scholarly journals Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction

2020 ◽  
Author(s):  
J. den Hoed ◽  
E. de Boer ◽  
N. Voisin ◽  
A.J.M. Dingemans ◽  
N. Guex ◽  
...  
Keyword(s):  
Neurodevelopmental Disorders ◽  
Transcriptional Repression ◽  
Large Scale ◽  
Phenotypic Variability ◽  
Single Gene ◽  
Independent Evidence ◽  
Mild Phenotype ◽  
Nonsense Mediated Decay ◽  
Pathophysiological Mechanisms ◽  
Binding Domains

AbstractWhereas large-scale statistical analyses can robustly identify disease-gene relationships, they do not accurately capture genotype-phenotype correlations or disease mechanisms. We use multiple lines of independent evidence to show that different variant types in a single gene, SATB1, cause clinically overlapping but distinct neurodevelopmental disorders. Clinical evaluation of 42 individuals carrying SATB1 variants identified overt genotype-phenotype relationships, associated with different pathophysiological mechanisms, established by functional assays. Missense variants in the CUT1 and CUT2 DNA-binding domains result in stronger chromatin binding, increased transcriptional repression and a severe phenotype. Contrastingly, variants predicted to result in haploinsufficiency are associated with a milder clinical presentation. A similarly mild phenotype is observed for individuals with premature protein truncating variants that escape nonsense-mediated decay and encode truncated proteins, which are transcriptionally active but mislocalized in the cell. Our results suggest that in-depth mutation-specific genotype-phenotype studies are essential to capture full disease complexity and to explain phenotypic variability.

scholarly journals Systematic Detection of Large-Scale Multi-Gene Horizontal Transfer in Prokaryotes

2021 ◽  
Author(s):  
Lina Kloub ◽  
Sean Gosselin ◽  
Matthew Fullmer ◽  
Joerg Graf ◽  
J Peter Gogarten ◽  
...  
Keyword(s):  
Gene Transfer ◽  
Large Scale ◽  
Single Gene ◽  
Gene Families ◽  
Microbial Evolution ◽  
Phylogenetic Distance ◽  
Secretion Systems ◽  
Type Iii Secretion Systems ◽  
A Genome ◽  
Conserved Gene

Abstract Horizontal gene transfer (HGT) is central to prokaryotic evolution. However, little is known about the “scale” of individual HGT events. In this work, we introduce the first computational framework to help answer the following fundamental question: How often does more than one gene get horizontally transferred in a single HGT event? Our method, called HoMer, uses phylogenetic reconciliation to infer single-gene HGT events across a given set of species/strains, employs several techniques to account for inference error and uncertainty, combines that information with gene order information from extant genomes, and uses statistical analysis to identify candidate horizontal multi-gene transfers (HMGTs) in both extant and ancestral species/strains. HoMer is highly scalable and can be easily used to infer HMGTs across hundreds of genomes. We apply HoMer to a genome-scale dataset of over 22000 gene families from 103 Aeromonas genomes and identify a large number of plausible HMGTs of various scales at both small and large phylogenetic distances. Analysis of these HMGTs reveals interesting relationships between gene function, phylogenetic distance, and frequency of multi-gene transfer. Among other insights, we find that (i) the observed relative frequency of HMGT increases as divergence between genomes increases, (ii) HMGTs often have conserved gene functions, and (iii) rare genes are frequently acquired through HMGT. We also analyze in detail HMGTs involving the zonula occludens toxin and type III secretion systems. By enabling the systematic inference of HMGTs on a large scale, HoMer will facilitate a more accurate and more complete understanding of HGT and microbial evolution.

scholarly journals Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Tianyun Wang ◽  
◽  
Kendra Hoekzema ◽  
Davide Vecchio ◽  
Huidan Wu ◽  
...  
Keyword(s):  
Neurodevelopmental Disorders ◽  
Large Scale ◽  
De Novo ◽  
Targeted Sequencing ◽  
Published Data ◽  
De Novo Mutations ◽  
Risk Genes ◽  
Mutation Burden ◽  
Number Of Patients ◽  
Significant Burden

Abstract Most genes associated with neurodevelopmental disorders (NDDs) were identified with an excess of de novo mutations (DNMs) but the significance in case–control mutation burden analysis is unestablished. Here, we sequence 63 genes in 16,294 NDD cases and an additional 62 genes in 6,211 NDD cases. By combining these with published data, we assess a total of 125 genes in over 16,000 NDD cases and compare the mutation burden to nonpsychiatric controls from ExAC. We identify 48 genes (25 newly reported) showing significant burden of ultra-rare (MAF < 0.01%) gene-disruptive mutations (FDR 5%), six of which reach family-wise error rate (FWER) significance (p < 1.25E−06). Among these 125 targeted genes, we also reevaluate DNM excess in 17,426 NDD trios with 6,499 new autism trios. We identify 90 genes enriched for DNMs (FDR 5%; e.g., GABRG2 and UIMC1); of which, 61 reach FWER significance (p < 3.64E−07; e.g., CASZ1). In addition to doubling the number of patients for many NDD risk genes, we present phenotype–genotype correlations for seven risk genes (CTCF, HNRNPU, KCNQ3, ZBTB18, TCF12, SPEN, and LEO1) based on this large-scale targeted sequencing effort.

scholarly journals Do supernovae indicate an accelerating universe?

2021 ◽  
Author(s):  
Roya Mohayaee ◽  
Mohamed Rameez ◽  
Subir Sarkar
Keyword(s):  
Dark Energy ◽  
Large Scale ◽  
Bulk Flow ◽  
Expansion Rate ◽  
Accelerated Expansion ◽  
Accelerating Universe ◽  
Acoustic Oscillations ◽  
Independent Evidence ◽  
Peculiar Velocity ◽  
Hubble Expansion

AbstractIn the late 1990’s, observations of two directionally-skewed samples of, in total, 93 Type Ia supernovae were analysed in the framework of the Friedmann–Lemaître–Robertson–Walker (FLRW) cosmology. Assuming these to be ‘standard(isable) candles’ it was inferred that the Hubble expansion rate is accelerating as if driven by a positive Cosmological Constant $$\varLambda $$ Λ in Einstein’s theory of gravity. This is still the only direct evidence for the ‘dark energy’ that is the dominant component of today’s standard $$\varLambda $$ Λ CDM cosmological model. Other data such as baryon acoustic oscillations (BAO) in the large-scale distribution of galaxies, temperature fluctuations in the cosmic microwave background (CMB), measurement of stellar ages, the rate of growth of structure, etc are all ‘concordant’ with this model but do not provide independent evidence for accelerated expansion. The recent discussions about whether the inferred acceleration is real rests on analysis of a larger sample of 740 SNe Ia which shows that these are not quite standard candles, and more importantly highlights the ‘corrections’ that are applied to analyse the data in the FLRW framework. The latter holds in the reference frame in which the CMB is isotropic, whereas observations are carried out in our heliocentric frame in which the CMB has a large dipole anisotropy. This is assumed to be of kinematic origin i.e. due to our non-Hubble motion driven by local inhomogeneity in the matter distribution which has grown under gravity from primordial density perturbations traced by the CMB fluctuations. The $$\varLambda $$ Λ CDM model predicts how this peculiar velocity should fall off as the averaging scale is raised and the universe becomes sensibly homogeneous. However observations of the local ‘bulk flow’ are inconsistent with this expectation and convergence to the CMB frame is not seen. Moreover, the kinematic interpretation implies a corresponding dipole in the sky distribution of high redshift quasars, which is rejected by observations at $$4.9\sigma $$ 4.9 σ . Hence the peculiar velocity corrections employed in supernova cosmology are inconsistent and discontinuous within the data. The acceleration of the Hubble expansion rate is in fact anisotropic at $$3.9\sigma $$ 3.9 σ and aligned with the bulk flow. Thus dark energy could be an artefact of analysing data assuming that we are idealised observers in an FLRW universe, when in fact the real universe is inhomogeneous and anisotropic out to distances large enough to impact on cosmological analyses.

Abstract 64: An Integrated Model for Titin Truncation Mutation Interpretation

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Jun Zou ◽  
Diana Tran ◽  
Angelo Pelonero ◽  
Rahul C Deo
Keyword(s):  
Large Scale ◽  
Characteristic Curve ◽  
Severe Disease ◽  
Predictive Performance ◽  
Transcript Level ◽  
Data Interpretation ◽  
Integrated Model ◽  
Integrative Model ◽  
Nonsense Mediated Decay ◽  
Cardiac Phenotype

Background: We recently discovered a conserved internal promoter in the Titin gene, which explains why truncating mutations in the C-terminal two thirds of the zebrafish ttna protein result in more severe disease, recapitulating a puzzling observation in human dilated cardiomyopathy (DCM) patients. Here we focus on the contribution of alternative splicing to the DCM phenotype, both in zebrafish Titin truncation mutants and in the context of an integrative model for Titin mutation interpretation. Methods and Results: Using CRISPR/Cas9, we disrupted an alternatively spliced exon in the I-band of Titin , normally present in zebrafish heart but absent in skeletal muscle. The resulting mutants had, on average, a milder cardiac phenotype than those with mutations in constitutive exons but also showed striking inter-sibling variability in disease expression, ranging from intact cardiac blood flow to severe early demise. The mutant exon demonstrated nonsense-altered splicing and disease severity paralleled selective deficiency in Titin transcript level, implying that variability in mutated exon inclusion coupled with nonsense-mediated decay (NMD) modulated phenotype. We next amassed Titin mutation information from 1785 human DCM cases and >68,000 controls to model mutation distribution and found three variance components 1) splicing; 2) internal isoform disruption; and 3) targeting of the C-terminal 2000 amino acids. An integrated model demonstrated strong predictive performance with an area under the receiver operating characteristic curve of 0.79 and correctly identified the highest risk individuals. Conclusions: We conclude that genetically targeted models and large-scale human data can be complementary in overcoming the challenges of genetic data interpretation.

scholarly journals NETWORKS FROM GENE EXPRESSION TIME SERIES: CHARACTERIZATION OF CORRELATION PATTERNS

2007 ◽  
Vol 17 (07) ◽  
pp. 2477-2483 ◽  
Author(s):  
D. REMONDINI ◽  
N. NERETTI ◽  
C. FRANCESCHI ◽  
P. TIERI ◽  
J. M. SEDIVY ◽  
...  
Keyword(s):  
Gene Expression ◽  
Time Series ◽  
Large Scale ◽  
Molecular Mechanisms ◽  
Single Gene ◽  
Biological Information ◽  
Reconstruction Method ◽  
Gene Expression Time Series ◽  
Expression Time

We address the problem of finding large-scale functional and structural relationships between genes, given a time series of gene expression data, namely mRNA concentration values measured from genetically engineered rat fibroblasts cell lines responding to conditional cMyc proto-oncogene activation. We show how it is possible to retrieve suitable information about molecular mechanisms governing the cell response to conditional perturbations. This task is complex because typical high-throughput genomics experiments are performed with high number of probesets (103–104 genes) and a limited number of observations (< 102 time points). In this paper, we develop a deepest analysis of our previous work [Remondini et al., 2005] in which we characterized some of the main features of a gene-gene interaction network reconstructed from temporal correlation of gene expression time series. One first advancement is based on the comparison of the reconstructed network with networks obtained from randomly generated data, in order to characterize which features retrieve real biological information, and which are instead due to the characteristics of the network reconstruction method. The second and perhaps more relevant advancement is the characterization of the global change in co-expression pattern following cMyc activation as compared to a basal unperturbed state. We propose an analogy with a physical system in a critical state close to a phase transition (e.g. Potts ferromagnet), since the cell responds to the stimulus with high susceptibility, such that a single gene activation propagates to almost the entire genome. Our result is relative to temporal properties of gene network dynamics, and there are experimental evidence that this can be related to spatial properties regarding the global organization of chromatine structure [Knoepfler et al., 2006].

scholarly journals Role of the C-Terminal Binding Protein PXDLS Motif Binding Cleft in Protein Interactions and Transcriptional Repression

2006 ◽  
Vol 26 (21) ◽  
pp. 8202-8213 ◽  
Author(s):  
Kate G. R. Quinlan ◽  
Alexis Verger ◽  
Alister Kwok ◽  
Stella H. Y. Lee ◽  
José Perdomo ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Dna Binding ◽  
Protein Interactions ◽  
Transcriptional Repression ◽  
Histone Deacetylases ◽  
Gene Repression ◽  
Dna Binding Domains ◽  
Binding Domains ◽  
Binding Cleft ◽  
Partner Proteins

ABSTRACT C-terminal binding proteins (CtBPs) are multifunctional proteins that can mediate gene repression. CtBPs contain a cleft that binds Pro-X-Asp-Leu-Ser (PXDLS) motifs. PXDLS motifs occur in numerous transcription factors and in effectors of gene repression, such as certain histone deacetylases. CtBPs have been depicted as bridging proteins that self-associate and link PXDLS-containing transcription factors to PXDLS-containing chromatin-modifying enzymes. CtBPs also recruit effectors that do not contain recognizable PXDLS motifs. We have investigated the importance of the PXDLS binding cleft to CtBP's interactions with various partner proteins and to its ability to repress transcription. We used CtBP cleft mutant and cleft-filled fusion derivatives to distinguish between partner proteins that bind in the cleft and elsewhere on the CtBP surface. Functional assays demonstrate that CtBP mutants that carry defective clefts retain repression activity when fused to heterologous DNA-binding domains. This result suggests that the cleft is not essential for recruiting effectors. In contrast, when tested in the absence of a fused DNA-binding domain, disruption of the cleft abrogates repression activity. These results demonstrate that the PXDLS binding cleft is functionally important but suggest that it is primarily required for localization of the CtBP complex to promoter-bound transcription factors.

scholarly journals Virulence Characterization of Puccinia striiformis f. sp. tritici Using a New Set of Yr Single-Gene Line Differentials in the United States in 2010

Plant Disease ◽  
2014 ◽  
Vol 98 (11) ◽  
pp. 1534-1542 ◽  
Author(s):  
Anmin Wan ◽  
Xianming Chen
Keyword(s):  
United States ◽  
Stripe Rust ◽  
Large Scale ◽  
Puccinia Striiformis ◽  
Yellow Rust ◽  
Single Gene ◽  
The United States ◽  
The Past ◽  
History Of

Puccinia striiformis f. sp. tritici causes stripe rust (yellow rust) of wheat and is highly variable in virulence toward wheat with race-specific resistance. During 2010, wheat stripe rust was the most widespread in the recorded history of the United States, resulting in large-scale application of fungicides and substantial yield loss. A new differential set with 18 yellow rust (Yr) single-gene lines was established and used to differentiate races of P. striiformis f. sp. tritici, which were named as race PSTv in distinction from the PST races identified in the past. An octal system was used to describe the virulence and avirulence patterns of the PSTv races. From 348 viable P. striiformis f. sp. tritici isolates recovered from a total of 381 wheat and grass stripe rust samples collected in 24 states, 41 races, named PSTv-1 to PSTv-41, were identified using the new set of 18 Yr single-gene differentials, and their equivalent PST race names were determined on the previous set of 20 wheat cultivar differentials. The frequencies and distributions of the races and their virulences were determined. The five most predominant races were PSTv-37 (34.5%), PSTv-11 (17.5%), PSTv-14 (7.2%), PSTv-36 (5.2%), and PSTv-34 (4.9%). PSTv-37 was distributed throughout the country while PSTv-11 and PSTv-14 were almost restricted to states west of the Rocky Mountains. The races had virulence to 0 to 13 of the 18 Yr genes. Frequencies of virulences toward resistance genes Yr6, Yr7, Yr8, Yr9, Yr17, Yr27, Yr43, Yr44, YrTr1, and YrExp2 were high (67.0 to 93.7%); those to Yr1 (32.8%) and YrTye (31.3%) were moderate; and those to Yr10, Yr24, Yr32, and YrSP were low (3.4 to 5.7%). All of the isolates were avirulent to Yr5 and Yr15.

scholarly journals Human plasma fibronectin. Demonstration of structural differences between the A- and B-chains in the III CS region

1991 ◽  
Vol 274 (3) ◽  
pp. 731-738 ◽  
Author(s):  
T Tressel ◽  
J B McCarthy ◽  
J Calaycay ◽  
T D Lee ◽  
K Legesse ◽  
...  
Keyword(s):  
Amino Acid ◽  
Rna Splicing ◽  
Single Gene ◽  
Cell Types ◽  
Binding Domain ◽  
Peptide Sequence ◽  
Heparin Binding ◽  
Plasma Fibronectin ◽  
Binding Domains ◽  
A Chain

Fibronectins are a class of cell-adhesion proteins produced from a single gene. The soluble plasma form is synthesized by hepatocytes and the insoluble cellular form by fibroblasts and other cell types. The proteins possess multiple binding domains for macromolecules including collagen, fibrin and heparin along with at least one cell-binding domain. Cellular as well as plasma fibronectins are dimers of similar but not identical polypeptides. Their differences are the result of internal amino acid sequence variability due to alternative RNA splicing in at least three regions (ED-A, ED-B and III CS). We have been studying this polymorphism at the protein level in plasma fibronectin (pFn). Cathepsin D-digested pFn applied to a heparin-agarose column and eluted with an NaCl stepwise gradient (0.1 M, 0.25 M and 0.5 M) released two polypeptides (75 kDa and 65 kDa) in the 0.5 M-NaCl peak. Immunoblots with monoclonal antibodies IST-2 (specific for the C-terminal heparin-binding domain) and AHB-3 (specific for the III CS domain) suggest that both peptides contain the C-terminal heparin-binding (Hep-2) domain, but that only the larger fragment possesses the III CS region. These two polypeptides (75 kDa and 65 kDa) were digested with trypsin, and the resulting peptides were analyzed by fast-atom-bombardment mass spectrometry and compared with the known cDNA-derived peptide sequence. Peptides that were unique to the III CS region were further characterized by micro sequence analysis. The 75 kDa fragment is derived from the A-chain and contains the III CS region (89 amino acid residues) along with the C-terminal heparin-binding (Hep-2) domain and the fibrin-binding (Fib-2) domain. A single galactosamine-based carbohydrate group was detected at Thr-73/74 of the III CS region present in the 75 kDa fragment. The 65 kDa fragment is derived from the B-chain and lacks the entire III CS region but does contain the Hep-2 and Fib-2 domains.

scholarly journals Cognitive dysfunction in hereditary spastic paraplegias and other motor neuron disorders

2016 ◽  
Vol 10 (4) ◽  
pp. 276-279 ◽  
Author(s):  
Ingrid Faber ◽  
Lucas Melo T. Branco ◽  
Marcondes Cavalvante França Júnior
Keyword(s):  
Phenotypic Variability ◽  
Single Gene ◽  
Executive Dysfunction ◽  
Clinical Feature ◽  
Severe Dementia ◽  
Hereditary Spastic Paraplegias ◽  
Single Gene Disorders ◽  
Genetic Subtype ◽  
Limb Spasticity ◽  
Lower Limb Spasticity

ABSTRACT Hereditary spastic paraplegia (HSP) is a diverse group of single-gene disorders that share the predominant clinical feature of progressive lower limb spasticity and weakness. More than 70 different genetic subtypes have been described and all modes of inheritance are possible. Intellectual dysfunction in HSP is frequent in recessive forms but rare in dominant families. It may manifest by either mental retardation and/or cognitive decline. The latter may be subtle, restricted to executive dysfunction or may evolve to severe dementia. The cognitive profile is thought to depend largely on the genetic subtype of HSP, although wide phenotypic variability within the same genetic subtype and also within the same family can be found.

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