Browse
Submit Data
Databases
API
Help

Dataset Information

17 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Missense-depleted regions in population exomes implicate ras superfamily nucleotide-binding protein alteration in patients with brain malformation.

ABSTRACT: Genomic sequence interpretation can miss clinically relevant missense variants for several reasons. Rare missense variants are numerous in the exome and difficult to prioritise. Affected genes may also not have existing disease association. To improve variant prioritisation, we leverage population exome data to identify intragenic missense-depleted regions (MDRs) genome-wide that may be important in disease. We then use missense depletion analyses to help prioritise undiagnosed disease exome variants. We demonstrate application of this strategy to identify a novel gene association for human brain malformation. We identified de novo missense variants that affect the GDP/GTP-binding site of ARF1 in three unrelated patients. Corresponding functional analysis suggests ARF1 GDP/GTP-activation is affected by the specific missense mutations associated with heterotopia. These findings expand the genetic pathway underpinning neurologic disease that classically includes FLNA. ARF1 along with ARFGEF2 add further evidence implicating ARF/GEFs in the brain. Using functional ontology, top MDR-containing genes were highly enriched for nucleotide-binding function, suggesting these may be candidates for human disease. Routine consideration of MDR in the interpretation of exome data for rare diseases may help identify strong genetic factors for many severe conditions, infertility/reduction in reproductive capability, and embryonic conditions contributing to preterm loss.

SUBMITTER: Ge X

PROVIDER: S-EPMC5576364 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Optogenetic modulation of guanine nucleotide exchange factors of Ras superfamily proteins directly controls cell shape and movement.

Project description:In this article, we provide detailed protocols on using optogenetic dimerizers to acutely perturb activities of guanine nucleotide exchange factors (GEFs) specific to Ras, Rac or Rho small GTPases of the migratory networks in various mammalian and amoeba cell lines. These GEFs are crucial components of signal transduction networks which link upstream G-protein coupled receptors to downstream cytoskeletal components and help cells migrate through their dynamic microenvironment. Conventional approaches to perturb and examine these signaling and cytoskeletal networks, such as gene knockout or overexpression, are protracted which allows networks to readjust through gene expression changes. Moreover, these tools lack spatial resolution to probe the effects of local network activations. To overcome these challenges, blue light-inducible cryptochrome- and LOV domain-based dimerization systems have been recently developed to control signaling or cytoskeletal events in a spatiotemporally precise manner. We illustrate that, within minutes of global membrane recruitment of full-length GEFs or their catalytic domains only, widespread increases or decreases in F-actin rich protrusions and cell size occur, depending on the particular node in the networks targeted. Additionally, we demonstrate localized GEF recruitment as a robust assay system to study local network activation-driven changes in polarity and directed migration. Altogether, these optical tools confirmed GEFs of Ras superfamily GTPases as regulators of cell shape, actin dynamics, and polarity. Furthermore, this optogenetic toolbox may be exploited in perturbing complex signaling interactions in varied physiological contexts including mammalian embryogenesis.

| S-EPMC10363612 | biostudies-literature

Human RAS superfamily proteins and related GTPases.

Project description:The tumor oncoproteins HRAS, KRAS, and NRAS are the founding members of a larger family of at least 35 related human proteins. Using a somewhat broader definition of sequence similarity reveals a more extended superfamily of more than 170 RAS-related proteins. The RAS superfamily of GTP (guanosine triphosphate) hydrolysis-coupled signal transduction relay proteins can be subclassified into RAS, RHO, RAB, and ARF families, as well as the closely related Galpha family. The members of each family can, in turn, be arranged into evolutionarily conserved branches. These groupings reflect structural, biochemical, and functional conservation. Recent findings have provided insights into the signaling characteristics of representative members of most RAS superfamily branches. The analysis presented here may serve as a guide for predicting the function of numerous uncharacterized superfamily members. Also described are guanosine triphosphatases (GTPases) distinct from members of the RAS superfamily. These related proteins employ GTP binding and GTPase domains in diverse structural contexts, expanding the scope of their function in humans.

| S-EPMC2828947 | biostudies-literature

Systematic analysis of paralogous regions in 41,755 exomes uncovers clinically relevant variation.

Project description:The short lengths of short-read sequencing reads challenge the analysis of paralogous genomic regions in exome and genome sequencing data. Most genetic variants within these homologous regions therefore remain unidentified in standard analyses. Here, we present a method (Chameleolyser) that accurately identifies single nucleotide variants and small insertions/deletions (SNVs/Indels), copy number variants and ectopic gene conversion events in duplicated genomic regions using whole-exome sequencing data. Application to a cohort of 41,755 exome samples yields 20,432 rare homozygous deletions and 2,529,791 rare SNVs/Indels, of which we show that 338,084 are due to gene conversion events. None of the SNVs/Indels are detectable using regular analysis techniques. Validation by high-fidelity long-read sequencing in 20 samples confirms >88% of called variants. Focusing on variation in known disease genes leads to a direct molecular diagnosis in 25 previously undiagnosed patients. Our method can readily be applied to existing exome data.

| S-EPMC10611741 | biostudies-literature

Landscape of multi-nucleotide variants in 125,748 human exomes and 15,708 genomes.

Project description:Multi-nucleotide variants (MNVs), defined as two or more nearby variants existing on the same haplotype in an individual, are a clinically and biologically important class of genetic variation. However, existing tools typically do not accurately classify MNVs, and understanding of their mutational origins remains limited. Here, we systematically survey MNVs in 125,748 whole exomes and 15,708 whole genomes from the Genome Aggregation Database (gnomAD). We identify 1,792,248 MNVs across the genome with constituent variants falling within 2 bp distance of one another, including 18,756 variants with a novel combined effect on protein sequence. Finally, we estimate the relative impact of known mutational mechanisms - CpG deamination, replication error by polymerase zeta, and polymerase slippage at repeat junctions - on the generation of MNVs. Our results demonstrate the value of haplotype-aware variant annotation, and refine our understanding of genome-wide mutational mechanisms of MNVs.

| S-EPMC7253413 | biostudies-literature

Characterization of Prochlorococcus clades from iron-depleted oceanic regions.

Project description:Prochlorococcus describes a diverse and abundant genus of marine photosynthetic microbes. It is primarily found in oligotrophic waters across the globe and plays a crucial role in energy and nutrient cycling in the ocean ecosystem. The abundance, global distribution, and availability of isolates make Prochlorococcus a model system for understanding marine microbial diversity and biogeochemical cycling. Analysis of 73 metagenomic samples from the Global Ocean Sampling expedition acquired in the Atlantic, Pacific, and Indian Oceans revealed the presence of two uncharacterized Prochlorococcus clades. A phylogenetic analysis using six different genetic markers places the clades close to known lineages adapted to high-light environments. The two uncharacterized clades consistently cooccur and dominate the surface waters of high-temperature, macronutrient-replete, and low-iron regions of the Eastern Equatorial Pacific upwelling and the tropical Indian Ocean. They are genetically distinct from each other and other high-light Prochlorococcus isolates and likely define a previously unrecognized ecotype. Our detailed genomic analysis indicates that these clades comprise organisms that are adapted to iron-depleted environments by reducing their iron quota through the loss of several iron-containing proteins that likely function as electron sinks in the photosynthetic pathway in other Prochlorococcus clades from high-light environments. The presence and inferred physiology of these clades may explain why Prochlorococcus populations from iron-depleted regions do not respond to iron fertilization experiments and further expand our understanding of how phytoplankton adapt to variations in nutrient availability in the ocean.

| S-EPMC2941326 | biostudies-literature

Krit1 missense mutations lead to splicing errors in cerebral cavernous malformation.

Project description:At least 40% of families affected with cerebral cavernous malformation have a mutation in Krit1. We previously identified two point mutations in Krit1 leading to changes in amino acids (D137G and Q210E) in two different families. Further RNA analysis reveals that both point mutations actually activate cryptic splice-donor sites, causing aberrant splicing and leading to a frameshift and protein truncation. To date, no simple missense mutations have been detected in Krit1.

| S-EPMC379143 | biostudies-literature

Negative regulation of p53 by Ras superfamily protein RBEL1A.

Project description:We had previously reported that RBEL1A, a novel Ras-like GTPase, was overexpressed in multiple human malignancies and that its depletion suppressed cell growth. However, the underlying molecular mechanism remained to be elucidated. Here we report that depletion of endogenous RBEL1A results in p53 accumulation due to increased p53 half-life whereas increased expression of RBEL1A reduces p53 levels under unstressed and genotoxic stress conditions. RBEL1A directly interacts with p53 and MDM2, and strongly enhances MDM2-dependent p53 ubiquitylation and degradation. We also found that RBEL1A modulation of p53 ubiquitylation by MDM2 does not depend on its GTPase activity. We have also defined the p53 oligomeric domain and RBEL1A GTPase domain to be the crucial regions for p53-RBEL1A interactions. Importantly, we have found that RBEL1A strongly interferes with p53 transactivation function; thus our results indicate that RBEL1A appears to function as a novel p53 negative regulator that facilitates MDM2-dependent p53 ubiquitylation and degradation.

| S-EPMC3679486 | biostudies-literature

RAS signaling in colorectal carcinomas through alteration of RAS, RAF, NF1, and/or RASSF1A.

Project description:More than half of all colorectal carcinomas are known to exhibit an activated mitogen-activated protein kinase pathway. The NF1 gene, a negative regulator of KRAS, has not previously been examined in a series of colorectal cancer. In the present study, primary colorectal carcinomas stratified according to microsatellite instability status were analyzed. The whole coding region of NF1 was analyzed for mutations using denaturing high-performance liquid chromatography and sequencing, and the copy number alterations of NF1 were examined using multiple ligation-dependent probe amplification and real-time polymerase chain reaction. The mutational hot spots in KRAS and BRAF were sequenced, and promoter hypermethylation status of RASSF1A was assessed with a methylation-specific polymerase chain reaction. One sample had two missense mutations in NF1, whereas nine additional tumors had intronic mutations likely to affect exon splicing. Interestingly, 8 of these 10 tumors were microsatellite-unstable. Four other tumors showed a duplication of NF1. Mutations in KRAS and BRAF were mutually exclusive and were present at 40% and 22%, respectively. RASSF1A was hypermethylated in 31% of the samples. We show that the RAS signaling network is extensively dysregulated in colorectal carcinomas, because more than 70% of the tumors had an alteration in one or more of the four examined components.

| S-EPMC2434205 | biostudies-literature

Thermodynamic modeling of genome-wide nucleosome depleted regions in yeast.

Project description:Nucleosome positioning in the genome is essential for the regulation of many nuclear processes. We currently have limited capability to predict nucleosome positioning in vivo, especially the locations and sizes of nucleosome depleted regions (NDRs). Here, we present a thermodynamic model that incorporates the intrinsic affinity of histones, competitive binding of sequence-specific factors, and nucleosome remodeling to predict nucleosome positioning in budding yeast. The model shows that the intrinsic affinity of histones, at near-saturating histone concentration, is not sufficient in generating NDRs in the genome. However, the binding of a few factors, especially RSC towards GC-rich and poly(A/T) sequences, allows us to predict ~ 66% of genome-wide NDRs. The model also shows that nucleosome remodeling activity is required to predict the correct NDR sizes. The validity of the model was further supported by the agreement between the predicted and the measured nucleosome positioning upon factor deletion or on exogenous sequences introduced into yeast. Overall, our model quantitatively evaluated the impact of different genetic components on NDR formation and illustrated the vital roles of sequence-specific factors and nucleosome remodeling in this process.

| S-EPMC7822557 | biostudies-literature

Interhemispheric co-alteration of brain homotopic regions.

Project description:Asymmetries in gray matter alterations raise important issues regarding the pathological co-alteration between hemispheres. Since homotopic areas are the most functionally connected sites between hemispheres and gray matter co-alterations depend on connectivity patterns, it is likely that this relationship might be mirrored in homologous interhemispheric co-altered areas. To explore this issue, we analyzed data of patients with Alzheimer's disease, schizophrenia, bipolar disorder and depressive disorder from the BrainMap voxel-based morphometry database. We calculated a map showing the pathological homotopic anatomical co-alteration between homologous brain areas. This map was compared with the meta-analytic homotopic connectivity map obtained from the BrainMap functional database, so as to have a meta-analytic connectivity modeling map between homologous areas. We applied an empirical Bayesian technique so as to determine a directional pathological co-alteration on the basis of the possible tendencies in the conditional probability of being co-altered of homologous brain areas. Our analysis provides evidence that: the hemispheric homologous areas appear to be anatomically co-altered; this pathological co-alteration is similar to the pattern of connectivity exhibited by the couples of homologues; the probability to find alterations in the areas of the left hemisphere seems to be greater when their right homologues are also altered than vice versa, an intriguing asymmetry that deserves to be further investigated and explained.

| S-EPMC8354999 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data