scholarly journals Functional Annotation Signatures of Disease Susceptibility Loci Improve SNP Association Analysis

2013 ◽  
Author(s):  
Edwin S Iversen ◽  
Gary Lipton ◽  
Merlise A. Clyde ◽  
Alvaro N. A. Monteiro
Keyword(s):  
Functional Annotation ◽  
Association Studies ◽  
Function Class ◽  
Regulatory Elements ◽  
Likelihood Method ◽  
Annotation Database ◽  
Genomic Variants ◽  
Genome Wide ◽  
A Genome ◽  
The Impact

We describe the development and application of a Bayesian statistical model for the prior probability of phenotype-genotype association that incorporates data from past association studies and publicly available functional annotation data regarding the susceptibility variants under study. The model takes the form of a binary regression of association status on a set of annotation variables whose coefficients were estimated through an analysis of associated SNPs housed in the GWAS Catalog (GC). The set of functional predictors we examined includes measures that have been demonstrated to correlate with the association status of SNPs in the GC and some whose utility in this regard is speculative: summaries of the UCSC Human Genome Browser ENCODE super-track data, dbSNP function class, sequence conservation summaries, proximity to genomic variants included in the Database of Genomic Variants (DGV) and known regulatory elements included in the Open Regulatory Annotation database (ORegAnno), PolyPhen-2 probabilities and RegulomeDB categories. Because we expected that only a fraction of the annotation variables would contribute to predicting association, we employed a penalized likelihood method to reduce the impact of non-informative predictors and evaluated the model's ability to predict GC SNPs not used to construct the model. We show that the functional data alone are predictive of a SNP's presence in the GC. Further, using data from a genome-wide study of ovarian cancer, we demonstrate that their use as prior data when testing for association is practical at the genome-wide scale and improves power to detect associations.

scholarly journals Antipsychotic-induced epigenomic reorganization in frontal cortex samples from individuals with schizophrenia

2021 ◽  
Author(s):  
Bohan Zhu ◽  
Richard I Ainsworth ◽  
Zengmiao Wang ◽  
Salvador Sierra ◽  
Chengyu Deng ◽  
...  
Keyword(s):  
Frontal Cortex ◽  
Histone Modifications ◽  
Association Studies ◽  
Regulatory Elements ◽  
Postmortem Brain ◽  
Antipsychotic Treatment ◽  
Genome Wide Association Studies ◽  
Epigenetic Marks ◽  
Genome Wide ◽  
The Impact

Genome wide association studies have revealed >150 loci associated with schizophrenia risk, yet these genetic factors do not seem to be sufficient to fully explain the molecular determinants behind this psychiatric condition. Epigenetic marks such as post-translational histone modifications remain largely plastic during development and adulthood, allowing a dynamic impact of environmental factors, including antipsychotic medications, on access to genes and regulatory elements. However, no study so far has profiled cell-specific genome-wide histone modifications in postmortem brain samples from schizophrenia subjects or the effect of antipsychotic treatment on such epigenetic marks. Here we show the first comprehensive epigenomic characterization of the frontal cortex of 29 individuals with schizophrenia and 29 matched controls, including histone modifications associated with active promoters and enhancers H3K4me3 and H3K27ac along with RNA expression in neuronal and glial nuclei. Schizophrenia subjects exhibited thousands of cell type-specific epigenetic differences at regions that included several susceptibility genetic loci, such as NRG1, RGS4 and HTR2A. Comparing untreated and treated schizophrenia subjects with controls, our findings provide entirely new insights into differentially modified genes associated with unexpected pathways that are potential markers of antipsychotic treatment. Additionally, we show that the effect of age on the epigenomic landscape is more pronounced in frontal cortex samples of antipsychotic-treated schizophrenia subjects. Together, our data provide important evidence of epigenetic alterations in the frontal cortex of individuals with schizophrenia, and remark the impact of age and antipsychotic treatment on chromatin organization.

scholarly journals A cross-disorder dosage sensitivity map of the human genome

2021 ◽  
Author(s):  
Ryan L. Collins ◽  
Joseph T. Glessner ◽  
Eleonora Porcu ◽  
Lisa-Marie Niestroj ◽  
Jacob Ulirsch ◽  
...  
Keyword(s):  
Human Genome ◽  
Molecular Mechanisms ◽  
De Novo ◽  
Association Studies ◽  
Disease Genes ◽  
Driver Genes ◽  
Genome Wide ◽  
A Genome ◽  
The Impact ◽  
Dosage Sensitivity

SUMMARYRare deletions and duplications of genomic segments, collectively known as rare copy number variants (rCNVs), contribute to a broad spectrum of human diseases. To date, most disease-association studies of rCNVs have focused on recognized genomic disorders or on the impact of haploinsufficiency caused by deletions. By comparison, our understanding of duplications in disease remains rudimentary as very few individual genes are known to be triplosensitive (i.e., duplication intolerant). In this study, we meta-analyzed rCNVs from 753,994 individuals across 30 primarily neurological disease phenotypes to create a genome-wide catalog of rCNV association statistics across disorders. We discovered 114 rCNV-disease associations at 52 distinct loci surpassing genome-wide significance (P=3.72×10−6), 42% of which involve duplications. Using Bayesian fine-mapping methods, we further prioritized 38 novel triplosensitive disease genes (e.g., GMEB2 in brain abnormalities), including three known haploinsufficient genes that we now reveal as bidirectionally dosage sensitive (e.g., ANKRD11 in growth abnormalities). By integrating our results with prior literature, we found that disease-associated rCNV segments were enriched for genes constrained against damaging coding variation and identified likely dominant driver genes for about one-third (32%) of rCNV segments based on de novo mutations from exome sequencing studies of developmental disorders. However, while the presence of constrained driver genes was a common feature of many pathogenic large rCNVs across disorders, most of the rCNVs showing genome-wide significant association were incompletely penetrant (mean odds ratio=11.6) and we also identified two examples of noncoding disease-associated rCNVs (e.g., intronic CADM2 deletions in behavioral disorders). Finally, we developed a statistical model to predict dosage sensitivity for all genes, which defined 3,006 haploinsufficient and 295 triplosensitive genes where the effect sizes of rCNVs were comparable to deletions of genes constrained against truncating mutations. These dosage sensitivity scores classified disease genes across molecular mechanisms, prioritized pathogenic de novo rCNVs in children with autism, and revealed features that distinguished haploinsufficient and triplosensitive genes, such as insulation from other genes and local cis-regulatory complexity. Collectively, the cross-disorder rCNV maps and metrics derived in this study provide the most comprehensive assessment of dosage sensitive genomic segments and genes in disease to date and set the foundation for future studies of dosage sensitivity throughout the human genome.

scholarly journals A genome-wide map of regulatory elements in zebrafish

Lab Animal ◽  
2020 ◽  
Vol 50 (1) ◽  
pp. 17-17
Author(s):  
Alexandra Le Bras
Keyword(s):  
Regulatory Elements ◽  
Genome Wide ◽  
A Genome

scholarly journals A Genome-Wide Analysis of Pathogenesis-Related Protein-1 (PR-1) Genes from Piper nigrum Reveals Its Critical Role during Phytophthora capsici Infection

Genes ◽  
2021 ◽  
Vol 12 (7) ◽  
pp. 1007
Author(s):  
Divya Kattupalli ◽  
Asha Sreenivasan ◽  
Eppurathu Vasudevan Soniya
Keyword(s):  
Phytophthora Capsici ◽  
Regulatory Elements ◽  
Piper Nigrum ◽  
Binding Motif ◽  
Altered Expression ◽  
Genome Wide ◽  
A Genome ◽  
Pathogenesis Related Protein ◽  
Pathogenesis Related

Black pepper (Piper nigrum L.) is a prominent spice that is an indispensable ingredient in cuisine and traditional medicine. Phytophthora capsici, the causative agent of footrot disease, causes a drastic constraint in P. nigrum cultivation and productivity. To counterattack various biotic and abiotic stresses, plants employ a broad array of mechanisms that includes the accumulation of pathogenesis-related (PR) proteins. Through a genome-wide survey, eleven PR-1 genes that belong to a CAP superfamily protein with a caveolin-binding motif (CBM) and a CAP-derived peptide (CAPE) were identified from P. nigrum. Despite the critical functional domains, PnPR-1 homologs differ in their signal peptide motifs and core amino acid composition in the functional protein domains. The conserved motifs of PnPR-1 proteins were identified using MEME. Most of the PnPR-1 proteins were basic in nature. Secondary and 3D structure analyses of the PnPR-1 proteins were also predicted, which may be linked to a functional role in P. nigrum. The GO and KEGG functional annotations predicted their function in the defense responses of plant-pathogen interactions. Furthermore, a transcriptome-assisted FPKM analysis revealed PnPR-1 genes mapped to the P. nigrum-P. capsici interaction pathway. An altered expression pattern was detected for PnPR-1 transcripts among which a significant upregulation was noted for basic PnPR-1 genes such as CL10113.C1 and Unigene17664. The drastic variation in the transcript levels of CL10113.C1 was further validated through qRT-PCR and it showed a significant upregulation in infected leaf samples compared with the control. A subsequent analysis revealed the structural details, phylogenetic relationships, conserved sequence motifs and critical cis-regulatory elements of PnPR-1 genes. This is the first genome-wide study that identified the role of PR-1 genes during P. nigrum-P. capsici interactions. The detailed in silico experimental analysis revealed the vital role of PnPR-1 genes in regulating the first layer of defense towards a P. capsici infection in Panniyur-1 plants.

scholarly journals Transcriptional Regulation of RUNX1: An Informatics Analysis

Genes ◽  
2021 ◽  
Vol 12 (8) ◽  
pp. 1175
Author(s):  
Amarni L. Thomas ◽  
Judith Marsman ◽  
Jisha Antony ◽  
William Schierding ◽  
Justin M. O’Sullivan ◽  
...  
Keyword(s):  
Association Studies ◽  
Regulatory Elements ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Genome Wide ◽  
Runx1 Gene ◽  
Gene Regulatory Elements ◽  
Important Regulator ◽  
Aml1 Gene ◽  
Regulatory Landscape

The RUNX1/AML1 gene encodes a developmental transcription factor that is an important regulator of haematopoiesis in vertebrates. Genetic disruptions to the RUNX1 gene are frequently associated with acute myeloid leukaemia. Gene regulatory elements (REs), such as enhancers located in non-coding DNA, are likely to be important for Runx1 transcription. Non-coding elements that modulate Runx1 expression have been investigated over several decades, but how and when these REs function remains poorly understood. Here we used bioinformatic methods and functional data to characterise the regulatory landscape of vertebrate Runx1. We identified REs that are conserved between human and mouse, many of which produce enhancer RNAs in diverse tissues. Genome-wide association studies detected single nucleotide polymorphisms in REs, some of which correlate with gene expression quantitative trait loci in tissues in which the RE is active. Our analyses also suggest that REs can be variant in haematological malignancies. In summary, our analysis identifies features of the RUNX1 regulatory landscape that are likely to be important for the regulation of this gene in normal and malignant haematopoiesis.

scholarly journals Genomic basis of striking fin shapes and colours in the fighting fish

2021 ◽  
Author(s):  
Le Wang ◽  
Fei Sun ◽  
Zi Yi Wan ◽  
Baoqing Ye ◽  
Yanfei Wen ◽  
...  
Keyword(s):  
Evolutionary Biology ◽  
Association Studies ◽  
Regulatory Element ◽  
Regulatory Elements ◽  
Major Effect ◽  
Betta Splendens ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Phenotypic Variations ◽  
Genomic Basis

Abstract Resolving the genomic basis underlying phenotypic variations is a question of great importance in evolutionary biology. However, understanding how genotypes determine the phenotypes is still challenging. Centuries of artificial selective breeding for beauty and aggression resulted in a plethora of colors, long fin varieties, and hyper-aggressive behavior in the air-breathing Siamese fighting fish (Betta splendens), supplying an excellent system for studying the genomic basis of phenotypic variations. Combining whole genome sequencing, QTL mapping, genome-wide association studies and genome editing, we investigated the genomic basis of huge morphological variation in fins and striking differences in coloration in the fighting fish. Results revealed that the double tail, elephant ear, albino and fin spot mutants each were determined by single major-effect loci. The elephant ear phenotype was likely related to differential expression of a potassium ion channel gene, kcnh8. The albinotic phenotype was likely linked to a cis-regulatory element acting on the mitfa gene and the double tail mutant was suggested to be caused by a deletion in a zic1/zic4 co-enhancer. Our data highlight that major loci and cis-regulatory elements play important roles in bringing about phenotypic innovations and establish Bettas as new powerful model to study the genomic basis of evolved changes.

scholarly journals Functional annotation of risk loci identified through genome-wide association studies for prostate cancer

The Prostate ◽  
2010 ◽  
Vol 71 (9) ◽  
pp. 955-963 ◽  
Author(s):  
Yizhen Lu ◽  
Zheng Zhang ◽  
Hongjie Yu ◽  
S. Lily Zheng ◽  
William B. Isaacs ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Functional Annotation ◽  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genome Wide

scholarly journals Comprehensive Genomic Discovery of Non-Coding Transcriptional Enhancers in the African Malaria Vector Anopheles coluzzii

2022 ◽  
Vol 12 ◽  
Author(s):  
Inge Holm ◽  
Luisa Nardini ◽  
Adrien Pain ◽  
Emmanuel Bischoff ◽  
Cameron E. Anderson ◽  
...  
Keyword(s):  
Malaria Vector ◽  
Regulatory Elements ◽  
Specific Cell ◽  
Insect Vector ◽  
Anopheles Coluzzii ◽  
Gene Promoters ◽  
Transcriptional Enhancers ◽  
Genome Wide ◽  
A Genome

Almost all regulation of gene expression in eukaryotic genomes is mediated by the action of distant non-coding transcriptional enhancers upon proximal gene promoters. Enhancer locations cannot be accurately predicted bioinformatically because of the absence of a defined sequence code, and thus functional assays are required for their direct detection. Here we used a massively parallel reporter assay, Self-Transcribing Active Regulatory Region sequencing (STARR-seq), to generate the first comprehensive genome-wide map of enhancers in Anopheles coluzzii, a major African malaria vector in the Gambiae species complex. The screen was carried out by transfecting reporter libraries created from the genomic DNA of 60 wild A. coluzzii from Burkina Faso into A. coluzzii 4a3A cells, in order to functionally query enhancer activity of the natural population within the homologous cellular context. We report a catalog of 3,288 active genomic enhancers that were significant across three biological replicates, 74% of them located in intergenic and intronic regions. The STARR-seq enhancer screen is chromatin-free and thus detects inherent activity of a comprehensive catalog of enhancers that may be restricted in vivo to specific cell types or developmental stages. Testing of a validation panel of enhancer candidates using manual luciferase assays confirmed enhancer function in 26 of 28 (93%) of the candidates over a wide dynamic range of activity from two to at least 16-fold activity above baseline. The enhancers occupy only 0.7% of the genome, and display distinct composition features. The enhancer compartment is significantly enriched for 15 transcription factor binding site signatures, and displays divergence for specific dinucleotide repeats, as compared to matched non-enhancer genomic controls. The genome-wide catalog of A. coluzzii enhancers is publicly available in a simple searchable graphic format. This enhancer catalogue will be valuable in linking genetic and phenotypic variation, in identifying regulatory elements that could be employed in vector manipulation, and in better targeting of chromosome editing to minimize extraneous regulation influences on the introduced sequences.Importance: Understanding the role of the non-coding regulatory genome in complex disease phenotypes is essential, but even in well-characterized model organisms, identification of regulatory regions within the vast non-coding genome remains a challenge. We used a large-scale assay to generate a genome wide map of transcriptional enhancers. Such a catalogue for the important malaria vector, Anopheles coluzzii, will be an important research tool as the role of non-coding regulatory variation in differential susceptibility to malaria infection is explored and as a public resource for research on this important insect vector of disease.

scholarly journals In-silico genome wide analysis of Mitogen activated protein kinase kinase kinase gene family in C. sinensis

PLoS ONE ◽  
2021 ◽  
Vol 16 (11) ◽  
pp. e0258657
Author(s):  
Abhirup Paul ◽  
Anurag P. Srivastava ◽  
Shreya Subrahmanya ◽  
Guoxin Shen ◽  
Neelam Mishra
Keyword(s):  
Protein Kinase ◽  
Regulatory Elements ◽  
Stress Factors ◽  
Mitogen Activated Protein Kinase ◽  
Functional Study ◽  
Functional Domain ◽  
Genome Wide ◽  
A Genome ◽  
Mitogen Activated Protein ◽  
Protein Kinase Kinase

Mitogen activated protein kinase kinase kinase (MAPKKK) form the upstream component of MAPK cascade. It is well characterized in several plants such as Arabidopsis and rice however the knowledge about MAPKKKs in tea plant is largely unknown. In the present study, MAPKKK genes of tea were obtained through a genome wide search using Arabidopsis thaliana as the reference genome. Among 59 candidate MAPKKK genes in tea, 17 genes were MEKK-like, 31 genes were Raf-like and 11 genes were ZIK- like. Additionally, phylogenetic relationships were established along with structural analysis, which includes gene structure, its location as well as conserved motifs, cis-acting regulatory elements and functional domain signatures that were systematically examined. Also, on the basis of one orthologous gene found between tea and Arabidopsis, functional interaction was carried out in C. sinensis based on an Arabidopsis association model. The expressional profiles indicated major involvement of MAPKKK genes from tea in response to various abiotic stress factors. Taken together, this study provides the targets for additional inclusive identification, functional study, and provides comprehensive knowledge for a better understanding of the MAPKKK cascade regulatory network in C. sinensis.

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