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Identification of human genetic variants controlling circular RNA expression [article]

Ikhlak Ahmed, Thasni Karedath, Fatima M. Al-Dasim, Joel A. Malek
2018 bioRxiv   pre-print
AbstractCircular RNAs (circRNAs) are abundant in eukaryotic transcriptomes and have been linked to various human disorders. However, understanding genetic control of circular RNA expression is in early stages. Here we present the first integrated analysis of circRNAs and genome sequence variation from lymphoblastoid cell lines of the 1000 genomes project. We identified thousands of circRNAs in the RNA-seq data and show their association with local single nucleotide polymorphic sites, referred
more » ... as circQTLs, which influence the circRNA transcript abundance. Strikingly, we found that circQTLs exist independently of eQTLs with most circQTLs having no effect on mRNA expression. Only a fraction of the polymorphic sites are shared and linked to both circRNA and mRNA expression with mostly similar effects on circular and linear RNA. A shared intronic QTL, rs55928920, of HMSD gene drives the circular and linear expression in opposite directions, potentially modulating circRNA levels at the expense of mRNA. Finally, circQTLs and eQTLs are largely independent and exist in separate linkage disequilibrium (LD) blocks with circQTLs highly enriched for functional genomic elements and regulatory regions. This study reveals a previously uncharacterized role of DNA sequence variation in human circular RNA regulation.
doi:10.1101/472977 fatcat:5xbfvtr4vjgsjm2gmstnrdghri

Human leukocyte antigen class II gene diversity tunes antibody repertoires to common pathogens [article]

Taushif Khan, Mahbuba Rahman, Ikhlak Ahmed, Fatima Al Ali, Puthen Veettil Jithesh, Nico Marr
2021 bioRxiv   pre-print
Allelic diversity of HLA class II genes may help maintain humoral immunity against infectious diseases. We investigated the relative contribution of specific HLA class II alleles, haplotypes and genotypes on the variation of antibody responses to a variety of common pathogens in a cohort of 800 adults representing the general Arab population. We found that classical HLA class II gene heterozygosity confers a selective advantage. Moreover, we demonstrated that multiple HLA class II alleles play
more » ... synergistic role in shaping the antibody repertoire. Interestingly, associations of HLA-DRB1 genotypes with specific antigens were identified. Our findings suggest that HLA class II gene polymorphisms confer specific humoral immunity against common pathogens, which may have contributed to the genetic diversity of HLA class II loci during hominine evolution.
doi:10.1101/2021.01.11.426296 fatcat:34i7uhdwd5gqhcvss24dy6pacu

Regulation of circular RNA circNFATc3 in cancer cells alters proliferation, migration and oxidative phosphorylation [article]

Thasni Karedath, Ikhlak Ahmed, Fatima Al DAsim, Albandary Al-Qurashi, Afsheen Raza, Simeon Scott Andrews, Stephanie Aron Ramadan, Nayra M. Al-Thani, Ayeda Abdulsalam Ahmed, Yasmin Ali Mohamoud, Said Dermime, Joel A Malek
2019 bioRxiv   pre-print
Circular RNAs were onced considered artifacts of transcriptome sequencing but have recently been identified as functionally relevant in multiple cancers. Although there is still no clear main function of circRNAs, several studies have revealed that circRNAs are expressed in a variety of eukaryotic organisms, demonstrate conservation across species, and are expressed in a regulated manner often independent of their parental linear isoforms. circNFATC3, an abundant and uncharacterized circular
more » ... form of NFATC3 gene in solid tumors was identified from transcriptomic data. Here we show that circNFATC3 gain of and loss of function experiments using RNAi mediated circRNA silencing and circular Mini vector-mediated overexpression of circularized constructs in breast and ovarian cancer cell lines affects molecular phenotypes. Knockdown of circNFATC3 induces a reduction in cell proliferation, invasion, migration, and oxidative phosphorylation. Gain of function of circNFATc3 in MDA-MB -231 cells and SKOV3 cells show a significant increase in cell proliferation, migration, and respiration. The above results suggest that circNFATC3 is a functionally relevant circular RNA in cancer.
doi:10.1101/741041 fatcat:7pjx5edvpvbjxbtjtzlxhm5qva

High resolution protein-protein interaction mapping using all-versus-all sequencing (AVA-seq) [article]

Simeon S. Andrews, Stephanie Schaefer-Ramadan, Nayra M. Al-Thani, Ikhlak Ahmed, Yasmin A. Mohamoud, Joel A. Malek
2018 bioRxiv   pre-print
AbstractTwo-hybrid systems test for protein-protein interactions and can provide important information for genes with unknown function. Despite their success, two-hybrid systems have remained mostly untouched by improvements from next-generation DNA sequencing. Here we present a method for all-versus-all protein interaction mapping (AVA-seq) that utilizes next-generation sequencing to remove multiple bottlenecks of the two-hybrid process. The method allows for high resolution protein-protein
more » ... eraction mapping of a small set of proteins, or the potential for lower-resolution mapping of entire proteomes. Features of the system include open-reading frame selection to improve efficiency, high bacterial transformation efficiency, a convergent fusion vector to allow paired-end sequencing of interactors, and the use of protein fragments rather than full-length genes to better resolve specific protein contact points. We demonstrate the system's strengths and limitations on a set of proteins known to interact in humans and provide a framework for future large-scale projects.
doi:10.1101/462309 fatcat:vghf2rp74re5rjyzlrnnmlnsem

Identification of human genetic variants controlling circular RNA expression

Ikhlak Ahmed, Thasni Karedath, Fatima M Al-Dasim, Joel A. Malek
2019 RNA: A publication of the RNA Society  
We analyzed the circRNA expression of these samples using our in-house developed circular RNA detection pipeline (Ahmed et al. 2016) .  ...  CircRNA pipeline (Ahmed et al. 2016) was run on all 358 RNA-seq data sets on a Linux cluster managing batches of jobs as per the load on the cluster.  ... 
doi:10.1261/rna.071654.119 pmid:31519742 pmcid:PMC6859849 fatcat:g3zecx2yjjbxvaavw6nvt3sgo4

Human leukocyte antigen class II gene diversity tunes antibody repertoires to common pathogens

Taushif Khan, Mahbuba Rahman, Ikhlak Ahmed, Fatima Al Ali, Puthen Veettil Jithesh, Nico Marr
2022 Frontiers in Immunology  
Allelic diversity of human leukocyte antigen (HLA) class II genes may help maintain humoral immunity against infectious diseases. In this study, we investigated germline genetic variation in classical HLA class II genes and employed a systematic, unbiased approach to explore the relative contribution of this genetic variation in the antibody repertoire to various common pathogens. We leveraged a well-defined cohort of 800 adults representing the general Arab population in which genetic material
more » ... is shared because of the high frequency of consanguineous unions. By applying a high-throughput method for large-scale antibody profiling to this well-defined cohort, we were able to dissect the overall effect of zygosity for classical HLA class II genes, as well as the effects associated with specific HLA class II alleles, haplotypes and genotypes, on the antimicrobial antibody repertoire breadth and antibody specificity with unprecedented resolution. Our population genetic studies revealed that zygosity of the classical HLA class II genes is a strong predictor of antibody responses to common human pathogens, suggesting that classical HLA class II gene heterozygosity confers a selective advantage. Moreover, we demonstrated that multiple HLA class II alleles can have additive effects on the antibody repertoire to common pathogens. We also identified associations of HLA-DRB1 genotypes with specific antigens. Our findings suggest that HLA class II gene polymorphisms confer specific humoral immunity against common pathogens, which may have contributed to the genetic diversity of HLA class II loci during hominine evolution.
doi:10.3389/fimmu.2022.856497 fatcat:25fu64kkufbljep7svaymnmy2u

Regulation of Circular RNA CircNFATC3 in Cancer Cells Alters Proliferation, Migration, and Oxidative Phosphorylation

Thasni Karedath, Fatima M. Al-Dasim, Ikhlak Ahmed, Albandary Al-Qurashi, Afsheen Raza, Simeon Scott Andrews, Ayeda Abdulsalam Ahmed, Yasmin Ali Mohamoud, Said Dermime, Joel A. Malek
2021 Frontiers in Cell and Developmental Biology  
RESULTS Validation of CircNFATC3 in Cancer Cells Our previous studies reported that circNFATC3 is one of the most abundant circRNAs in cancer cells (Ahmed et al., 2016) .  ...  Circular RNAs have attracted increasing attention from cancer researchers as potential biomarkers due to their highly stable nature (Ahmed et al., 2016; Zheng et al., 2016; Karedath et al., 2019a) . circRNAs  ... 
doi:10.3389/fcell.2021.595156 pmid:33816459 pmcid:PMC8017239 fatcat:zqrax74awvc4vfevo2co2rqxxa

Utilizing linkage disequilibrium information from Indian Genome Variation Database for mapping mutations: SCA12 case study

Samira Bahl, Ikhlak Ahmed, Mitali Mukerji
2009 Journal of Genetics  
., Ahmed I., Indian Genome Variation Consortium and Mukerji M. 2009 Utilizing linkage disequilibrium information from Indian Genome Variation Database for mapping mutations: SCA12 case study. J.  ... 
doi:10.1007/s12041-009-0007-0 pmid:19417544 fatcat:jniizphdijeczkypdgsumvpfpy

Genus-wide sequencing supports a two-locus model for sex-determination inPhoenix [article]

Maria F Torres, Lisa S Mathew, Ikhlak Ahmed, Iman K Al-Azwani, Robert Krueger, Diego Rivera, Yasmin A. Mohamoud, Andrew G. Clark, Karsten Suhre, Joel A. Malek
2018 bioRxiv   pre-print
The date palm tree is a commercially important member of the genusPhoenixwhose 14 species are all dioecious with separate male and female individuals. Previous studies identified a multi-megabase region of the date palm genome linked to sex and showed that dioecy likely developed in Phoenix prior to speciation. To identify genes critical to sex determination we sequenced the genomes of 28Phoenixtrees representing all 14 species. Male-specific sequences were identified and extended using phased
more » ... ingle molecule sequencing or BAC clones to distinguish X and Y alleles. Here we show that only four genes contain sequences conserved in all analyzed males, likely identifying the changes foundational to dioecy inPhoenix. The majority of these sequences show similarity to a single genomic locus in the closely related oil palm. CYP703 and GPAT3, two genes critical to male flower development in other monocots, appear fully deleted in females while maintained as single copy in males. A LOG-like gene appears translocated into the Y chromosome and a cytidine deaminase-like appears at the border of a chromosomal rearrangement. Our data supports a two-mutation model for the evolution from hermaphroditism to dioecy through a gynodioecious intermediate.
doi:10.1101/245514 fatcat:47nhpf4nhnbllpjhcg5pws4ryi

Silencing of ANKRD12 circRNA induces molecular and functional changes associated with invasive phenotypes [article]

Thasni Karedath, Ikhlak Ahmed, Wafaa Al Ameri, Fatima Al-Dasim, Simeon S Andrews, Samson Samuel, Iman K Al Azwani, Yasmin Ali Mohamoud, Arash Rafii, Joel A Malek
2018 bioRxiv   pre-print
Circular RNAs (circRNA) that form through non-canonical backsplicing events of pre-mRNA transcripts are evolutionarily conserved and abundantly expressed across species. However, the functional relevance of circRNAs remains a topic of debate. In this study, we identified and characterized a circular RNA derived from Exon 2 and Exon 8 of the ANKRD12 gene, termed here as circANKRD12. We show that this circRNA is abundantly expressed in breast and ovarian cancers. The circANKRD12 is RNase R
more » ... nt and predominantly localized in the cytoplasm in contrast to its source gene mRNA. We confirmed the expression of this circRNA across a variety of cancer cell lines and provide evidence for its functional relevance through downstream regulation of several tumor invasion genes. We show that silencing of circANKRD12 induces a phenotypic change by significantly regulating cell cycle, increasing invasion and migration, altering the metabolism in cancer cells. These results reveal the functional significance of circANKRD12 and provide evidence of a regulatory role for this circRNA in cancer progression.
doi:10.1101/366245 fatcat:rlag6px4lfg5fmchqos7kv6bo4

Genome-wide evidence for local DNA methylation spreading from small RNA-targeted sequences in Arabidopsis

Ikhlak Ahmed, Alexis Sarazin, Chris Bowler, Vincent Colot, Hadi Quesneville
2011 Nucleic Acids Research  
Transposable elements (TEs) and their relics play major roles in genome evolution. However, mobilization of TEs is usually deleterious and strongly repressed. In plants and mammals, this repression is typically associated with DNA methylation, but the relationship between this epigenetic mark and TE sequences has not been investigated systematically. Here, we present an improved annotation of TE sequences and use it to analyze genome-wide DNA methylation maps obtained at singlenucleotide
more » ... ion in Arabidopsis. We show that although the majority of TE sequences are methylated, $26% are not. Moreover, a significant fraction of TE sequences densely methylated at CG, CHG and CHH sites (where H = A, T or C) have no or few matching small interfering RNA (siRNAs) and are therefore unlikely to be targeted by the RNAdirected DNA methylation (RdDM) machinery. We provide evidence that these TE sequences acquire DNA methylation through spreading from adjacent siRNA-targeted regions. Further, we show that although both methylated and unmethylated TE sequences located in euchromatin tend to be more abundant closer to genes, this trend is least pronounced for methylated, siRNA-targeted TE sequences located 5 0 to genes. Based on these and other findings, we propose that spreading of DNA methylation through promoter regions explains at least in part the negative impact of siRNA-targeted TE sequences on neighboring gene expression.
doi:10.1093/nar/gkr324 pmid:21586580 pmcid:PMC3167636 fatcat:6omw73qnd5hqta4wpbpdjxw3pi

Silencing of ANKRD12 circRNA induces molecular and functional changes associated with invasive phenotypes

Thasni Karedath, Ikhlak Ahmed, Wafa Al Ameri, Fatima M. Al-Dasim, Simeon S. Andrews, Samson Samuel, Iman K. Al-Azwani, Yasmin Ali Mohamoud, Arash Rafii, Joel A. Malek
2019 BMC Cancer  
Circular RNAs (circRNAs) that form through non-canonical backsplicing events of pre-mRNA transcripts are evolutionarily conserved and abundantly expressed across species. However, the functional relevance of circRNAs remains a topic of debate. We identified one of the highly expressed circRNA (circANKRD12) in cancer cell lines and characterized it validated it by Sanger sequencing, Real-Time PCR. siRNA mediated silencing of the circular junction of circANKRD12 was followed by RNA Seq analysis
more » ... circANKRD12 silenced cells and control cells to identify the differentially regulated genes. A series of cell biology and molecular biology techniques (MTS assay, Migration analysis, 3D organotypic models, Real-Time PCR, Cell cycle analysis, Western blot analysis, and Seahorse Oxygen Consumption Rate analysis) were performed to elucidate the function, and underlying mechanisms involved in circANKRD12 silenced breast and ovarian cancer cells. In this study, we identified and characterized a circular RNA derived from Exon 2 and Exon 8 of the ANKRD12 gene, termed here as circANKRD12. We show that this circRNA is abundantly expressed in breast and ovarian cancers. The circANKRD12 is RNase R resistant and predominantly localized in the cytoplasm in contrast to its source mRNA. We confirmed the expression of this circRNA across a variety of cancer cell lines and provided evidence for its functional relevance through downstream regulation of several tumor invasion genes. Silencing of circANKRD12 induces a strong phenotypic change by significantly regulating cell cycle, increasing invasion and migration and altering the metabolism in cancer cells. These results reveal the functional significance of circANKRD12 and provide evidence of a regulatory role for this circRNA in cancer progression. Our study demonstrates the functional relevance of circANKRD12 in various cancer cell types and, based on its expression pattern, has the potential to become a new clinical biomarker.
doi:10.1186/s12885-019-5723-0 pmid:31185953 pmcid:PMC6558796 fatcat:hojbe77qhzaqdmee4xhlpf3m6m

Genus-wide sequencing supports a two-locus model for sex-determination in Phoenix

Maria F. Torres, Lisa S. Mathew, Ikhlak Ahmed, Iman K. Al-Azwani, Robert Krueger, Diego Rivera-Nuñez, Yasmin A. Mohamoud, Andrew G. Clark, Karsten Suhre, Joel A. Malek
2018 Nature Communications  
The date palm tree is a commercially important member of the genus Phoenix whose 14 species are dioecious with separate male and female individuals. To identify sex determining genes we sequenced the genomes of 15 female and 13 male Phoenix trees representing all 14 species. We identified male-specific sequences and extended them using phased single-molecule sequencing or BAC clones. We observed that only four genes contained sequences conserved in all analyzed Phoenix males. Most of these
more » ... nces showed similarity to a single genomic locus in the closely related monoecious oil palm. CYP703 and GPAT3, two single copy genes present in males and critical for male flower development in other monocots, were absent in females. A LOG-like gene appears translocated into the Ylinked region and is suggested to play a role in suppressing female flowers. Our data are consistent with a two-mutation model for the evolution of dioecy in Phoenix.
doi:10.1038/s41467-018-06375-y fatcat:cnadlx7wfneq5ewy6h7nxskgbm

Histone H2B Monoubiquitination Facilitates the Rapid Modulation of Gene Expression during Arabidopsis Photomorphogenesis

Clara Bourbousse, Ikhlak Ahmed, François Roudier, Gérald Zabulon, Eddy Blondet, Sandrine Balzergue, Vincent Colot, Chris Bowler, Fredy Barneche, Caroline Dean
2012 PLoS Genetics  
Performed bioinformatics analyses: I Ahmed.  ...  Analyzed the data: C Bourbousse, I Ahmed, F Barneche. Contributed reagents/materials/ analysis tools: C Bourbousse, I Ahmed, F Roudier, E Blondet, S Balzergue, V Colot, C Bowler, F Barneche.  ... 
doi:10.1371/journal.pgen.1002825 pmid:22829781 pmcid:PMC3400566 fatcat:dtezrhc5fzewlja2agpyqbnjyu

Integrative Transcript and Metabolite Analysis of Nutritionally EnhancedDE-ETIOLATED1Downregulated Tomato Fruit

Eugenia M.A. Enfissi, Fredy Barneche, Ikhlak Ahmed, Christiane Lichtlé, Christopher Gerrish, Ryan P. McQuinn, James J. Giovannoni, Enrique Lopez-Juez, Chris Bowler, Peter M. Bramley, Paul D. Fraser
2010 The Plant Cell  
Fruit-specific downregulation of the DE-ETIOLATED1 (DET1) gene product results in tomato fruits (Solanum lycopersicum) containing enhanced nutritional antioxidants, with no detrimental effects on yield. In an attempt to further our understanding of how modulation of this gene leads to improved quality traits, detailed targeted and multilevel omic characterization has been performed. Metabolite profiling revealed quantitative increases in carotenoid, tocopherol, phenylpropanoids, flavonoids, and
more » ... anthocyanidins. Qualitative differences could also be identified within the phenolics, including unique formation in fruit pericarp tissues. These changes resulted in increased total antioxidant content both in the polar and nonpolar fractions. Increased transcription of key biosynthetic genes is a likely mechanism producing elevated phenolicbased metabolites. By contrast, high levels of isoprenoids do not appear to result from transcriptional regulation but are more likely related to plastid-based parameters, such as increased plastid volume per cell. Parallel metabolomic and transcriptomic analyses reveal the widespread effects of DET1 downregulation on diverse sectors of metabolism and sites of synthesis. Correlation analysis of transcripts and metabolites independently indicated strong coresponses within and between related pathways/processes. Interestingly, despite the fact that secondary metabolites were the most severely affected in ripe tomato fruit, our integrative analyses suggest that the coordinated activation of core metabolic processes in cell types amenable to plastid biogenesis is the main effect of DET1 loss of function.
doi:10.1105/tpc.110.073866 pmid:20435899 pmcid:PMC2879742 fatcat:ahtd7r2cl5avrerjq65yote3bu
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