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1دورية أكاديمية
المؤلفون: Flint, Jonathan, Heffel, Matthew G, Chen, Zeyuan, Mefford, Joel, Marcus, Emilie, Chen, Patrick B, Ernst, Jason, Luo, Chongyuan
المصدر: Cell Genomics. 3(12)
مصطلحات موضوعية: Biological Sciences, Bioinformatics and Computational Biology, Genetics, Human Genome, 2.1 Biological and endogenous factors, Aetiology, hippocampus, inbred mouse strains, methylation, variant function
الوصف: Relating genetic variants to behavior remains a fundamental challenge. To assess the utility of DNA methylation marks in discovering causative variants, we examined their relationship to genetic variation by generating single-nucleus methylomes from the hippocampus of eight inbred mouse strains. At CpG sequence densities under 40 CpG/Kb, cells compensate for loss of methylated sites by methylating additional sites to maintain methylation levels. At higher CpG sequence densities, the exact location of a methylated site becomes more important, suggesting that variants affecting methylation will have a greater effect when occurring in higher CpG densities than in lower. We found this to be true for a variant's effect on transcript abundance, indicating that candidate variants can be prioritized based on CpG sequence density. Our findings imply that DNA methylation influences the likelihood that mutations occur at specific sites in the genome, supporting the view that the distribution of mutations is not random.
وصف الملف: application/pdf
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2دورية أكاديمية
المؤلفون: Yulin Dai, Toshiyuki Itai, Guangsheng Pei, Fangfang Yan, Yan Chu, Xiaoqian Jiang, Seth M. Weinberg, Nandita Mukhopadhyay, Mary L. Marazita, Lukas M. Simon, Peilin Jia, Zhongming Zhao
المصدر: HGG Advances, Vol 5, Iss 3, Pp 100312- (2024)
مصطلحات موضوعية: human embryonic craniofacial development, orofacial clefts, convolutional neural network, genome-wide association studies, variant function, epigenomic assay, Genetics, QH426-470
الوصف: Summary: Orofacial clefts (OFCs) are among the most common human congenital birth defects. Previous multiethnic studies have identified dozens of associated loci for both cleft lip with or without cleft palate (CL/P) and cleft palate alone (CP). Although several nearby genes have been highlighted, the “casual” variants are largely unknown. Here, we developed DeepFace, a convolutional neural network model, to assess the functional impact of variants by SNP activity difference (SAD) scores. The DeepFace model is trained with 204 epigenomic assays from crucial human embryonic craniofacial developmental stages of post-conception week (pcw) 4 to pcw 10. The Pearson correlation coefficient between the predicted and actual values for 12 epigenetic features achieved a median range of 0.50–0.83. Specifically, our model revealed that SNPs significantly associated with OFCs tended to exhibit higher SAD scores across various variant categories compared to less related groups, indicating a context-specific impact of OFC-related SNPs. Notably, we identified six SNPs with a significant linear relationship to SAD scores throughout developmental progression, suggesting that these SNPs could play a temporal regulatory role. Furthermore, our cell-type specificity analysis pinpointed the trophoblast cell as having the highest enrichment of risk signals associated with OFCs. Overall, DeepFace can harness distal regulatory signals from extensive epigenomic assays, offering new perspectives for prioritizing OFC variants using contextualized functional genomic features. We expect DeepFace to be instrumental in accessing and predicting the regulatory roles of variants associated with OFCs, and the model can be extended to study other complex diseases or traits.
وصف الملف: electronic resource
العلاقة: http://www.sciencedirect.com/science/article/pii/S2666247724000514Test; https://doaj.org/toc/2666-2477Test
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3دورية أكاديمية
المؤلفون: Niccolo Alberto Elia Venanzi, Andrea Basciu, Attilio Vittorio Vargiu, Alexandros Kiparissides, Paul A. Dalby, Duygu Dikicioglu
مصطلحات موضوعية: Biophysics, Biochemistry, Genetics, Molecular Biology, Biotechnology, Cancer, Infectious Diseases, Plant Biology, Biological Sciences not elsewhere classified, Mathematical Sciences not elsewhere classified, Physical Sciences not elsewhere classified, Information Systems not elsewhere classified, multiple point mutations, machine learning algorithms, bovine enterokinase variants, achieve improved prediction, protein variant function, computational protein science, provide predictive insights, protein dynamics descriptors, sequence information alone, protein structure, protein functionality, structure information, predictive capabilities, study highlights, peptide sequence, industrial contexts, fold improvement, dynamic data
الوصف: Despite recent advances in computational protein science, the dynamic behavior of proteins, which directly governs their biological activity, cannot be gleaned from sequence information alone. To overcome this challenge, we propose a framework that integrates the peptide sequence, protein structure, and protein dynamics descriptors into machine learning algorithms to enhance their predictive capabilities and achieve improved prediction of the protein variant function. The resulting machine learning pipeline integrates traditional sequence and structure information with molecular dynamics simulation data to predict the effects of multiple point mutations on the fold improvement of the activity of bovine enterokinase variants. This study highlights how the combination of structural and dynamic data can provide predictive insights into protein functionality and address protein engineering challenges in industrial contexts.
الإتاحة: https://doi.org/10.1021/acs.jcim.3c00999.s001Test
https://figshare.com/articles/journal_contribution/Machine_Learning_Integrating_Protein_Structure_Sequence_and_Dynamics_to_Predict_the_Enzyme_Activity_of_Bovine_Enterokinase_Variants/25267280Test -
4دورية أكاديمية
المؤلفون: Jessica C. McAfee, Sool Lee, Jiseok Lee, Jessica L. Bell, Oleh Krupa, Jessica Davis, Kimberly Insigne, Marielle L. Bond, Nanxiang Zhao, Alan P. Boyle, Douglas H. Phanstiel, Michael I. Love, Jason L. Stein, W. Brad Ruzicka, Jose Davila-Velderrain, Sriram Kosuri, Hyejung Won
المصدر: Cell Genomics, Vol 3, Iss 10, Pp 100404- (2023)
مصطلحات موضوعية: MPRA, schizophrenia, GWAS, non-coding variants, accessibility-by-contact model, variant function, Genetics, QH426-470, Internal medicine, RC31-1245
الوصف: Summary: Genome-wide association studies (GWASs) have successfully identified 145 genomic regions that contribute to schizophrenia risk, but linkage disequilibrium makes it challenging to discern causal variants. We performed a massively parallel reporter assay (MPRA) on 5,173 fine-mapped schizophrenia GWAS variants in primary human neural progenitors and identified 439 variants with allelic regulatory effects (MPRA-positive variants). Transcription factor binding had modest predictive power, while fine-map posterior probability, enhancer overlap, and evolutionary conservation failed to predict MPRA-positive variants. Furthermore, 64% of MPRA-positive variants did not exhibit expressive quantitative trait loci signature, suggesting that MPRA could identify yet unexplored variants with regulatory potentials. To predict the combinatorial effect of MPRA-positive variants on gene regulation, we propose an accessibility-by-contact model that combines MPRA-measured allelic activity with neuronal chromatin architecture.
وصف الملف: electronic resource
العلاقة: http://www.sciencedirect.com/science/article/pii/S2666979X23002185Test; https://doaj.org/toc/2666-979XTest
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5دورية أكاديمية
المؤلفون: Macnee, Marie, Pérez-Palma, Eduardo, López-Rivera, Javier A., Ivaniuk, Alina, May, Patrick, Møller, Rikke S., Lal, Dennis
المصدر: Macnee , M , Pérez-Palma , E , López-Rivera , J A , Ivaniuk , A , May , P , Møller , R S & Lal , D 2023 , ' Data-driven historical characterization of epilepsy-associated genes ' , European Journal of Paediatric Neurology , vol. 42 , pp. 82-87 . https://doi.org/10.1016/j.ejpn.2022.12.005Test
مصطلحات موضوعية: Epilepsy, Epilepsy genes, Genetics, Literature review, Monogenic, Variant function
الوصف: Many epilepsy-associated genes have been identified over the last three decades, revealing a remarkable molecular heterogeneity with the shared outcome of recurrent seizures. Information about the genetic landscape of epilepsies is scattered throughout the literature and answering the simple question of how many genes are associated with epilepsy is not straightforward. Here, we present a computationally driven analytical review of epilepsy-associated genes using the complete scientific literature in PubMed. Based on our search criteria, we identified a total of 738 epilepsy-associated genes. We further classified these genes into two Tiers. A broad gene list of 738 epilepsy-associated genes (Tier 2) and a narrow gene list composed of 143 epilepsy-associated genes (Tier 1). Our search criteria do not reflect the degree of association. The average yearly number of identified epilepsy-associated genes between 1992 and 2021 was 4.8. However, most of these genes were only identified in the last decade (2010–2019). Ion channels represent the largest class of epilepsy-associated genes. For many of these, both gain- and loss-of-function effects have been associated with epilepsy in recent years. We identify 28 genes frequently reported with heterogenous variant effects which should be considered for variant interpretation. Overall, our study provides an updated and manually curated list of epilepsy-related genes together with additional annotations and classifications reflecting the current genetic landscape of epilepsy.
وصف الملف: application/pdf
العلاقة: https://portal.findresearcher.sdu.dk/da/publications/77dbdd1f-a271-41cc-b6e6-f53a720d03a2Test
الإتاحة: https://doi.org/10.1016/j.ejpn.2022.12.005Test
https://portal.findresearcher.sdu.dk/da/publications/77dbdd1f-a271-41cc-b6e6-f53a720d03a2Test
https://findresearcher.sdu.dk/ws/files/218647927/Open_Access_Version.pdfTest -
6دورية أكاديمية
المساهمون: Department of Applied Mathematics
مصطلحات موضوعية: Unitary similarity in variant function, Generalized numerical radius, Pseudo spectrum
الوصف: 202305 bcch ; Accepted Manuscript ; RGC ; Others ; PolyU ; Published
العلاقة: http://hdl.handle.net/10397/98637Test; 716; 729; 454; 2-s2.0-85019904714; AMA-0461; 6749308
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7دورية أكاديمية
المؤلفون: Dai, Yulin, Itai, Toshiyuki, Pei, Guangsheng, Yan, Fangfang, Chu, Yan, Jiang, Xiaoqian, Weinberg, Seth M, Mukhopadhyay, Nandita, Marazita, Mary L, Simon, Lukas M, Jia, Peilin, Zhao, Zhongming
المصدر: HGG Adv ; ISSN:2666-2477 ; Volume:5 ; Issue:3
مصطلحات موضوعية: SNP activity difference prediction, convolutional neural network, epigenomic assay, genome-wide association studies, human embryonic craniofacial development, noncoding variant, orofacial clefts, variant function
الوصف: Orofacial clefts (OFCs) are among the most common human congenital birth defects. Previous multiethnic studies have identified dozens of associated loci for both cleft lip with or without cleft palate (CL/P) and cleft palate alone (CP). Although several nearby genes have been highlighted, the "casual" variants are largely unknown. Here, we developed DeepFace, a convolutional neural network model, to assess the functional impact of variants by SNP activity difference (SAD) scores. The DeepFace model is trained with 204 epigenomic assays from crucial human embryonic craniofacial developmental stages of post-conception week (pcw) 4 to pcw 10. The Pearson correlation coefficient between the predicted and actual values for 12 epigenetic features achieved a median range of 0.50-0.83. Specifically, our model revealed that SNPs significantly associated with OFCs tended to exhibit higher SAD scores across various variant categories compared to less related groups, indicating a context-specific impact of OFC-related SNPs. Notably, we identified six SNPs with a significant linear relationship to SAD scores throughout developmental progression, suggesting that these SNPs could play a temporal regulatory role. Furthermore, our cell-type specificity analysis pinpointed the trophoblast cell as having the highest enrichment of risk signals associated with OFCs. Overall, DeepFace can harness distal regulatory signals from extensive epigenomic assays, offering new perspectives for prioritizing OFC variants using contextualized functional genomic features. We expect DeepFace to be instrumental in accessing and predicting the regulatory roles of variants associated with OFCs, and the model can be extended to study other complex diseases or traits.
العلاقة: https://doi.org/10.1016/j.xhgg.2024.100312Test; https://pubmed.ncbi.nlm.nih.gov/38796699Test; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11193024Test/
الإتاحة: https://doi.org/10.1016/j.xhgg.2024.100312Test
https://pubmed.ncbi.nlm.nih.gov/38796699Test
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11193024Test/ -
8دورية أكاديمية
المؤلفون: Macnee, Marie, Perez-Palma, Eduardo, Lopez-Rivera, Javier A., Ivaniuk, Alina, May, Patrick, Møller, Rikke S., Lal, Dennis
المساهمون: Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group)
المصدر: European Journal of Paediatric Neurology (2022-12-13)
مصطلحات موضوعية: Epilepsy, monogenic, Literature review, Genetics, Variant function, Epilepsy genes, Human health sciences, Neurology, Life sciences, Genetics & genetic processes, Pediatrics, Sciences de la santé humaine, Neurologie, Sciences du vivant, Génétique & processus génétiques, Pédiatrie
الوصف: peer reviewed ; Many epilepsy-associated genes have been identified over the last three decades, revealing a remarkable molecular heterogeneity with the shared outcome of recurrent seizures. Information about the genetic landscape of epilepsies is scattered throughout the literature and answering the simple question of how many genes are associated with epilepsy is not straightforward. Here, we present a computationally driven analytical review of epilepsy-associated genes using the complete scientific literature in PubMed. Based on our search criteria, we identified a total of 738 epilepsy-associated genes. We further classified these genes into two Tiers. A broad gene list of 738 epilepsy-associated genes (Tier 2) and a narrow gene list composed of 143 epilepsy-associated genes (Tier 1). Our search criteria do not reflect the degree of association. The average yearly number of identified epilepsy-associated genes between 1992 and 2021 was 4.8. However, most of these genes were only identified in the last decade (2010–2019). Ion channels represent the largest class of epilepsy-associated genes. For many of these, both gain- and loss-of-function effects have been associated with epilepsy in recent years. We identify 28 genes frequently reported with heterogenous variant effects which should be considered for variant interpretation. Overall, our study provides an updated and manually curated list of epilepsy-related genes together with additional annotations and classifications reflecting the current genetic landscape of epilepsy.
العلاقة: https://www.ejpn-journal.com/article/S1090-3798Test(22)00170-2/fulltext; FNR16394868 - Epileptogenesis Of Genetic Epilepsies, 2021 (01/10/2021-.) - Alexander Skupin; urn:issn:1532-2130; https://orbilu.uni.lu/handle/10993/53119Test; info:hdl:10993/53119; https://orbilu.uni.lu/bitstream/10993/53119/1/MacNee%20EurJPedNeurol2022.pdfTest; scopus-id:2-s2.0-85145335345; info:pmid:36586220; wos:000921469700001
الإتاحة: https://doi.org/10.1016/j.ejpn.2022.12.005Test
https://orbilu.uni.lu/handle/10993/53119Test
https://orbilu.uni.lu/bitstream/10993/53119/1/MacNee%20EurJPedNeurol2022.pdfTest -
9دورية أكاديمية
المؤلفون: Alexis M. Thornton (11068403), Lishan Fang (10101825), April Lo (11068406), Maria McSharry (11068409), David Haan (11068412), Casey O’Brien (4671856), Alice H. Berger (11068415), Marios Giannakis (3564314), Angela N. Brooks (11068418)
مصطلحات موضوعية: Biochemistry, Medicine, Microbiology, Genetics, Molecular Biology, Physiology, Cancer, Infectious Diseases, Virology, Biological Sciences not elsewhere classified, RAS, RNF 43 R 117fs RNF 43 G 659fs, KRAS, eVIP 2 software, Additional eVIP Pathways analysis, expression-based variant impact phe., Western blot analysis, change-of-function mutation, G 659fs variants, RNF 43 WT, GOF, eVIP 2 method, GFP control cDNA, gene variants, RNF 43 WT function, gene variant function, decision tree-based algorithm, eVIP 2, RNF 43 G 659fs, HEK 293T cells
الوصف: (DOCX)
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10دورية أكاديمية
المؤلفون: Alexis M. Thornton (11068403), Lishan Fang (10101825), April Lo (11068406), Maria McSharry (11068409), David Haan (11068412), Casey O’Brien (4671856), Alice H. Berger (11068415), Marios Giannakis (3564314), Angela N. Brooks (11068418)
مصطلحات موضوعية: Biochemistry, Medicine, Microbiology, Genetics, Molecular Biology, Physiology, Cancer, Infectious Diseases, Virology, Biological Sciences not elsewhere classified, RAS, RNF 43 R 117fs RNF 43 G 659fs, KRAS, eVIP 2 software, Additional eVIP Pathways analysis, expression-based variant impact phe., Western blot analysis, change-of-function mutation, G 659fs variants, RNF 43 WT, GOF, eVIP 2 method, GFP control cDNA, gene variants, RNF 43 WT function, gene variant function, decision tree-based algorithm, eVIP 2, RNF 43 G 659fs, HEK 293T cells
الوصف: Pathway reporter assay results are more consistent with eVIP Pathway prediction than with GSEA. Results from a pathway reporter array using different sample group comparisons (first 3 columns). Pathways were considered significant with p-value under .05, then the direction of difference is reported as inhibited or activated. The last two columns are eVIP Pathway and GSEA Investigate Gene Sets results (GOF = Gain of Function, COF = Change of function). GSEA Investigate Gene Sets was run on RNF43 G659fs mutation-specific genes. Only significant pathways (FDR q-value < .05) that contain at least 10 genes in the overlap are shown. (DOCX)
النص الكامل