scholarly journals Ranking of non-coding pathogenic variants and putative essential regions of the human genome

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Alex Wells ◽  
David Heckerman ◽  
Ali Torkamani ◽  
Li Yin ◽  
Jonathan Sebat ◽  
...  
Keyword(s):  
Genome Organization ◽  
Regulatory Elements ◽  
Structural Features ◽  
Loss Of Function ◽  
3D Genome ◽  
Coding Regions ◽  
Pathogenic Variants ◽  
Machine Learning Model ◽  
Using Data

AbstractA gene is considered essential if loss of function results in loss of viability, fitness or in disease. This concept is well established for coding genes; however, non-coding regions are thought less likely to be determinants of critical functions. Here we train a machine learning model using functional, mutational and structural features, including new genome essentiality metrics, 3D genome organization and enhancer reporter data to identify deleterious variants in non-coding regions. We assess the model for functional correlates by using data from tiling-deletion-based and CRISPR interference screens of activity of cis-regulatory elements in over 3 Mb of genome sequence. Finally, we explore two user cases that involve indels and the disruption of enhancers associated with a developmental disease. We rank variants in the non-coding genome according to their predicted deleteriousness. The model prioritizes non-coding regions associated with regulation of important genes and with cell viability, an in vitro surrogate of essentiality.

scholarly journals Identification of essential regulatory elements in the human genome

2018 ◽  
Author(s):  
Alex Wells ◽  
David Heckerman ◽  
Ali Torkamani ◽  
Li Yin ◽  
Bing Ren ◽  
...  
Keyword(s):  
Human Genome ◽  
Regulatory Elements ◽  
Structural Features ◽  
Machine Learning Techniques ◽  
3D Genome ◽  
Learning Techniques ◽  
Topologically Associated Domains ◽  
Using Data ◽  
Accuracy Of Prediction ◽  
And Control

The identification of essential regulatory elements is central to the understanding of the consequences of genetic variation. Here we use novel genomic data and machine learning techniques to map essential regulatory elements and to guide functional validation. We train an XGBoost model using 38 functional and structural features, including genome essentiality metrics, 3D genome organization and enhancer reporter STARR-seq data to differentiate between pathogenic and control non-coding genetic variants. We validate the accuracy of prediction by using data from tiling-deletion-based and CRISPR interference screens of activity of cis-regulatory elements. In neurodevelopmental disorders, the model (ncER, non-coding Essential Regulation) maps essential genomic segments within deletions and rearranged topologically associated domains linked to human disease. We show that the approach successfully identifies essential regulatory elements in the human genome.

scholarly journals Loss-of-function and missense variants in NSD2 cause decreased methylation activity and are associated with a distinct developmental phenotype

2021 ◽  
Author(s):  
Paolo Zanoni ◽  
Katharina Steindl ◽  
Deepanwita Sengupta ◽  
Pascal Joset ◽  
Angela Bahr ◽  
...  
Keyword(s):  
Loss Of Function ◽  
Mild Phenotype ◽  
Psychological Issues ◽  
Missense Variants ◽  
Mild Developmental Delay ◽  
Pathogenic Variants ◽  
In Silico Modeling ◽  
And Function ◽  
Methylation Activity

Abstract Purpose Despite a few recent reports of patients harboring truncating variants in NSD2, a gene considered critical for the Wolf–Hirschhorn syndrome (WHS) phenotype, the clinical spectrum associated with NSD2 pathogenic variants remains poorly understood. Methods We collected a comprehensive series of 18 unpublished patients carrying heterozygous missense, elongating, or truncating NSD2 variants; compared their clinical data to the typical WHS phenotype after pooling them with ten previously described patients; and assessed the underlying molecular mechanism by structural modeling and measuring methylation activity in vitro. Results The core NSD2-associated phenotype includes mostly mild developmental delay, prenatal-onset growth retardation, low body mass index, and characteristic facial features distinct from WHS. Patients carrying missense variants were significantly taller and had more frequent behavioral/psychological issues compared with those harboring truncating variants. Structural in silico modeling suggested interference with NSD2’s folding and function for all missense variants in known structures. In vitro testing showed reduced methylation activity and failure to reconstitute H3K36me2 in NSD2 knockout cells for most missense variants. Conclusion NSD2 loss-of-function variants lead to a distinct, rather mild phenotype partially overlapping with WHS. To avoid confusion for patients, NSD2 deficiency may be named Rauch–Steindl syndrome after the delineators of this phenotype.

scholarly journals The 3D Genome Browser: a web-based browser for visualizing 3D genome organization and long-range chromatin interactions

2017 ◽  
Author(s):  
Yanli Wang ◽  
Bo Zhang ◽  
Lijun Zhang ◽  
Lin An ◽  
Jie Xu ◽  
...  
Keyword(s):  
Genome Organization ◽  
Target Genes ◽  
Genome Structure ◽  
Regulatory Elements ◽  
Genomic Region ◽  
Genome Browser ◽  
Chromatin Interaction ◽  
Interaction Data ◽  
3D Genome ◽  
Chromatin Interactions

ABSTRACTRecent advent of 3C-based technologies such as Hi-C and ChIA-PET provides us an opportunity to explore chromatin interactions and 3D genome organization in an unprecedented scale and resolution. However, it remains a challenge to visualize chromatin interaction data due to its size and complexity. Here, we introduce the 3D Genome Browser (http://3dgenome.org), which allows users to conveniently explore both publicly available and their own chromatin interaction data. Users can also seamlessly integrate other “omics” data sets, such as ChIP-Seq and RNA-Seq for the same genomic region, to gain a complete view of both regulatory landscape and 3D genome structure for any given gene. Finally, our browser provides multiple methods to link distal cis-regulatory elements with their potential target genes, including virtual 4C, ChIA-PET, Capture Hi-C and cross-cell-type correlation of proximal and distal DNA hypersensitive sites, and therefore represents a valuable resource for the study of gene regulation in mammalian genomes.

scholarly journals Biallelic ERBB3 loss-of-function variants are associated with a novel multisystem syndrome without congenital contracture

2019 ◽  
Vol 14 (1) ◽  
Author(s):  
Niu Li ◽  
Yufei Xu ◽  
Yi Zhang ◽  
Guoqiang Li ◽  
Tingting Yu ◽  
...  
Keyword(s):  
Postnatal Growth ◽  
Compound Heterozygous ◽  
Loss Of Function ◽  
Atrioventricular Canal ◽  
Multiple Systems ◽  
Feeding Difficulties ◽  
Functional Studies ◽  
Pathogenic Variants ◽  
Compound Heterozygous Variants

Abstract Background Gain-of-function pathogenic variants of the Erb-B2 receptor tyrosine kinase 3 (ERBB3) gene contribute to the occurrence and development of a variety of human carcinomas through activation of phosphatidylinositol 3-kinase (PI3K)/AKT and extracellular signal-regulated kinase (ERK) signaling. ERBB3 gene homozygous germline variants, whose loss of function may cause autosomal recessive congenital contractural syndrome, were recently identified. This study aims to identify the disease-causing gene in a Chinese pedigree with variable phenotypes involving multiple systems, including developmental delay, postnatal growth retardation, transient lower limb asymmetry, facial malformations, atrioventricular canal malformation, bilateral nystagmus and amblyopia, feeding difficulties, immunodeficiency, anemia, and liver damage, but without congenital contracture. Methods Trio-whole exome sequencing (WES) was performed to identify the disease-causing gene in a 24-month-old Chinese female patient. The pathogenicity of the identified variants was evaluated using in silico tools and in vitro functional studies. Results Trio-WES revealed compound heterozygous variants of c.1253 T > C (p.I418T) and c.3182dupA (p.N1061Kfs*16) in the ERBB3 gene. Functional studies showed that p.I418T resulted in normal expression of ERBB3, which was capable of interacting with ERBB2. However, the variant impaired ERBB3 phosphorylation, consequently blocking ERBB2 phosphorylation and AKT and ERK activation. The truncated protein resulting from the c.3182dupA variant also lacked the capacity to activate downstream signaling pathways. Conclusions We report the first patient with a novel multisystem syndrome disorder without congenital contracture resulting from biallelic loss-of-function variants of ERBB3.

scholarly journals Pathogenic Variants in ABHD16A Cause a Novel Psychomotor Developmental Disorder With Spastic Paraplegia

2021 ◽  
Vol 12 ◽  
Author(s):  
Ashraf Yahia ◽  
Liena E. O. Elsayed ◽  
Remi Valter ◽  
Ahlam A. A. Hamed ◽  
Inaam N. Mohammed ◽  
...  
Keyword(s):  
Hereditary Spastic Paraplegia ◽  
Loss Of Function ◽  
Spastic Paraplegia ◽  
Cellular Processes ◽  
Pathogenic Variants ◽  
Neurological Phenotype ◽  
Limb Spasticity ◽  
Lower Limb Spasticity ◽  
Generation Sequencing

Introduction: Hereditary spastic paraplegia is a clinically and genetically heterogeneous neurological entity that includes more than 80 disorders which share lower limb spasticity as a common feature. Abnormalities in multiple cellular processes are implicated in their pathogenesis, including lipid metabolism; but still 40% of the patients are undiagnosed. Our goal was to identify the disease-causing variants in Sudanese families excluded for known genetic causes and describe a novel clinico-genetic entity.Methods: We studied four patients from two unrelated consanguineous Sudanese families who manifested a neurological phenotype characterized by spasticity, psychomotor developmental delay and/or regression, and intellectual impairment. We applied next-generation sequencing, bioinformatics analysis, and Sanger sequencing to identify the genetic culprit. We then explored the consequences of the identified variants in patients-derived fibroblasts using targeted-lipidomics strategies.Results and Discussion: Two homozygous variants in ABHD16A segregated with the disease in the two studied families. ABHD16A encodes the main brain phosphatidylserine hydrolase. In vitro, we confirmed that ABHD16A loss of function reduces the levels of certain long-chain lysophosphatidylserine species while increases the levels of multiple phosphatidylserine species in patient's fibroblasts.Conclusion:ABHD16A loss of function is implicated in the pathogenesis of a novel form of complex hereditary spastic paraplegia.

scholarly journals Targeted mutations on 3D hub loci alter spatial interaction environment

2015 ◽  
Author(s):  
Bo Ding ◽  
Lina Zheng ◽  
David Medovoy ◽  
Wei Wang
Keyword(s):  
Genome Organization ◽  
Spatial Organization ◽  
Spatial Interaction ◽  
Genome Structure ◽  
Chromosomal Structure ◽  
Scale Free ◽  
3D Genome ◽  
Coding Regions ◽  
Gene Coding ◽  
Related Genotype

Many disease-related genotype variations (GVs) reside in non-gene coding regions and the mechanisms of their association with diseases are largely unknown. A possible impact of GVs on disease formation is to alter the spatial organization of chromosome. However, the relationship between GVs and 3D genome structure has not been studied at the chromosome scale. The kilobase resolution of chromosomal structures measured by Hi-C have provided an unprecedented opportunity to tackle this problem. Here we proposed a network-based method to capture global properties of the chromosomal structure. We uncovered that genome organization is scale free and the genomic loci interacting with many other loci in space, termed as hubs, are critical for stabilizing local chromosomal structure. Importantly, we found that cancer-specific GVs target hubs to drastically alter the local chromosomal interactions. These analyses revealed the general principles of 3D genome organization and provided a new direction to pinpoint genotype variations in non-coding regions that are critical for disease formation.

scholarly journals Resolving the 3D landscape of transcription-linked mammalian chromatin folding

2019 ◽  
Author(s):  
Tsung-Han S. Hsieh ◽  
Elena Slobodyanyuk ◽  
Anders S. Hansen ◽  
Claudia Cattoglio ◽  
Oliver J. Rando ◽  
...  
Keyword(s):  
Stem Cells ◽  
Gene Regulation ◽  
Genome Organization ◽  
Regulatory Elements ◽  
Genome Architecture ◽  
Transcriptional Regulatory Elements ◽  
3D Genome ◽  
Topologically Associating Domains ◽  
Transcriptional Regulatory ◽  
Chromatin Folding

ABSTRACTChromatin folding below the scale of topologically associating domains (TADs) remains largely unexplored in mammals. Here, we used a high-resolution 3C-based method, Micro-C, to probe links between 3D-genome organization and transcriptional regulation in mouse stem cells. Combinatorial binding of transcription factors, cofactors, and chromatin modifiers spatially segregate TAD regions into “microTADs” with distinct regulatory features. Enhancer-promoter and promoter-promoter interactions extending from the edge of these domains predominantly link co-regulated loci, often independently of CTCF/Cohesin. Acute inhibition of transcription disrupts the gene-related folding features without altering higher-order chromatin structures. Intriguingly, we detect “two-start” zig-zag 30-nanometer chromatin fibers. Our work uncovers the finer-scale genome organization that establishes novel functional links between chromatin folding and gene regulation.ONE SENTENCE SUMMARYTranscriptional regulatory elements shape 3D genome architecture of microTADs.

scholarly journals Understanding 3D Genome Organization and Its Effect on Transcriptional Gene Regulation Under Environmental Stress in Plant: A Chromatin Perspective

2021 ◽  
Vol 9 ◽  
Author(s):  
Suresh Kumar ◽  
Simardeep Kaur ◽  
Karishma Seem ◽  
Santosh Kumar ◽  
Trilochan Mohapatra
Keyword(s):  
Gene Expression ◽  
Environmental Stress ◽  
Genome Organization ◽  
Regulation Of Gene Expression ◽  
Three Dimensional ◽  
Regulatory Elements ◽  
Chromosome Conformation ◽  
3D Genome ◽  
Chromatin Architecture ◽  
Capture Techniques

The genome of a eukaryotic organism is comprised of a supra-molecular complex of chromatin fibers and intricately folded three-dimensional (3D) structures. Chromosomal interactions and topological changes in response to the developmental and/or environmental stimuli affect gene expression. Chromatin architecture plays important roles in DNA replication, gene expression, and genome integrity. Higher-order chromatin organizations like chromosome territories (CTs), A/B compartments, topologically associating domains (TADs), and chromatin loops vary among cells, tissues, and species depending on the developmental stage and/or environmental conditions (4D genomics). Every chromosome occupies a separate territory in the interphase nucleus and forms the top layer of hierarchical structure (CTs) in most of the eukaryotes. While the A and B compartments are associated with active (euchromatic) and inactive (heterochromatic) chromatin, respectively, having well-defined genomic/epigenomic features, TADs are the structural units of chromatin. Chromatin architecture like TADs as well as the local interactions between promoter and regulatory elements correlates with the chromatin activity, which alters during environmental stresses due to relocalization of the architectural proteins. Moreover, chromatin looping brings the gene and regulatory elements in close proximity for interactions. The intricate relationship between nucleotide sequence and chromatin architecture requires a more comprehensive understanding to unravel the genome organization and genetic plasticity. During the last decade, advances in chromatin conformation capture techniques for unravelling 3D genome organizations have improved our understanding of genome biology. However, the recent advances, such as Hi-C and ChIA-PET, have substantially increased the resolution, throughput as well our interest in analysing genome organizations. The present review provides an overview of the historical and contemporary perspectives of chromosome conformation capture technologies, their applications in functional genomics, and the constraints in predicting 3D genome organization. We also discuss the future perspectives of understanding high-order chromatin organizations in deciphering transcriptional regulation of gene expression under environmental stress (4D genomics). These might help design the climate-smart crop to meet the ever-growing demands of food, feed, and fodder.

scholarly journals Understanding gene regulatory mechanisms based on gene classification

2021 ◽  
Author(s):  
Hao Tian ◽  
Yueying He ◽  
Yue Xue ◽  
Yi Qin Gao
Keyword(s):  
Gene Regulation ◽  
Density Distribution ◽  
Genome Organization ◽  
Housekeeping Genes ◽  
Structural Features ◽  
Regulatory Mechanisms ◽  
3D Genome ◽  
Human Genes ◽  
Cpg Dinucleotide ◽  
Gene Regulatory

The CpG dinucleotide and its methylation play vital roles in gene regulation as well as 3D genome organization. Previous studies have divided genes into several categories based on the CpG intensity around transcription starting sites (TSS) and found that housekeeping genes tend to possess high CpG density while tissue-specific genes are generally characterized by low CpG density. In this study, we investigated how the CpG density distribution of a gene affects its transcription and regulation pattern. Based on the CpG density distribution around TSS, the human genes are clearly divided into different categories. Not only sequence properties, these different clusters exhibited distinctly different structural features, regulatory mechanisms, and correlation patterns between expression level and CpG/TpG density. These results emphasized that the usage of epigenetic marks in gene regulation is partially rooted in the sequence property of genes, such as their CpG density distribution.

scholarly journals Silkworm 5S RNA and Alanine tRNA Genes Share Highly Conserved 5′ Flanking and Coding Sequences

1982 ◽  
Vol 2 (12) ◽  
pp. 1524-1531 ◽  
Author(s):  
Diane G. Morton ◽  
Karen U. Sprague
Keyword(s):  
Transcription Initiation ◽  
Genomic Dna ◽  
Structural Features ◽  
In Vitro Transcription ◽  
Trna Genes ◽  
5S Rna ◽  
Coding Sequences ◽  
Coding Regions ◽  
The One

A fragment ofBombyx morigenomic DNA containing one tRNA2Alagene and one 5S RNA gene has been used to compare the structural features of silkworm 5S RNA and tRNA genes. The nucleotide sequences of both genes and of the primary transcripts produced from them in homologous in vitro transcription systems have been determined. Comparison of the sequences of these two genes with that of another previously analyzedB. moritRNA2Alagene reveals common oligonucleotides which may be important transcriptional signals. The oligonucleotides TA(C)TAT, AATTTT, and TTC are located approximately (±1 nucleotide) 29, 19, and 3 nucleotides, respectively, before the transcription initiation sites of the two tRNA2Alagenes and the one 5S RNA gene we have analyzed. The sequence GGGCGTAG(C)TCAG lies within the coding regions of all three genes. The functional significance of these sequences is suggested by their location within regions required for the transcription of silkworm alanine tRNA genes in vitro.

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