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See detailInsights into protein structural, physicochemical, and functional consequences of missense variants in 1,330 disease-associated human genes 693259
Iqbal, Sumaiya; Jespersen, Jakob B.; Perez-Palma, Eduardo et al

E-print/Working paper (2019)

Inference of the structural and functional consequences of amino acid-altering missense variants is challenging and not yet scalable. Clinical and research applications of the colossal number of ... [more ▼]

Inference of the structural and functional consequences of amino acid-altering missense variants is challenging and not yet scalable. Clinical and research applications of the colossal number of identified missense variants is thus limited. Here we describe the aggregation and analysis of large-scale genomic variation and structural biology data for 1,330 disease-associated genes. Comparing the burden of 40 structural, physicochemical, and functional protein features of altered amino acids with 3-dimensional coordinates, we found 18 and 14 features that are associated with pathogenic and population missense variants, respectively. Separate analyses of variants from 24 protein functional classes revealed novel function-dependent vulnerable features. We then devised a quantitative spectrum, identifying variants with higher pathogenic variant-associated features. Finally, we developed a web resource (MISCAST; http://miscast.broadinstitute.org/) for interactive analysis of variants on linear and tertiary protein structures. The biological impact of missense variants available through the webtool will assist researchers in hypothesizing variant pathogenicity and disease trajectories. [less ▲]

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See detailSimple ClinVar:an interactive web server to explore and retrieve gene and disease variants 1 aggregated in ClinVar database
Pérez-Palma, Eduardo; Gramm, Marie; Nürnberg, Peter et al

in Nucleic Acids Research (2019)

Clinical genetic testing has exponentially expanded in recent years, leading to an overwhelming amount of patient variants with high variability in pathogenicity and heterogeneous phenotypes. A large part ... [more ▼]

Clinical genetic testing has exponentially expanded in recent years, leading to an overwhelming amount of patient variants with high variability in pathogenicity and heterogeneous phenotypes. A large part of the variant level data are comprehensively aggregated in public databases such as ClinVar. However, the ability to explore this rich resource and answer general questions such as “How many genes inside ClinVar are associated with a specific disease? or “In which part of the protein are patient variants located?” is limited and requires advanced bioinformatics processing. Here, we present Simple ClinVar (http://simple-clinvar.broadinstitute.org/) a web- server application that is able to provide variant, gene, and disease level summary statistics based on the entire ClinVar database in a dynamic and user-friendly web-interface. Overall, our web application is able to interactively answer basic questions regarding genetic variation and its known relationships to disease. By typing a disease term of interest, t he user can identify in seconds the genes and phenotypes most frequently reported to ClinVar. Subsets of variants can then be further explored, filtered, or mapped and visualized in the corresponding protein sequences. Our website will follow ClinVar monthly releases and provide easy access to rich ClinVar resources to a broader audience including basic and clinical scientists. [less ▲]

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See detailIdentification of pathogenic variant enriched regions across genes and gene families
Pérez-Palma, Eduardo; May, Patrick UL; Iqbal, Sumaiya et al

E-print/Working paper (2019)

Missense variant interpretation is challenging. Essential regions for protein function are conserved among gene family members, and genetic variants within these regions are potentially more likely to ... [more ▼]

Missense variant interpretation is challenging. Essential regions for protein function are conserved among gene family members, and genetic variants within these regions are potentially more likely to confer risk to disease. Here, we generated 2,871 gene family protein sequence alignments involving 9,990 genes and performed missense variant burden analyses to identify novel essential protein regions. We mapped 2,219,811 variants from the general population into these alignments and compared their distribution with 65,034 missense variants from patients. With this gene family approach, we identified 398 regions enriched for patient variants spanning 33,887 amino acids in 1,058 genes. As a comparison, testing the same genes individually we identified less patient variant enriched regions involving only 2,167 amino acids and 180 genes. Next, we selected de novo variants from 6,753 patients with neurodevelopmental disorders and 1,911 unaffected siblings, and observed a 5.56-fold enrichment of patient variants in our identified regions (95% C.I. =2.76-Inf, p-value = 6.66×10−8). Using an independent ClinVar variant set, we found missense variants inside the identified regions are 111-fold more likely to be classified as pathogenic in comparison to benign classification (OR = 111.48, 95% C.I = 68.09-195.58, p-value < 2.2e−16). All patient variant enriched regions identified (PERs) are available online through a user-friendly platform for interactive data mining, visualization and download at http://per.broadinstitute.org. In summary, our gene family burden analysis approach identified novel patient variant enriched regions in protein sequences. This annotation can empower variant interpretation. [less ▲]

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See detailA Recurrent Missense Variant in AP2M1 Impairs Clathrin-Mediated Endocytosis and Causes Developmental and Epileptic Encephalopathy.
Helbig, Ingo; Lopez-Hernandez, Tania; Shor, Oded et al

in American journal of human genetics (2019)

The developmental and epileptic encephalopathies (DEEs) are heterogeneous disorders with a strong genetic contribution, but the underlying genetic etiology remains unknown in a significant proportion of ... [more ▼]

The developmental and epileptic encephalopathies (DEEs) are heterogeneous disorders with a strong genetic contribution, but the underlying genetic etiology remains unknown in a significant proportion of individuals. To explore whether statistical support for genetic etiologies can be generated on the basis of phenotypic features, we analyzed whole-exome sequencing data and phenotypic similarities by using Human Phenotype Ontology (HPO) in 314 individuals with DEEs. We identified a de novo c.508C>T (p.Arg170Trp) variant in AP2M1 in two individuals with a phenotypic similarity that was higher than expected by chance (p = 0.003) and a phenotype related to epilepsy with myoclonic-atonic seizures. We subsequently found the same de novo variant in two individuals with neurodevelopmental disorders and generalized epilepsy in a cohort of 2,310 individuals who underwent diagnostic whole-exome sequencing. AP2M1 encodes the mu-subunit of the adaptor protein complex 2 (AP-2), which is involved in clathrin-mediated endocytosis (CME) and synaptic vesicle recycling. Modeling of protein dynamics indicated that the p.Arg170Trp variant impairs the conformational activation and thermodynamic entropy of the AP-2 complex. Functional complementation of both the mu-subunit carrying the p.Arg170Trp variant in human cells and astrocytes derived from AP-2mu conditional knockout mice revealed a significant impairment of CME of transferrin. In contrast, stability, expression levels, membrane recruitment, and localization were not impaired, suggesting a functional alteration of the AP-2 complex as the underlying disease mechanism. We establish a recurrent pathogenic variant in AP2M1 as a cause of DEEs with distinct phenotypic features, and we implicate dysfunction of the early steps of endocytosis as a disease mechanism in epilepsy. [less ▲]

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See detailVariant Score Ranker - a web application for intuitive missense variant prioritization
Du, Juanjiangmeng; Sudarsanam, Monica; Pérez-Palma, Eduardo et al

in Bioinformatics (2019)

The correct classification of missense variants as benign or pathogenic remains challenging. Pathogenic variants are expected to have higher deleterious prediction scores than benign variants in the same ... [more ▼]

The correct classification of missense variants as benign or pathogenic remains challenging. Pathogenic variants are expected to have higher deleterious prediction scores than benign variants in the same gene. However, most of the existing variant annotation tools do not reference the score range of benign population variants on gene level. Here, we present a web-application, Variant Score Ranker, which enables users to rapidly annotate variants and perform gene-specific variant score ranking on the population level. We also provide an intuitive example of how gene- and population-calibrated variant ranking scores can improve epilepsy variant prioritization. [less ▲]

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See detailIntestinal-Cell Kinase and Juvenile Myoclonic Epilepsy.
Lerche, Holger; Berkovic, Sam F.; Lowenstein, Daniel H. et al

in New England Journal of Medicine (2019), 380(16), 24

With regard to the article by Bailey et al. (March 15, 2018, issue) on the potential role of variants in the gene encoding intestinal cell kinase (ICK) in genetic generalized epilepsies, including ... [more ▼]

With regard to the article by Bailey et al. (March 15, 2018, issue) on the potential role of variants in the gene encoding intestinal cell kinase (ICK) in genetic generalized epilepsies, including juvenile myoclonic epilepsy: We attempted replication by rechecking for enrichment of ICK variants in two previously published analyses of mainly familial cases of genetic generalized epilepsy, which included a total of 1149 cases of genetic generalized epilepsy and 5911 ethnically matched controls. We analyzed the burden of single-gene rare variants with the use of whole exome sequencing data, applying population stratification and both sample and variant quality control. We found no evidence of an enrichment of ICK variants in genetic generalized epilepsies or juvenile myoclonic epilepsy. Specifically, we did not detect a nonsynonymous variant in 357 persons with juvenile myoclonic epilepsy at a minor allele frequency at or below 0.1%. Although we cannot exclude the possibility that ICK variants may be population-specific risk factors for juvenile myoclonic epilepsy, the lack of validation in our cohorts does not support a true disease association but rather suggests that the authors’ results may be due to chance, possibly owing to methodologic issues (see the Supplementary Appendix, available with the full text of this letter at NEJM.org). [less ▲]

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See detailHemap: An nteractive online resource for characterizing molecular phenotypes across hematologic malignancies
Pölönen, Petri; Mehtonen, Juha; Lin, Jake et al

in Cancer Research (2019)

Large collections of genome-wide data can facilitate the characterization of disease states and subtypes, permitting pan-cancer analysis of molecular phenotypes and evaluation of disease contexts for new ... [more ▼]

Large collections of genome-wide data can facilitate the characterization of disease states and subtypes, permitting pan-cancer analysis of molecular phenotypes and evaluation of disease contexts for new therapeutic approaches. We analyzed 9,544 transcriptomes from over 30 hematologic malignancies, normal blood cell types and cell lines, and show that the disease types can be stratified in a data-driven manner. We utilized the obtained molecular clustering for discovery of cluster-specific pathway activity, new biomarkers and in silico drug target prioritization through integration with drug target databases. Using known vulnerabilities and available drug screens in benchmarking, we highlight the importance of integrating the molecular phenotype context and drug target expression for in silico prediction of drug responsiveness. Our analysis implicates BCL2 expression level as important indicator of venetoclax responsiveness and provides a rationale for its targeting in specific leukemia subtypes and multiple myeloma, links several polycomb group proteins that could be targeted by small molecules (SFMBT1, CBX7 and EZH1) with CLL, and supports CDK6 as disease-specific target in AML. Through integration with proteomics data, we characterized target protein expression for pre-B leukemia immunotherapy candidates, including DPEP1. These molecular data can be explored using our freely available interactive resource, Hemap, for expediting therapeutic innovations in hematologic malignancies. [less ▲]

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See detailFunctional Interpretation of Single Amino Acid Substitutions in 1,330 Disease-Associated Genes
Iqbal, Sumaiya; Jespersen, Jakob Berg; Perez-Palma, Eduardo et al

in Biophysical Journal (2019, February 15), 116(3), 420-421

Elucidating molecular consequences of amino-acid-altering missense variants at scale is challenging. In this work, we explored whether features derived from three-dimensional (3D) protein structures can ... [more ▼]

Elucidating molecular consequences of amino-acid-altering missense variants at scale is challenging. In this work, we explored whether features derived from three-dimensional (3D) protein structures can characterize patient missense variants across different protein classes with similar molecular level activities. The identified disease-associated features can advance our understanding of how a single amino acid substitution can lead to the etiology of monogenic disorders. For 1,330 disease-associated genes (>80%, 1,077/1,330 implicated in Mendelian disorders), we collected missense variants from the general population (gnomAD database, N=164,915) and patients (ClinVar and HGMD databases, N=32,923). We in silico mapped the variant positions onto >14k human protein 3D structures. We annotated the protein positions of variants with 40 structural, physiochemical, and functional features. We then grouped the genes into 24 protein classes based on their molecular functions and performed statistical association analyses with the features of population and patient variants. We identified 18 (out of 40) features that are associated with patient variants in general. Specifically, patient variants are less exposed to solvent (p<1.0e-100), enriched on b-sheets (p<2.37e-39), frequently mutate aromatic residues (p<1.0e-100), occur in ligand binding sites (p<1.0e-100) and are spatially close to phosphorylation sites (p<1.0e-100). We also observed differential protein-class-specific features. For three protein classes (signaling molecules, proteases and hydrolases), patient variants significantly perturb the disulfide bonds (p<1.0e-100). Only in immunity proteins, patient variants are enriched in flexible coils (p<1.65e-06). Kinases and cell junction proteins exhibit enrichment of patient variants around SUMOylation (p<1.0e-100) and methylation sites (p<9.29e-11), respectively. In summary, we studied shared and unique features associated with patient variants on protein structure across 24 protein classes, providing novel mechanistic insights. We generated an online resource that contains amino-acid-wise feature annotation-track for 1,330 genes, summarizes the patient-variant-associated features on residue level, and can guide variant interpretation. [less ▲]

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See detailBiallelic VARS variants cause developmental encephalopathy with microcephaly that is recapitulated in vars knockout zebrafish
Siekierska, Aleksandra; Stamberger, Hannah; Deconinck, Tine et al

in Nature Communications (2019), 10(1), 708

Aminoacyl tRNA synthetases (ARSs) link specific amino acids with their cognate transfer RNAs in a critical early step of protein translation. Mutations in ARSs have emerged as a cause of recessive, often ... [more ▼]

Aminoacyl tRNA synthetases (ARSs) link specific amino acids with their cognate transfer RNAs in a critical early step of protein translation. Mutations in ARSs have emerged as a cause of recessive, often complex neurological disease traits. Here we report an allelic series consisting of seven novel and two previously reported biallelic variants in valyl-tRNA synthetase (VARS) in ten patients with a developmental encephalopathy with microcephaly, often associated with early-onset epilepsy. In silico, in vitro, and yeast complementation assays demonstrate that the underlying pathomechanism of these mutations is most likely a loss of protein function. Zebrafish modeling accurately recapitulated some of the key neurological disease traits. These results provide both genetic and biological insights into neurodevelopmental disease and pave the way for further in-depth research on ARS related recessive disorders and precision therapies. [less ▲]

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See detailClinical spectrum of STX1B-related epileptic disorders
Wolking, Stefan; May, Patrick UL; Mei, Davide et al

in Neurology (2019), 92

Objective: The aim of this study was to expand the spectrum of epilepsy syndromes related to STX1B, encoding the presynaptic protein syntaxin-1B, and to establish genotype-phenotype correlations by ... [more ▼]

Objective: The aim of this study was to expand the spectrum of epilepsy syndromes related to STX1B, encoding the presynaptic protein syntaxin-1B, and to establish genotype-phenotype correlations by identifying further disease-related variants. Methods: We used next generation sequencing in the framework of research projects and diagnostic testing. Clinical data and EEGs were reviewed, including already published cases. To estimate the pathogenicity of the variants, we used established and newly developed in silico prediction tools. Results: We describe fifteen new variants in STX1B which are distributed across the whole gene. We discerned four different phenotypic groups across the newly identified and previously published patients (49 in 23 families): 1) Six sporadic patients or families (31 affected individuals) with febrile and afebrile seizures with a benign course, generally good drug response, normal development and without permanent neurological deficits; 2) two patients of genetic generalized epilepsy without febrile seizures and cognitive deficits; 3) thirteen patients or families with intractable seizures, developmental regression after seizure onset and additional neuropsychiatric symptoms; 4) two patients with focal epilepsy. Nonsense mutations were found more often in benign syndromes, whereas missense variants in the SNARE motif of syntaxin-1B were associated with more severe phenotypes. Conclusion: These data expand the genetic and phenotypic spectrum of STX1B-related epilepsies to a diverse range of epilepsies that span the ILAE classification. Variants in STX1B are protean, and able to contribute to many different epilepsy phenotypes, similar to SCN1A, the most important gene associated with fever-associated epilepsies. [less ▲]

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See detailSpectrum of GABAA receptor variants in epilepsy
Maljevic, Snezana; Møller, Rikke S.; Reid, Christopher A. et al

in Current Opinion in Neurology (2019)

Purpose of review: Recent publications point to an increasingly important role of variants in genes encoding GABAA receptor subunits associated with both common and rare forms of epilepsies. The aim of ... [more ▼]

Purpose of review: Recent publications point to an increasingly important role of variants in genes encoding GABAA receptor subunits associated with both common and rare forms of epilepsies. The aim of this review is to give an overview of the current clinical phenotypes, genetic findings and pathophysiological mechanisms related to GABAA receptor variants. Recent findings: Early work showed that inherited variants in GABRG2 and GABRA1 cause relatively mild forms of monogenic epilepsies in large families. More recent studies have revealed that de novo variants in several GABAA receptor genes cause severe developmental and epileptic encephalopathies, inherited variants cause remarkably variable phenotypes within the same pedigrees ranging from asymptomatic carriers to developmental and epileptic encephalopathies, and variants in all GABAA receptor genes are enriched in common forms of epilepsy, namely rolandic epilepsy and genetic generalized epilepsy. Analyses from cellular expression systems and mouse models suggest that all variants cause a loss of GABAA receptor function resulting in GABAergic disinhibition. Summary: Genetic studies have revealed a crucial role of the GABAergic system in the underlying pathogenesis of various forms of common and rare epilepsies. Our understanding of functional consequences of GABAA receptor variants provide an opportunity to develop precision-based therapeutic strategies that are hopefully free from the side-effect burden seen with currently available GABAergic drugs. [less ▲]

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See detailPredicting Functional Effects of Missense Variants in Voltage-Gated Sodium and Calcium Channels
Heyne, Henrike O.; Baez-Nieto, David; Iqbal, Sumaiya et al

E-print/Working paper (2019)

Malfunctions of voltage-gated sodium and calcium channels (SCN and CACNA1 genes) have been associated with severe neurologic, psychiatric, cardiac and other diseases. Altered channel activity is ... [more ▼]

Malfunctions of voltage-gated sodium and calcium channels (SCN and CACNA1 genes) have been associated with severe neurologic, psychiatric, cardiac and other diseases. Altered channel activity is frequently grouped into gain or loss of ion channel function (GOF or LOF, respectively) which is not only corresponding to clinical disease manifestations, but also to differences in drug response. Experimental studies of channel function are therefore important, but laborious and usually focus only on a few variants at a time. Based on known gene-disease-mechanisms, we here infer LOF (518 variants) and GOF (309 variants) of likely pathogenic variants from disease phenotypes of variant carriers. We show regional clustering of inferred GOF and LOF variants, respectively, across the alignment of the entire gene family, suggesting shared pathomechanisms in the SCN/CACNA1 genes. By training a machine learning model on sequence- and structure-based features we predict LOF- or GOF- associated disease phenotypes (ROC = 0.85) of likely pathogenic missense variants. We then successfully validate the GOF versus LOF prediction on 87 functionally tested variants in SCN1/2/8A and CACNA1I (ROC = 0.73) and in exome-wide data from > 100.000 cases and controls. Ultimately, functional prediction of missense variants in clinically relevant genes will facilitate precision medicine in clinical practice. [less ▲]

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See detailWeb-based QTL linkage analysis and bulk segregant analysis of yeast sequencing data
Zhang, Zhi; Jung, Paul; Groues, Valentin UL et al

in GigaScience (2019), 8(6), 060

Quantitative Trait Loci (QTL) mapping using bulk segregants is an effective approach for identifying genetic variants associated with phenotypes of interest in model organisms. By exploiting next ... [more ▼]

Quantitative Trait Loci (QTL) mapping using bulk segregants is an effective approach for identifying genetic variants associated with phenotypes of interest in model organisms. By exploiting next-generation sequencing technology, the QTL mapping accuracy can be improved significantly, providing a valuable means to annotate new genetic variants. However, setting up a comprehensive analysis framework for this purpose is a time-consuming and error prone task, posing many challenges for scientists with limited experience in this domain. Findings: Here, we present BSA4Yeast, a comprehensive web-application for QTL mapping via bulk segregant analysis of yeast sequencing data. The software provides an automated and efficiency-optimized data processing, up-to-date functional annotations, and an interactive web-interface to explore identified QTLs. Conclusion: BSA4Yeast enables researchers to identify plausible candidate genes in QTL regions efficiently in order to validate their genetic variations experimentally as causative for a phenotype of interest. BSA4Yeast is freely available at https://bsa4yeast.lcsb.uni.lu. [less ▲]

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See detailGuideline-based and bioinformatic reassessment of lesion-associated gene and variant pathogenicity in focal human epilepsies
Niestroj, Lisa-Marie; Du, Juanjiangmeng; Nothnagel, Michael et al

in Epilepsia (2018)

Objective: Increasing availability of surgically resected brain tissue from patients with focal epilepsy and Focal Cortical Dysplasia (FCD) or low-grade glio-neuronal tumors has fostered large-scale ... [more ▼]

Objective: Increasing availability of surgically resected brain tissue from patients with focal epilepsy and Focal Cortical Dysplasia (FCD) or low-grade glio-neuronal tumors has fostered large-scale genetic examination. However, assessment of pathogenicity of germline and somatic variants remains difficult. Here, we present a state of the art evaluation of reported genes and variants associated with epileptic brain lesions. Methods: We critically re-evaluated the pathogenicity for all neuropathology-associated variants reported to date in PubMed and ClinVar databases including 101 neuropathology-associated missense variants encompassing 11 disease-related genes. We assessed gene variant tolerance and classified all identified missense variants according to guidelines from the American College of Medical Genetics and Genomics (ACMG). We further extended the bioinformatic variant prediction by introducing a novel gene-specific deleteriousness ranking for prediction scores. Results: Application of ACMG guidelines and in silico gene variant tolerance analysis classified only seven out of 11 genes to be likely disease-associated according to the reported a disease mechanism, while 61 (60.4%) of 101 variants of those genes were classified as of uncertain significance (VUS), 37 (36.6%) as being likely pathogenic (LP) and 3 (3%) as being pathogenic (P). Significance: We concluded that the majority of neuropathology-associated variants reported to date do not have enough evidence to be classified as pathogenic. Interpretation of lesion-associated variants remains challenging and application of current ACMG guidelines is recommended for interpretation and prediction. [less ▲]

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See detailMajor changes of cell function and toxicant sensitivity in cultured cells undergoing mild, quasi-natural genetic drift
Gutbier, Simon; May, Patrick UL; Berthelot, Sylvie et al

in Archives of Toxicology (2018)

Genomic drift affects the functional properties of cell lines, and the reproducibility of data from in vitro studies. While chromosomal aberrations and mutations in single pivotal genes are well explored ... [more ▼]

Genomic drift affects the functional properties of cell lines, and the reproducibility of data from in vitro studies. While chromosomal aberrations and mutations in single pivotal genes are well explored, little is known about effects of minor, possibly pleiotropic, genome changes. We addressed this question for the human dopaminergic neuronal precursor cell line LUHMES by comparing two subpopulations (SP) maintained either at the American-Type-Culture-Collection (ATCC) or by the original provider (UKN). Drastic differences in susceptibility towards the specific dopaminergic toxicant 1-methyl-4-phenylpyridinium (MPP+) were observed. Whole-genome sequencing was performed to identify underlying genetic differences. While both SP had normal chromosome structures, they displayed about 70 differences on the level of amino acid changing events. Some of these differences were confirmed biochemically, but none offered a direct explanation for the altered toxicant sensitivity pattern. As second approach, markers known to be relevant for the intended use of the cells were specifically tested. The “ATCC” cells rapidly down-regulated the dopamine-transporter and tyrosine-hydroxylase after differentiation, while “UKN” cells maintained functional levels. As the respective genes were not altered themselves, we conclude that polygenic complex upstream changes can have drastic effects on biochemical features and toxicological responses of relatively similar SP of cells. [less ▲]

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See detailA multi-omic view of invasive genetic elements and their linked prokaryotic population dynamics within a mixed microbial community
Martinez Arbas, Susana UL; Narayanasamy, Shaman; Herold, Malte et al

Poster (2018, September 11)

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See detailRare gene deletions in genetic generalized and Rolandic epilepsies
Jabbari, Kamel; Bobbili, Dheeraj Reddy UL; Lal, Dennis et al

in PLoS ONE (2018)

Genetic Generalized Epilepsy (GGE) and benign epilepsy with centro-temporal spikes or Rolandic Epilepsy (RE) are common forms of genetic epilepsies. Rare copy number variants have been recognized as ... [more ▼]

Genetic Generalized Epilepsy (GGE) and benign epilepsy with centro-temporal spikes or Rolandic Epilepsy (RE) are common forms of genetic epilepsies. Rare copy number variants have been recognized as important risk factors in brain disorders. We performed a systematic survey of rare deletions affecting protein-coding genes derived from exome data of patients with common forms of genetic epilepsies. We analysed exomes from 390 European patients (196 GGE and 194 RE) and 572 population controls to identify low-frequency genic deletions. We found that 75 (32 GGE and 43 RE) patients out of 390, i.e. ~19%, carried rare genic deletions. In particular, large deletions (>400 kb) represent a higher burden in both GGE and RE syndromes as compared to controls. The detected low-frequency deletions (1) share genes with brain-expressed exons that are under negative selection, (2) overlap with known autism and epilepsy-associated candidate genes, (3) are enriched for CNV intolerant genes recorded by the Exome Aggregation Consortium (ExAC) and (4) coincide with likely disruptive de novo mutations from the NPdenovo database. Employing several knowledge databases, we discuss the most prominent epilepsy candidate genes and their protein-protein networks for GGE and RE. [less ▲]

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See detailRare coding variants in genes encoding GABAA receptors in genetic generalised epilepsies: an exome-based case-control study
May, Patrick UL; Girard, Simon; Harrer, Merle et al

in Lancet Neurology (2018), 17(8), 699-708

Background Genetic generalised epilepsy is the most common type of inherited epilepsy. Despite a high concordance rate of 80% in monozygotic twins, the genetic background is still poorly understood. We ... [more ▼]

Background Genetic generalised epilepsy is the most common type of inherited epilepsy. Despite a high concordance rate of 80% in monozygotic twins, the genetic background is still poorly understood. We aimed to investigate the burden of rare genetic variants in genetic generalised epilepsy. Methods For this exome-based case-control study, we used three different genetic generalised epilepsy case cohorts and three independent control cohorts, all of European descent. Cases included in the study were clinically evaluated for genetic generalised epilepsy. Whole-exome sequencing was done for the discovery case cohort, a validation case cohort, and two independent control cohorts. The replication case cohort underwent targeted next-generation sequencing of the 19 known genes encoding subunits of GABAA receptors and was compared to the respective GABAA receptor variants of a third independent control cohort. Functional investigations were done with automated two-microelectrode voltage clamping in Xenopus laevis oocytes. Findings Statistical comparison of 152 familial index cases with genetic generalised epilepsy in the discovery cohort to 549 ethnically matched controls suggested an enrichment of rare missense (Nonsyn) variants in the ensemble of 19 genes encoding GABAA receptors in cases (odds ratio [OR] 2·40 [95% CI 1·41–4·10]; pNonsyn=0·0014, adjusted pNonsyn=0·019). Enrichment for these genes was validated in a whole-exome sequencing cohort of 357 sporadic and familial genetic generalised epilepsy cases and 1485 independent controls (OR 1·46 [95% CI 1·05–2·03]; pNonsyn=0·0081, adjusted pNonsyn=0·016). Comparison of genes encoding GABAA receptors in the independent replication cohort of 583 familial and sporadic genetic generalised epilepsy index cases, based on candidate-gene panel sequencing, with a third independent control cohort of 635 controls confirmed the overall enrichment of rare missense variants for 15 GABAA receptor genes in cases compared with controls (OR 1·46 [95% CI 1·02–2·08]; pNonsyn=0·013, adjusted pNonsyn=0·027). Functional studies for two selected genes (GABRB2 and GABRA5) showed significant loss-of-function effects with reduced current amplitudes in four of seven tested variants compared with wild-type receptors. Interpretation Functionally relevant variants in genes encoding GABAA receptor subunits constitute a significant risk factor for genetic generalised epilepsy. Examination of the role of specific gene groups and pathways can disentangle the complex genetic architecture of genetic generalised epilepsy. [less ▲]

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See detailIntegrated time-resolved multi-omics for understanding microbial niche ecology
Herold, Malte UL; Narayanasamy, Shaman UL; Martinez Arbas, Susana UL et al

Poster (2018, August)

Microbial communities are strongly shaped by the niche breadths of their constituent populations. However, a detailed understanding of microbial niche ecology is typically lacking. Integrated multi-omic ... [more ▼]

Microbial communities are strongly shaped by the niche breadths of their constituent populations. However, a detailed understanding of microbial niche ecology is typically lacking. Integrated multi-omic analyses of host- or environment-derived samples offer the prospect of resolving fundamental and realised niches in situ. In turn, this is considered a prerequisite for niche engineering in order to drive an individual population or a community towards a specific phenotype, e.g., improvement of a biotechnological process. Here, we sampled floating islets on the surface of an activated sludge tank in a time-series spanning 51 time-points over 14 months. Multi-omics datasets (metagenomics, metatranscriptomics, metaproteomics, and (meta-)metabolomics) were generated for all time-points. Leveraging nucleotide sequencing data, we analyzed the community structure and reconstructed genomes for specific populations of interest. Moreover, based on their metabolic potential, three major groups emerged, serving as proxies for their respective fundamental niches . Time-resolved linkage of the proteomic and transcriptomic data to the reconstructed genomes revealed a fine-grained picture of niche realization. In particular, environmental factors (temperature, metabolites, oxygen) were significantly associated with gene expression of individual populations. Furthermore, we subjected the community to controlled oxygen conditions (stable or dynamic) in a bioreactor experiment and measured the transcriptomic response. Our results suggest short-term adaptations of populations of interest with respect to lipid metabolism, among other pathways. In conclusion, our work demonstrates how longitudinal multi-omic datasets can be integrated in order to further our understanding of microbial niche ecology within a biotechnological process with potential applications beyond waste water treatment. [less ▲]

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