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Regulatory variants: from detection to predicting impact

BRIEFINGS IN BIOINFORMATICS 2019年第5期20卷 1639-1654页

作者： Rojano, Elena Seoane, Pedro Ranea, Juan A. G. Perkins, James R. Univ Malaga Dept Mol Biol & Biochem Malaga Spain Univ Malaga Supercomp & Bioinnovat Ctr SCBI Malaga Spain Reg Univ Hosp Malaga IBIMA Res Lab Malaga Spain

Variants within non-coding genomic regions can greatly affect disease. In recent years, increasing focus has been given to these variants, and how they can alter regulatory elements, such as enhancers, transcription factor binding sites and dna methylation regions. Such variants can be considered regulatory variants. Concurrently, much effort has been put into establishing international consortia to undertake large projects aimed at discovering regulatory elements in different tissues, cell lines and organisms, and probing the effects of genetic variants on regulation by measuring gene expression. Here, we describe methods and techniques for discovering disease-associated non-coding variants using sequencing technologies. We then explain the computational procedures that can be used for annotating these variants using the information from the aforementioned projects, and prediction of their putative effects, including potential pathogenicity, based on rule-based and machine learning approaches. We provide the details of techniques to validate these predictions, by mapping chromatin-chromatin and chromatin-protein interactions, and introduce Clustered Regularly Interspaced Short Palindromic Repeats-Associated Protein 9 (CRISPR-Cas9) technology, which has already been used in this field and is likely to have a big impact on its future evolution. We also give examples of regulatory variants associated with multiple complex diseases. This review is aimed at bioinformaticians interested in the characterization of regulatory variants, molecular biologists and geneticists interested in understanding more about the nature and potential role of such variants from a functional point of views, and clinicians who may wish to learn about variants in non-coding genomic regions associated with a given disease and find out what to do next to uncover how they impact on the underlying mechanisms.

关键词： variant analysis regulatory variants non-coding dna complex diseases GWAS

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Rare Variant Burden Analysis within Enhancers Identifies CAV1 as an ALS Risk Gene

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CELL REPORTS 2020年第9期33卷 108456-108456页

作者： Cooper-Knock, Johnathan Zhang, Sai Kenna, Kevin P. Moll, Tobias Franklin, John P. Allen, Samantha Nezhad, Helia Ghahremani Iacoangeli, Alfredo Yacovzada, Nancy Y. Eitan, Chen Hornstein, Eran Ehilak, Eran Celadova, Petra Bose, Daniel Farhan, Sali Fishilevich, Simon Lancet, Doron Morrison, Karen E. Shaw, Christopher E. Al-Chalabi, Ammar Veldink, Jan H. Kirby, Janine Snyder, Michael P. Shaw, Pamela J. Univ Sheffield Sheffield Inst Translat Neurosci SITraN Sheffield S Yorkshire England Stanford Univ Stanford Ctr Genom & Personalized Med Dept Genet Sch Med Stanford CA 94305 USA Univ Med Ctr Utrecht Brain Ctr Rudolf Magnus Dept Neurol Utrecht Netherlands Kings Coll London Inst Psychiat Psychol & Neurosci Dept Basic & Clin Neurosci London England Weizmann Inst Sci Dept Mol Genet Rehovot Israel Lund Univ Dept Biol Lund Sweden Univ Sheffield Sheffield Inst Nucle Acids Sheffield S Yorkshire England Massachusetts Gen Hosp Dept Med Analyt & Translat Genet Unit Boston MA 02114 USA Harvard Med Sch Boston MA 02115 USA Univ Southampton Fac Med Southampton Hants England

Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease. CAV1 and CAV2 organize membrane lipid rafts (MLRs) important for cell signaling and neuronal survival, and overexpression of CAV1 ameliorates ALS phenotypes in vivo. Genome-wide association studies localize a large proportion of ALS risk variants within the non-coding genome, but further characterization has been limited by lack of appropriate tools. By designing and applying a pipeline to identify pathogenic genetic variation within enhancer elements responsible for regulating gene expression, we identify disease-associated variation within CAV1/CAV2 enhancers, which replicate in an independent cohort. Discovered enhancer mutations reduce CAV1/CAV2 expression and disrupt MLRs in patient-derived cells, and CRISPR-Cas9 perturbation proximate to a patient mutation is sufficient to reduce CAV1/CAV2 expression in neurons. Additional enrichment of ALS-associated mutations within CAV1 exons positions CAV1 as an ALS risk gene. We propose CAV1/CAV2 overexpression as a personalized medicine target for ALS.

关键词： amyotrophic lateral sclerosis whole-genome sequencing CAV1 CAV2 non-coding dna gene enhancers membrane lipid rafts

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The Partial Order Kernel And Its Application To Understanding The Regulatory Grammar Of Conserved non-coding Elements

The Partial Order Kernel And Its Application To Understandin...

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作者： Maryam Abdollahyan Queen Mary University of London

学位级别：博士

Conserved non-coding elements (CNEs) are regions of non-coding dna which have remained evolutionarily conserved across various species over millions of years and are found to cluster near genes involved in early embryonic development, suggesting that they play an important role as regulatory elements. Indeed, many CNEs have been shown to act as enhancers; however, not all regulatory elements are conserved and in some cases, deletion of CNEs did not result in any notable phenotypes. These opposing ndings indicate that the functions of CNEs are still poorly understood and further research on these elements is needed to uncover the reasons for their extreme conservation. The aim of this thesis is to investigate the use and development of algorithms for decoding the regulatory grammar of CNEs. Initially, an assessment of several methods for functional classi cation of CNEs is provided. The results obtained using these methods are validated by functional assays and their limitations in capturing the grammar of CNEs are discussed. Motivated by these limitations, a partial order graph representation of the sequence of transcription factor binding sites (TFBSs) in a CNE that allows e cient handling of the overlapping sites is introduced. A dynamic programming-based method for aligning two such graphs and identifying regulatory signatures composed of co-occurring TFBSs is proposed and evaluated. The results demonstrate the predictive ability of this method, which can be used to prioritise regions for experimental validation. Building on this method, the partial order kernel (POKer) for comparison of strings containing alternative substrings and represented by partial order graphs is introduced. The POKer is evaluated in di erent sequence comparison tasks, including visual localisation. An approach using the POKer for functional classi cation of CNEs is introduced and its e ectiveness in capturing the grammar of CNEs is demonstrated. Finally, the implications of the results p

关键词： Conserved non-coding elements non-coding dna transcription factor binding sites partial order kernel

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The Partial Order Kernel and its Application to Understanding the Regulatory Grammar of Conserved non-coding Elements

The Partial Order Kernel and its Application to Understandin...

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作者： Abdollahyan, M Queen Mary University of London Queen Mary University of London

学位级别：博士

关键词： Conserved non-coding elements non-coding dna transcription factor binding sites partial order kernel

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CRISPR-based methods for high-throughput annotation of regulatory dna

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CURRENT OPINION IN BIOTECHNOLOGY 2018年 52卷 32-41页

作者： Klann, Tyler S. Black, Joshua B. Gersbach, Charles A. Duke Univ Dept Biomed Engn Durham NC 27708 USA Duke Univ Ctr Genom & Computat Biol Durham NC 27708 USA Duke Univ Med Ctr Dept Orthopaed Surg Durham NC 27710 USA

Developments in CRISPR/Cas9-based technologies provide a new paradigm in functional screening of the genome. Conventional screening methods have focused on high throughput perturbations of the protein-coding genome with technologies such as RNAi. However, equivalent methods for perturbing the non-coding genome have not existed until recently. CRISPR-based screening of genomic dna has enabled the study of both genes and non-coding gene regulatory elements. Here we review recent progress in assigning function to the non-coding genome using CRISPR-based genomic and epigenomic screens, and discuss the prospects of these technologies to transforming our understanding of genome structure and regulation.

关键词： CRISPRS (Genetics) non-coding dna GENOMES EPIGENOMICS GENE expression

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Divergent genome evolution caused by regional variation in dna gain and loss between human and mouse

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PLOS COMPUTATIONAL BIOLOGY 2018年第4期14卷 e1006091-e1006091页

作者： Buckley, Reuben M. Kortschak, R. Daniel Adelson, David L. Univ Adelaide Dept Genet & Evolut Adelaide SA Australia

The forces driving the accumulation and removal of non-coding dna and ultimately the evolution of genome size in complex organisms are intimately linked to genome structure and organisation. Our analysis provides a novel method for capturing the regional variation of lineage-specific dna gain and loss events in their respective genomic contexts. To further understand this connection we used comparative genomics to identify genome-wide individual dna gain and loss events in the human and mouse genomes. Focusing on the distribution of dna gains and losses, relationships to important structural features and potential impact on biological processes, we found that in autosomes, dna gains and losses both followed separate lineage-specific accumulation patterns. However, in both species chromosome X was particularly enriched for dna gain, consistent with its high L1 retrotransposon content required for X inactivation. We found that dna loss was associated with gene-rich open chromatin regions and dna gain events with gene-poor closed chromatin regions. Additionally, we found that dna loss events tended to be smaller than dna gain events suggesting that they were able to accumulate in gene-rich open chromatin regions due to their reduced capacity to interrupt gene regulatory architecture. GO term enrichment showed that mouse loss hotspots were strongly enriched for terms related to developmental processes. However, these genes were also located in regions with a high density of conserved elements, suggesting that despite high levels of dna loss, gene regulatory architecture remained conserved. This is consistent with a model in which dna gain and loss results in turnover or "churning" in regulatory element dense regions of open chromatin, where interruption of regulatory elements is selected against.

关键词： GENOMES non-coding dna EVOLUTIONARY theories GENE silencing GENE regulatory networks

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Duplication of host genes by transposable elements

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CURRENT OPINION IN GENETICS & DEVELOPMENT 2018年 49卷 63-69页

作者： Cerbin, Stefan Jiang, Ning Michigan State Univ Dept Hort 1066 Bogue St E Lansing MI 48824 USA

The availability of large amounts of genomic and transcriptome sequences have allowed systematic surveys about the host gene sequences that have been duplicated by transposable elements. It is now clear that all super-families of transposons are capable of duplicating genes or gene fragments, and such incidents have been detected in a wide spectrum of organisms. Emerging evidence suggests that a considerable portion of them function as coding or non-coding sequences, driving innovations at molecular and phenotypic levels. Interestingly, the duplication events not only have to occur in the reproductive tissues to become heritable, but the duplicated copies are also preferentially expressed in those tissues. As a result, reproductive tissues may serve as the 'incubator' for genes generated by transposable elements.

关键词： TRANSPOSONS TRANSCRIPTOMES CHROMOSOME duplication non-coding dna dna sequencing

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Filtering nucleotide sites by phylogenetic signal to noise ratio increases confidence in the Neoaves phylogeny generated from ultraconserved elements

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MOLECULAR PHYLOGENETICS AND EVOLUTION 2018年 126卷 116-128页

作者： Gilbert, Princess S. Wu, Jing Simon, Margaret W. Sinsheimer, Janet S. Alfaro, Michael E. Univ Calif Los Angeles Dept Ecol & Evolutionary Biol 621 Charles E Young Dr South Los Angeles CA 90095 USA Univ Calif Los Angeles Henry Samueli Sch Engn & Appl Sci Dept Comp Sci Los Angeles CA 90095 USA Univ Calif Los Angeles David Geffen Sch Med Dept Biomath Los Angeles CA 90095 USA Univ Calif Los Angeles David Geffen Sch Med Dept Human Genet Los Angeles CA 90095 USA Univ Calif Los Angeles Fielding Sch Publ Hlth Dept Biostat Los Angeles CA 90095 USA

Despite genome scale analyses, high-level relationships among Neoaves birds remain contentious. The placements of the Neoaves superorders are notoriously difficult to resolve because they involve deep splits followed by short internodes. Using our approach, we investigate whether filtering UCE loci on their phylogenetic signal to noise ratio helps to resolve key nodes in the Neoaves tree of life. We find that our analysis of data sets filtered for high signal to noise ratio results in topologies that are inconsistent with unfiltered results but that are congruent with whole-genome analyses. These relationships include the Columbea + Passerea sister relationship and the Phaethontimorphae + Aequornithia sister relationship. We also find increased statistical support for more recent nodes (i.e. the Pelecanidae + Ardeidae sister relationship, the Eucavitaves clade, and the Otidiformes + Musophagiformes sister relationship). We also find instances where support is reduced for well-established clades, possibly due to the removal of sites with moderate signal-to-noise ratio. Our results suggest that filtering on the basis of signal to noise ratio is a useful tool for resolving problematic splits in phylogenomic data sets.

关键词： Ultraconserved elements Neoaves Phylogenetic signal non-coding dna

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Control of Immune Cell Homeostasis and Function by lncRNAs

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TRENDS IN IMMUNOLOGY 2018年第1期39卷 55-69页

作者： Mowel, Walter K. Kotzin, Jonathan J. McCright, Sam J. Neal, Vanessa D. Henao-Mejia, Jorge Univ Penn Dept Pathol & Lab Med Philadelphia PA 19104 USA Univ Penn Perelman Sch Med Inst Immunol Philadelphia PA 19104 USA Univ Penn Childrens Hosp Philadelphia Dept Pathol & Lab Med Div Transplant Immunol Philadelphia PA 19104 USA

The immune system is composed of diverse cell types that coordinate responses to infection and maintain tissue homeostasis. In each of these cells, extracellular cues determine highly specific epigenetic landscapes and transcriptional profiles to promote immunity while maintaining homeostasis. New evidence indicates that long non-coding RNAs (lncRNAs) play crucial roles in epigenetic and transcriptional regulation in mammals. Thus, lncRNAs have emerged as key regulatory molecules of immune cell gene expression programs in response to microbial and tissue-derived cues. We review here how lncRNAs control the function and homeostasis of cell populations during immune responses, emphasizing the diverse molecular mechanisms by which lncRNAs tune highly contextualized transcriptional programs. In addition, we discuss the new challenges faced in interrogating lncRNA mechanisms and function in the immune system.

关键词： HOMEOSTASIS CELLULAR immunity IMMUNE system non-coding dna GENETIC transcription

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The chromatin accessibility landscape of primary human cancers

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SCIENCE 2018年第6413期362卷 420-+页

作者： Corces, M. Ryan Granja, Jeffrey M. Shams, Shadi Louie, Bryan H. Seoane, Jose A. Zhou, Wanding Silva, Tiago C. Groeneveld, Clarice Wong, Christopher K. Cho, Seung Woo Satpathy, Ansuman T. Mumbach, Maxwell R. Hoadley, Katherine A. Robertson, A. Gordon Sheffield, Nathan C. Felau, Ina Castro, Mauro A. A. Berman, Benjamin P. Staudt, Louis M. Zenklusen, Jean C. Laird, Peter W. Curtis, Christina Greenleaf, William J. Chang, Howard Y. Stanford Univ Ctr Personal Dynam Regulomes Stanford CA 94305 USA Stanford Univ Sch Med Dept Genet Stanford CA 94305 USA Stanford Univ Sch Med Program Biophys Stanford CA 94305 USA Stanford Univ Sch Med Dept Med Stanford CA 94305 USA Stanford Univ Sch Med Stanford Canc Inst Stanford CA 94305 USA Van Andel Res Inst Ctr Epigenet Grand Rapids MI 49503 USA Cedars Sinai Med Ctr Ctr Bioinformat & Funct Genom Los Angeles CA 90048 USA Univ Sao Paulo Ribeirao Preto Med Sch Dept Genet BR-14040905 Ribeirao Preto SP Brazil Univ Fed Parana Polytech Ctr Bioinformat & Syst Biol Lab BR-80060000 Curitiba PR Brazil Univ Calif Santa Cruz Ctr Biomol Sci & Engn Dept Biomol Engn Santa Cruz CA 95064 USA Univ N Carolina Lineberger Comprehens Canc Ctr Dept Genet Chapel Hill NC 27599 USA BC Canc Agcy Canadas Michael Smith Genome Sci Ctr Vancouver BC V5Z 4S6 Canada Univ Virginia Ctr Publ Hlth Genom Charlottesville VA 22908 USA NCI NIH Bethesda MD 20892 USA Stanford Univ Dept Appl Sci Menlo Pk CA 94025 USA Chan Zuckerberg Biohub San Francisco CA 94158 USA Stanford Univ Program Epithelial Biol Stanford CA 94305 USA Stanford Univ Howard Hughes Med Inst Stanford CA 94305 USA

We present the genome-wide chromatin accessibility profiles of 410 tumor samples spanning 23 cancer types from The Cancer Genome Atlas (TCGA). We identify 562,709 transposase-accessible dna elements that substantially extend the compendium of known cis-regulatory elements. Integration of ATAC-seq (the assay for transposase-accessible chromatin using sequencing) with TCGA multi-omic data identifies a large number of putative distal enhancers that distinguish molecular subtypes of cancers, uncovers specific driving transcription factors via protein-dna footprints, and nominates long-range gene-regulatory interactions in cancer. These data reveal genetic risk loci of cancer predisposition as active dna regulatory elements in cancer, identify gene-regulatory interactions underlying cancer immune evasion, and pinpoint noncoding mutations that drive enhancer activation and may affect patient survival. These results suggest a systematic approach to understanding the noncoding genome in cancer to advance diagnosis and therapy.

关键词： CHROMATIN GENETIC regulation CANCER genetics TRANSPOSASE genetics TRANSCRIPTION factors non-coding dna dna sequencing

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