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Identifying deleterious noncoding variation through gain and loss of CTCF binding activity

AMERICAN JOURNAL OF HUMAN GENETICS 2025年第4期112卷 892-902页

作者： Tubbs, Colby Benton, Mary Lauren McArthur, Evonne Capra, John A. Ruderfer, Douglas M. Vanderbilt Univ Vanderbilt Genet Inst Med Ctr Div Genet MedDept Med Nashville TN 37235 USA Baylor Univ Dept Comp Sci Waco TX USA Univ Washington Dept Med Seattle WA USA Univ Calif San Francisco Bakar Computat Hlth Sci Inst Dept Epidemiol & Biostat San Francisco CA USA Vanderbilt Univ Med Ctr Ctr Digital Genom Med Nashville TN 37235 USA

CCCTC binding factor (CTCF) regulates gene expression through DNA binding at thousands of genomic loci. Genetic variation in these CTCF binding sites (CBSs) is an important driver of phenotypic variation, yet extracting those that are likely to have functional consequences in whole-genome sequencing remains challenging. To address this, we develop a hypothesis-driven framework to identify and prioritize CBS variants in gnomAD. We synthesize CTCF's binding patterns at 1,063,878 genomic loci across 214 biological contexts into a summary of binding activity. We find that high binding activity significantly correlates with both conserved nucleotides (Pearson R = 0.35, p <2.2 3 10(-16)) and sequences that contain high-quality CTCF binding motifs (Pearson R = 0.63, p = 2.9 3 10(-12)). We then use binding activity to evaluate high-confidence allelic binding predictions for 1,253,329 single-nucleotide variations (SNVs) in gnomAD that disrupt a CBS. We find a strong, positive relationship between the mutability-adjusted proportion of singletons (MAPS) metric and the loss of CTCF binding at loci with high in vitro activity (Pearson R = 0.74, p < 2.2 3 10(-16)). To contextualize these findings, we apply MAPS to other functional classes of variation and find that a subset of 339,380 loss of CTCF binding variants is observed as infrequently as missense variants are. This work nominates these thousands of rare, noncoding variants that disrupt CTCF binding for further functional studies while providing a blueprint for prioritizing variation in other transcription factor binding sequences.

关键词： noncoding variation annotation regulatory CTCF CTCF binding sites selection prioritization functional disease

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Deletion of RAI1 noncoding exons 1-2 causes Smith-Magenis syndrome

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JOURNAL OF GENETICS 2025年第1期104卷 1-5页

作者： Hamiel, Uri Kurolap, Alina Gadot, Chofit Chai Mory, Adi Bar Shira, Anat Feldman, Hagit Baris Marom, Daphna Sourasky Med Ctr Genet Inst 6 Weizmann St IL-6423906 Tel Aviv Israel Sourasky Med Ctr Genom Ctr 6 Weizmann St IL-6423906 Tel Aviv Israel Tel Aviv Univ Fac Med & Hlth Sci IL-69978 Tel Aviv Israel

Smith-Magenis syndrome (SMS) is a complex genetic disorder characterized by developmental delay and a typical behavioral phenotype. Interstitial 17p11.2 deletions, which include the RAI1 gene are detected in >90% of patients, while single nucleotide variants (SNVs) are detected in the rest. The RAI1 gene is encoded from exons 3 onwards, while exons 1-2 are noncoding. It is unclear whether genetic variants preceding exon 3 cause SMS. We evaluated a 15-month-old infant for developmental delay and infantile spasms who was found to carry a deletion encompassing exons 1-2 of RAI. To determine whether the deletion of the noncoding exons 1-2 of the RAI1 gene is associated with SMS and to elucidate the underlying mechanism of this association. A singleton exome-based gene panel was performed, followed by chromosomal-microarray (CMA) to confirm the results. Real time quantitative PCR (RT-qPCR) analysis was conducted to evaluate RAI1 mRNA expression. CMA confirmed a de novo 737.8 kbp deletion on 17p11.2, which includes exons 1-2 of RAI1 but spares exons 3 onwards. RT-qPCR analysis on RNA extracted from the patient, father and three unrelated controls revealed that the patient has RAI1 haploinsufficiency. We show that deletion of the RAI1 noncoding exons 1-2, which spares the gene's coding region, causes RAI1 haploinsufficiency by eliminating regulatory elements, including the gene promoter, thus causing SMS and expanding the mutational spectrum of SMS.

关键词： Smith-Magennis syndrome RAI1 noncoding CMA microdeletion

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noncoding elements in wheat defence response to fusarium head blight

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Scientific reports 2025年第1期15卷 15167页

作者： Tugdem Muslu Kadriye Kahraman Bala Ani Akpinar Halise Busra Cagirici Egan Jaronski Cliff Bradley Hikmet Budak Montana BioAgriculture Inc. Missoula MT 59802 USA. Faculty of Engineering and Natural Sciences Sabanci University Istanbul Turkey. Sabanci University SUNUM Nanotechnology Research and Application Centre Istanbul Turkey. Division of Infectious Diseases and Geographic Medicine Department of Medicine Stanford University Stanford CA USA. Montana BioAgriculture Inc. Missoula MT 59802 USA. hikmet.budak1@azwestern.edu. Department of Agriculture Arizona Western Entrepreneurial College Yuma AZ 85366 USA. hikmet.budak1@azwestern.edu.

Wheat (Triticum aestivum L.) is a major source of global food security while various stressors, including biotic and abiotic factors, directly affect its production. Among these stressors, Fusarium infection poses a significant risk, leading to severe yield losses, and compromising the overall quality of the crop. To understand the regulatory mechanisms modulating wheat's response against Fusarium Head Blight (FHB) stress, a comprehensive analysis of the noncoding RNA profiles of two wheat varieties, Vida and Hank, was conducted. A dataset has been generated utilizing high throughput RNA sequencing (RNAseq) and small RNA sequencing (sRNAseq) technologies for identifying and characterizing microRNA (miRNA) and long noncoding RNA (lncRNA) profiles of these cultivars and the changes upon Fusarium infection. Our analysis revealed not only common but also cultivar- and condition-specific miRNAs and lncRNA transcripts, showing the unique regulatory responses exhibited by these wheat varieties under Fusarium stress. Furthermore, the functional properties of the identified miRNAs were investigated by identifying their putative coding sequence (CDS) targets. Additionally, the regulatory relationships between the putative miRNAs and lncRNAs were explored, providing a view of the complex molecular networks coordinating wheat's response against Fusarium infection. The proposed regulatory network includes the dynamic interplay between miRNAs, CDS targets, and lncRNAs, offering insights into potential key players in the adaptive responses of wheat to biotic stressors.

关键词： Fusarium Long noncoding RNA MicroRNA noncoding Wheat

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noncoding regions of C. elegans mRNA undergo selective adenosine to inosine deamination and contain a small number of editing sites per transcript

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RNA BIOLOGY 2015年第2期12卷 162-174页

作者： Wheeler, Emily C. Washburn, Michael C. Major, Francois Rusch, Douglas B. Hundley, Heather A. Indiana Univ Med Sci Program Bloomington IN 47405 USA Indiana Univ Dept Biol Bloomington IN USA Univ Montreal Inst Res Immunol & Canc Montreal PQ Canada Univ Montreal Dept Comp Sci & Operat Res Montreal PQ Canada Indiana Univ Ctr Genom & Bioinformat Bloomington IN USA

ADARs (Adenosine deaminases that act on RNA) "edit" RNA by converting adenosines to inosines within double-stranded regions. The primary targets of ADARs are long duplexes present within noncoding regions of mRNAs, such as introns and 3' untranslated regions (UTRs). Because adenosine and inosine have different base-pairing properties, editing within these regions can alter splicing and recognition by small RNAs. However, despite numerous studies identifying multiple editing sites in these genomic regions, little is known about the extent to which editing sites co-occur on individual transcripts or the functional output of these combinatorial editing events. To begin to address these questions, we performed an ultra-deep sequencing analysis of 4 Caenorhabditis elegans 3' UTRs that are known ADAR targets. Synchronous editing events were determined for the long duplexes in vivo. Furthermore, the validity of each editing event was confirmed by sequencing the same regions of mRNA from worms that lack A-to-I editing. This analysis identified a large number of editing sites that can occur within each 3' UTR, but interestingly, each individual transcript contained only a small fraction of these A-to-I editing events. In addition, editing patterns were not random, indicating that an editing event can affect the efficiency of editing at subsequent adenosines. Furthermore, we identified specific sites that can be both positively and negatively correlated with additional sites leading to mutually exclusive editing patterns. These results suggest that editing in noncoding regions is selective and hyper-editing of cellular RNAs is rare.

关键词： ADAR C. elegans inosine noncoding RNA-seq RNA editing UTR

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noncoding RNAs in gastric cancer: Research progress and prospects

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World Journal of Gastroenterology 2016年第29期22卷 6610-6618页

作者： Meng Zhang Xiang Du Department of Pathology Fudan University Shanghai Cancer Center Department of Pathology Shanghai Medical College Fudan University

noncoding RNAs(nc RNAs) have attracted much attention in cancer research field. They are involved in cellular development, proliferation, differentiation and apoptosis. The dysregulation of nc RNAs has been reported in tumor initiation, progression, invasion and metastasis in various cancers, including gastric cancer(GC). In the past few years, an accumulating body of evidence has deepened our understanding of nc RNAs, and several emerging nc RNAs have been identified, such as PIWI-interacting RNAs(pi RNAs) and circular RNAs(circ RNAs). The competing endogenous RNA(ce RNA) networks include m RNAs, micro RNAs, long nc RNAs(lnc RNAs) and circ RNAs, which play critical roles in the tumorigenesis of GC. This review summarizes the recent hotspots of nc RNAs involved in GC pathobiology and their potential applications in GC. Finally, we briefly discuss the advances in the ce RNA network in GC.

关键词： noncoding RNAs Gastric cancer Micro RNA long nc RNAs PIWI-interacting RNAs Competing endogenous RNA

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Expression of Antisense Long noncoding RNAs as Potential Regulators in Rainbow Trout with Different Tolerance to Plant-Based Diets

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ANIMAL BIOTECHNOLOGY 2019年第1期30卷 87-94页

作者： Abernathy, Jason Overturf, Ken ARS USDA Harry K Dupree Stuttgart Natl Aquaculture Res Ctr Stuttgart AR USA ARS USDA Hagerman Fish Culture Expt Stn 3059F Natl Fish Hatchery Rd Hagerman ID 83332 USA

Reformulation of aquafeeds in salmonid diets to include more plant proteins is critical for sustainable aquaculture. However, increasing plant proteins can lead to stunted growth and enteritis. Toward an understanding of the regulatory mechanisms behind plant protein utilization, directional RNA sequencing of liver tissues from a rainbow trout strain selected for growth on an all plant-protein diet and a control strain, both fed a plant diet for 12 weeks, were utilized to construct long noncoding RNAs. Antisense long noncoding RNAs were selected for differential expression and functional analyses since they have been shown to have regulatory actions within a genome. A total of 142 unique antisense long noncoding RNAs were differentially expressed between strains, 60 of which could be mapped to a gene. Genes underlying these noncoding RNAs are indicated in lipid metabolism and immunity. Six noncoding transcripts were also found to overlap with differentially expressed protein-coding genes, all of which were co-expressed. Associating variation in regulatory elements between rainbow trout strains with differing tolerance to plant-protein diets will assist in future studies toward increased gains throughout carnivorous aquaculture.

关键词： Alternative feeds antisense transcripts gene regulation lncRNA noncoding salmonid sustainable aquaculture

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Identification of seven long noncoding RNAs signature for prediction of biochemical recurrence in prostate cancer

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Asian Journal of Andrology 2019年第6期21卷 618-622页

作者： Ning Shao Wo Zhu Fang-Ning Wan Ding-Wei Ye Department of Urology Fudan University Shanghai Cancer CenterShanghai 200032China Department of Oncology Shanghai Medical CollegeFudan UniversityShanghai 200032China.

Accumulating evidenee suggested that long noncoding RNAs(IncRNAs)possess a potential role in prostate cancer(PCa)diagnosis and *** biochemical recurrence(BCR)is considered as a sign for clinical recurrence metastasis and PCa-specific ***,the aim of the present study was to identify a IncRNA signature that can predict BCR of PCa *** analysis,Kaplan-Meier analyses,Cox regression analyses,and Gene Set Enrichment Analysis(GSEA)were performed in a publicly available database with 499 PCa tissues and 52 matched normal tissues.A signature was *** these IncRNAs were differentially expressed between tumor and normal tissues and differentially expressed between high Gleason score and low Gleason score ***,we developed a seven IncRNAs signature that can predict PCa *** classified into low-risk group showed better BCR survival significantly than the patients in the high-risk group(hazard ratio=0.32,95%Cl:0.20-0.52,concordance index=0.63).The area under the curve was 0.68 for *** signature also had good discrimination for BCR in men with Gleason 7 *** conclusion,our results suggest that the seven IncRNAs signature is a new biomarker of BCR and high risk in *** addition,the in dividual In cRNA warrants further study to un cover the associated mechanisms of PCa progression and the signature could be used to design direct clinical trials for adjuvant therapy.

关键词： biochemical recurrence biomarker high risk Iong noncoding RNA prostate cancer

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CERENKOV2: improved detection of functional noncoding SNPs using data-space geometric features

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BMC BIOINFORMATICS 2019年第1期20卷 1-13页

作者： Yao, Yao Liu, Zheng Wei, Qi Ramsey, Stephen A. Oregon State Univ Sch Elect Engn & Comp Sci Corvallis OR 97330 USA Oregon State Univ Dept Biomed Sci 106 Dryden Hall Corvallis OR 97330 USA

BackgroundWe previously reported on CERENKOV, an approach for identifying regulatory single nucleotide polymorphisms (rSNPs) that is based on 246 annotation features. CERENKOV uses the xgboost classifier and is designed to be used to find causal noncoding SNPs in loci identified by genome-wide association studies (GWAS). We reported that CERENKOV has state-of-the-art performance (by two traditional measures and a novel GWAS-oriented measure, AVGRANK) in a comparison to nine other tools for identifying functional noncoding SNPs, using a comprehensive reference SNP set (OSU17, 15,331 SNPs). Given that SNPs are grouped within loci in the reference SNP set and given the importance of the data-space manifold geometry for machine-learning model selection, we hypothesized that within-locus inter-SNP distances would have class-based distributional biases that could be exploited to improve rSNP recognition accuracy. We thus defined an intralocus SNP radius as the average data-space distance from a SNP to the other intralocus neighbors, and explored radius likelihoods for five distance *** expanded the set of reference SNPs to 39,083 (the OSU18 set) and extracted CERENKOV SNP feature data. We computed radius empirical likelihoods and likelihood densities for rSNPs and control SNPs, and found significant likelihood differences between rSNPs and control SNPs. We fit parametric models of likelihood distributions for five different distance measures to obtain ten log-likelihood features that we combined with the 248-dimensional CERENKOV feature matrix. On the OSU18 SNP set, we measured the classification accuracy of CERENKOV with and without the new distance-based features, and found that the addition of distance-based features significantly improves rSNP recognition performance as measured by AUPVR, AUROC, and AVGRANK. Along with feature data for the OSU18 set, the software code for extracting the base feature matrix, estimating ten distance-based likelihood ratio

关键词： SNP GWAS noncoding rSNP Data space Machine learning

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Overexpressed long noncoding RNA CRNDE with distinct alternatively spliced isoforms in multiple cancers

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Frontiers of Medicine 2019年第3期13卷 330-343页

作者： Xuefei Ma Wei Zhang Rong Zhang Jingming Li Shufen Li Yunlin Ma Wen Jin Kankan Wang State Key Laboratory of Medical Genomics and Shanghai Institute of Hematology Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai 200025China School of Life Sciences and Biotechnology Shanghai Jiao Tong UniversityShanghai 200240China Department of Hematology Xi'an Gaoxin HospitalXi'an 710075China

Alternative splicing is a tightly regulated process that contributes to cancer *** is a long noncoding RNA with alternative splicing and is implicated in the pathogenesis of several ***,whether deregulated expression of CRNDE is common and which isoforms are mainly involved in cancers remain *** this study,we report that CRNDE is aberrantly expressed in the majority of solid and hematopoietic *** investigation of CRNDE expression in normal samples revealed that CRNDE was expressed in a tissue- and cell-specific *** comparison of CRNDE expression in 2938 patient samples from 15 solid and hematopoietic tumors showed that CRNDE was significantly overexpressed in 11 malignancies,including 3 reported and 8 unreported,and also implicated that the overexpressed isoforms differed in various cancer ***,anti-cancer drugs could efficiently repress CRNDE overexpression in cancer cell lines and primary samples,and even had different impacts on the expression of CRNDE ***,experimental profiles of 12 alternatively spliced isoforms demonstrated that the spliced variant CRNDE-g was the most highly expressed isoform in multiple cancer ***,our results emphasize the cancer-associated feature of CRNDE and its spliced isoforms,and may provide promising targets for cancer diagnosis and therapy.

关键词： long noncoding RNA CRNDE alternative splicing

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The Genome of Cucurbita argyrosperma (Silver- Seed Gourd) Reveals Faster Rates of Protein- Coding Gene and Long noncoding RNA Turnover and Neofunctionalization within Cucurbita

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Molecular Plant 2019年第4期12卷 506-520页

作者： Josue Barrera-Red on do Enrique Ibarra-Laclette Alejandra Vazquez-Lobo Yocelyn T. Gutierrez-Guerrero Guillermo Sanchez de la Vega Daniel Pinero Salvador Montes-Hernandez Rafael Lira-Saade Luis E. Eguiarte Departamento de Ecologia Evolutiva Instituto de Ecologia Universidad Nacional Aut6noma de Mexico Circuito Exterior s/n Anexo al Jardin Bot合nico 04510 Ciudad de Mexico Mexico Departamento de Estudios Moleculares Avanzados Instituto de Ecologia A.C. Carretera Antigua a Coatepec No. 351 Col. El Haya. C.P. Xalapa Veracruz 91070 Mexico Centro de Investigaciones en Biodiversidad y Conservacion Universidad Autdnoma del Estado de Morelos Av. Universidad 1001 Col. Chamilpa Cuernavaca Morelos 62209 Mexico Campo Experimental Bajio Instituto Nacional de In vestigaciones Forestales Agricolas y Pecuarias (INIFAP) Km 6.5 Carretera Celaya-San Miguel de Allen de Celaya Guanajuato 38110 Mexico UBIPRO Facultad de Estudios Superiores Iztacala Universidad Nacional Autdnoma de Mexico Av. de los Barrios #1 Col. Los Reyes Iztacala Tlanepantla Edo. de Mex 54090 Mexico

Whole-genome duplications are an important source of evolutionary novelties that change the mode and tempo at which genetic elements evolve within a genome. The Cucurbita genus experienced a wholegenome duplication around 30 million years ago, although the evolutionary dynamics of the coding and noncoding genes in this genus have not yet been scrutinized. Here, we analyzed the genomes of four Cucurbita species, in eluding a newly assembled genome of Cucurbita argyrosperma, and compared the gene con tents of these species with those of five other members of the Cucurbitaceae family to assess the evolutionary dynamics of protein-coding and long intergenic noncoding RNA (lincRNA) genes after the genome duplication. We report that Cucurbita genomes have a higher protein-coding gene birth-death rate compared with the genomes of the other members of the Cucurbitaceae family. C. argyrosperma gene families associated with pollination and transmembrane transport had significantly faster evolutionary rates. lincRNA families showed high levels of gene turnover throughout the phylogeny, and 67.7% of the lincRNA families in Cucurbita showed evidence of birth from the neofunctionalization of previously existing protein-coding genes. Collectively, our results suggest that the whole-genome duplication in Cucurbita resulted in faster rates of gene family evolution through the neofunctionalization of duplicated genes.

关键词： Cucurbita argyrosperma, comparative genomics molecular evolution neofunctionalization long noncoding RNA whole-genome duplication

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