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Editor’s Choice Articles

Editor’s Choice articles are based on recommendations by the scientific editors of MDPI journals from around the world. Editors select a small number of articles recently published in the journal that they believe will be particularly interesting to readers, or important in the respective research area. The aim is to provide a snapshot of some of the most exciting work published in the various research areas of the journal.

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17 pages, 2946 KiB  
Article
Identification and Interpretation of eQTL and eGenes for Hodgkin Lymphoma Susceptibility
by Yeeun An and Chaeyoung Lee
Genes 2023, 14(6), 1142; https://doi.org/10.3390/genes14061142 - 24 May 2023
Cited by 2 | Viewed by 2396
Abstract
Genome-wide association studies (GWAS) have revealed approximately 100 genomic signals associated with Hodgkin lymphoma (HL); however, their target genes and underlying mechanisms causing HL susceptibility remain unclear. In this study, transcriptome-wide analysis of expression quantitative trait loci (eQTL) was conducted to identify target [...] Read more.
Genome-wide association studies (GWAS) have revealed approximately 100 genomic signals associated with Hodgkin lymphoma (HL); however, their target genes and underlying mechanisms causing HL susceptibility remain unclear. In this study, transcriptome-wide analysis of expression quantitative trait loci (eQTL) was conducted to identify target genes associated with HL GWAS signals. A mixed model, which explains polygenic regulatory effects by the genomic covariance among individuals, was implemented to discover expression genes (eGenes) using genotype data from 462 European/African individuals. Overall, 80 eGenes were identified to be associated with 20 HL GWAS signals. Enrichment analysis identified apoptosis, immune responses, and cytoskeletal processes as functions of these eGenes. The eGene of rs27524 encodes ERAP1 that can cleave peptides attached to human leukocyte antigen in immune responses; its minor allele may help Reed–Sternberg cells to escape the immune response. The eGene of rs7745098 encodes ALDH8A1 that can oxidize the precursor of acetyl-CoA for the production of ATP; its minor allele may increase oxidization activity to evade apoptosis of pre-apoptotic germinal center B cells. Thus, these minor alleles may be genetic risk factors for HL susceptibility. Experimental studies on genetic risk factors are needed to elucidate the underlying mechanisms of HL susceptibility and improve the accuracy of precision oncology. Full article
(This article belongs to the Section Bioinformatics)
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2 pages, 182 KiB  
Editorial
Special Issue: Lipid Metabolism, Adipogenesis and Fat Tissue Metabolism: Gene Regulation
by Marek Skrzypski and Paweł A. Kołodziejski
Genes 2023, 14(5), 1121; https://doi.org/10.3390/genes14051121 - 22 May 2023
Cited by 2 | Viewed by 2237
Abstract
Lipid metabolism is pivotal in controlling energy homeostasis [...] Full article
(This article belongs to the Special Issue Lipid Metabolism, Adipogenesis and Fat Tissue Metabolism: Gene Regulation)
8 pages, 551 KiB  
Brief Report
ITGAM rs1143679 Variant in Systemic Lupus Erythematosus Is Associated with Increased Serum Calcification Propensity
by Matthieu Halfon, Li Zhang, Driss Ehirchiou, Vishnuprabu Durairaj Pandian, Suzan Dahdal, Uyen Huynh-Do, Andreas Pasch, Camillo Ribi and Nathalie Busso
Genes 2023, 14(5), 1105; https://doi.org/10.3390/genes14051105 - 18 May 2023
Cited by 1 | Viewed by 2378
Abstract
Objectives: CD11B/ITGAM (Integrin Subunit α M) mediates the adhesion of monocytes, macrophages, and granulocytes and promotes the phagocytosis of complement-coated particles. Variants of the ITGAM gene are candidates for genetic susceptibility to systemic lupus erythematosus (SLE). SNP rs1143679 (R77H) of CD11B particularly increases [...] Read more.
Objectives: CD11B/ITGAM (Integrin Subunit α M) mediates the adhesion of monocytes, macrophages, and granulocytes and promotes the phagocytosis of complement-coated particles. Variants of the ITGAM gene are candidates for genetic susceptibility to systemic lupus erythematosus (SLE). SNP rs1143679 (R77H) of CD11B particularly increases the risk of developing SLE. Deficiency of CD11B is linked to premature extra-osseous calcification, as seen in the cartilage of animals with osteoarthritis. Serum calcification propensity measured by the T50 test is a surrogate marker for systemic calcification and reflects increased cardiovascular (CV) risk. We aimed to assess whether the CD11B R77H gene variant is associated with a higher serum calcification propensity (i.e., a lower T50 value) in SLE patients compared to the wild-type allele (WT). Methods: Cross-sectional study incorporating adults with SLE genotyped for the CD11B variant R77H and assessed for serum calcification propensity with the T50 method. Participants were included in a multicenter trans-disciplinary cohort and fulfilled the 1997 revised American College of Rheumatology (ACR) criteria for SLE. We used descriptive statistics for comparing baseline characteristics and sequential T50 measurements in subjects with the R77H variant vs. WT CD11B. Results: Of the 167 patients, 108 (65%) were G/G (WT), 53 (32%) were G/A heterozygous, and 6 (3%) were A/A homozygous for the R77H variant. A/A patients cumulated more ACR criteria upon inclusion (7 ± 2 vs. 5 ± 1 in G/G and G/A; p = 0.02). There were no differences between the groups in terms of global disease activity, kidney involvement, and chronic renal failure. Complement C3 levels were lower in A/A individuals compared to others (0.6 ± 0.08 vs. 0.9 ± 0.25 g/L; p = 0.02). Baseline T50 did not differ between the groups (A/A 278 ± 42′ vs. 297 ± 50′ in G/G and G/A; p = 0.28). Considering all sequential T50 test results, serum calcification propensity was significantly increased in A/A individuals compared to others (253 ± 50 vs. 290 ± 54; p = 0.008). Conclusions: SLE patients with homozygosity for the R77H variant and repeated T50 assessment displayed an increased serum calcification propensity (i.e., a lower T50) and lower C3 levels compared to heterozygous and WT CD11B, without differing with respect to global disease activity and kidney involvement. This suggests an increased CV risk in SLE patients homozygous for the R77H variant of CD11B. Full article
(This article belongs to the Section Molecular Genetics and Genomics)
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23 pages, 1399 KiB  
Review
The Role of Pharmacogenetics in Personalizing the Antidepressant and Anxiolytic Therapy
by Milica Radosavljevic, Dubravka Svob Strac, Jasna Jancic and Janko Samardzic
Genes 2023, 14(5), 1095; https://doi.org/10.3390/genes14051095 - 16 May 2023
Cited by 23 | Viewed by 8928
Abstract
Pharmacotherapy for neuropsychiatric disorders, such as anxiety and depression, has been characterized by significant inter-individual variability in drug response and the development of side effects. Pharmacogenetics, as a key part of personalized medicine, aims to optimize therapy according to a patient’s individual genetic [...] Read more.
Pharmacotherapy for neuropsychiatric disorders, such as anxiety and depression, has been characterized by significant inter-individual variability in drug response and the development of side effects. Pharmacogenetics, as a key part of personalized medicine, aims to optimize therapy according to a patient’s individual genetic signature by targeting genetic variations involved in pharmacokinetic or pharmacodynamic processes. Pharmacokinetic variability refers to variations in a drug’s absorption, distribution, metabolism, and elimination, whereas pharmacodynamic variability results from variable interactions of an active drug with its target molecules. Pharmacogenetic research on depression and anxiety has focused on genetic polymorphisms affecting metabolizing cytochrome P450 (CYP) and uridine 5’-diphospho-glucuronosyltransferase (UGT) enzymes, P-glycoprotein ATP-binding cassette (ABC) transporters, and monoamine and γ-aminobutyric acid (GABA) metabolic enzymes, transporters, and receptors. Recent pharmacogenetic studies have revealed that more efficient and safer treatments with antidepressants and anxiolytics could be achieved through genotype-guided decisions. However, because pharmacogenetics cannot explain all observed heritable variations in drug response, an emerging field of pharmacoepigenetics investigates how epigenetic mechanisms, which modify gene expression without altering the genetic code, might influence individual responses to drugs. By understanding the epi(genetic) variability of a patient’s response to pharmacotherapy, clinicians could select more effective drugs while minimizing the likelihood of adverse reactions and therefore improve the quality of treatment. Full article
(This article belongs to the Special Issue Genetic Basis of Stress-Related Neuropsychiatric Disorders)
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11 pages, 1620 KiB  
Article
phox2ba: The Potential Genetic Link behind the Overlap in the Symptomatology between CHARGE and Central Congenital Hypoventilation Syndromes
by Jessica E. MacLean, Jaime N. Wertman, Sergey V. Prykhozhij, Emily Chedrawe, Stewart Langley, Shelby L. Steele, Kevin Ban, Kim Blake and Jason N. Berman
Genes 2023, 14(5), 1086; https://doi.org/10.3390/genes14051086 - 15 May 2023
Cited by 1 | Viewed by 2037
Abstract
CHARGE syndrome typically results from mutations in the gene encoding chromodomain helicase DNA-binding protein 7 (CHD7). CHD7 is involved in regulating neural crest development, which gives rise to tissues of the skull/face and the autonomic nervous system (ANS). Individuals with CHARGE [...] Read more.
CHARGE syndrome typically results from mutations in the gene encoding chromodomain helicase DNA-binding protein 7 (CHD7). CHD7 is involved in regulating neural crest development, which gives rise to tissues of the skull/face and the autonomic nervous system (ANS). Individuals with CHARGE syndrome are frequently born with anomalies requiring multiple surgeries and often experience adverse events post-anesthesia, including oxygen desaturations, decreased respiratory rates, and heart rate abnormalities. Central congenital hypoventilation syndrome (CCHS) affects ANS components that regulate breathing. Its hallmark feature is hypoventilation during sleep, clinically resembling observations in anesthetized CHARGE patients. Loss of PHOX2B (paired-like homeobox 2b) underlies CCHS. Employing a chd7-null zebrafish model, we investigated physiologic responses to anesthesia and compared these to loss of phox2b. Heart rates were lower in chd7 mutants compared to the wild-type. Exposure to tricaine, a zebrafish anesthetic/muscle relaxant, revealed that chd7 mutants took longer to become anesthetized, with higher respiratory rates during recovery. chd7 mutant larvae demonstrated unique phox2ba expression patterns. The knockdown of phox2ba reduced larval heart rates similar to chd7 mutants. chd7 mutant fish are a valuable preclinical model to investigate anesthesia in CHARGE syndrome and reveal a novel functional link between CHARGE syndrome and CCHS. Full article
(This article belongs to the Special Issue Zebrafish Models for Human Genetic Disease Studies)
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15 pages, 6409 KiB  
Article
Stacking Multiple Genes Improves Resistance to Chilo suppressalis, Magnaporthe oryzae, and Nilaparvata lugens in Transgenic Rice
by Bai Li, Zhongkai Chen, Huizhen Chen, Chunlei Wang, Liyan Song, Yue Sun, Yicong Cai, Dahu Zhou, Linjuan Ouyang, Changlan Zhu, Haohua He and Xiaosong Peng
Genes 2023, 14(5), 1070; https://doi.org/10.3390/genes14051070 - 12 May 2023
Cited by 2 | Viewed by 2390
Abstract
The ability of various pests and diseases to adapt to a single plant resistance gene over time leads to loss of resistance in transgenic rice. Therefore, introduction of different pest and disease resistance genes is critical for successful cultivation of transgenic rice strains [...] Read more.
The ability of various pests and diseases to adapt to a single plant resistance gene over time leads to loss of resistance in transgenic rice. Therefore, introduction of different pest and disease resistance genes is critical for successful cultivation of transgenic rice strains with broad-spectrum resistance to multiple pathogens. Here, we produced resistance rice lines with multiple, stacked resistance genes by stacking breeding and comprehensively evaluated their resistance to Chilo suppressalis (striped rice stemborer), Magnaporthe oryzae (rice blast), and Nilaparvata lugens (brown planthopper) in a pesticide-free environment. CRY1C and CRY2A are exogenous genes from Bacillus thuringiensis. Pib, Pikm, and Bph29 are natural genes in rice. CH121TJH was introduced into CRY 1C, Pib, Pikm, and Bph29. CH891TJH and R205XTJH were introduced into CRY 2A, Pib, Pikm, and Bph29. Compared with those observed in their recurrent parents, CH121TJH significantly increased the mortality of borers. The other two lines CH891TJH and R205XTJH are the same result. Three lines introduction of Pib and Pikm significantly reduced the area of rice blast lesions, and introduction of Bph29 significantly reduced seedling mortality from N. lugens. Introduction of the exogenous genes had relatively few effects on agronomic and yield traits of the original parents. These findings suggest that stacking of rice resistance genes through molecular marker-assisted backcross breeding can confer broad spectrum and multiple resistance in differently genetic backgrounds. Full article
(This article belongs to the Topic Genetic Engineering in Agriculture)
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31 pages, 1326 KiB  
Review
Crosstalk between miRNAs and DNA Methylation in Cancer
by Michela Saviana, Patricia Le, Lavender Micalo, Daniel Del Valle-Morales, Giulia Romano, Mario Acunzo, Howard Li and Patrick Nana-Sinkam
Genes 2023, 14(5), 1075; https://doi.org/10.3390/genes14051075 - 12 May 2023
Cited by 32 | Viewed by 5633
Abstract
miRNAs are some of the most well-characterized regulators of gene expression. Integral to several physiological processes, their aberrant expression often drives the pathogenesis of both benign and malignant diseases. Similarly, DNA methylation represents an epigenetic modification influencing transcription and playing a critical role [...] Read more.
miRNAs are some of the most well-characterized regulators of gene expression. Integral to several physiological processes, their aberrant expression often drives the pathogenesis of both benign and malignant diseases. Similarly, DNA methylation represents an epigenetic modification influencing transcription and playing a critical role in silencing numerous genes. The silencing of tumor suppressor genes through DNA methylation has been reported in many types of cancer and is associated with tumor development and progression. A growing body of literature has described the crosstalk between DNA methylation and miRNAs as an additional layer in the regulation of gene expression. Methylation in miRNA promoter regions inhibits its transcription, while miRNAs can target transcripts and subsequently regulate the proteins responsible for DNA methylation. Such relationships between miRNA and DNA methylation serve an important regulatory role in several tumor types and highlight a novel avenue for potential therapeutic targets. In this review, we discuss the crosstalk between DNA methylation and miRNA expression in the pathogenesis of cancer and describe how miRNAs influence DNA methylation and, conversely, how methylation impacts the expression of miRNAs. Finally, we address how these epigenetic modifications may be leveraged as biomarkers in cancer. Full article
(This article belongs to the Section Molecular Genetics and Genomics)
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12 pages, 4052 KiB  
Article
The Complete Chloroplast Genomes of Blepharoglossum elegans and B. grossum and Comparative Analysis with Related Species (Orchidaceae, Malaxideae)
by Wenting Yang, Kunlin Wu, Lin Fang, Songjun Zeng and Lin Li
Genes 2023, 14(5), 1069; https://doi.org/10.3390/genes14051069 - 11 May 2023
Cited by 1 | Viewed by 2289
Abstract
Blepharoglossum is a rare orchid genus of the Malaxidinae primarily distributed in tropical Pacific islands, with several species occurring in the Taiwan and Hainan Islands of China. Currently, the monophyletic status of Blepharoglossum has been challenged, and the phylogenetic relationships among its allied [...] Read more.
Blepharoglossum is a rare orchid genus of the Malaxidinae primarily distributed in tropical Pacific islands, with several species occurring in the Taiwan and Hainan Islands of China. Currently, the monophyletic status of Blepharoglossum has been challenged, and the phylogenetic relationships among its allied groups have remained unresolved with traditional DNA markers. In this study, we initially sequenced and annotated the chloroplast (cp) genomes of two Blepharoglossum species, Blepharoglossum elegans (Lindl.) L. Li and Blepharoglossum grossum (Rchb.f.) L. Li. These cp genomes of Blepharoglossum share the typical quadripartite and circular structure. Each of the genomes encodes a total of 133 functional genes, including 87 protein-coding genes (CDS), 38 tRNA genes and 8 rRNA genes. By comparing the sequence differences between these two cp genomes, it was found that they are relatively conserved in terms of overall gene content and gene arrangement. However, a total of 684 SNPs and 2664 indels were still identified, with ycf1, clpP, and trnK-UUU protein-coding genes having the highest number of SNPs and indels. In further comparative analyses among the six cp genomes in Malaxidinae, significant sequence divergences were identified in the intergenic regions, namely rps16–trnQ-UUG, trnS-GCU–trnG-GCC, rpoB–trnC-GCA, trnE-UUC–trnT-GGU, trnF-GAA–trnV-UAC, atpB–rbcL, petA–psbJ, psbE–petL, psbB–psbT, trnN-GUU–rpl32, trnV-GAC–rps7, and rps7–trnL-CAA, and five coding regions, including matK, and rpoC2, ycf1, and two ycf2 genes. Phylogenetic analysis indicated that Blepharoglossum and Oberonia form a highly supported sister group relationship. Our results are consistent with previous studies and present increased resolution among major clades. Full article
(This article belongs to the Section Plant Genetics and Genomics)
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9 pages, 901 KiB  
Brief Report
Expression of Transposable Elements in the Brain of the Drosophila melanogaster Model for Fragile X Syndrome
by Maria Dolores De Donno, Antonietta Puricella, Simona D’Attis, Valeria Specchia and Maria Pia Bozzetti
Genes 2023, 14(5), 1060; https://doi.org/10.3390/genes14051060 - 9 May 2023
Cited by 1 | Viewed by 2434
Abstract
Fragile X syndrome is a neuro-developmental disease affecting intellectual abilities and social interactions. Drosophila melanogaster represents a consolidated model to study neuronal pathways underlying this syndrome, especially because the model recapitulates complex behavioural phenotypes. Drosophila Fragile X protein, or FMRP, is required for [...] Read more.
Fragile X syndrome is a neuro-developmental disease affecting intellectual abilities and social interactions. Drosophila melanogaster represents a consolidated model to study neuronal pathways underlying this syndrome, especially because the model recapitulates complex behavioural phenotypes. Drosophila Fragile X protein, or FMRP, is required for a normal neuronal structure and for correct synaptic differentiation in both the peripheral and central nervous systems, as well as for synaptic connectivity during development of the neuronal circuits. At the molecular level, FMRP has a crucial role in RNA homeostasis, including a role in transposon RNA regulation in the gonads of D. m. Transposons are repetitive sequences regulated at both the transcriptional and post-transcriptional levels to avoid genomic instability. De-regulation of transposons in the brain in response to chromatin relaxation has previously been related to neurodegenerative events in Drosophila models. Here, we demonstrate for the first time that FMRP is required for transposon silencing in larval and adult brains of Drosophila “loss of function” dFmr1 mutants. This study highlights that flies kept in isolation, defined as asocial conditions, experience activation of transposable elements. In all, these results suggest a role for transposons in the pathogenesis of certain neurological alterations in Fragile X as well as in abnormal social behaviors. Full article
(This article belongs to the Special Issue Epigenetics of Fragile X and Other Neurodevelopmental Disorders)
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12 pages, 1850 KiB  
Article
Ribonuclease D Processes a Small RNA Regulator of Multicellular Development in Myxobacteria
by Sarah M. Cossey, Gregory J. Velicer and Yuen-Tsu Nicco Yu
Genes 2023, 14(5), 1061; https://doi.org/10.3390/genes14051061 - 9 May 2023
Cited by 2 | Viewed by 2223
Abstract
By targeting mRNA transcripts, non-coding small RNAs (sRNAs) regulate the expression of genes governing a wide range of bacterial functions. In the social myxobacterium Myxococcus xanthus, the sRNA Pxr serves as a gatekeeper of the regulatory pathway controlling the life-cycle transition from [...] Read more.
By targeting mRNA transcripts, non-coding small RNAs (sRNAs) regulate the expression of genes governing a wide range of bacterial functions. In the social myxobacterium Myxococcus xanthus, the sRNA Pxr serves as a gatekeeper of the regulatory pathway controlling the life-cycle transition from vegetative growth to multicellular fruiting body development. When nutrients are abundant, Pxr prevents the initiation of the developmental program, but Pxr-mediated inhibition is alleviated when cells starve. To identify genes essential for Pxr function, a developmentally defective strain in which Pxr-mediated blockage of development is constitutively active (strain “OC”) was transposon-mutagenized to identify suppressor mutations that inactivate or bypass Pxr inhibition and thereby restore development. One of the four loci in which a transposon insertion restored development is rnd, encoding the Ribonuclease D protein (RNase D). RNase D is an exonuclease important for tRNA maturation. Here, we show that disruption of rnd abolishes the accumulation of Pxr-S, the product of Pxr processing from a longer precursor form (Pxr-L) and the active inhibitor of development. Additionally, the decrease in Pxr-S caused by rnd disruption was associated with increased accumulation primarily of a longer novel Pxr-specific transcript (Pxr-XL) rather than of Pxr-L. The introduction of a plasmid expressing rnd reverted cells back to OC-like phenotypes in development and Pxr accumulation, indicating that a lack of RNase D alone suppresses the developmental defect of OC. Moreover, an in vitro Pxr-processing assay demonstrated that RNase D processes Pxr-XL into Pxr-L; this implies that overall, Pxr sRNA maturation requires a sequential two-step processing. Collectively, our results indicate that a housekeeping ribonuclease plays a central role in a model form of microbial aggregative development. To our knowledge, this is the first evidence implicating RNase D in sRNA processing. Full article
(This article belongs to the Special Issue The Genetic Basis of Microbial Sociality)
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15 pages, 8411 KiB  
Article
Developing CuS for Predicting Aggressiveness and Prognosis in Lung Adenocarcinoma
by Honghao Liu, Haijun Che, Mengyan Zhang, Jinyue Lv, Chengjie Pu, Jiawei Wu, Yan Zhang and Yue Gu
Genes 2023, 14(5), 1055; https://doi.org/10.3390/genes14051055 - 8 May 2023
Cited by 1 | Viewed by 2250
Abstract
Cuproptosis is a newfound cell death form that depends on copper (Cu) ionophores to transport Cu into cancer cells. Studies on the relationship have covered most common cancer types and analyzed the links between cuproptosis-related genes (CRGs) and various aspects of tumor characteristics. [...] Read more.
Cuproptosis is a newfound cell death form that depends on copper (Cu) ionophores to transport Cu into cancer cells. Studies on the relationship have covered most common cancer types and analyzed the links between cuproptosis-related genes (CRGs) and various aspects of tumor characteristics. In this study, we evaluated the role of cuproptosis in lung adenocarcinoma (LUAD) and constructed the cuproptosis-related score (CuS) to predict aggressiveness and prognosis in LUAD, so as to achieve precise treatment for patients. CuS had a better predictive performance than cuproptosis genes, possibly due to the synergy of SLC family genes, and patients with a high CuS had a poor prognosis. Functional enrichment analysis revealed the correlation between CuS and immune and mitochondrial pathways in multiple datasets. Furthermore, we predicted six potential drugs targeting high-CuS patients, including AZD3759, which is a targeted drug for LUAD. In conclusion, cuproptosis is involved in LUAD aggressiveness, and CuS can accurately predict the prognosis of patients. These findings provide a basis for precise treatment of patients with high CuS in LUAD. Full article
(This article belongs to the Special Issue DNA and RNA Epigenetics and Transcriptomics Research, 2nd Edition)
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18 pages, 4443 KiB  
Article
Preliminary Study: DNA Transfer and Persistence on Non-Porous Surfaces Submerged in Spring Water
by Morgan L. Korzik, Josep De Alcaraz-Fossoul, Michael S. Adamowicz and David San Pietro
Genes 2023, 14(5), 1045; https://doi.org/10.3390/genes14051045 - 6 May 2023
Cited by 2 | Viewed by 3455
Abstract
Submerged items are often thought to lack evidentiary value. However, previous studies have shown the ability to recover DNA from submerged porous items for upwards of six weeks. The crevices or interweaving fibers in porous items are thought to protect DNA from being [...] Read more.
Submerged items are often thought to lack evidentiary value. However, previous studies have shown the ability to recover DNA from submerged porous items for upwards of six weeks. The crevices or interweaving fibers in porous items are thought to protect DNA from being washed away. It is hypothesized that, because non-porous surfaces do not have the same traits that might aid in DNA retention, then DNA quantities and the number of donor alleles recovered would decrease over longer submersion periods. Additionally, it is hypothesized that DNA quantity and the number of alleles would be negatively affected by flow conditions. Neat saliva of known DNA quantity was applied to glass slides and exposed to stagnant and flowing spring water to observe the effects on both DNA quantity and STR detection. Results supported that DNA deposited onto glass and subsequently submerged in water experienced a decrease in DNA quantity over time, yet submersion did not have as strong of a negative effect on the detected amplification product. Additionally, an increase in DNA quantity and detected amplification product from designated blank slides (no initial DNA added) could indicate the possibility of DNA transfer. Full article
(This article belongs to the Special Issue Advances in Forensic Molecular Genetics)
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13 pages, 640 KiB  
Review
A Glimpse into Chromatin Organization and Nuclear Lamina Contribution in Neuronal Differentiation
by Salvatore Martino, Pietro Salvatore Carollo and Viviana Barra
Genes 2023, 14(5), 1046; https://doi.org/10.3390/genes14051046 - 6 May 2023
Cited by 3 | Viewed by 3067
Abstract
During embryonic development, stem cells undergo the differentiation process so that they can specialize for different functions within the organism. Complex programs of gene transcription are crucial for this process to happen. Epigenetic modifications and the architecture of chromatin in the nucleus, through [...] Read more.
During embryonic development, stem cells undergo the differentiation process so that they can specialize for different functions within the organism. Complex programs of gene transcription are crucial for this process to happen. Epigenetic modifications and the architecture of chromatin in the nucleus, through the formation of specific regions of active as well as inactive chromatin, allow the coordinated regulation of the genes for each cell fate. In this mini-review, we discuss the current knowledge regarding the regulation of three-dimensional chromatin structure during neuronal differentiation. We also focus on the role the nuclear lamina plays in neurogenesis to ensure the tethering of the chromatin to the nuclear envelope. Full article
(This article belongs to the Special Issue Chromatin Organization in Cell Differentiation)
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15 pages, 1662 KiB  
Article
Freezing Does Not Alter Sperm Telomere Length despite Increasing DNA Oxidation and Fragmentation
by Charlène Gouhier, Hanae Pons-Rejraji, Sandra Dollet, Laure Chaput, Céline Bourgne, Marc Berger, Bruno Pereira, Andrei Tchirkov and Florence Brugnon
Genes 2023, 14(5), 1039; https://doi.org/10.3390/genes14051039 - 3 May 2023
Cited by 4 | Viewed by 2393
Abstract
Correlations were reported between sperm telomere length (STL) and male fertility, sperm DNA fragmentation, and oxidation. Sperm freezing is widely used for assisted reproductive techniques, fertility preservation, and sperm donation. However, its impact on STL remains unknown. For this study, semen surplus from [...] Read more.
Correlations were reported between sperm telomere length (STL) and male fertility, sperm DNA fragmentation, and oxidation. Sperm freezing is widely used for assisted reproductive techniques, fertility preservation, and sperm donation. However, its impact on STL remains unknown. For this study, semen surplus from patients who underwent routine semen analysis were used. The impact of slow freezing on STL was analyzed by performing qPCR before and after freezing. Sperm populations with different STL were evaluated using Q-FISH. The relationship between sperm DNA oxidation, DNA fragmentation, and STL was assessed in fresh and frozen sperm samples. No significant impact of slow freezing on STL was observed, neither measured by qPCR nor Q-FISH. However, Q-FISH allowed for the distinguishing of sperm populations with different STLs within individual sperm samples. Slow freezing induced different STL distributions for some of the analyzed sperm samples, but no correlation was found between STL and sperm DNA fragmentation or oxidation. Slow freezing does not alter STL despite increasing sperm DNA oxidation and fragmentation. As STL alterations could be transmitted to offspring, the lack of impact of the slow freezing method on STL ensures the safety of this procedure. Full article
(This article belongs to the Section Molecular Genetics and Genomics)
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31 pages, 416 KiB  
Review
Hereditary Cancer Syndromes: A Comprehensive Review with a Visual Tool
by Mattia Garutti, Lorenzo Foffano, Roberta Mazzeo, Anna Michelotti, Lucia Da Ros, Alessandra Viel, Gianmaria Miolo, Alberto Zambelli and Fabio Puglisi
Genes 2023, 14(5), 1025; https://doi.org/10.3390/genes14051025 - 30 Apr 2023
Cited by 38 | Viewed by 11066
Abstract
Hereditary cancer syndromes account for nearly 10% of cancers even though they are often underdiagnosed. Finding a pathogenic gene variant could have dramatic implications in terms of pharmacologic treatments, tailored preventive programs, and familiar cascade testing. However, diagnosing a hereditary cancer syndrome could [...] Read more.
Hereditary cancer syndromes account for nearly 10% of cancers even though they are often underdiagnosed. Finding a pathogenic gene variant could have dramatic implications in terms of pharmacologic treatments, tailored preventive programs, and familiar cascade testing. However, diagnosing a hereditary cancer syndrome could be challenging because of a lack of validated testing criteria or because of their suboptimal performance. In addition, many clinicians are not sufficiently well trained to identify and select patients that could benefit from a genetic test. Herein, we searched the available literature to comprehensively review and categorize hereditary cancer syndromes affecting adults with the aim of helping clinicians in their daily clinical practice through a visual tool. Full article
(This article belongs to the Section Human Genomics and Genetic Diseases)
16 pages, 658 KiB  
Article
Comparison of Genetic Susceptibility to Coronary Heart Disease in the Hungarian Populations: Risk Prediction Models for Coronary Heart Disease
by Nayla Nasr, Beáta Soltész, János Sándor, Róza Ádány and Szilvia Fiatal
Genes 2023, 14(5), 1033; https://doi.org/10.3390/genes14051033 - 30 Apr 2023
Cited by 2 | Viewed by 2371
Abstract
Background and Aim: It was evaluated whether the integration of genetic risk scores (GRS-unweighted, wGRS-weighted) into conventional risk factor (CRF) models for coronary heart disease or acute myocardial infarction (CHD/AMI) could improve the predictive ability of the models. Methods: Subjects and [...] Read more.
Background and Aim: It was evaluated whether the integration of genetic risk scores (GRS-unweighted, wGRS-weighted) into conventional risk factor (CRF) models for coronary heart disease or acute myocardial infarction (CHD/AMI) could improve the predictive ability of the models. Methods: Subjects and data collected in a previous survey were used to perform regression and ROC curve analyses as well as to examine the role of genetic components. Thirty SNPs were selected, and genotype and phenotype data were available for 558 participants (general: N = 279 and Roma: N = 279). Results: The mean GRS (27.27 ± 3.43 vs. 26.68 ± 3.51, p = 0.046) and wGRS (3.52 ± 0.68 vs. 3.33 ± 0.62, p = 0.001) were significantly higher in the general population. The addition of the wGRS to the CRF model yielded the strongest improvement in discrimination among Roma (from 0.8616 to 0.8674), while the addition of GRS to the CRF model yielded the strongest improvement in discrimination in the general population (from 0.8149 to 0.8160). In addition to that, the Roma individuals were likely to develop CHD/AMI at a younger age than subjects in the general population. Conclusions: The combination of the CRFs and genetic components improved the model’s performance and predicted AMI/CHD better than CRFs alone. Full article
(This article belongs to the Section Human Genomics and Genetic Diseases)
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21 pages, 2405 KiB  
Review
Lagging Strand Initiation Processes in DNA Replication of Eukaryotes—Strings of Highly Coordinated Reactions Governed by Multiprotein Complexes
by Heinz Peter Nasheuer and Nichodemus O. Onwubiko
Genes 2023, 14(5), 1012; https://doi.org/10.3390/genes14051012 - 29 Apr 2023
Cited by 5 | Viewed by 3490
Abstract
In their influential reviews, Hanahan and Weinberg coined the term ‘Hallmarks of Cancer’ and described genome instability as a property of cells enabling cancer development. Accurate DNA replication of genomes is central to diminishing genome instability. Here, the understanding of the initiation of [...] Read more.
In their influential reviews, Hanahan and Weinberg coined the term ‘Hallmarks of Cancer’ and described genome instability as a property of cells enabling cancer development. Accurate DNA replication of genomes is central to diminishing genome instability. Here, the understanding of the initiation of DNA synthesis in origins of DNA replication to start leading strand synthesis and the initiation of Okazaki fragment on the lagging strand are crucial to control genome instability. Recent findings have provided new insights into the mechanism of the remodelling of the prime initiation enzyme, DNA polymerase α-primase (Pol-prim), during primer synthesis, how the enzyme complex achieves lagging strand synthesis, and how it is linked to replication forks to achieve optimal initiation of Okazaki fragments. Moreover, the central roles of RNA primer synthesis by Pol-prim in multiple genome stability pathways such as replication fork restart and protection of DNA against degradation by exonucleases during double-strand break repair are discussed. Full article
(This article belongs to the Special Issue DNA Replication/Repair, and the DNA Damage Response in Human Disease 2023)
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21 pages, 4991 KiB  
Article
Metabarcoding of Antarctic Lichens from Areas with Different Deglaciation Times Reveals a High Diversity of Lichen-Associated Communities
by Andreas Beck, Angélica Casanova-Katny and Julia Gerasimova
Genes 2023, 14(5), 1019; https://doi.org/10.3390/genes14051019 - 29 Apr 2023
Cited by 5 | Viewed by 3014
Abstract
Lichens have developed numerous adaptations to optimise their survival under harsh abiotic stress, colonise different substrates, and reach substantial population sizes and high coverage in ice-free Antarctic areas, benefiting from a symbiotic lifestyle. As lichen thalli represent consortia with an unknown number of [...] Read more.
Lichens have developed numerous adaptations to optimise their survival under harsh abiotic stress, colonise different substrates, and reach substantial population sizes and high coverage in ice-free Antarctic areas, benefiting from a symbiotic lifestyle. As lichen thalli represent consortia with an unknown number of participants, it is important to know about the accessory organisms and their relationships with various environmental conditions. To this end, we analysed lichen-associated communities from Himantormia lugubris, Placopsis antarctica, P. contortuplicata, and Ramalina terebrata, collected from soils with differing deglaciation times, using a metabarcoding approach. In general, many more Ascomycete taxa are associated with the investigated lichens compared to Basidiomycota. Given our sampling, a consistently higher number of lichen-associated eukaryotes are estimated to be present in areas with deglaciation times of longer than 5000 years compared to more recently deglaciated areas. Thus far, members of Dothideomycetes, Leotiomycetes, and Arthoniomycetes have been restricted to the Placopsis specimens from areas with deglaciation times longer than 5000 years. Striking differences between the associated organisms of R. terebrata and H. lugubris have also been discovered. Thus, a species-specific basidiomycete, Tremella, was revealed for R. terebrata, as was a member of Capnodiales for H. lugubris. Our study provides further understanding of the complex terricolous lichen-associated mycobiome using the metabarcoding approach. It also illustrates the necessity to extend our knowledge of complex lichen symbiosis and further improve the coverage of microbial eukaryotes in DNA barcode libraries, including more extended sampling. Full article
(This article belongs to the Special Issue Polar Genomics)
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14 pages, 344 KiB  
Review
The Genomic Landscape of Melanoma and Its Therapeutic Implications
by Ting-Ting Yang, Sebastian Yu, Chiao-Li Khale Ke and Shih-Tsung Cheng
Genes 2023, 14(5), 1021; https://doi.org/10.3390/genes14051021 - 29 Apr 2023
Cited by 15 | Viewed by 3820
Abstract
Melanoma is one of the most aggressive malignancies of the skin. The genetic composition of melanoma is complex and varies among different subtypes. With the aid of recent technologies such as next generation sequencing and single-cell sequencing, our understanding of the genomic landscape [...] Read more.
Melanoma is one of the most aggressive malignancies of the skin. The genetic composition of melanoma is complex and varies among different subtypes. With the aid of recent technologies such as next generation sequencing and single-cell sequencing, our understanding of the genomic landscape of melanoma and its tumor microenvironment has become increasingly clear. These advances may provide explanation to the heterogenic treatment outcomes of melanoma patients under current therapeutic guidelines and provide further insights to the development of potential new therapeutic targets. Here, we provide a comprehensive review on the genetics related to melanoma tumorigenesis, metastasis, and prognosis. We also review the genetics affecting the melanoma tumor microenvironment and its relation to tumor progression and treatment. Full article
(This article belongs to the Special Issue Genetics of Complex Cutaneous Disorders)
45 pages, 1654 KiB  
Review
The Interplay between T Cells and Cancer: The Basis of Immunotherapy
by Christina Chen, Xin Liu, Che-Yu Chang, Helen Y. Wang and Rong-Fu Wang
Genes 2023, 14(5), 1008; https://doi.org/10.3390/genes14051008 - 28 Apr 2023
Cited by 21 | Viewed by 6732
Abstract
Over the past decade, immunotherapy has emerged as one of the most promising approaches to cancer treatment. The use of immune checkpoint inhibitors has resulted in impressive and durable clinical responses in the treatment of various cancers. Additionally, immunotherapy utilizing chimeric antigen receptor [...] Read more.
Over the past decade, immunotherapy has emerged as one of the most promising approaches to cancer treatment. The use of immune checkpoint inhibitors has resulted in impressive and durable clinical responses in the treatment of various cancers. Additionally, immunotherapy utilizing chimeric antigen receptor (CAR)-engineered T cells has produced robust responses in blood cancers, and T cell receptor (TCR)-engineered T cells are showing promising results in the treatment of solid cancers. Despite these noteworthy advancements in cancer immunotherapy, numerous challenges remain. Some patient populations are unresponsive to immune checkpoint inhibitor therapy, and CAR T cell therapy has yet to show efficacy against solid cancers. In this review, we first discuss the significant role that T cells play in the body’s defense against cancer. We then delve into the mechanisms behind the current challenges facing immunotherapy, starting with T cell exhaustion due to immune checkpoint upregulation and changes in the transcriptional and epigenetic landscapes of dysfunctional T cells. We then discuss cancer-cell-intrinsic characteristics, including molecular alterations in cancer cells and the immunosuppressive nature of the tumor microenvironment (TME), which collectively facilitate tumor cell proliferation, survival, metastasis, and immune evasion. Finally, we examine recent advancements in cancer immunotherapy, with a specific emphasis on T-cell-based treatments. Full article
(This article belongs to the Special Issue Cell Signalling and Inflammation in Cancer)
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12 pages, 2725 KiB  
Article
The YBR056W-A and Its Ortholog YDR034W-B of S. cerevisiae Belonging to CYSTM Family Participate in Manganese Stress Overcoming
by Anton Zvonarev, Larisa Ledova, Lubov Ryazanova, Airat Valiakhmetov, Vasilina Farofonova and Tatiana Kulakovskaya
Genes 2023, 14(5), 987; https://doi.org/10.3390/genes14050987 - 27 Apr 2023
Cited by 4 | Viewed by 1897
Abstract
The CYSTM (cysteine-rich transmembrane module) protein family comprises small molecular cysteine-rich tail-anchored membrane proteins found in many eukaryotes. The Saccharomyces cerevisiae strains carrying the CYSTM genes YDRO34W-B and YBR056W-A (MNC1) fused with GFP were used to test the expression of these [...] Read more.
The CYSTM (cysteine-rich transmembrane module) protein family comprises small molecular cysteine-rich tail-anchored membrane proteins found in many eukaryotes. The Saccharomyces cerevisiae strains carrying the CYSTM genes YDRO34W-B and YBR056W-A (MNC1) fused with GFP were used to test the expression of these genes under different stresses. The YBR056W-A (MNC1) and YDR034W-B genes are expressed under stress conditions caused by the toxic concentrations of heavy metal ions, such as manganese, cobalt, nickel, zinc, cuprum, and 2.4-dinitrophenol uncoupler. The expression level of YDR034W-B was higher than that of YBR056W-A under alkali and cadmium stresses. The Ydr034w-b-GFP and Ybr056w-a-GFP proteins differ in the cellular localization: Ydr034w-b-GFP was mainly observed in the plasma membrane and vacuolar membrane, while Ybr056w-a-GFP was observed in the cytoplasm, probably in intracellular membranes. The null-mutants in both genes demonstrated decreased cell concentration and lytic phenotype when cultivated in the presence of excess manganese. This allows for speculations about the involvement of Mnc1 and Ydr034w-b proteins in manganese stress overcoming. Full article
(This article belongs to the Special Issue Feature Papers in Microbial Genetics in 2023)
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17 pages, 7261 KiB  
Article
Coronin 1C, Regulated by Multiple microRNAs, Facilitates Cancer Cell Aggressiveness in Pancreatic Ductal Adenocarcinoma
by Kosuke Fukuda, Naohiko Seki, Ryutaro Yasudome, Reiko Mitsueda, Shunichi Asai, Mayuko Kato, Tetsuya Idichi, Hiroshi Kurahara and Takao Ohtsuka
Genes 2023, 14(5), 995; https://doi.org/10.3390/genes14050995 - 27 Apr 2023
Cited by 3 | Viewed by 2659
Abstract
Coronin proteins are actin-related proteins containing WD repeat domains encoded by seven genes (CORO1A, CORO1B, CORO1C, CORO2A, CORO2B, CORO6, and CORO7) in the human genome. Analysis of large cohort data from The Cancer Genome Atlas [...] Read more.
Coronin proteins are actin-related proteins containing WD repeat domains encoded by seven genes (CORO1A, CORO1B, CORO1C, CORO2A, CORO2B, CORO6, and CORO7) in the human genome. Analysis of large cohort data from The Cancer Genome Atlas revealed that expression of CORO1A, CORO1B, CORO1C, CORO2A, and CORO7 was significantly upregulated in pancreatic ductal adenocarcinoma (PDAC) tissues (p < 0.05). Moreover, high expression of CORO1C and CORO2A significantly predicted the 5 year survival rate of patients with PDAC (p = 0.0071 and p = 0.0389, respectively). In this study, we focused on CORO1C and investigated its functional significance and epigenetic regulation in PDAC cells. Knockdown assays using siRNAs targeting CORO1C were performed in PDAC cells. Aggressive cancer cell phenotypes, especially cancer cell migration and invasion, were inhibited by CORO1C knockdown. The involvement of microRNAs (miRNAs) is a molecular mechanism underlying the aberrant expression of cancer-related genes in cancer cells. Our in silico analysis revealed that five miRNAs (miR-26a-5p, miR-29c-3p, miR-130b-5p, miR-148a-5p, and miR-217) are putative candidate miRNAs regulating CORO1C expression in PDAC cells. Importantly, all five miRNAs exhibited tumor-suppressive functions and four miRNAs except miR-130b-5p negatively regulated CORO1C expression in PDAC cells. CORO1C and its downstream signaling molecules are potential therapeutic targets in PDAC. Full article
(This article belongs to the Special Issue Genomics and Epigenomics of Gastrointestinal Disorders)
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14 pages, 3897 KiB  
Article
Contribution of Genetic Test to Early Diagnosis of Methylenetetrahydrofolate Reductase (MTHFR) Deficiency: The Experience of a Reference Center in Southern Italy
by Ferdinando Barretta, Fabiana Uomo, Simona Fecarotta, Lucia Albano, Daniela Crisci, Alessandra Verde, Maria Grazia Fisco, Giovanna Gallo, Daniela Dottore Stagna, Maria Rosaria Pricolo, Marianna Alagia, Gaetano Terrone, Alessandro Rossi, Giancarlo Parenti, Margherita Ruoppolo, Cristina Mazzaccara and Giulia Frisso
Genes 2023, 14(5), 980; https://doi.org/10.3390/genes14050980 - 26 Apr 2023
Cited by 4 | Viewed by 4931
Abstract
Background: the deficiency of 5,10-Methylenetetrahydrofolate reductase (MTHFR) constitutes a rare and severe metabolic disease and is included in most expanded newborn screening (NBS) programs worldwide. Patients with severe MTHFR deficiency develop neurological disorders and premature vascular disease. Timely diagnosis through NBS allows early [...] Read more.
Background: the deficiency of 5,10-Methylenetetrahydrofolate reductase (MTHFR) constitutes a rare and severe metabolic disease and is included in most expanded newborn screening (NBS) programs worldwide. Patients with severe MTHFR deficiency develop neurological disorders and premature vascular disease. Timely diagnosis through NBS allows early treatment, resulting in improved outcomes. Methods: we report the diagnostic yield of genetic testing for MTHFR deficiency diagnosis, in a reference Centre of Southern Italy between 2017 and 2022. MTHFR deficiency was suspected in four newborns showing hypomethioninemia and hyperhomocysteinemia; otherwise, one patient born in pre-screening era showed clinical symptoms and laboratory signs that prompted to perform genetic testing for MTHFR deficiency. Results: molecular analysis of the MTHFR gene revealed a genotype compatible with MTHFR deficiency in two NBS-positive newborns and in the symptomatic patient. This allowed for promptly beginning the adequate metabolic therapy. Conclusions: our results strongly support the need for genetic testing to quickly support the definitive diagnosis of MTHFR deficiency and start therapy. Furthermore, our study extends knowledge of the molecular epidemiology of MTHFR deficiency by identifying a novel mutation in the MTHFR gene. Full article
(This article belongs to the Special Issue Newborn Genetic Screening)
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12 pages, 1175 KiB  
Article
Evaluation and Verification of a microRNA Panel Using Quadratic Discriminant Analysis for the Classification of Human Body Fluids in DNA Extracts
by Ciara Rhodes, Carolyn Lewis, Kelsey Price, Anaya Valentine, Mary-Randall A. Creighton, Edward Boone and Sarah Seashols-Williams
Genes 2023, 14(5), 968; https://doi.org/10.3390/genes14050968 - 25 Apr 2023
Cited by 1 | Viewed by 4374
Abstract
There is significant interest in the use of miRNA analysis for forensic body fluid identification. Demonstrated co-extraction and detection in DNA extracts could make the use of miRNAs a more streamlined molecular body fluid identification method than other RNA-based methods. We previously reported [...] Read more.
There is significant interest in the use of miRNA analysis for forensic body fluid identification. Demonstrated co-extraction and detection in DNA extracts could make the use of miRNAs a more streamlined molecular body fluid identification method than other RNA-based methods. We previously reported a reverse transcription-quantitative PCR (RT-qPCR) panel of eight miRNAs that classified venous and menstrual blood, feces, urine, saliva, semen, and vaginal secretions using a quadratic discriminant analysis (QDA) model with 93% accuracy in RNA extracts. Herein, miRNA expression in DNA extracts from 50 donors of each body fluid were tested using the model. Initially, a classification rate of 87% was obtained, which increased to 92% when three additional miRNAs were added. Body fluid identification was found to be reliable across population samples of mixed ages, ethnicities, and sex, with 72–98% of the unknown samples classifying correctly. The model was then tested against compromised samples and over biological cycles, where classification accuracy varied, depending on the body fluid. In conclusion, we demonstrated the ability to classify body fluids using miRNA expression from DNA extracts, eliminating the need for RNA extraction, greatly reducing evidentiary sample consumption and processing time in forensic laboratories, but acknowledge that compromised semen and saliva samples can fail to classify properly, and mixed sample classification remains untested and may have limitations. Full article
(This article belongs to the Special Issue Advances in Forensic Molecular Genetics)
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12 pages, 734 KiB  
Article
LncRNA-SNPs in a Brazilian Breast Cancer Cohort: A Case-Control Study
by Carolina Mathias, Anelis Maria Marin, Ana Flávia Kohler, Heloisa Bruna Soligo Sanchuki, Natalie Sukow, Marcia Holsbach Beltrame, Suelen Cristina Soares Baal, Ana Paula Martins Sebastião, Enilze Maria de Souza Fonseca Ribeiro, Daniela Fiori Gradia, Mateus Nóbrega Aoki and Jaqueline Carvalho de Oliveira
Genes 2023, 14(5), 971; https://doi.org/10.3390/genes14050971 - 25 Apr 2023
Cited by 2 | Viewed by 2177
Abstract
Long noncoding RNAs (lncRNAs) are a class of non-coding RNAs that contain more than 200 nucleotides and exhibit a versatile regulatory capacity. Genomic alterations in lncRNAs have already been investigated in several complex diseases, including breast cancer (BC). BC is a highly heterogeneous [...] Read more.
Long noncoding RNAs (lncRNAs) are a class of non-coding RNAs that contain more than 200 nucleotides and exhibit a versatile regulatory capacity. Genomic alterations in lncRNAs have already been investigated in several complex diseases, including breast cancer (BC). BC is a highly heterogeneous disease and is the most prevalent cancer type among women worldwide. Single nucleotide polymorphisms (SNPs) in lncRNA regions appear to have an important role in BC susceptibility; however, little is known about lncRNA-SNPs in the Brazilian population. This study used Brazilian tumor samples to identify lncRNA-SNPs with a biological role in BC development. We applied a bioinformatic approach intersecting lncRNAs that are differentially expressed in BC tumor samples using The Cancer Genome Atlas (TCGA) cohort data and looked for lncRNAs with SNPs associated with BC in the Genome Wide Association Studies (GWAS) catalog. We highlight four lncRNA-SNPs—rs3803662, rs4415084, rs4784227, and rs7716600—which were genotyped in Brazilian BC samples in a case-control study. The SNPs rs4415084 and rs7716600 were associated with BC development at higher risk. These SNPs were also associated with progesterone status and lymph node status, respectively. The rs3803662/rs4784227 haplotype GT was associated with BC risk. These genomic alterations were also evaluated in light of the lncRNA’s secondary structure and gain/loss of miRNA binding sites to better understand its biological functions. We emphasize that our bioinformatics approach could find lncRNA-SNPs with a potential biological role in BC development and that lncRNA-SNPs should be more deeply investigated in a highly heterogeneous disease population. Full article
(This article belongs to the Section Molecular Genetics and Genomics)
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14 pages, 2161 KiB  
Article
Identification of LncRNAs and Functional Analysis of ceRNA Related to Fatty Acid Synthesis during Flax Seed Development
by Xinsen Yang, Caiyue Liu, Qiaoling Tang, Tianbao Zhang, Limin Wang, Lida Han, Jianping Zhang and Xinwu Pei
Genes 2023, 14(5), 967; https://doi.org/10.3390/genes14050967 - 24 Apr 2023
Cited by 3 | Viewed by 1798
Abstract
Flax is a flowering plant cultivated for its oil and contains various unsaturated fatty acids. Linseed oil is known as the “deep-sea fish oil” of plants, and is beneficial to brain and blood lipids, among other positive effects. Long non-coding RNAs (lncRNAs) play [...] Read more.
Flax is a flowering plant cultivated for its oil and contains various unsaturated fatty acids. Linseed oil is known as the “deep-sea fish oil” of plants, and is beneficial to brain and blood lipids, among other positive effects. Long non-coding RNAs (lncRNAs) play an important role in plant growth and development. There are not many studies assessing how lncRNAs are related to the fatty acid synthesis of flax. The relative oil contents of the seeds of the variety Heiya NO.14 (for fiber) and the variety Macbeth (for oil) were determined at 5 day, 10 day, 20 day, and 30 day after flowering. We found that 10–20 day is an important period for ALA accumulation in the Macbeth variety. The strand-specific transcriptome data were analyzed at these four time points, and a series of lncRNAs related to flax seed development were screened. A competing endogenous RNA (ceRNA) network was constructed and the accuracy of the network was verified using qRT-PCR. MSTRG.20631.1 could act with miR156 on the same target, squamosa promoter-binding-like protein (SPL), to influence fatty acid biosynthesis through a gluconeogenesis-related pathway during flax seed development. This study provides a theoretical basis for future studies assessing the potential functions of lncRNAs during seed development. Full article
(This article belongs to the Section Plant Genetics and Genomics)
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18 pages, 1025 KiB  
Review
Neuroprotective Peptides and New Strategies for Ischemic Stroke Drug Discoveries
by Lyudmila V. Dergunova, Ivan B. Filippenkov, Svetlana A. Limborska and Nikolay F. Myasoedov
Genes 2023, 14(5), 953; https://doi.org/10.3390/genes14050953 - 22 Apr 2023
Cited by 17 | Viewed by 5751
Abstract
Ischemic stroke continues to be one of the leading causes of death and disability in the adult population worldwide. The currently used pharmacological methods for the treatment of ischemic stroke are not effective enough and require the search for new tools and approaches [...] Read more.
Ischemic stroke continues to be one of the leading causes of death and disability in the adult population worldwide. The currently used pharmacological methods for the treatment of ischemic stroke are not effective enough and require the search for new tools and approaches to identify therapeutic targets and potential neuroprotectors. Today, in the development of neuroprotective drugs for the treatment of stroke, special attention is paid to peptides. Namely, peptide action is aimed at blocking the cascade of pathological processes caused by a decrease in blood flow to the brain tissues. Different groups of peptides have therapeutic potential in ischemia. Among them are small interfering peptides that block protein–protein interactions, cationic arginine-rich peptides with a combination of various neuroprotective properties, shuttle peptides that ensure the permeability of neuroprotectors through the blood–brain barrier, and synthetic peptides that mimic natural regulatory peptides and hormones. In this review, we consider the latest achievements and trends in the development of new biologically active peptides, as well as the role of transcriptomic analysis in identifying the molecular mechanisms of action of potential drugs aimed at the treatment of ischemic stroke. Full article
(This article belongs to the Special Issue Genomics of Stroke)
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24 pages, 1555 KiB  
Review
On the Future Perspectives of Some Medicinal Plants within Lamiaceae Botanic Family Regarding Their Comprehensive Properties and Resistance against Biotic and Abiotic Stresses
by Dan Ioan Avasiloaiei, Mariana Calara, Petre Marian Brezeanu, Otilia Cristina Murariu and Creola Brezeanu
Genes 2023, 14(5), 955; https://doi.org/10.3390/genes14050955 - 22 Apr 2023
Cited by 21 | Viewed by 3930
Abstract
Lamiaceae is one of the largest botanical families, encompassing over 6000 species that include a variety of aromatic and medicinal spices. The current study is focused on three plants within this botanical family: basil (Ocimum basilicum L.), thyme (Thymus vulgaris L.), [...] Read more.
Lamiaceae is one of the largest botanical families, encompassing over 6000 species that include a variety of aromatic and medicinal spices. The current study is focused on three plants within this botanical family: basil (Ocimum basilicum L.), thyme (Thymus vulgaris L.), and summer savory (Satureja hortensis L.). These three species contain primary and secondary metabolites such as phenolic and flavonoid compounds, fatty acids, antioxidants, and essential oils and have traditionally been used for flavoring, food preservation, and medicinal purposes. The goal of this study is to provide an overview of the nutraceutical, therapeutic, antioxidant, and antibacterial key features of these three aromatics to explore new breeding challenges and opportunities for varietal development. In this context, a literature search has been performed to describe the phytochemical profile of both primary and secondary metabolites and their pharmacological uses, as well as to further explore accession availability in the medicine industry and also to emphasize their bioactive roles in plant ecology and biotic and abiotic stress adaptability. The aim of this review is to explore future perspectives on the development of new, highly valuable basil, summer savory, and thyme cultivars. The findings of the current review emphasize the importance of identifying the key compounds and genes involved in stress resistance that can also provide valuable insights for further improvement of these important medicinal plants. Full article
(This article belongs to the Special Issue Phylogenetics, Genetics, and Breeding of Medicinal Plants)
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12 pages, 1531 KiB  
Article
Japanese Flounder pol-miR-155 Is Involved in Edwardsiella tarda Infection via ATG3
by Zhanwei Zhang and Xiaolu Guan
Genes 2023, 14(5), 958; https://doi.org/10.3390/genes14050958 - 22 Apr 2023
Cited by 4 | Viewed by 1962
Abstract
MicroRNAs (miRNAs) are small RNA molecules that function in the post-transcriptionally regulation of the expression of diverse genes, including those involved in immune defense. Edwardsiella tarda can infect a broad range of hosts and cause severe disease in aquatic species, including Japanese flounder [...] Read more.
MicroRNAs (miRNAs) are small RNA molecules that function in the post-transcriptionally regulation of the expression of diverse genes, including those involved in immune defense. Edwardsiella tarda can infect a broad range of hosts and cause severe disease in aquatic species, including Japanese flounder (Paralichthys olivaceus). In this study, we examined the regulation mechanism of a flounder miRNA, pol-miR-155, during the infection of E. tarda. Pol-miR-155 was identified to target flounder ATG3. Overexpression of pol-miR-155 or knockdown of ATG3 expression suppressed autophagy and promoted the intracellular replication of E. tarda in flounder cells. Overexpression of pol-miR-155 activated the NF-κB signaling pathway and further promoted the expression of downstream immune related genes of interleukin (IL)-6 and IL-8. These results unraveled the regulatory effect of pol-miR-155 in autophagy and in E. tarda infection. Full article
(This article belongs to the Special Issue Advances in Genes and Genomics of Aquatic Animals and Pathogens)
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20 pages, 2990 KiB  
Review
The Operon as a Conundrum of Gene Dynamics and Biochemical Constraints: What We Have Learned from Histidine Biosynthesis
by Sara Del Duca, Giulia Semenzato, Antonia Esposito, Pietro Liò and Renato Fani
Genes 2023, 14(4), 949; https://doi.org/10.3390/genes14040949 - 21 Apr 2023
Cited by 2 | Viewed by 4431
Abstract
Operons represent one of the leading strategies of gene organization in prokaryotes, having a crucial influence on the regulation of gene expression and on bacterial chromosome organization. However, there is no consensus yet on why, how, and when operons are formed and conserved, [...] Read more.
Operons represent one of the leading strategies of gene organization in prokaryotes, having a crucial influence on the regulation of gene expression and on bacterial chromosome organization. However, there is no consensus yet on why, how, and when operons are formed and conserved, and many different theories have been proposed. Histidine biosynthesis is a highly studied metabolic pathway, and many of the models suggested to explain operons origin and evolution can be applied to the histidine pathway, making this route an attractive model for the study of operon evolution. Indeed, the organization of his genes in operons can be due to a progressive clustering of biosynthetic genes during evolution, coupled with a horizontal transfer of these gene clusters. The necessity of physical interactions among the His enzymes could also have had a role in favoring gene closeness, of particular importance in extreme environmental conditions. In addition, the presence in this pathway of paralogous genes, heterodimeric enzymes and complex regulatory networks also support other operon evolution hypotheses. It is possible that histidine biosynthesis, and in general all bacterial operons, may result from a mixture of several models, being shaped by different forces and mechanisms during evolution. Full article
(This article belongs to the Section Molecular Genetics and Genomics)
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15 pages, 3736 KiB  
Article
Intrafollicular Retinoic Acid Signaling Is Important for Luteinizing Hormone-Induced Oocyte Meiotic Resumption
by Fupeng Wang, Yawen Tang, Yijie Cai, Ran Yang, Zongyu Wang, Xiaodong Wang, Qianying Yang, Wenjing Wang, Jianhui Tian and Lei An
Genes 2023, 14(4), 946; https://doi.org/10.3390/genes14040946 - 20 Apr 2023
Cited by 4 | Viewed by 2295
Abstract
It has been clear that retinoic acid (RA), the most active vitamin A (VA) derivative, plays a central role in governing oocyte meiosis initiation. However, it has not been functionally determined if RA participates in luteinizing hormone (LH)-induced resumption from long-lasting oocyte meiotic [...] Read more.
It has been clear that retinoic acid (RA), the most active vitamin A (VA) derivative, plays a central role in governing oocyte meiosis initiation. However, it has not been functionally determined if RA participates in luteinizing hormone (LH)-induced resumption from long-lasting oocyte meiotic arrest, which is essential for haploid oocyte formation. In the present study, using well-established in vivo and in vitro models, we identified that intrafollicular RA signaling is important for normal oocyte meiotic resumption. A mechanistic study indicated that mural granulosa cells (MGCs) are the indispensable follicular compartment for RA-prompted meiotic resumption. Moreover, retinoic acid receptor (RAR) is essential for mediating RA signaling to regulate meiotic resumption. Furthermore, we found zinc finger protein 36 (ZFP36) is the transcriptional target of RAR. Both RA signaling and epidermal growth factor (EGF) signaling were activated in MGCs in response to LH surge, and two intrafollicular signalings cooperate to induce rapid Zfp36 upregulation and Nppc mRNA decrease, which is critical to LH-induced meiotic resumption. These findings extend our understanding of the role of RA in oocyte meiosis: RA not only governs meiotic initiation but also regulates LH-induced meiotic resumption. We also emphasize the importance of LH-induced metabolic changes in MGCs in this process. Full article
(This article belongs to the Special Issue Genetic Regulation of Animal Reproduction)
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42 pages, 3406 KiB  
Review
The Hexosamine Biosynthesis Pathway: Regulation and Function
by Alysta Paneque, Harvey Fortus, Julia Zheng, Guy Werlen and Estela Jacinto
Genes 2023, 14(4), 933; https://doi.org/10.3390/genes14040933 - 18 Apr 2023
Cited by 77 | Viewed by 14363
Abstract
The hexosamine biosynthesis pathway (HBP) produces uridine diphosphate-N-acetyl glucosamine, UDP-GlcNAc, which is a key metabolite that is used for N- or O-linked glycosylation, a co- or post-translational modification, respectively, that modulates protein activity and expression. The production of hexosamines [...] Read more.
The hexosamine biosynthesis pathway (HBP) produces uridine diphosphate-N-acetyl glucosamine, UDP-GlcNAc, which is a key metabolite that is used for N- or O-linked glycosylation, a co- or post-translational modification, respectively, that modulates protein activity and expression. The production of hexosamines can occur via de novo or salvage mechanisms that are catalyzed by metabolic enzymes. Nutrients including glutamine, glucose, acetyl-CoA, and UTP are utilized by the HBP. Together with availability of these nutrients, signaling molecules that respond to environmental signals, such as mTOR, AMPK, and stress-regulated transcription factors, modulate the HBP. This review discusses the regulation of GFAT, the key enzyme of the de novo HBP, as well as other metabolic enzymes that catalyze the reactions to produce UDP-GlcNAc. We also examine the contribution of the salvage mechanisms in the HBP and how dietary supplementation of the salvage metabolites glucosamine and N-acetylglucosamine could reprogram metabolism and have therapeutic potential. We elaborate on how UDP-GlcNAc is utilized for N-glycosylation of membrane and secretory proteins and how the HBP is reprogrammed during nutrient fluctuations to maintain proteostasis. We also consider how O-GlcNAcylation is coupled to nutrient availability and how this modification modulates cell signaling. We summarize how deregulation of protein N-glycosylation and O-GlcNAcylation can lead to diseases including cancer, diabetes, immunodeficiencies, and congenital disorders of glycosylation. We review the current pharmacological strategies to inhibit GFAT and other enzymes involved in the HBP or glycosylation and how engineered prodrugs could have better therapeutic efficacy for the treatment of diseases related to HBP deregulation. Full article
(This article belongs to the Special Issue Signaling and Gene Regulation in Metabolism)
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12 pages, 1060 KiB  
Article
Comprehensive Genetic Analysis of Druze Provides Insights into Carrier Screening
by Eden Avnat, Guy Shapira, Shelly Shoval, Ifat Israel-Elgali, Anna Alkelai, Alan R. Shuldiner, Claudia Gonzaga-Jauregui, Jamal Zidan, Taiseer Maray, Noam Shomron and Eitan Friedman
Genes 2023, 14(4), 937; https://doi.org/10.3390/genes14040937 - 18 Apr 2023
Cited by 1 | Viewed by 2608
Abstract
Background: Druze individuals, like many genetically homogeneous and isolated populations, harbor recurring pathogenic variants (PV) in autosomal recessive (AR) disorders. Methods: Variant calling of whole-genome sequencing (WGS) of 40 Druze from the Human Genome Diversity Project (HGDP) was performed (HGDP-cohort). Additionally, we performed [...] Read more.
Background: Druze individuals, like many genetically homogeneous and isolated populations, harbor recurring pathogenic variants (PV) in autosomal recessive (AR) disorders. Methods: Variant calling of whole-genome sequencing (WGS) of 40 Druze from the Human Genome Diversity Project (HGDP) was performed (HGDP-cohort). Additionally, we performed whole exome sequencing (WES) of 118 Druze individuals: 38 trios and 2 couples, representing geographically distinct clans (WES-cohort). Rates of validated PV were compared with rates in worldwide and Middle Eastern populations, from the gnomAD and dbSNP datasets. Results: Overall, 34 PVs were identified: 30 PVs in genes underlying AR disorders, 3 additional PVs were associated with autosomal dominant (AD) disorders, and 1 PV with X-linked-dominant inherited disorder in the WES cohort. Conclusions: The newly identified PVs associated with AR conditions should be considered for incorporation into prenatal-screening options offered to Druze individuals after an extension and validation of the results in a larger study. Full article
(This article belongs to the Special Issue Genetic Variants in Human Population and Diseases)
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14 pages, 5790 KiB  
Article
Deep-Learning-Based Hepatic Ploidy Quantification Using H&E Histopathology Images
by Zhuoyu Wen, Yu-Hsuan Lin, Shidan Wang, Naoto Fujiwara, Ruichen Rong, Kevin W. Jin, Donghan M. Yang, Bo Yao, Shengjie Yang, Tao Wang, Yang Xie, Yujin Hoshida, Hao Zhu and Guanghua Xiao
Genes 2023, 14(4), 921; https://doi.org/10.3390/genes14040921 - 16 Apr 2023
Cited by 2 | Viewed by 3142
Abstract
Polyploidy, the duplication of the entire genome within a single cell, is a significant characteristic of cells in many tissues, including the liver. The quantification of hepatic ploidy typically relies on flow cytometry and immunofluorescence (IF) imaging, which are not widely available in [...] Read more.
Polyploidy, the duplication of the entire genome within a single cell, is a significant characteristic of cells in many tissues, including the liver. The quantification of hepatic ploidy typically relies on flow cytometry and immunofluorescence (IF) imaging, which are not widely available in clinical settings due to high financial and time costs. To improve accessibility for clinical samples, we developed a computational algorithm to quantify hepatic ploidy using hematoxylin-eosin (H&E) histopathology images, which are commonly obtained during routine clinical practice. Our algorithm uses a deep learning model to first segment and classify different types of cell nuclei in H&E images. It then determines cellular ploidy based on the relative distance between identified hepatocyte nuclei and determines nuclear ploidy using a fitted Gaussian mixture model. The algorithm can establish the total number of hepatocytes and their detailed ploidy information in a region of interest (ROI) on H&E images. This is the first successful attempt to automate ploidy analysis on H&E images. Our algorithm is expected to serve as an important tool for studying the role of polyploidy in human liver disease. Full article
(This article belongs to the Special Issue Feature Papers in Technologies and Resources for Genetics 2023)
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17 pages, 1243 KiB  
Article
Interaction between KLOTHO-VS Heterozygosity and APOE ε4 Allele Predicts Rate of Cognitive Decline in Late-Onset Alzheimer’s Disease
by Xi Richard Chen, Yongzhao Shao, Martin J. Sadowski and on behalf of the Alzheimer’s Disease Neuroimaging Initiative
Genes 2023, 14(4), 917; https://doi.org/10.3390/genes14040917 - 15 Apr 2023
Cited by 2 | Viewed by 3076
Abstract
KLOTHO-VS heterozygosity (KL-VShet+) promotes longevity and protects against cognitive decline in aging. To determine whether KL-VShet+ mitigates Alzheimer’s disease (AD) progression, we used longitudinal linear-mixed models to compare the rate of change in multiple cognitive measures [...] Read more.
KLOTHO-VS heterozygosity (KL-VShet+) promotes longevity and protects against cognitive decline in aging. To determine whether KL-VShet+ mitigates Alzheimer’s disease (AD) progression, we used longitudinal linear-mixed models to compare the rate of change in multiple cognitive measures in AD patients stratified by APOE ε4 carrier status. We aggregated data on 665 participants (208 KL-VShet−/ε4−, 307 KL-VShet−/ε4+, 66 KL-VShet+/ε4−, and 84 KL-VShet+/ε4+) from two prospective cohorts, the National Alzheimer’s Coordinating Center and the Alzheimer’s Disease Neuroimaging Initiative. All participants were initially diagnosed with mild cognitive impairment, later developed AD dementia during the study, and had at least three subsequent visits. KL-VShet+ conferred slower cognitive decline in ε4 non-carriers (+0.287 MMSE points/year, p = 0.001; −0.104 CDR-SB points/year, p = 0.026; −0.042 ADCOMS points/year, p < 0.001) but not in ε4 carriers who generally had faster rates of decline than non-carriers. Stratified analyses showed that the protective effect of KL-VShet+ was particularly prominent in male participants, those who were older than the median baseline age of 76 years, or those who had an education level of at least 16 years. For the first time, our study provides evidence that KL-VShet+ status has a protective effect on AD progression and interacts with the ε4 allele. Full article
(This article belongs to the Special Issue Molecular Biomarkers in Alzheimer’s Disease)
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15 pages, 3467 KiB  
Article
The Potential Regulation of A-to-I RNA Editing on Genes in Parkinson’s Disease
by Sijia Wu, Qiuping Xue, Xinyu Qin, Xiaoming Wu, Pora Kim, Jacqueline Chyr, Xiaobo Zhou and Liyu Huang
Genes 2023, 14(4), 919; https://doi.org/10.3390/genes14040919 - 15 Apr 2023
Cited by 3 | Viewed by 2509
Abstract
Parkinson’s disease (PD) is characterized by dopaminergic neurodegeneration and an abnormal accumulation of α-synuclein aggregates. A number of genetic factors have been shown to increase the risk of PD. Exploring the underlying molecular mechanisms that mediate PD’s transcriptomic diversity can help us understand [...] Read more.
Parkinson’s disease (PD) is characterized by dopaminergic neurodegeneration and an abnormal accumulation of α-synuclein aggregates. A number of genetic factors have been shown to increase the risk of PD. Exploring the underlying molecular mechanisms that mediate PD’s transcriptomic diversity can help us understand neurodegenerative pathogenesis. In this study, we identified 9897 A-to-I RNA editing events associated with 6286 genes across 372 PD patients. Of them, 72 RNA editing events altered miRNA binding sites and this may directly affect miRNA regulations of their host genes. However, RNA editing effects on the miRNA regulation of genes are more complex. They can (1) abolish existing miRNA binding sites, which allows miRNAs to regulate other genes; (2) create new miRNA binding sites that may sequester miRNAs from regulating other genes; or (3) occur in the miRNA seed regions and change their targets. The first two processes are also referred to as miRNA competitive binding. In our study, we found 8 RNA editing events that may alter the expression of 1146 other genes via miRNA competition. We also found one RNA editing event that modified a miRNA seed region, which was predicted to disturb the regulation of four genes. Considering the PD-related functions of the affected genes, 25 A-to-I RNA editing biomarkers for PD are proposed, including the 3 editing events in the EIF2AK2, APOL6, and miR-4477b seed regions. These biomarkers may alter the miRNA regulation of 133 PD-related genes. All these analyses reveal the potential mechanisms and regulations of RNA editing in PD pathogenesis. Full article
(This article belongs to the Special Issue Transcriptomics and Bioinformatics in Precision Medicine)
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3 pages, 186 KiB  
Editorial
Special Issue “DNA Replication/Repair, and the DNA Damage Response in Human Disease”
by Dong Zhang, Kristin A. Eckert and Marietta Y. W. T. Lee
Genes 2023, 14(4), 893; https://doi.org/10.3390/genes14040893 - 11 Apr 2023
Cited by 1 | Viewed by 2222
Abstract
Mutations of numerous genes involved in DNA replication, DNA repair, and DNA damage response (DDR) pathways lead to a variety of human diseases, including aging and cancer [...] Full article
(This article belongs to the Special Issue DNA Replication/Repair, and the DNA Damage Response in Human Disease)
16 pages, 326 KiB  
Article
Molecular and Sociodemographic Colorectal Cancer Disparities in Latinos Living in Puerto Rico
by Julyann Perez-Mayoral, Maria Gonzalez-Pons, Hilmaris Centeno-Girona, Ingrid M. Montes-Rodríguez, Marievelisse Soto-Salgado, Belisa Suárez, Natalia Rodríguez, Giancarlo Colón, Javier Sevilla, Daphne Jorge, Xavier Llor, Rosa M. Xicola, Doris H. Toro, Luis Tous-López, Marla Torres-Torres, José S. Reyes, Nicolas López-Acevedo, Ajay Goel, Segundo Rodríguez-Quilichini and Marcia Cruz-Correa
Genes 2023, 14(4), 894; https://doi.org/10.3390/genes14040894 - 11 Apr 2023
Cited by 5 | Viewed by 2834
Abstract
Background: The incidence of sporadic colorectal cancer (CRC) among individuals <50 years (early-onset CRC) has been increasing in the United States (U.S.) and Puerto Rico. CRC is currently the leading cause of cancer death among Hispanic men and women living in Puerto Rico [...] Read more.
Background: The incidence of sporadic colorectal cancer (CRC) among individuals <50 years (early-onset CRC) has been increasing in the United States (U.S.) and Puerto Rico. CRC is currently the leading cause of cancer death among Hispanic men and women living in Puerto Rico (PRH). The objective of this study was to characterize the molecular markers and clinicopathologic features of colorectal tumors from PRH to better understand the molecular pathways leading to CRC in this Hispanic subpopulation. Methods: Microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and KRAS and BRAF mutation status were analyzed. Sociodemographic and clinicopathological characteristics were evaluated using Chi-squared and Fisher’s exact tests. Results: Of the 718 tumors analyzed, 34.2% (n = 245) were early-onset CRC, and 51.7% were males. Among the tumors with molecular data available (n = 192), 3.2% had MSI, 9.7% had BRAF, and 31.9% had KRAS mutations. The most common KRAS mutations observed were G12D (26.6%) and G13D (20.0%); G12C was present in 4.4% of tumors. A higher percentage of Amerindian admixture was significantly associated with early-onset CRC. Conclusions: The differences observed in the prevalence of the molecular markers among PRH tumors compared to other racial/ethnic groups suggest a distinct molecular carcinogenic pathway among Hispanics. Additional studies are warranted. Full article
(This article belongs to the Section Molecular Genetics and Genomics)
12 pages, 1726 KiB  
Case Report
Rare 15q21.1q22.31 Duplication Due to a Familial Chromosomal Insertion and Diagnostic Investigation in a Carrier of Balanced Chromosomal Rearrangement and Intellectual Disability
by Carolina Gama Nascimento, Joana Rosa Marques Prota, Ilária Cristina Sgardioli, Samira Spineli-Silva, Nilma Lúcia Viguetti Campos, Vera Lúcia Gil-da-Silva-Lopes and Társis Paiva Vieira
Genes 2023, 14(4), 885; https://doi.org/10.3390/genes14040885 - 9 Apr 2023
Viewed by 2951
Abstract
Insertions are rare balanced chromosomal rearrangements with an increased risk of imbalances for the offspring. Moreover, balanced rearrangements in individuals with abnormal phenotypes may be associated to the phenotype by different mechanisms. This study describes a three-generation family with a rare chromosomal insertion. [...] Read more.
Insertions are rare balanced chromosomal rearrangements with an increased risk of imbalances for the offspring. Moreover, balanced rearrangements in individuals with abnormal phenotypes may be associated to the phenotype by different mechanisms. This study describes a three-generation family with a rare chromosomal insertion. G-banded karyotype, chromosomal microarray analysis (CMA), whole-exome sequencing (WES), and low-pass whole-genome sequencing (WGS) were performed. Six individuals had the balanced insertion [ins(9;15)(q33;q21.1q22.31)] and three individuals had the derivative chromosome 9 [der(9)ins(9;15)(q33;q21.1q22.31)]. The three subjects with unbalanced rearrangement showed similar clinical features, including intellectual disability, short stature, and facial dysmorphisms. CMA of these individuals revealed a duplication of 19.3 Mb at 15q21.1q22.31. A subject with balanced rearrangement presented with microcephaly, severe intellectual disability, absent speech, motor stereotypy, and ataxia. CMA of this patient did not reveal pathogenic copy number variations and low-pass WGS showed a disruption of the RABGAP1 gene at the 9q33 breakpoint. This gene has been recently associated with a recessive disorder, which is not compatible with the mode of inheritance in this patient. WES revealed an 88 bp deletion in the MECP2 gene, consistent with Rett syndrome. This study describes the clinical features associated with the rare 15q21.1–q22.31 duplication and reinforces that searching for other genetic causes is warranted for individuals with inherited balanced chromosomal rearrangements and abnormal phenotypes. Full article
(This article belongs to the Special Issue Advances in Clinical Cytogenetics)
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8 pages, 479 KiB  
Case Report
SATB2-Associated Syndrome Due to a c.715C>T:p(Arg239*) Variant in Adulthood: Natural History and Literature Review
by Matheus de Mello Copelli, Eleonore Pairet, Milena Atique-Tacla, Társis Paiva Vieira, Simone Appenzeller, Raphaël Helaers, Miikka Vikkula and Vera Lúcia Gil-da-Silva-Lopes
Genes 2023, 14(4), 882; https://doi.org/10.3390/genes14040882 - 8 Apr 2023
Cited by 1 | Viewed by 4069
Abstract
SATB2-associated syndrome (SAS) is a rare condition, and it is characterized by severe developmental delay/intellectual disability, especially severe speech delay/or absence, craniofacial abnormalities, and behavioral problems. Most of the published reports are limited to children, with little information about the natural history [...] Read more.
SATB2-associated syndrome (SAS) is a rare condition, and it is characterized by severe developmental delay/intellectual disability, especially severe speech delay/or absence, craniofacial abnormalities, and behavioral problems. Most of the published reports are limited to children, with little information about the natural history of the disease and the possible novel signs and symptoms or behavioral changes in adulthood. We describe the management and follow-up of a 25-year-old male with SAS due to a de novo heterozygous nonsense variant SATB2:c.715C>T:p.(Arg239*) identified by whole-exome sequencing and review the literature. The case herein described contributes to a better characterization of the natural history of this genetic condition and in addition to the genotype–phenotype correlation of the SATB2:c.715C>T:p.(Arg239*) variant in SAS, highlights some particularities of its management. Full article
(This article belongs to the Special Issue Genetic Disorders with Developmental Delay and Intellectual Disability)
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27 pages, 13999 KiB  
Article
Chromosome-Level Genome Assembly of the Blue Mussel Mytilus chilensis Reveals Molecular Signatures Facing the Marine Environment
by Cristian Gallardo-Escárate, Valentina Valenzuela-Muñoz, Gustavo Nuñez-Acuña, Diego Valenzuela-Miranda, Fabian J. Tapia, Marco Yévenes, Gonzalo Gajardo, Jorge E. Toro, Pablo A. Oyarzún, Gloria Arriagada, Beatriz Novoa, Antonio Figueras, Steven Roberts and Marco Gerdol
Genes 2023, 14(4), 876; https://doi.org/10.3390/genes14040876 - 7 Apr 2023
Cited by 15 | Viewed by 4604
Abstract
The blue mussel Mytilus chilensis is an endemic and key socioeconomic species inhabiting the southern coast of Chile. This bivalve species supports a booming aquaculture industry, which entirely relies on artificially collected seeds from natural beds that are translocated to diverse physical–chemical ocean [...] Read more.
The blue mussel Mytilus chilensis is an endemic and key socioeconomic species inhabiting the southern coast of Chile. This bivalve species supports a booming aquaculture industry, which entirely relies on artificially collected seeds from natural beds that are translocated to diverse physical–chemical ocean farming conditions. Furthermore, mussel production is threatened by a broad range of microorganisms, pollution, and environmental stressors that eventually impact its survival and growth. Herein, understanding the genomic basis of the local adaption is pivotal to developing sustainable shellfish aquaculture. We present a high-quality reference genome of M. chilensis, which is the first chromosome-level genome for a Mytilidae member in South America. The assembled genome size was 1.93 Gb, with a contig N50 of 134 Mb. Through Hi-C proximity ligation, 11,868 contigs were clustered, ordered, and assembled into 14 chromosomes in congruence with the karyological evidence. The M. chilensis genome comprises 34,530 genes and 4795 non-coding RNAs. A total of 57% of the genome contains repetitive sequences with predominancy of LTR-retrotransposons and unknown elements. Comparative genome analysis of M. chilensis and M. coruscus was conducted, revealing genic rearrangements distributed into the whole genome. Notably, transposable Steamer-like elements associated with horizontal transmissible cancer were explored in reference genomes, suggesting putative relationships at the chromosome level in Bivalvia. Genome expression analysis was also conducted, showing putative genomic differences between two ecologically different mussel populations. The evidence suggests that local genome adaptation and physiological plasticity can be analyzed to develop sustainable mussel production. The genome of M. chilensis provides pivotal molecular knowledge for the Mytilus complex. Full article
(This article belongs to the Special Issue Genetics and Genomics in Aquatic Animals)
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12 pages, 1337 KiB  
Article
Leri–Weill Dyschondrosteosis Caused by a Leaky Homozygous SHOX Splice-Site Variant
by Julia Vodopiutz, Lisa-Maria Steurer, Florentina Haufler, Franco Laccone, Dorota Garczarczyk-Asim, Matthias Hilkenmeier, Philipp Steinbauer and Andreas R. Janecke
Genes 2023, 14(4), 877; https://doi.org/10.3390/genes14040877 - 7 Apr 2023
Cited by 2 | Viewed by 2290
Abstract
SHOX deficiency is a common genetic cause of short stature of variable degree. SHOX haploinsufficiency causes Leri–Weill dyschondrosteosis (LWD) as well as nonspecific short stature. SHOX haploinsufficiency is known to result from heterozygous loss-of-function variants with pseudo-autosomal dominant inheritance, while biallelic SHOX loss-of-function [...] Read more.
SHOX deficiency is a common genetic cause of short stature of variable degree. SHOX haploinsufficiency causes Leri–Weill dyschondrosteosis (LWD) as well as nonspecific short stature. SHOX haploinsufficiency is known to result from heterozygous loss-of-function variants with pseudo-autosomal dominant inheritance, while biallelic SHOX loss-of-function variants cause the more severe skeletal dysplasia, Langer mesomelic dyschondrosteosis (LMD). Here we report for the first time the pseudo-autosomal recessive inheritance of LWD in two siblings caused by a novel homozygous non-canonical, leaky splice-site variant in intron 3 of SHOX: c.544+5G>C. Transcript analyses in patient-derived fibroblasts showed homozygous patients to produce approximately equal amounts of normally spliced mRNA and mRNA with the abnormal retention of intron 3 and containing a premature stop codon (p.Val183Glyfs*31). The aberrant transcript was shown to undergo nonsense-mediated mRNA decay, and thus resulting in SHOX haploinsufficiency in the homozygous patient. Six healthy relatives who are of normal height are heterozygous for this variant and fibroblasts from a heterozygote for the c.544+5G>C variant produced wild-type transcript amounts comparable to healthy control. The unique situation reported here highlights the fact that the dosage of SHOX determines the clinical phenotype rather than the Mendelian inheritance pattern of SHOX variants. This study extends the molecular and inheritance spectrum of SHOX deficiency disorder and highlights the importance of functional testing of SHOX variants of unknown significance in order to allow appropriate counseling and precision medicine for each family individual. Full article
(This article belongs to the Section Human Genomics and Genetic Diseases)
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34 pages, 2226 KiB  
Review
An Update of Epigenetic Drugs for the Treatment of Cancers and Brain Diseases: A Comprehensive Review
by Zahra Sahafnejad, Shahin Ramazi and Abdollah Allahverdi
Genes 2023, 14(4), 873; https://doi.org/10.3390/genes14040873 - 6 Apr 2023
Cited by 44 | Viewed by 7556
Abstract
Epigenetics has long been recognized as a significant field in biology and is defined as the investigation of any alteration in gene expression patterns that is not attributed to changes in the DNA sequences. Epigenetic marks, including histone modifications, non-coding RNAs, and DNA [...] Read more.
Epigenetics has long been recognized as a significant field in biology and is defined as the investigation of any alteration in gene expression patterns that is not attributed to changes in the DNA sequences. Epigenetic marks, including histone modifications, non-coding RNAs, and DNA methylation, play crucial roles in gene regulation. Numerous studies in humans have been carried out on single-nucleotide resolution of DNA methylation, the CpG island, new histone modifications, and genome-wide nucleosome positioning. These studies indicate that epigenetic mutations and aberrant placement of these epigenetic marks play a critical role in causing the disease. Consequently, significant development has occurred in biomedical research in identifying epigenetic mechanisms, their interactions, and changes in health and disease conditions. The purpose of this review article is to provide comprehensive information about the different types of diseases caused by alterations in epigenetic factors such as DNA methylation and histone acetylation or methylation. Recent studies reported that epigenetics could influence the evolution of human cancer via aberrant methylation of gene promoter regions, which is associated with reduced gene function. Furthermore, DNA methyltransferases (DNMTs) in the DNA methylation process as well as histone acetyltransferases (HATs)/histone deacetylases (HDACs) and histone methyltransferases (HMTs)/demethylases (HDMs) in histone modifications play important roles both in the catalysis and inhibition of target gene transcription and in many other DNA processes such as repair, replication, and recombination. Dysfunction in these enzymes leads to epigenetic disorders and, as a result, various diseases such as cancers and brain diseases. Consequently, the knowledge of how to modify aberrant DNA methylation as well as aberrant histone acetylation or methylation via inhibitors by using epigenetic drugs can be a suitable therapeutic approach for a number of diseases. Using the synergistic effects of DNA methylation and histone modification inhibitors, it is hoped that many epigenetic defects will be treated in the future. Numerous studies have demonstrated a link between epigenetic marks and their effects on brain and cancer diseases. Designing appropriate drugs could provide novel strategies for the management of these diseases in the near future. Full article
(This article belongs to the Special Issue Epigenetics in Brain Development and Neurodevelopmental Disorders)
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17 pages, 2051 KiB  
Article
Leishmania infantum (JPCM5) Transcriptome, Gene Models and Resources for an Active Curation of Gene Annotations
by Esther Camacho, Sandra González-de la Fuente, Jose Carlos Solana, Laura Tabera, Fernando Carrasco-Ramiro, Begoña Aguado and Jose M. Requena
Genes 2023, 14(4), 866; https://doi.org/10.3390/genes14040866 - 4 Apr 2023
Cited by 2 | Viewed by 2527
Abstract
Leishmania infantum is one of the causative agents of visceral leishmaniases, the most severe form of leishmaniasis. An improved assembly for the L. infantum genome was published five years ago, yet delineation of its transcriptome remained to be accomplished. In this work, the [...] Read more.
Leishmania infantum is one of the causative agents of visceral leishmaniases, the most severe form of leishmaniasis. An improved assembly for the L. infantum genome was published five years ago, yet delineation of its transcriptome remained to be accomplished. In this work, the transcriptome annotation was attained by a combination of both short and long RNA-seq reads. The good agreement between the results derived from both methodologies confirmed that transcript assembly based on Illumina RNA-seq and further delimitation according to the positions of spliced leader (SAS) and poly-A (PAS) addition sites is an adequate strategy to annotate the transcriptomes of Leishmania, a procedure previously used for transcriptome annotation in other Leishmania species and related trypanosomatids. These analyses also confirmed that the Leishmania transcripts boundaries are relatively slippery, showing extensive heterogeneity at the 5′- and 3′-ends. However, the use of RNA-seq reads derived from the PacBio technology (referred to as Iso-Seq) allowed the authors to uncover some complex transcription patterns occurring at particular loci that would be unnoticed by the use of short RNA-seq reads alone. Thus, Iso-Seq analysis provided evidence that transcript processing at particular loci would be more dynamic than expected. Another noticeable finding was the observation of a case of allelic heterozygosity based on the existence of chimeric Iso-Seq reads that might be generated by an event of intrachromosomal recombination. In addition, we are providing the L. infantum gene models, including both UTRs and CDS regions, that would be helpful for undertaking whole-genome expression studies. Moreover, we have built the foundations of a communal database for the active curation of both gene/transcript models and functional annotations for genes and proteins. Full article
(This article belongs to the Section Microbial Genetics and Genomics)
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13 pages, 4343 KiB  
Article
Molecular Characterization of the Acyl-CoA-Binding Protein Genes Reveals Their Significant Roles in Oil Accumulation and Abiotic Stress Response in Cotton
by Yizhen Chen, Mingchuan Fu, Hao Li, Liguo Wang, Renzhong Liu and Zhanji Liu
Genes 2023, 14(4), 859; https://doi.org/10.3390/genes14040859 - 1 Apr 2023
Cited by 3 | Viewed by 1852
Abstract
Members of the acyl-CoA-binding protein (ACBP) gene family play vital roles in diverse processes related to lipid metabolism, growth and development, and environmental response. Plant ACBP genes have been well-studied in a variety of species including Arabidopsis, soybean, rice and maize. However, the [...] Read more.
Members of the acyl-CoA-binding protein (ACBP) gene family play vital roles in diverse processes related to lipid metabolism, growth and development, and environmental response. Plant ACBP genes have been well-studied in a variety of species including Arabidopsis, soybean, rice and maize. However, the identification and functions of ACBP genes in cotton remain to be elucidated. In this study, a total of 11 GaACBP, 12 GrACBP, 20 GbACBP, and 19 GhACBP genes were identified in the genomes of Gossypium arboreum, Gossypium raimondii, Gossypium babardense, and Gossypium hirsutum, respectively, and grouped into four clades. Forty-nine duplicated gene pairs were identified in Gossypium ACBP genes, and almost all of which have undergone purifying selection during the long evolutionary process. In addition, expression analyses showed that most of the GhACBP genes were highly expressed in the developing embryos. Furthermore, GhACBP1 and GhACBP2 were induced by salt and drought stress based on a real-time quantitative PCR (RT-qPCR) assay, indicating that these genes may play an important role in salt- and drought-stress tolerance. This study will provide a basic resource for further functional analysis of the ACBP gene family in cotton. Full article
(This article belongs to the Special Issue Cotton Genes, Genetics, and Genomics)
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15 pages, 4754 KiB  
Article
Stable Isotope Tracing Reveals an Altered Fate of Glucose in N-Acetyltransferase 1 Knockout Breast Cancer Cells
by James T. F. Wise, Xinmin Yin, Xipeng Ma, Xiang Zhang and David W. Hein
Genes 2023, 14(4), 843; https://doi.org/10.3390/genes14040843 - 31 Mar 2023
Cited by 2 | Viewed by 2440
Abstract
Breast cancer is one of the leading causes of cancer death. Recent studies found that arylamine N-acetyltransferase 1 (NAT1) is frequently upregulated in breast cancer, further suggesting NAT1 could be a potential therapeutic target for breast cancer. Previous publications have established that [...] Read more.
Breast cancer is one of the leading causes of cancer death. Recent studies found that arylamine N-acetyltransferase 1 (NAT1) is frequently upregulated in breast cancer, further suggesting NAT1 could be a potential therapeutic target for breast cancer. Previous publications have established that NAT1 knockout (KO) in breast cancer cell lines leads to growth reduction both in vitro and in vivo and metabolic changes. These reports suggest that NAT1 contributes to the energy metabolism of breast cancer cells. Proteomic analysis and non-targeted metabolomics suggested that NAT1 KO may change the fate of glucose as it relates to the TCA/KREB cycle of the mitochondria of breast cancer cells. In this current study, we used [U-13C]-glucose stable isotope resolved metabolomics to determine the effect of NAT1 KO on the metabolic profile of MDA-MB-231 breast cancer cells. We incubated breast cancer cells (MDA-MB-231 cells) and NAT1 Crispr KO cells (KO#2 and KO#5) with [U-13C]-glucose for 24 h. Tracer incubation polar metabolites from the cells were extracted and analyzed by 2DLC-MS, and metabolite differences were compared between the parental and NAT1 KO cells. Differences consistent between the two KO cells were considered changes due to the loss of NAT1. The data revealed decreases in the 13C enrichment of TCA/Krebs cycle intermediates in NAT1 KO cells compared to the MDA-MB-231 cells. Specifically, 13C-labeled citrate, isocitrate, a-ketoglutarate, fumarate, and malate were all decreased in NAT1 KO cells. We also detected increased 13C-labeled L-lactate levels in the NAT1 KO cells and decreased 13C enrichment in some nucleotides. Pathway analysis showed that arginine biosynthesis, alanine, aspartate and glutamate metabolism, and the TCA cycle were most affected. These data provide additional evidence supporting the impacts of NAT1 knockout on cellular energy metabolism. The data suggest that NAT1 expression is important for the proper functioning of mitochondria and the flux of glucose through the TCA/Krebs cycle in breast cancer cells. The metabolism changes in the fate of glucose in NAT1 KO breast cancer cells offer more insight into the role of NAT1 in energy metabolism and the growth of breast cancer cells. These data provide additional evidence that NAT1 may be a useful therapeutic target for breast cancer. Full article
(This article belongs to the Topic Advances in Genetics and Precision Medicine in Human Diseases)
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10 pages, 2654 KiB  
Case Report
A Complex Intrachromosomal Rearrangement Disrupting IRF6 in a Family with Popliteal Pterygium and Van der Woude Syndromes
by Alya A. Al-Kurbi, Elbay Aliyev, Sana AlSa’afin, Waleed Aamer, Sasirekha Palaniswamy, Aljazi Al-Maraghi, Houda Kilani, Ammira Al-Shabeeb Akil, Mitchell A. Stotland and Khalid A. Fakhro
Genes 2023, 14(4), 849; https://doi.org/10.3390/genes14040849 - 31 Mar 2023
Cited by 2 | Viewed by 4261
Abstract
Clefts of the lip and/or palate (CL/P) are considered the most common form of congenital anomalies occurring either in isolation or in association with other clinical features. Van der woude syndrome (VWS) is associated with about 2% of all CL/P cases and is [...] Read more.
Clefts of the lip and/or palate (CL/P) are considered the most common form of congenital anomalies occurring either in isolation or in association with other clinical features. Van der woude syndrome (VWS) is associated with about 2% of all CL/P cases and is further characterized by having lower lip pits. Popliteal pterygium syndrome (PPS) is a more severe form of VWS, normally characterized by orofacial clefts, lower lip pits, skin webbing, skeletal anomalies and syndactyly of toes and fingers. Both syndromes are inherited in an autosomal dominant manner, usually caused by heterozygous mutations in the Interferon Regulatory Factor 6 (IRF6) gene. Here we report the case of a two-generation family where the index presented with popliteal pterygium syndrome while both the father and sister had clinical features of van der woude syndrome, but without any point mutations detected by re-sequencing of known gene panels or microarray testing. Using whole genome sequencing (WGS) followed by local de novo assembly, we discover and validate a copy-neutral, 429 kb complex intra-chromosomal rearrangement in the long arm of chromosome 1, disrupting the IRF6 gene. This variant is copy-neutral, novel against publicly available databases, and segregates in the family in an autosomal dominant pattern. This finding suggests that missing heritability in rare diseases may be due to complex genomic rearrangements that can be resolved by WGS and de novo assembly, helping deliver answers to patients where no genetic etiology was identified by other means. Full article
(This article belongs to the Section Human Genomics and Genetic Diseases)
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21 pages, 3345 KiB  
Review
The CRISPR/Cas System: A Customizable Toolbox for Molecular Detection
by Yuxuan He, Wei Yan, Likun Long, Liming Dong, Yue Ma, Congcong Li, Yanbo Xie, Na Liu, Zhenjuan Xing, Wei Xia and Feiwu Li
Genes 2023, 14(4), 850; https://doi.org/10.3390/genes14040850 - 31 Mar 2023
Cited by 22 | Viewed by 6202
Abstract
Clustered regularly interspaced short palindromic repeats (CRISPR) and their associated proteins (Cas) are promising molecular diagnostic tools for rapidly and precisely elucidating the structure and function of genomes due to their high specificity, programmability, and multi-system compatibility in nucleic acid recognition. Multiple parameters [...] Read more.
Clustered regularly interspaced short palindromic repeats (CRISPR) and their associated proteins (Cas) are promising molecular diagnostic tools for rapidly and precisely elucidating the structure and function of genomes due to their high specificity, programmability, and multi-system compatibility in nucleic acid recognition. Multiple parameters limit the ability of a CRISPR/Cas system to detect DNA or RNA. Consequently, it must be used in conjunction with other nucleic acid amplification techniques or signal detection techniques, and the reaction components and reaction conditions should be modified and optimized to maximize the detection performance of the CRISPR/Cas system against various targets. As the field continues to develop, CRISPR/Cas systems have the potential to become an ultra-sensitive, convenient, and accurate biosensing platform for the detection of specific target sequences. The design of a molecular detection platform employing the CRISPR/Cas system is asserted on three primary strategies: (1) Performance optimization of the CRISPR/Cas system; (2) enhancement of the detection signal and its interpretation; and (3) compatibility with multiple reaction systems. This article focuses on the molecular characteristics and application value of the CRISPR/Cas system and reviews recent research progress and development direction from the perspectives of principle, performance, and method development challenges to provide a theoretical foundation for the development and application of the CRISPR/CAS system in molecular detection technology. Full article
(This article belongs to the Section Molecular Genetics and Genomics)
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15 pages, 1856 KiB  
Article
Phenotypes and Genotypes in Patients with SMC1A-Related Developmental and Epileptic Encephalopathy
by Xiuhua L. Bozarth, Jonathan Lopez, He Fang, Jacqueline Lee-Eng, Zhijun Duan and Xinxian Deng
Genes 2023, 14(4), 852; https://doi.org/10.3390/genes14040852 - 31 Mar 2023
Cited by 13 | Viewed by 3463
Abstract
The X-linked SMC1A gene encodes a core subunit of the cohesin complex that plays a pivotal role in genome organization and gene regulation. Pathogenic variants in SMC1A are often dominant-negative and cause Cornelia de Lange syndrome (CdLS) with growth retardation and typical facial [...] Read more.
The X-linked SMC1A gene encodes a core subunit of the cohesin complex that plays a pivotal role in genome organization and gene regulation. Pathogenic variants in SMC1A are often dominant-negative and cause Cornelia de Lange syndrome (CdLS) with growth retardation and typical facial features; however, rare SMC1A variants cause a developmental and epileptic encephalopathy (DEE) with intractable early-onset epilepsy that is absent in CdLS. Unlike the male-to-female ratio of 1:2 in those with CdLS associated with dominant-negative SMC1A variants, SMC1A-DEE loss-of-function (LOF) variants are found exclusively in females due to presumed lethality in males. It is unclear how different SMC1A variants cause CdLS or DEE. Here, we report on phenotypes and genotypes of three females with DEE and de novo SMC1A variants, including a novel splice-site variant. We also summarize 41 known SMC1A-DEE variants to characterize common and patient-specific features. Interestingly, compared to 33 LOFs detected throughout the gene, 7/8 non-LOFs are specifically located in the N/C-terminal ATPase head or the central hinge domain, both of which are predicted to affect cohesin assembly, thus mimicking LOFs. Along with the characterization of X-chromosome inactivation (XCI) and SMC1A transcription, these variants strongly suggest that a differential SMC1A dosage effect of SMC1A-DEE variants is closely associated with the manifestation of DEE phenotypes. Full article
(This article belongs to the Section Human Genomics and Genetic Diseases)
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11 pages, 1442 KiB  
Communication
Retinal Phenotyping of a Murine Model of Lafora Disease
by Ajoy Vincent, Kashif Ahmed, Rowaida Hussein, Zorana Berberovic, Anupreet Tumber, Xiaochu Zhao and Berge A. Minassian
Genes 2023, 14(4), 854; https://doi.org/10.3390/genes14040854 - 31 Mar 2023
Cited by 1 | Viewed by 2405
Abstract
Lafora disease (LD) is a progressive neurologic disorder caused by biallelic pathogenic variants in EPM2A or EPM2B, leading to tissue accumulation of polyglucosan aggregates termed Lafora bodies (LBs). This study aimed to characterize the retinal phenotype in Epm2a−/− mice by examining [...] Read more.
Lafora disease (LD) is a progressive neurologic disorder caused by biallelic pathogenic variants in EPM2A or EPM2B, leading to tissue accumulation of polyglucosan aggregates termed Lafora bodies (LBs). This study aimed to characterize the retinal phenotype in Epm2a−/− mice by examining knockout (KO; Epm2a−/−) and control (WT) littermates at two time points (10 and 14 months, respectively). In vivo exams included electroretinogram (ERG) testing, optical coherence tomography (OCT) and retinal photography. Ex vivo retinal testing included Periodic acid Schiff Diastase (PASD) staining, followed by imaging to assess and quantify LB deposition. There was no significant difference in any dark-adapted or light-adapted ERG parameters between KO and WT mice. The total retinal thickness was comparable between the groups and the retinal appearance was normal in both groups. On PASD staining, LBs were observed in KO mice within the inner and outer plexiform layers and in the inner nuclear layer. The average number of LBs within the inner plexiform layer in KO mice were 1743 ± 533 and 2615 ± 915 per mm2, at 10 and 14 months, respectively. This is the first study to characterize the retinal phenotype in an Epm2a−/− mouse model, demonstrating significant LB deposition in the bipolar cell nuclear layer and its synapses. This finding may be used to monitor the efficacy of experimental treatments in mouse models. Full article
(This article belongs to the Topic Animal Models of Human Disease)
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