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VarI-COSI 2022: Identification and Annotation of Genetic Variants in the Context of Structure, Function and Disease

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (31 July 2023) | Viewed by 11458

Special Issue Editors


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Guest Editor
Department of Pharmacy and Biotechnology (FaBiT), University of Bologna, Via F. Selmi 3 - 2nd Floor, Room 104, 40126 Bologna, Italy
Interests: protein and RNA structure analysis and prediction; protein folding and function; protein stability and kinetic; predicting the impact of protein variants; genotype interpretation

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Guest Editor
Hôpital Necker Enfants Malades, Paris, France
Interests: bioinformatics; functional genomics; rare diseases; genome analysis; single-cell omics

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Guest Editor
Division of Medical Genetics, UC San Diego, 9500 Gilman Drive, La Jolla, CA, USA
Interests: cancer genomics; bioinformatics; systems biology

Special Issue Information

Dear Colleagues, 

This Special Issue focus on the recent works presented during the VarI-COSI session at the ISMB 2022 meeting. For this Special Issue, we are interested in works presenting original studies or reviews in all fields of genetic variant research, including, but not limited to, "genetic variants in" sequence analysis, protein structure and function, protein interactions and molecular networks, transcriptomics and gene regulation, disease models and epidemiology, population genetics and evolution and comparative genomics. The Special Issue aims to focus on themes related to genetic variants as markers; evolution, populations, GWAS and genetic variants as effectors; and function, structure and regulation. In detail, submissions on the following major research topics of the field are welcome:

  • Databases of genetic variants;
  • Data mining algorithms for variant annotation;
  • Variant visualization tools;
  • Computational methods for predicting the impact of variants;
  • Experimental studies on variant effects;
  • GWAS studies and variant prioritization;
  • Population genomics and phylogenetic analysis;
  • Impact of variants on human health.

Dr. Emidio Capriotti
Dr. Antonio Rausell
Dr. Hannah Carter
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

  • variant interpretation
  • protein stability
  • protein function
  • non coding variants
  • pathogenic variants
  • machine learning
  • variant databases

Published Papers (5 papers)

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Research

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22 pages, 2440 KiB  
Article
Choosing Variant Interpretation Tools for Clinical Applications: Context Matters
by Josu Aguirre, Natàlia Padilla, Selen Özkan, Casandra Riera, Lídia Feliubadaló and Xavier de la Cruz
Int. J. Mol. Sci. 2023, 24(14), 11872; https://doi.org/10.3390/ijms241411872 - 24 Jul 2023
Viewed by 1726
Abstract
Pathogenicity predictors are computational tools that classify genetic variants as benign or pathogenic; this is currently a major challenge in genomic medicine. With more than fifty such predictors available, selecting the most suitable tool for clinical applications like genetic screening, molecular diagnostics, and [...] Read more.
Pathogenicity predictors are computational tools that classify genetic variants as benign or pathogenic; this is currently a major challenge in genomic medicine. With more than fifty such predictors available, selecting the most suitable tool for clinical applications like genetic screening, molecular diagnostics, and companion diagnostics has become increasingly challenging. To address this issue, we have developed a cost-based framework that naturally considers the various components of the problem. This framework encodes clinical scenarios using a minimal set of parameters and treats pathogenicity predictors as rejection classifiers, a common practice in clinical applications where low-confidence predictions are routinely rejected. We illustrate our approach in four examples where we compare different numbers of pathogenicity predictors for missense variants. Our results show that no single predictor is optimal for all clinical scenarios and that considering rejection yields a different perspective on classifiers. Full article
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15 pages, 2047 KiB  
Article
Identification of Driver Epistatic Gene Pairs Combining Germline and Somatic Mutations in Cancer
by Jairo Rocha, Jaume Sastre, Emilia Amengual-Cladera, Jessica Hernandez-Rodriguez, Victor Asensio-Landa, Damià Heine-Suñer and Emidio Capriotti
Int. J. Mol. Sci. 2023, 24(11), 9323; https://doi.org/10.3390/ijms24119323 - 26 May 2023
Viewed by 1305
Abstract
Cancer arises from the complex interplay of various factors. Traditionally, the identification of driver genes focuses primarily on the analysis of somatic mutations. We describe a new method for the detection of driver gene pairs based on an epistasis analysis that considers both [...] Read more.
Cancer arises from the complex interplay of various factors. Traditionally, the identification of driver genes focuses primarily on the analysis of somatic mutations. We describe a new method for the detection of driver gene pairs based on an epistasis analysis that considers both germline and somatic variations. Specifically, the identification of significantly mutated gene pairs entails the calculation of a contingency table, wherein one of the co-mutated genes can exhibit a germline variant. By adopting this approach, it is possible to select gene pairs in which the individual genes do not exhibit significant associations with cancer. Finally, a survival analysis is used to select clinically relevant gene pairs. To test the efficacy of the new algorithm, we analyzed the colon adenocarcinoma (COAD) and lung adenocarcinoma (LUAD) samples available at The Cancer Genome Atlas (TCGA). In the analysis of the COAD and LUAD samples, we identify epistatic gene pairs significantly mutated in tumor tissue with respect to normal tissue. We believe that further analysis of the gene pairs detected by our method will unveil new biological insights, enhancing a better description of the cancer mechanism. Full article
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16 pages, 5887 KiB  
Article
Dimerisation of the Yeast K+ Translocation Protein Trk1 Depends on the K+ Concentration
by Natalia Kulik, Deepika Kale, Karin Spurna, Katsiaryna Shamayeva, Fabian Hauser, Sandra Milic, Hannah Janout, Vasilina Zayats, Jaroslaw Jacak and Jost Ludwig
Int. J. Mol. Sci. 2023, 24(1), 398; https://doi.org/10.3390/ijms24010398 - 26 Dec 2022
Cited by 1 | Viewed by 1906
Abstract
In baker’s yeast (Saccharomyces cerevisiae), Trk1, a member of the superfamily of K-transporters (SKT), is the main K+ uptake system under conditions when its concentration in the environment is low. Structurally, Trk1 is made up of four domains, each similar [...] Read more.
In baker’s yeast (Saccharomyces cerevisiae), Trk1, a member of the superfamily of K-transporters (SKT), is the main K+ uptake system under conditions when its concentration in the environment is low. Structurally, Trk1 is made up of four domains, each similar and homologous to a K-channel α subunit. Because most K-channels are proteins containing four channel-building α subunits, Trk1 could be functional as a monomer. However, related SKT proteins TrkH and KtrB were crystallised as dimers, and for Trk1, a tetrameric arrangement has been proposed based on molecular modelling. Here, based on Bimolecular Fluorescence Complementation experiments and single-molecule fluorescence microscopy combined with molecular modelling; we provide evidence that Trk1 can exist in the yeast plasma membrane as a monomer as well as a dimer. The association of monomers to dimers is regulated by the K+ concentration. Full article
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Review

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17 pages, 2205 KiB  
Review
MicroRNAs and Gene Regulatory Networks Related to Cleft Lip and Palate
by Chihiro Iwaya, Akiko Suzuki and Junichi Iwata
Int. J. Mol. Sci. 2023, 24(4), 3552; https://doi.org/10.3390/ijms24043552 - 10 Feb 2023
Cited by 8 | Viewed by 2819
Abstract
Cleft lip and palate is one of the most common congenital birth defects and has a complex etiology. Either genetic or environmental factors, or both, are involved at various degrees, and the type and severity of clefts vary. One of the longstanding questions [...] Read more.
Cleft lip and palate is one of the most common congenital birth defects and has a complex etiology. Either genetic or environmental factors, or both, are involved at various degrees, and the type and severity of clefts vary. One of the longstanding questions is how environmental factors lead to craniofacial developmental anomalies. Recent studies highlight non-coding RNAs as potential epigenetic regulators in cleft lip and palate. In this review, we will discuss microRNAs, a type of small non-coding RNAs that can simultaneously regulate expression of many downstream target genes, as a causative mechanism of cleft lip and palate in humans and mice. Full article
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23 pages, 405 KiB  
Review
Sex-Related Changes in the Clinical, Genetic, Electrophysiological, Connectivity, and Molecular Presentations of ASD: A Comparison between Human and Animal Models of ASD with Reference to Our Data
by Asher Ornoy, Denis Gorobets, Liza Weinstein-Fudim and Maria Becker
Int. J. Mol. Sci. 2023, 24(4), 3287; https://doi.org/10.3390/ijms24043287 - 7 Feb 2023
Cited by 3 | Viewed by 2683
Abstract
The etiology of autism spectrum disorder (ASD) is genetic, environmental, and epigenetic. In addition to sex differences in the prevalence of ASD, which is 3–4 times more common in males, there are also distinct clinical, molecular, electrophysiological, and pathophysiological differences between sexes. In [...] Read more.
The etiology of autism spectrum disorder (ASD) is genetic, environmental, and epigenetic. In addition to sex differences in the prevalence of ASD, which is 3–4 times more common in males, there are also distinct clinical, molecular, electrophysiological, and pathophysiological differences between sexes. In human, males with ASD have more externalizing problems (i.e., attention-deficit hyperactivity disorder), more severe communication and social problems, as well as repetitive movements. Females with ASD generally exhibit fewer severe communication problems, less repetitive and stereotyped behavior, but more internalizing problems, such as depression and anxiety. Females need a higher load of genetic changes related to ASD compared to males. There are also sex differences in brain structure, connectivity, and electrophysiology. Genetic or non-genetic experimental animal models of ASD-like behavior, when studied for sex differences, showed some neurobehavioral and electrophysiological differences between male and female animals depending on the specific model. We previously carried out studies on behavioral and molecular differences between male and female mice treated with valproic acid, either prenatally or early postnatally, that exhibited ASD-like behavior and found distinct differences between the sexes, the female mice performing better on tests measuring social interaction and undergoing changes in the expression of more genes in the brain compared to males. Interestingly, co-administration of S-adenosylmethionine alleviated the ASD-like behavioral symptoms and the gene-expression changes to the same extent in both sexes. The mechanisms underlying the sex differences are not yet fully understood. Full article
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