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Fishing for Function in the Human Gene Pool

TRENDS IN GENETICS 2016年第7期32卷 392-394页

作者： Barozzi, Iros Visel, Axel Dickel, Diane E. Lawrence Berkeley Natl Lab Berkeley CA 94720 USA US DOE Joint Genome Inst Walnut Creek CA 94598 USA Univ Calif Sch Nat Sci Merced CA USA

Identification and characterization of causal non-coding variants in human genomes is challenging and requires substantial experimental resources. A new study by Tehranchi et al. describes a cost-effective approach for accurate mapping of molecular quantitative trait loci (QTLs) from pooled samples, a powerful way to link disease associated changes to molecular functions.

关键词： non-coding dna cis-regulation QTL GWAS

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A GPS for Navigating dna

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SCIENCE 2012年第6099期337卷 1179-1180页

作者： Schadt, Eric Chang, Rui Mt Sinai Sch Med Inst Genom & Multiscale Biol New York NY 10029 USA

A complete characterization of genetic and epigenetic variations in germ-line and somatic dna can provide a blueprint for understanding causal relationships between genes and phenotypes, from hydrogen production in bacteria to glucose homeostasis in humans. Detecting small nucleotide differences, structural variations (such as duplications), and a range of chemical modifications to nucleic acids have pointed to variations that potentially underlie the risk of disease, disease severity, and response to treatments for specific diseases. However, these changes alone are not sufficient to explain how a given variant or constellation of variants increases the risk of disease. What is needed is an integration of many different kinds of genetic and molecular data to elucidate regulatory networks underlying disease (1). On page 1190 of this issue, Maurano et al. (2) contribute such data by characterizing how dna variants associated with common disease traits are concentrated in noncoding regulatory regions of the human genomes that are marked by hypersensitivity to the enzyme deoxyribonuclease I (dnase I). When appropriately integrated with other molecular, cellular, and physiological data, such information may improve the way we understand normal conditions and diagnose and treat disease.

关键词： dna RESEARCH MEDICAL genetics SINGLE nucleotide polymorphisms HUMAN genome DEOXYRIBONUCLEASES -- Genetics GENE regulatory networks non-coding dna MEDICAL databases

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Strategies for characterising cis-regulatory elements in Xenopus

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Briefings in Functional Genomics and Proteomics 2005年第1期4卷 58-68页

作者： Khokha, Mustafa K. Loots, Gabriela G. Department of Molecular and Cell Biology University of California Berkeley CA United States Department of Pediatrics University of California San Francisco CA United States Genome Biology Division Biosciences Department Lawrence Livermore National Laboratory Livermore CA 94550 7000 East Avenue United States

Understanding the cis-regulatory architecture of metazoan organisms is the greatest challenge facing genome biology today. In vertebrate organisms, distinct sequence elements mediate transcriptional regulation and are scattered throughout the genome, either proximal or distal to promoters. The identification of transcriptional enhancers has proven rather difficult by conventional experimental approaches. In the past decade, the rapid generation of genomic sequences for multiple vertebrate organisms, accompanied by sophisticated comparative tools, has facilitated the identification of non-coding evolutionarily conserved regions that may encode cis-regulatory elements. Validating computational predictions and characterising cis-regulatory elements in vivo, however, has been a major bottleneck, mainly because the most commonly used organism for these experiments has been the mouse, and generating transgenic mice or modifying the mouse genome continues to be a labour-intensive, low-throughput, expensive process. This has led to the use of Xenopus, which holds great promise for high-throughput interrogation of putative cis-regulatory elements. In particular, Xenopus tropicalis may become particularly powerful for elucidating regulatory networks, chiefly because it is amenable to genetic manipulations, and its genome is being sequenced. © Henry Stewart Publications.

关键词： Cis-regulatory elements Comparative genomics Evolutionary conserved elements non-coding dna Transcriptional regulation Xenopus transgenics

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Design of an Efficient Model for Detecting Diseases using Genomics with Graph Relationship Networks 4

Design of an Efficient Model for Detecting Diseases using Ge...

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4th International Conference on Artificial Intelligence and Signal Processing

作者： Alparthi, Kumuda Panigrahy, Saroj Kumar VIT AP Univ Sch Comp Sci & Engn Amaravati Andhra Pradesh 522241 India

ISBN: (纸本)9798350350661;9798350350654

This paper introduces novel approaches utilizing Convolutional Neural Networks (CNNs), Recurrent Neural Networks (RNNs), Deep Autoencoders, and Graph Neural Networks (GNNs) in genomics. As the existing methods, while valuable, have limitations that hinder their effectiveness and often struggle with precision, accuracy, and speed in genome classification, leading to suboptimal results. Moreover, their inability to efficiently analyze multiple omics data and non-coding dna limits our understanding of complex disease mechanisms. In contrast, our proposed models harness the power of CNNs for identifying disease-related genetic markers, achieving automatic feature detection, reducing bias, and enhancing accuracy. Additionally, the utilization of RNNs, specifically Long Short-Term Memory (LSTM) networks, enables the precise annotation of genomic variants by understanding long-term dependencies in genetic sequences. Deep Autoencoders facilitate comprehensive disease analysis and Graph Neural Networks (GNNs) delve into non-coding dna, revealing intricate regulatory mechanisms and functions previously hidden. Our models exhibit a remarkable 9.5% improvement in genome classification precision, 8.5% higher accuracy, 6.5% enhanced recall, 8.3% increased speed, and a 10.5% superior Area Under the Curve (AUC) when compared to existing methods. This paper represents a significant step forward in genomics research, paving the way for more precise diagnostics and treatments for genetic diseases.

关键词： Genomics Deep Learning Convolutional Neural Networks Recurrent Neural Networks Multi-Omics Data non-coding dna Disease Analysis

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Pan-vertebrate conserved non-coding sequences associated with developmental regulation

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Briefings in Functional Genomics and Proteomics 2009年第4期8卷 256-265页

作者： Elgar, Greg School of Biological and Chemical Sciences Queen Mary University of London London E1 4NS Mile End Rd United Kingdom

Whilst coding sequences are readily recognised in vertebrate genomes using computational approaches, the identification of non-coding regulatory sequences has traditionally been much more difficult, due to their small size and, as a general rule, low sequence homology between genomes. Nevertheless, a small proportion of non-coding sequence is very highly conserved across the entire vertebrate radiation. This review will look at the specific properties of these sequences, how they have been identified and assayed functionally, and current progress in the quest to identify and understand the underlying language and grammar encoded within them. I will also discuss the evolution of these elements, and examine their emerging and likely roles in disease. Together these analyses are starting to unravel how conserved non-coding regions function at the molecular level. © The Author 2009. Published by Oxford University Press.

关键词： Bioinformatics CNEs Comparative genomics non-coding dna Regulatory sequence Vertebrate evolution

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Reading Between the Genes: Computational Models to Discover Function from noncoding dna 23rd

Reading Between the Genes: Computational Models to Discover ...

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23rd Pacific Symposium on Biocomputing (PSB)

作者： Lussier, Yves A. Berghout, Joanne Vitali, Francesca Ramos, Kenneth S. Kann, Maricel Moore, Jason H. Univ Arizona UA Canc Ctr Ctr Biomed Informat & Biostat BIO5 InstCtr Appl Genet & Genom Med 1657 E Helen St Tucson AZ 85719 USA Univ Arizona Dept Med 1657 E Helen St Tucson AZ 85719 USA Univ Maryland Baltimore Cty Dept Biol Sci 1000 Hilltop Circle Baltimore MD 21250 USA Univ Penn Dept Biostat Epidemiol & Informat 3700 Hamilton Walk Philadelphia PA 19104 USA

ISBN: (纸本)9789813235533;9789813235526

noncoding dna - once called "junk" has revealed itself to be full of function. Technology development has allowed researchers to gather genome-scale data pointing towards complex regulatory regions, expression and function of noncoding RNA genes, and conserved elements. Variation in these regions has been tied to variation in biological function and human disease. This PSB session tackles the problem of handling, analyzing and interpreting the data relating to variation in and interactions between noncoding regions through computational biology. We feature an invited speaker to how variation in transcription factor coding sequences impacts on sequence preference, along with submitted papers that span graph based methods, integrative analyses, machine learning, and dimension reduction to explore questions of basic biology, cancer, diabetes, and clinical relevance.

关键词： non-coding dna intergenic LncRNA microRNA sncRNA miRNA piRNA LINEs LINE1 repetitive elements

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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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Birds as a Model for Comparative Genomic Studies

Birds as a Model for Comparative Genomic Studies

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作者： AXEL KUNSTNER Uppsala University

学位级别：博士

Comparative genomics provides a tool to investigate large biological datasets, i. e. genomic datasets. In my thesis I focused on inferring patterns of selection in coding and non-coding regions of avian genomes. Until recently, large comparative studies on selection were mainly restricted to model species with sequenced genomes. This limitation has been overcome with advances in sequencing technologies and it is now possible to gather large genomic data sets for non-model species. Next-generation sequencing data was used to study patterns of nucleotide substitutions and from this we inferred how selection has acted in the genomes of 10 non-model bird species. In general, we found evidence for a negative correlation between neutral substitution rate and chromosome size in birds. In a follow up study, we investigated two closely related bird species, to study expression levels in different tissues and pattern of selection. We found that between 2% and 18% of all genes were differentially expressed between the two species. We showed that non-coding regions adjacent to genes are under evolutionary constraint in birds, which suggests that noncoding dna plays an important functional role in the genome. Regions downstream to genes (3') showed particularly high level of constraint. The level of constraint in these regions was not correlated to the length of untranslated regions, which suggests that other causes play also a role in sequence conservation. We compared the rate of nonsynonymous substitutions to the rate of synonymous substitutions in order to infer levels of selection in protein-coding sequences. Synonymous substitutions are often assumed to evolve neutrally. We studied synonymous substitutions by estimating constraint on 4-fold degenerate sites of avian genes and found signiﬁcant evolutionary constraint on this category of sites (between 24% and 43%). These results call for a reappraisal of synonymous substitution rates being used as neutral standards in molec

关键词： Birds Selection Gene expression Sequence evolution Next-generation sequencing Comparative genomics Molecular evolution Genomics Substitution Rates non-coding dna

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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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Integrating regulatory and methylome data for the discovery of clear cell Renal Cell Carcinoma (ccRCC) variants

Integrating regulatory and methylome data for the discovery ...

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作者： Calvert-Joshua, Tracey University of the Western Cape

学位级别：master

Kidney cancers, of which clear cell renal cell carcinoma comprises an estimated 70%, have been placed amongst the top ten most common cancers in both males and females. With a mortality rate that exceeds 40%, kidney cancer is considered the most lethal cancer of the genitourinary system. Despite advances in its treatment, the mortality- and incidence rates across all stages of the disease have continued to climb. Since the release of the Human Genome Project in the early 2000’s, most genetics studies have focused on the protein coding region of the human genome, which accounts for a mere 2% of the entire genome. It has been suggested that diverting our focus to the other 98% of the genome, which was previously dismissed as non-functional “junk dna”, could possibly contribute significantly to our understanding of the underlying mechanisms of complex *** this study a whole genome sequencing somatic mutation data set from the International Cancer Genome Consortium was used. The non-coding somatic mutations within the promoter, intronic, 5-prime untranslated and 3-prime untranslated regions of clear cell renal cell carcinoma-implicated genes were extracted and submitted to RegulomDB for their functional *** expected, most of the variants were located within the intronic regions and only a small subset of identified variants was predicted to be deleterious. Although the variants all belonged to a selected subset of kidney cancer-associated genes, the genes frequently mutated in the non-coding regions were not the same genes that were frequently mutated in the whole exome studies (where the focus is on the coding sequences). This indicates that with whole genome sequencing studies a new set of genes/variants previously unassociated with the clear cell renal cell carcinoma could be identified. In addition, most of the non-coding somatic variants fell within multiple transcriptions factor binding sites. Since many of these variants were also deleterious (a

关键词： non-coding dna Gene dysregulation Aberrant methylation Renal cell carcinoma Clear cell renal cell carcinoma

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