the correct orientation is crucial for many tasks, including the classification of CRISPR conservation, the detection of leader regions, the identification of target sites (protospacers) on invading genetic elements and the characterization of protospacer-adjacent motifs. Results: We present a fast and accurate tool to determine the crRNA-encoding strand at CRISPR loci by predicting the correct orientation of repeats based on an advanced machine learning approach. Both the repeat sequence and mutation information were encoded and processed by an efficient graph kernel to learn higher-order correlations. The model was trained and tested on curated data comprising >4500 CRISPRs and yielded a remarkable performance of 0.95 AUC ROC (area under the curve of the receiver operator characteristic). In addition, we show that accurate orientation information greatly improved detection of conserved repeat sequence families and structure motifs. We integrated CRISPRstrand predictions into our CRISPRmap web server of CRISPR conservation and updated the latter to version 2.0. Availability: CRISPRmap and CRISPRstrand are available at http://rna.informatik.uni-freiburg.de/CRISPRmap. Contact: backofen@informatik.uni-freiburg.de Supplementary information: Supplementary data are available at Bioinformatics online.
- Published
- 2014
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.