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8th ACM International Conference on Bioinformatics, Computational Biology,and Health Informatics (ACM-BCB)

作者： Yao, Yao Liu, Zheng Singh, Satpreet Wei, Qi Ramsey, Stephen A. Oregon State Univ Dept Biomed Sci Corvallis OR 97330 USA Oregon State Univ Dept Biomed Sci Corvallis OR 97330 USA

ISBN: (纸本)9781450347228

We describe a novel computational approach, CERENKOV (Computational Elucidation of the REgulatory NonKOding Variome), for discriminating regulatory single nucleotide polymorphisms (rSNPs) from non-regulatory SNPs within noncoding genetic loci. CERENKOV is specifically designed for recognizing rSNPs in the context of a post-analysis of a genome-wide association study (GWAS);it includes a novel accuracy scoring metric (which we call average rank, or AVGRANK) and a novel cross-validation strategy (locus-based sampling) that both correctly account for the "sparse positive bag" nature of the GWAS post-analysis rSNP recognition problem. We trained and validated CERENKOV using a reference set of 15,331 SNPs (the OSU17 SNP set) whose composition is based on selection criteria (linkage disequilibrium and minor allele frequency) that we designed to ensure relevance to GWAS post-analysis. CERENKOV is based on a machine-learning algorithm (gradient boosted decision trees) incorporating 246 SNP annotation features that we extracted from genomic, epigenomic, phylogenetic, and chromatin datasets. CERENKOV includes novel features based on replication timing and DNA shape. We found that tuning a classifier for AUPVR performance does not guarantee optimality for AVGRANK. We compared the validation performance of CERENKOV to nine other methods for rSNP recognition (including GWAVA, RSVP, DeltaSVM, DeepSEA, Eigen, and DANQ), and found that CERENKOV's validation performance is the strongest out of all of the classifiers that we tested, by both traditional global rank-based measures (< AUPVR > = 0.506;< AUROC > = 0.855) and AVGRANK (< AVGRANK > = 3.877). The source code for CERENKOV is available on GitHub and the SNP feature data files are available for download via the CERENKOV website.

关键词： SNP GWAS noncoding rSNP SNV machine learning

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CERENKOV3: Clustering and molecular network-derived features improve computational prediction of functional noncoding SNPs 25

CERENKOV3: Clustering and molecular network-derived features...

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Pacific Symposium on Biocomputing

作者： Yao, Yao Ramsey, Stephen A. Oregon State Univ Sch Elect Engn & Comp Sci Corvallis OR 97330 USA Oregon State Univ Dept Biomed Sci Corvallis OR 97330 USA

ISBN: (纸本)9789811215636;9789811215629

Identification of causal noncoding single nucleotide polymorphisms (SNPs) is important for maximizing the knowledge dividend from human genome-wide association studies (GWAS). Recently, diverse machine learning-based methods have been used for functional SNP identification;however, this task remains a fundamental challenge in computational biology. We report CERENKOV3, a machine learning pipeline that leverages clustering-derived and molecular network-derived features to improve prediction accuracy of regulatory SNPs (rSNPs) in the context of post-GWAS analysis. The clustering-derived feature, locus size (number of SNPs in the locus), derives from our locus partitioning procedure and represents the sizes of clusters based on SNP locations. We generated two molecular network-derived features from representation learning on a network representing SNP-gene and gene-gene relations. Based on empirical studies using a ground-truth SNP dataset, CERENKOV3 significantly improves rSNP recognition performance in AUPRC, AUROC, and AVGRANK (a locus-wise rank-based measure of classification accuracy we previously proposed).

关键词： SNP GWAS noncoding rSNP clustering molecular network machine learning

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Convergent downstream candidate mechanisms of independent intergenic polymorphisms between co-classified diseases implicate epistasis among noncoding elements 23rd

Convergent downstream candidate mechanisms of independent in...

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23rd Pacific Symposium on Biocomputing (PSB)

作者： Han, Jiali Li, Jianrong Achour, Ikbel Pesce, Lorenzo Foster, Ian Li, Haiquan Lussier, Yves A. Univ Arizona Ctr Biomed Informat & Biostat CB2 Tucson AZ 85721 USA Univ Arizona Dept Med Tucson AZ 85721 USA Univ Arizona Dept Syst & Ind Engn Tucson AZ 85721 USA Argonne Natl Lab Computat Inst Chicago IL 60637 USA Univ Chicago Chicago IL 60637 USA Univ Arizona UACC BIO5 Inst CB2 Tucson AZ 85721 USA AstraZeneca MedImmune Gaithersburg MD USA

ISBN: (纸本)9789813235533;9789813235526

Eighty percent of DNA outside protein coding regions was shown biochemically functional by the ENCODE project, enabling studies of their interactions. Studies have since explored how convergent downstream mechanisms arise from independent genetic risks of one complex disease. However, the cross-talk and epistasis between intergenic risks associated with distinct complex diseases have not been comprehensively characterized. Our recent integrative genomic analysis unveiled downstream biological effectors of disease-specific polymorphisms buried in intergenic regions, and we then validated their genetic synergy and antagonism in distinct GWAS. We extend this approach to characterize convergent downstream candidate mechanisms of distinct intergenic SNPs across distinct diseases within the same clinical classification. We construct a multipartite network consisting of 467 diseases organized in 15 classes, 2,358 disease-associated SNPs, 6,301 SNPassociated mRNAs by eQTL, and mRNA annotations to 4,538 Gene Ontology mechanisms. Functional similarity between two SNPs (similar SNP pairs) is imputed using a nested information theoretic distance model for which p-values are assigned by conservative scale-free permutation of network edges without replacement (node degrees constant). At FDR <= 5%, we prioritized 3,870 intergenic SNP pairs associated, among which 755 are associated with distinct diseases sharing the same disease class, implicating 167 intergenic SNPs, 14 classes, 230 mRNAs, and 134 GO terms. Co-classified SNP pairs were more likely to be prioritized as compared to those of distinct classes confirming a noncoding genetic underpinning to clinical classification (odds ratio similar to 3.8;p <= 10(-25) ). The prioritized pairs were also enriched in regions bound to the same/interacting transcription factors and/or interacting in long-range chromatin interactions suggestive of epistasis (odds ratio similar to 2,500;p <= 10(-25 )). This prioritized network implicates co

关键词： SNP Intergenic noncoding Disease class Biological similarity Enrichment

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Pathogenic noncoding variants in the neurofibromatosis and schwannomatosis predisposition genes

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HUMAN MUTATION 2021年第10期42卷 1187-1207页

作者： Perez-Becerril, Cristina Evans, D. Gareth Smith, Miriam J. Univ Manchester Manchester Acad Hlth Sci Ctr Manchester Ctr Genom Med Div Evolut & Genom SciSt Marys HospSch Biol Sci Manchester M13 9WL Lancs England

Neurofibromatosis type 1 (NF1), type 2 (NF2), and schwannomatosis are a group of autosomal dominant disorders that predispose to the development of nerve sheath tumors. Pathogenic variants (PVs) that cause NF1 and NF2 are located in the NF1 and NF2 loci, respectively. To date, most variants associated with schwannomatosis have been identified in the SMARCB1 and LZTR1 genes, and a missense variant in the DGCR8 gene was recently reported to predispose to schwannomas. In spite of the high detection rate for PVs in NF1 and NF2 (over 90% of non-mosaic germline variants can be identified by routine genetic screening) underlying PVs for a proportion of clinical cases remain undetected. A higher proportion of non-NF2 schwannomatosis cases have no detected PV, with PVs currently only identified in around 70%-86% of familial cases and 30%-40% of non-NF2 sporadic schwannomatosis cases. A number of variants of uncertain significance have been observed for each disorder, many of them located in noncoding, regulatory, or intergenic regions. Here we summarize noncoding variants in this group of genes and discuss their established or potential role in the pathogenesis of NF1, NF2, and schwannomatosis.

关键词： intronic neurofibromatosis noncoding pathogenic variants regulatory schwannomatosis

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A mouse tissue atlas of small noncoding RNA

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2020年第41期117卷 25634-25645页

作者： Isakova, Alina Fehlmann, Tobias Keller, Andreas Quake, Stephen R. Stanford Univ Dept Bioengn Stanford CA 94305 USA Saarland Univ Chair Clin Bioinformat D-66123 Saarbrucken Germany Stanford Univ Sch Med Dept Neurol Stanford CA 94305 USA Stanford Univ Dept Appl Phys Stanford CA 94305 USA Chan Zuckerberg Biohub San Francisco CA 94158 USA

Small noncoding RNAs (ncRNAs) play a vital role in a broad range of biological processes both in health and disease. A comprehensive quantitative reference of small ncRNA expression would significantly advance our understanding of ncRNA roles in shaping tissue functions. Here, we systematically profiled the levels of five ncRNA classes (microRNA [miRNA], small nucleolar RNA [snoRNA], small nuclear RNA [snRNA], small Cajal body-specific RNA [scaRNA], and transfer RNA [tRNA] fragments) across 11 mouse tissues by deep sequencing. Using 14 biological replicates spanning both sexes, we identified that similar to 30% of small ncRNAs are distributed across the body in a tissue-specific manner with some also being sexually dimorphic. We found that some miRNAs are subject to "arm switching" between healthy tissues and that tRNA fragments are retained within tissues in both a gene- and a tissue-specific manner. Out of 11 profiled tissues, we confirmed that brain contains the largest number of unique small ncRNA transcripts, some of which were previously annotated while others are identified in this study. Furthermore, by combining these findings with single-cell chromatin accessibility (scATAC-seq) data, we were able to connect identified brain-specific ncRNAs with their cell types of origin. These results yield the most comprehensive characterization of specific and ubiquitous small RNAs in individual murine tissues to date, and we expect that these data will be a resource for the further identification of ncRNAs involved in tissue function in health and dysfunction in disease.

关键词： miRNA noncoding sex dimorphism tissue specificity

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The many faces of long noncoding RNAs

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FEBS JOURNAL 2015年第9期282卷 1647-1657页

作者： Gardini, Alessandro Shiekhattar, Ramin Univ Miami Miller Sch Med Sylvester Comprehens Canc Ctr Miami FL 33136 USA

Over the past few years, the field of noncoding RNAs has grown from a niche for geneticists into a prominent domain of mainstream biology. Advances in genomic technologies have provided a more comprehensive view of the mammalian genome, improving our knowledge of regions of the genome devoid of protein-coding potential. A large body of evidence supports the proposal that noncoding RNAs account for a large proportion of the transcriptional output of any given cell and tissue type. This review will delve into the biogenesis and function of long noncoding RNAs. We will discuss our current understanding of these molecules as major chromatin players, and explore future directions in the field.

关键词： enhancer eRNAs lncRNAs noncoding transcription

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Differentially expressed long noncoding RNAs and regulatory mechanism of LINC02407 in human gastric adenocarcinoma

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World Journal of Gastroenterology 2019年第39期25卷 5973-5990页

作者： Li-Li Zhou Yan Jiao Hong-Mei Chen Li-Hua Kang Qi Yang Jing Li Meng Guan Ge Zhu Fei-Qi Liu Shuang Wang Xue Bai Yan-Qiu Song Cancer Center The First Hospital of Jilin UniversityChangchun 130021Jilin ProvinceChina Department of Hepatobiliary and Pancreatic Surgery The First Hospital of Jilin UniversityChangchun 130021Jilin ProvinceChina Department of Radiology The First Hospital of Jilin UniversityChangchun 130021Jilin ProvinceChina

BACKGROUND Long noncoding RNAs(lncRNAs)have been identified to play important roles in the development and progression of various tumors,including gastric cancer(GC).However,the molecular role of lncRNAs in GC progression remains *** To investigate the differential expression of lncRNAs in human GC and elucidate the function and regulatory mechanism of *** The Cancer Genome Atlas database was used to investigate the involvement of lncRNAs in *** real-time polymerase chain reaction was used to estimate the relative expression level of LINC02407 in GC tissues and *** experiments including CCK8 assay,apoptosis assay,wound healing assay,and transwell assay were used to investigate the effect of LINC02407 on GC *** microRNAs were predicted and verified via bioinformatics analysis and the luciferase reporter *** analysis and Western blot assay were used to analyze the expression of related *** Many differentially expressed lncRNAs were identified in GC,and some of them including LINC02407 can affect the ***02407 was upregulated in tumor tissues compared with adjacent ***-27 cells showed the highest LINC02407 expression and HaCaT cells exhibited the lowest *** experiment groups were constructed using LINC02407 overexpressing plasmids and related *** results of functional experiments showed that LINC02407 can promote the proliferation,migration,and invasion of GC cells but inhibit *** reporter assay showed that hsa-miR-6845-5p and hsa-miR-4455 was downstream regulated by *** blot analysis showed that adhesion G protein-coupled receptor D1(ADGRD1)was regulated by the LINC02407-miR-6845-5p/miR-4455-ADGRD1 *** LINC02407 plays a role in GC through the LINC02407-miR-6845-5p/miR-4455-ADGRD1 pathways,and thus,it may be an important oncogene and has potential value in GC diagnosis and treatment.

关键词： Gastric cancer Long noncoding RNAs LINC02407 Adhesion G proteincoupled receptor D1 MicroRNA-6845-5p MicroRNA-4455

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An in vivo screen of noncoding loci reveals that Daedalus is a gatekeeper of an Ikaros-dependent checkpoint during haematopoiesis

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2021年第3期118卷 1918062118-1918062118页

作者： Harman, Christian C. D. Bailis, Will Zhao, Jun Hill, Louisa Qu, Rihao Jackson, Ruaidhri P. Shyer, Justin A. Steach, Holly R. Kluger, Yuval Goff, Loyal A. Rinn, John L. Williams, Adam Henao-Mejia, Jorge Flavell, Richard A. Yale Sch Med Dept Genet New Haven CT 06520 USA Howard Hughes Med Inst New Haven CT 06520 USA Childrens Hosp Philadelphia Div Protect Immun Philadelphia PA 19104 USA Univ Penn Dept Pathol & Lab Med Philadelphia PA 19104 USA Yale Sch Med Dept Immunobiol New Haven CT 06520 USA Yale Sch Med Dept Pathol New Haven CT 06510 USA Yale Univ Program Computat Biol & Bioinformat New Haven CT 06520 USA Vienna Bioctr Res Inst Mol Pathol A-1030 Vienna Austria Yale Univ Appl Math Program New Haven CT 06511 USA Broad Inst MIT & Harvard Cambridge MA 02142 USA Johns Hopkins Univ Sch Med Solomon H Snyder Dept Neurosci Baltimore MD 21205 USA Harvard Univ Dept Stem Cell & Regenerat Biol Cambridge MA 02138 USA Beth Israel Deaconess Med Ctr Dept Pathol Boston MA 02115 USA Univ Colorado BioFrontiers Inst Dept Biochem Boulder CO 80301 USA Jackson Lab Genom Med Farmington CT 06032 USA Univ Connecticut Dept Genet & Genom Sci Hlth Ctr Farmington CT 06030 USA

Haematopoiesis relies on tightly controlled gene expression patterns as development proceeds through a series of progenitors. While the regulation of hematopoietic development has been well studied, the role of noncoding elements in this critical process is a developing field. In particular, the discovery of new regulators of lymphopoiesis could have important implications for our understanding of the adaptive immune system and disease. Here we elucidate how a noncoding element is capable of regulating a broadly expressed transcription factor, Ikaros, in a lymphoid lineage-specific manner, such that it imbues Ikaros with the ability to specify the lymphoid lineage over alternate fates. Deletion of the Daedalus locus, which is proximal to Ikaros, led to a severe reduction in early lymphoid progenitors, exerting control over the earliest fate decisions during lymphoid lineage commitment. Daedalus locus deletion led to alterations in Ikaros isoform expression and a significant reduction in Ikaros protein. The Daedalus locus may function through direct DNA interaction as Hi-C analysis demonstrated an interaction between the two loci. Finally, we identify an Ikaros-regulated erythroid-lymphoid checkpoint that is governed by Daedalus in a lymphoid-lineage-specific manner. Daedalus appears to act as a gatekeeper of Ikaros's broad lineage-specifying functions, selectively stabilizing Ikaros activity in the lymphoid lineage and permitting diversion to the erythroid fate in its absence. These findings represent a key illustration of how a transcription factor with broad lineage expression must work in concert with noncoding elements to orchestrate hematopoietic lineage commitment.

关键词： lymphocytes Ikaros noncoding hematopoiesis

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Long noncoding RNA HOTTIP expression predicts tumor recurrence in hepatocellular carcinoma patients following liver transplantation

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Hepatobiliary Surgery and Nutrition 2018年第6期7卷 429-439页

作者： Liming Wu Zhe Yang Jie Zhang Haiyang Xie Lin Zhou Shusen Zheng Department of Hepatobiliary and Pancreatic Surgery The First Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhou 310003China Innovation Center for Diagnosis and Treatment of Infectious Diseases Hangzhou 310003China Jingning National Hospital of the First Affiliated Hospital School of MedicineZhejiang UniversityHangzhou 310003China Department of Hepatobiliary Surgery First Hospital of JiaxingJiaxing UniversityJiaxing 314000China

Background:The long noncoding RNA HOTTIP has recently been described as a biomarker of poor prognosis in patients with hepatocellular carcinoma(HCC).Methods:In the present study,we evaluated the clinical significance of HOTTIP expression in predicting the rate of tumor recurrence in HCC patients after liver transplantation(LT).We examined the expression pattern and single nucleotide polymorphism(SNP)genotype of HOTTIP in HCC samples from 155 patients underwent LT,and its correlation with clinical parameters and patient prognosis was *** was suppressed using siRNA to explore the role HOTTIP plays in tumor ***:The expression level of HOTTIP in cancer tissues was higher than in adjacent noncancerous *** analyses revealed that HOTTIP expression was an independent prognostic factor for tumor recurrence and lower overall survival times in HCC patients after *** who beyond the Milan criteria and exhibit decreased HOTTIP expression experienced longer recurrence-free survival and overall *** rs2071265 is associated with an earlier recurrence in HCC ***,the suppression of HOTTIP in liver cancer cell lines reduced cell invasion rates and increased ***:In summary,the high expression level of HOTTIP in HCC could serve as a candidate biomarker for predicting poor prognosis in HCC patients underwent liver transplant ***,HOTTIP might be a potential therapeutic target.

关键词： Hepatocellular carcinoma(HCC) liver transplantation HOTTIP long noncoding RNA HOTTIP

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DNA sequence variation in a 3.7-kb noncoding sequence 5′ of the CYP1A2 gene:: Implications for human population history and natural selection

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AMERICAN JOURNAL OF HUMAN GENETICS 2002年第3期71卷 528-542页

作者： Wooding, SP Watkins, WS Bamshad, MJ Dunn, DM Weiss, RB Jorde, LB Univ Utah Dept Human Genet Salt Lake City UT 84112 USA Univ Utah Dept Pediat Salt Lake City UT 84112 USA

CYP1A2 is a cytochrome P450 gene that is involved in human physiological responses to a variety of drugs and toxins. To investigate the role of population history and natural selection in shaping genetic diversity in CYP1A2, we sequenced a 3.7-kb region 5 from CYP1A2 in a diverse collection of 113 individuals from three major continental regions of the Old World (Africa, Asia, and Europe). We also examined sequences in the 90-member National Institutes of Health DNA Polymorphism Discovery Resource (PDR). Eighteen single-nucleotide polymorphisms (SNPs) were found. Most of the high-frequency SNPs found in the Old World sample were also found in the PDR sample. However, six SNPs were detected in the Old World sample but not in the PDR sample, and two SNPs found in the PDR sample were not found in the Old World sample. Most pairs of SNPs were in complete linkage disequilibrium with one another, and there was no indication of a decline of disequilibrium with physical distance in this region. The average +/- SD nucleotide diversity in the Old World sample was. The 0.00043 +/- 0.00026 African population had the highest level of nucleotide diversity and the lowest level of linkage disequilibrium. Two distinct haplotype clusters with broadly overlapping geographical distributions were present. Of the 17 haplotypes found in the Old World sample, 12 were found in the African sample, 8 were found in Indians, 5 were found in non-Indian Asians, and 5 were found in Europeans. Haplotypes found outside Africa were mostly a subset of those found within Africa. These patterns are all consistent with an African origin of modern humans. Seven SNPs were singletons, and the site-frequency spectrum showed a significant departure from neutral expectations, suggesting population expansion and/ or natural selection. Comparison with outgroup species showed that four derived SNPs have achieved high ( 0.90) frequencies in human populations, a trend consistent with the action of positive natural

关键词： .SNPs human population noncoding Haplotype DNA sequence cytochrome diverse sequenced single-nucleotide kb region high-frequency CYP History and Natural Old World sample PDR sample

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