Mammalian genomes are organized into megabase-scale topologically associated domains (TADs). We demonstrate that disruption of TADs can rewire long-range regulatory architecture and result in ...pathogenic phenotypes. We show that distinct human limb malformations are caused by deletions, inversions, or duplications altering the structure of the TAD-spanning WNT6/IHH/EPHA4/PAX3 locus. Using CRISPR/Cas genome editing, we generated mice with corresponding rearrangements. Both in mouse limb tissue and patient-derived fibroblasts, disease-relevant structural changes cause ectopic interactions between promoters and non-coding DNA, and a cluster of limb enhancers normally associated with Epha4 is misplaced relative to TAD boundaries and drives ectopic limb expression of another gene in the locus. This rewiring occurred only if the variant disrupted a CTCF-associated boundary domain. Our results demonstrate the functional importance of TADs for orchestrating gene expression via genome architecture and indicate criteria for predicting the pathogenicity of human structural variants, particularly in non-coding regions of the human genome.
Display omitted
•Disruptions of TADs lead to de novo enhancer-promoter interactions and misexpression•Misexpression occurs when CTCF-associated TAD boundary elements are disrupted•Structural variations disrupting TAD structures can cause malformation syndromes•Different phenotypes can result from one enhancer acting on different target genes
Disease-associated structural variants, when affecting CTCF-associated boundary elements, cause pathogenicity by disrupting the structure of topologically associated chromatin domains leading to ectopic promoter interactions and altered gene expression.
The identification of genes associated with hereditary disorders has contributed to improving medical care and to a better understanding of gene functions, interactions, and pathways. However, there ...are well over 1500 Mendelian disorders whose molecular basis remains unknown. At present, methods such as linkage analysis can identify the chromosomal region in which unknown disease genes are located, but the regions could contain up to hundreds of candidate genes. In this work, we present a method for prioritization of candidate genes by use of a global network distance measure, random walk analysis, for definition of similarities in protein-protein interaction networks. We tested our method on 110 disease-gene families with a total of 783 genes and achieved an area under the ROC curve of up to 98% on simulated linkage intervals of 100 genes surrounding the disease gene, significantly outperforming previous methods based on local distance measures. Our results not only provide an improved tool for positional-cloning projects but also add weight to the assumption that phenotypically similar diseases are associated with disturbances of subnetworks within the larger protein interactome that extend beyond the disease proteins themselves.
There are many thousands of hereditary diseases in humans, each of which has a specific combination of phenotypic features, but computational analysis of phenotypic data has been hampered by lack of ...adequate computational data structures. Therefore, we have developed a Human Phenotype Ontology (HPO) with over 8000 terms representing individual phenotypic anomalies and have annotated all clinical entries in Online Mendelian Inheritance in Man with the terms of the HPO. We show that the HPO is able to capture phenotypic similarities between diseases in a useful and highly significant fashion.
Loss-of-function mutations in the gene COH1, also known as VPS13B, lead to autosomal recessive Cohen syndrome. However, the cellular distribution and function of the encoded protein COH1 (3997 amino ...acids), which lacks functional homologies to other mammalian proteins, have remained enigmatic. We show here that COH1 is a peripheral Golgi membrane protein that strongly co-localizes with the cis-Golgi matrix protein GM130. Consistent with its subcellular localization, COH1 depletion using RNAi causes fragmentation of the Golgi ribbon into ministacks. Disruption of Golgi organization observed in fibroblasts from Cohen syndrome patients suggests that Golgi dysfunction contributes to Cohen syndrome pathology. In conclusion, our findings establish COH1 as a Golgi-associated matrix protein required for Golgi integrity.
Background: Cohen syndrome, characterized mainly by mental retardation, is caused by loss-of-function mutations in the gene COH1.
Results:COH1 encodes a Golgi matrix protein important for Golgi integrity.
Conclusion: Altered Golgi integrity and function probably underlie Cohen syndrome.
Significance: Our study highlights the importance of regular Golgi function during brain development and maintenance.
While characteristic facial features provide important clues for finding the correct diagnosis in genetic syndromes, valid assessment can be challenging. The next-generation phenotyping algorithm ...DeepGestalt analyzes patient images and provides syndrome suggestions. GestaltMatcher matches patient images with similar facial features. The new D-Score provides a score for the degree of facial dysmorphism.
We aimed to test state-of-the-art facial phenotyping tools by benchmarking GestaltMatcher and D-Score and comparing them to DeepGestalt.
Using a retrospective sample of 4796 images of patients with 486 different genetic syndromes (London Medical Database, GestaltMatcher Database, and literature images) and 323 inconspicuous control images, we determined the clinical use of D-Score, GestaltMatcher, and DeepGestalt, evaluating sensitivity; specificity; accuracy; the number of supported diagnoses; and potential biases such as age, sex, and ethnicity.
DeepGestalt suggested 340 distinct syndromes and GestaltMatcher suggested 1128 syndromes. The top-30 sensitivity was higher for DeepGestalt (88%, SD 18%) than for GestaltMatcher (76%, SD 26%). DeepGestalt generally assigned lower scores but provided higher scores for patient images than for inconspicuous control images, thus allowing the 2 cohorts to be separated with an area under the receiver operating characteristic curve (AUROC) of 0.73. GestaltMatcher could not separate the 2 classes (AUROC 0.55). Trained for this purpose, D-Score achieved the highest discriminatory power (AUROC 0.86). D-Score's levels increased with the age of the depicted individuals. Male individuals yielded higher D-scores than female individuals. Ethnicity did not appear to influence D-scores.
If used with caution, algorithms such as D-score could help clinicians with constrained resources or limited experience in syndromology to decide whether a patient needs further genetic evaluation. Algorithms such as DeepGestalt could support diagnosing rather common genetic syndromes with facial abnormalities, whereas algorithms such as GestaltMatcher could suggest rare diagnoses that are unknown to the clinician in patients with a characteristic, dysmorphic face.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Less than half of patients with suspected genetic disease receive a molecular diagnosis. We have therefore integrated next-generation sequencing (NGS), bioinformatics, and clinical data into an ...effective diagnostic workflow. We used variants in the 2741 established Mendelian disease genes the disease-associated genome (DAG) to develop a targeted enrichment DAG panel (7.1 Mb), which achieves a coverage of 20-fold or better for 98% of bases. Furthermore, we established a computational method Phenotypic Interpretation of eXomes (PhenIX) that evaluated and ranked variants based on pathogenicity and semantic similarity of patients' phenotype described by Human Phenotype Ontology (HPO) terms to those of 3991 Mendelian diseases. In computer simulations, ranking genes based on the variant score put the true gene in first place less than 5% of the time; PhenIX placed the correct gene in first place more than 86% of the time. In a retrospective test of PhenIX on 52 patients with previously identified mutations and known diagnoses, the correct gene achieved a mean rank of 2.1. In a prospective study on 40 individuals without a diagnosis, PhenIX analysis enabled a diagnosis in 11 cases (28%, at a mean rank of 2.4). Thus, the NGS of the DAG followed by phenotype-driven bioinformatic analysis allows quick and effective differential diagnostics in medical genetics.
Introduction to “Displacement” Horn, Denise M.; Parekh, Serena
Signs: Journal of Women in Culture and Society,
03/2018, Letnik:
43, Številka:
3
Journal Article
Recenzirano
This piece introduces the rationale for the special issue and highlights some of its key features. The authors have identified four broad themes in this issue, including displacement and gendered ...labor, displacement in art and literature, displacement embodied, and methods and theories to explore displacement. While recognizing that displacement has always been part of the human experience, these articles explore the gendered aspect of displacement as an emerging body of literature.
Over the past decade, democratization and civil society promotion became key variables in preserving global security and the liberal economic market. This book examines the prevalence of ...democratization policies as a hegemonic geopolitical tool; these policies represent a concerted political effort in which civil society organizations are manipulated through funding strategies. Denise Horn offers a fresh, innovative feminist-constructivist perspective by arguing that Western gender norms—i.e. those norms that determine degrees of participation within civil society—inform the policies of hegemonic powers and transform the foundations of civil society in transitional states. This powerful volume will be of interest to students and scholars in Gender and Women’s Studies, Political Science, and International Relations.
Denise M. Horn is an Assistant Professor of International Affairs at Northeastern University in Boston, MA. Her research examines the effects of US foreign funding in the development of civil society in transitional states, particularly in the areas of women's issues and women's NGOs.
Part 1: Constructing Gender and Democratization Within a Framework of Geopolitics 1. Gentle Invasions: Creating Pro-American and Pro-European Spaces for Global Democracy 2. Gentle Invasions and the Development of Civil Society in Transitional States 3. Post-Soviet US and EU Foreign Policy: Exploiting the Tools of Democratization Part 2: Case Studies: Gentle Invasions and the Newly Independent States 4. Setting the Agenda: US and Nordic Gender Policies in the Estonian Transition to Democracy 5. Constructing Agency: Civil Society and Gender Identity in Moldova 6. Gentle Invasions: Universally Applicable or Culturally Specific?
Structural variants are a common cause of disease and contribute to a large extent to inter-individual variability, but their detection and interpretation remain a challenge. Here, we investigate 11 ...individuals with complex genomic rearrangements including germline chromothripsis by combining short- and long-read genome sequencing (GS) with Hi-C. Large-scale genomic rearrangements are identified in Hi-C interaction maps, allowing for an independent assessment of breakpoint calls derived from the GS methods, resulting in >300 genomic junctions. Based on a comprehensive breakpoint detection and Hi-C, we achieve a reconstruction of whole rearranged chromosomes. Integrating information on the three-dimensional organization of chromatin, we observe that breakpoints occur more frequently than expected in lamina-associated domains (LADs) and that a majority reshuffle topologically associating domains (TADs). By applying phased RNA-seq, we observe an enrichment of genes showing allelic imbalanced expression (AIG) within 100 kb around the breakpoints. Interestingly, the AIGs hit by a breakpoint (19/22) display both up- and downregulation, thereby suggesting different mechanisms at play, such as gene disruption and rearrangements of regulatory information. However, the majority of interpretable genes located 200 kb around a breakpoint do not show significant expression changes. Thus, there is an overall robustness in the genome towards large-scale chromosome rearrangements.
PDF
