Genes

11 pages, 1442 KiB

Open AccessEditor’s ChoiceCommunication

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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13 pages, 928 KiB

Open AccessEditor’s ChoiceReview

Human Genes Involved in the Interaction between Host and Gut Microbiome: Regulation and Pathogenic Mechanisms

by Luigi Boccuto, Jan Tack, Gianluca Ianiro, Ludovico Abenavoli and Emidio Scarpellini

Genes 2023, 14(4), 857; https://doi.org/10.3390/genes14040857 - 31 Mar 2023

Cited by 17 | Viewed by 5785

Abstract

Introduction: The umbrella term “human gut microbiota” describes the complex ecosystem harboring our gut. It includes bacteria, viruses, protozoa, archaea, fungi, and yeasts. This taxonomic classification does not describe its functions, which encompass nutrients digestion and absorption, immune system regulation, and host metabolism. [...] Read more.

Introduction: The umbrella term “human gut microbiota” describes the complex ecosystem harboring our gut. It includes bacteria, viruses, protozoa, archaea, fungi, and yeasts. This taxonomic classification does not describe its functions, which encompass nutrients digestion and absorption, immune system regulation, and host metabolism. “Gut microbiome” indicates instead the genome belonging to these “microbes” actively involved in these functions. However, the interaction between the host genome and the microbial ones determines the fine functioning of our organism. Methods: We reviewed the data available in the scientific literature on the definition of gut microbiota, gut microbiome, and the data on human genes involved in the interaction with the latter. We consulted the main medical databases using the following keywords, acronyms, and their associations: gut microbiota, gut microbiome, human genes, immune function, and metabolism. Results: Candidate human genes encoding enzymes, inflammatory cytokines, and proteins show similarity with those included in the gut microbiome. These findings have become available through newer artificial intelligence (AI) algorithms allowing big data analysis. From an evolutionary point of view, these pieces of evidence explain the strict and sophisticated interaction at the basis of human metabolism and immunity regulation in humans. They unravel more and more physiopathologic pathways included in human health and disease. Discussion: Several lines of evidence also obtained through big data analysis support the bi-directional role of gut microbiome and human genome in host metabolism and immune system regulation. Full article

(This article belongs to the Special Issue Human Microbiota: Current Updates on Pathogenetic Mechanisms and Methodological Advances)

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15 pages, 3298 KiB

Open AccessEditor’s ChoiceArticle

Chronic Stress Alters Hippocampal Renin-Angiotensin-Aldosterone System Component Expression in an Aged Rat Model of Wolfram Syndrome

by Marite Punapart, Riin Reimets, Kadri Seppa, Silvia Kirillov, Nayana Gaur, Kattri-Liis Eskla, Toomas Jagomäe, Eero Vasar and Mario Plaas

Genes 2023, 14(4), 827; https://doi.org/10.3390/genes14040827 - 30 Mar 2023

Cited by 2 | Viewed by 2803

Abstract

Biallelic mutations in the gene encoding WFS1 underlie the development of Wolfram syndrome (WS), a rare neurodegenerative disorder with no available cure. We have previously shown that Wfs1 deficiency can impair the functioning of the renin-angiotensin-aldosterone system (RAAS). The expression of two key [...] Read more.

Biallelic mutations in the gene encoding WFS1 underlie the development of Wolfram syndrome (WS), a rare neurodegenerative disorder with no available cure. We have previously shown that Wfs1 deficiency can impair the functioning of the renin-angiotensin-aldosterone system (RAAS). The expression of two key receptors, angiotensin II receptor type 2 (Agtr2) and bradykinin receptor B1 (Bdkrb1), was downregulated both in vitro and in vivo across multiple organs in a rat model of WS. Here, we show that the expression of key RAAS components is also dysregulated in neural tissue from aged WS rats and that these alterations are not normalized by pharmacological treatments (liraglutide (LIR), 7,8-dihydroxyflavone (7,8-DHF) or their combination). We found that the expression of angiotensin II receptor type 1a (Agtr1a), angiotensin II receptor type 1b (Agtr1b), Agtr2 and Bdkrb1 was significantly downregulated in the hippocampus of WS animals that experienced chronic experimental stress. Treatment-naïve WS rats displayed different gene expression patterns, underscoring the effect of prolonged experiment-induced stress. Altogether, we posit that Wfs1 deficiency disturbs RAAS functioning under chronic stressful conditions, thereby exacerbating neurodegeneration in WS. Full article

(This article belongs to the Section Human Genomics and Genetic Diseases)

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13 pages, 2893 KiB

Open AccessEditor’s ChoiceArticle

SODD Promotes Lung Cancer Tumorigenesis by Activating the PDK1/AKT and RAF/MEK/ERK Signaling

by Fan Bao, Su An, Yang Yang and Tian-Rui Xu

Genes 2023, 14(4), 829; https://doi.org/10.3390/genes14040829 - 30 Mar 2023

Cited by 2 | Viewed by 2435

Abstract

Background: The Bcl2-associated athanogene4 (BAG4/SODD) protein could be identified as a tumor marker for several malignancies and plays a major role in the occurrence, development, and drug resistance of tumors. However, the role of Silencer of death domains (SODD) in lung carcinogenesis is [...] Read more.

Background: The Bcl2-associated athanogene4 (BAG4/SODD) protein could be identified as a tumor marker for several malignancies and plays a major role in the occurrence, development, and drug resistance of tumors. However, the role of Silencer of death domains (SODD) in lung carcinogenesis is still elusive. Objective: To illuminate the effect of SODD on the proliferation, migration, invasion, and apoptosis of lung cancer cells and tumor growth in vivo and explore the corresponding mechanism. Methods: The expression of SODD in tumor and normal tissues was determined and compared via western blot. SODD gene knockout lung cancer cells (H1299 cells) were established through a CRISPR/Cas9 gene deleting system, and a transient SODD overexpression of H1299 cells was also constructed. Then, cell proliferation and invasion were assessed through colony formation and cell counting kit-8 assays, transwell migration assays, and wound healing assays. Cell drug sensitivity is also analyzed by Cell Counting Kit-8 assay. The flow cytometer was used to perform cell circle and apoptosis analysis. The interaction of SODD and RAF-1 was confirmed by co-immunoprecipitation, and the phosphorylated level of Phosphatidylinositol 3-kinase (PI3K), Serine/threonine-protein kinase (AKT), Rapidly accelerated fibrosarcoma (RAF)-1,and extracellular signal regulated kinase (ERK) in cells was examined by western blot to evaluate the activation of PI3K/PDK1/AKT and RAF/MEK/ERK pathways. In vivo, Xenograft tumor assay of SODD knockout H1299 cells was used to evaluate further the role of SODD on the proliferation of H1299 cells. Results: SODD binds to RAF-1 and is over-expressed in lung tissues, and promotes the proliferation, migration, invasion, and drug sensitivity of H1299 cells. The reduced cells in the S phase and increased cells arrested in the G2/M phase were found in SODD knockout H1299 cells, and more cells got apoptosis. The expression of 3-phosphoinositide-dependent protein kinase 1(PDK1) protein in SODD knockout H1299 cells decreases distinctively, and the phosphorylated level of AKT, RAF-1, and ERK-1 kinase in SODD knockout H1299 cells is also less than that in normal H1299 cells. In contrast, SODD overexpression significantly increases the phosphorylation of AKT. In vivo, SODD promotes the tumorigenicity of H1299 cells in nude mice. Conclusions: SODD is overexpressed in lung tissues and plays a considerable role in the development and progression of lung cancer by regulating the PI3K/PDK1/AKT and RAF/MEK/ERK pathways. Full article

(This article belongs to the Special Issue Signaling Pathway of Cancer)

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16 pages, 788 KiB

Open AccessEditor’s ChoiceArticle

Rare Coding Variants in Patients with Non-Syndromic Vestibular Dysfunction

by Angelo Augusto M. Sumalde, Melissa A. Scholes, Olivia A. Kalmanson, Elizabeth A. Terhune, Lidia Frejo, Cambria I. Wethey, Pablo Roman-Naranjo, Patrick M. Carry, Samuel P. Gubbels, Jose A. Lopez-Escamez, Nancy Hadley-Miller and Regie Lyn P. Santos-Cortez

Genes 2023, 14(4), 831; https://doi.org/10.3390/genes14040831 - 30 Mar 2023

Cited by 3 | Viewed by 3172

Abstract

Vertigo due to vestibular dysfunction is rare in children. The elucidation of its etiology will improve clinical management and the quality of life of patients. Genes for vestibular dysfunction were previously identified in patients with both hearing loss and vertigo. This study aimed [...] Read more.

Vertigo due to vestibular dysfunction is rare in children. The elucidation of its etiology will improve clinical management and the quality of life of patients. Genes for vestibular dysfunction were previously identified in patients with both hearing loss and vertigo. This study aimed to identify rare, coding variants in children with peripheral vertigo but no hearing loss, and in patients with potentially overlapping phenotypes, namely, Meniere’s disease or idiopathic scoliosis. Rare variants were selected from the exome sequence data of 5 American children with vertigo, 226 Spanish patients with Meniere’s disease, and 38 European–American probands with scoliosis. In children with vertigo, 17 variants were found in 15 genes involved in migraine, musculoskeletal phenotypes, and vestibular development. Three genes, OTOP1, HMX3, and LAMA2, have knockout mouse models for vestibular dysfunction. Moreover, HMX3 and LAMA2 were expressed in human vestibular tissues. Rare variants within ECM1, OTOP1, and OTOP2 were each identified in three adult patients with Meniere’s disease. Additionally, an OTOP1 variant was identified in 11 adolescents with lateral semicircular canal asymmetry, 10 of whom have scoliosis. We hypothesize that peripheral vestibular dysfunction in children may be due to multiple rare variants within genes that are involved in the inner ear structure, migraine, and musculoskeletal disease. Full article

(This article belongs to the Special Issue Feature Papers in Human Genomics and Genetic Diseases 2023)

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32 pages, 1390 KiB

Open AccessEditor’s ChoiceArticle

Gene Association Analysis of Quantitative Trait Based on Functional Linear Regression Model with Local Sparse Estimator

by Jingyu Wang, Fujie Zhou, Cheng Li, Ning Yin, Huiming Liu, Binxian Zhuang, Qingyu Huang and Yongxian Wen

Genes 2023, 14(4), 834; https://doi.org/10.3390/genes14040834 - 30 Mar 2023

Cited by 1 | Viewed by 1757

Abstract

Functional linear regression models have been widely used in the gene association analysis of complex traits. These models retain all the genetic information in the data and take full advantage of spatial information in genetic variation data, which leads to brilliant detection power. [...] Read more.

Functional linear regression models have been widely used in the gene association analysis of complex traits. These models retain all the genetic information in the data and take full advantage of spatial information in genetic variation data, which leads to brilliant detection power. However, the significant association signals identified by the high-power methods are not all the real causal SNPs, because it is easy to regard noise information as significant association signals, leading to a false association. In this paper, a method based on the sparse functional data association test (SFDAT) of gene region association analysis is developed based on a functional linear regression model with local sparse estimation. The evaluation indicators CSR and DL are defined to evaluate the feasibility and performance of the proposed method with other indicators. Simulation studies show that: (1) SFDAT performs well under both linkage equilibrium and linkage disequilibrium simulation; (2) SFDAT performs successfully for gene regions (including common variants, low-frequency variants, rare variants and mix variants); (3) With power and type I error rates comparable to OLS and Smooth, SFDAT has a better ability to handle the zero regions. The Oryza sativa data set is analyzed by SFDAT. It is shown that SFDAT can better perform gene association analysis and eliminate the false positive of gene localization. This study showed that SFDAT can lower the interference caused by noise while maintaining high power. SFDAT provides a new method for the association analysis between gene regions and phenotypic quantitative traits. Full article

(This article belongs to the Section Bioinformatics)

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12 pages, 1854 KiB

Open AccessEditor’s ChoiceArticle

Whole Genome Sequencing Provides Information on the Genomic Architecture and Diversity of Cultivated Gilthead Seabream (Sparus aurata) Broodstock Nuclei

by Francesca Bertolini, Anisa Ribani, Fabrizio Capoccioni, Luca Buttazzoni, Samuele Bovo, Giuseppina Schiavo, Massimo Caggiano, Max F. Rothschild and Luca Fontanesi

Genes 2023, 14(4), 839; https://doi.org/10.3390/genes14040839 - 30 Mar 2023

Cited by 1 | Viewed by 2693

Abstract

The gilthead seabream (Sparus aurata) is a species of relevance for the Mediterranean aquaculture industry. Despite the advancement of genetic tools for the species, breeding programs still do not often include genomics. In this study, we designed a genomic strategy to [...] Read more.

The gilthead seabream (Sparus aurata) is a species of relevance for the Mediterranean aquaculture industry. Despite the advancement of genetic tools for the species, breeding programs still do not often include genomics. In this study, we designed a genomic strategy to identify signatures of selection and genomic regions of high differentiation among populations of farmed fish stocks. A comparative DNA pooling sequencing approach was applied to identify signatures of selection in gilthead seabream from the same hatchery and from different nuclei that had not been subjected to genetic selection. Identified genomic regions were further investigated to detect SNPs with predicted high impact. The analyses underlined major genomic differences in the proportion of fixed alleles among the investigated nuclei. Some of these differences highlighted genomic regions, including genes involved in general metabolism and development already detected in QTL for growth, size, skeletal deformity, and adaptation to variation of oxygen levels in other teleosts. The obtained results pointed out the need to control the genetic effect of breeding programs in this species to avoid the reduction of genetic variability within populations and the increase in inbreeding level that, in turn, might lead to an increased frequency of alleles with deleterious effects. Full article

(This article belongs to the Special Issue Genomics in Aquaculture and Fisheries)

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14 pages, 2999 KiB

Open AccessEditor’s ChoiceArticle

Genome-Wide Identification, and In-Silico Expression Analysis of YABBY Gene Family in Response to Biotic and Abiotic Stresses in Potato (Solanum tuberosum)

by Hafiz Sabah-Ud-Din Mazhar, Muhammad Shafiq, Haider Ali, Muhammad Ashfaq, Alia Anwar, Javaria Tabassum, Qurban Ali, Ghulam Jilani, Muhammad Awais, Ravi Sahu and Muhammad Arshad Javed

Genes 2023, 14(4), 824; https://doi.org/10.3390/genes14040824 - 29 Mar 2023

Cited by 14 | Viewed by 3462

Abstract

YABBY is among the specific transcription factor (TF) gene family in plants and plays an important role in the development of the leaves and floral organs. Its specific roles include lateral organ development, the establishment of dorsoventral polarity, and response to abiotic stress. [...] Read more.

YABBY is among the specific transcription factor (TF) gene family in plants and plays an important role in the development of the leaves and floral organs. Its specific roles include lateral organ development, the establishment of dorsoventral polarity, and response to abiotic stress. Potato is an important crop worldwide and YABBY genes are not still identified and characterized in potato. So, little has been known about YABBY genes in potato until now. This study was carried out to perform genome-wide analysis, which will provide an in-depth analysis about the role of YABBY genes in potato. There have been seven StYAB genes identified, which are found to be located on seven different chromosomes. Through multiple sequence analyses, it has been predicted that the YABBY domain was present in all seven genes while the C2-C2 domain was found to be absent only in StYAB2. With the help of cis-element analysis, the involvement of StYAB genes in light, stress developmental, and hormonal responsiveness has been found. Furthermore, expression analysis from RNA-seq data of different potato organs indicated that all StYAB genes have a role in the vegetative growth of the potato plant. In addition to this, RNA-seq data also identified StYAB3, StYAB5, and StYAB7 genes showing expression during cadmium, and drought stress, while StYAB6 was highly expressed during a viral attack. Moreover, during the attack of Phytophthora infestans on a potato plant StYAB3, StYAB5, StYAB6, and StYAB7 showed high expression. This study provides significant knowledge about the StYAB gene structures and functions, which can later be used for gene cloning, and functional analysis; this information may be utilized by molecular biologists and plant breeders for the development of new potato lines. Full article

(This article belongs to the Special Issue Plant Breeding: Molecular Genetics, Challenges, Opportunities and Future Perspectives)

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11 pages, 1689 KiB

Open AccessEditor’s ChoiceArticle

The Expanding Phenotypical Spectrum of WARS2-Related Disorder: Four Novel Cases with a Common Recurrent Variant

by Martje G. Pauly, G. Christoph Korenke, Sokhna Haissatou Diaw, Anne Grözinger, Ana Cazurro-Gutiérrez, Belén Pérez-Dueñas, Victoria González, Alfons Macaya, Ana Teresa Serrano Antón, Borut Peterlin, Ivana Babić Božović, Aleš Maver, Alexander Münchau and Katja Lohmann

Genes 2023, 14(4), 822; https://doi.org/10.3390/genes14040822 - 29 Mar 2023

Cited by 2 | Viewed by 3519

Abstract

Biallelic variants in the mitochondrial form of the tryptophanyl-tRNA synthetases (WARS2) can cause a neurodevelopmental disorder with movement disorders including early-onset tremor–parkinsonism syndrome. Here, we describe four new patients, who all presented at a young age with a tremor–parkinsonism syndrome and [...] Read more.

Biallelic variants in the mitochondrial form of the tryptophanyl-tRNA synthetases (WARS2) can cause a neurodevelopmental disorder with movement disorders including early-onset tremor–parkinsonism syndrome. Here, we describe four new patients, who all presented at a young age with a tremor–parkinsonism syndrome and responded well to levodopa. All patients carry the same recurrent, hypomorphic missense variant (NM_015836.4: c.37T>G; p.Trp13Gly) either together with a previously described truncating variant (NM_015836.4: c.797Cdel; p.Pro266ArgfsTer10), a novel truncating variant (NM_015836.4: c.346C>T; p.Gln116Ter), a novel canonical splice site variant (NM_015836.4: c.349-1G>A), or a novel missense variant (NM_015836.4: c.475A>C, p.Thr159Pro). We investigated the mitochondrial function in patients and found increased levels of mitochondrially encoded cytochrome C Oxidase II as part of the mitochondrial respiratory chain as well as decreased mitochondrial integrity and branching. Finally, we conducted a literature review and here summarize the broad phenotypical spectrum of reported WARS2-related disorders. In conclusion, WARS2-related disorders are diagnostically challenging diseases due to the broad phenotypic spectrum and the disease relevance of a relatively common missense change that is often filtered out in a diagnostic setting since it occurs in ~0.5% of the general European population. Full article

(This article belongs to the Section Neurogenomics)

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17 pages, 13774 KiB

Open AccessEditor’s ChoiceArticle

Identification and Functional Analysis of ToBPI1/LBP and ToBPI2/LBP in Anti-Bacterial Infection of Trachinotus ovatus

by Ze-Chang Bian, Xiao-Hui Cai, Kian Ann Tan, Ya-Dan Wang, Zhuang Huang, Kit Yue Kwan and Peng Xu

Genes 2023, 14(4), 826; https://doi.org/10.3390/genes14040826 - 29 Mar 2023

Cited by 2 | Viewed by 1911

Abstract

Bactericidal/permeability-increasing protein (BPI) and lipopolysaccharide-binding protein (LBP) are a group of antibacterial proteins that play an important role in the host’s innate immune defense against pathogen infection. In this study, two BPI/LBPs, named ToBPI1/LBP (1434 bp in length, 478 amino acids) and ToBPI2/LBP [...] Read more.

Bactericidal/permeability-increasing protein (BPI) and lipopolysaccharide-binding protein (LBP) are a group of antibacterial proteins that play an important role in the host’s innate immune defense against pathogen infection. In this study, two BPI/LBPs, named ToBPI1/LBP (1434 bp in length, 478 amino acids) and ToBPI2/LBP (1422 bp in length, 474 amino acids), were identified from the golden pompano. ToBPI1/LBP and ToBPI2/LBP were significantly expressed in immune-related tissues after being challenged with Streptococcus agalactiae and Vibrio alginolyticus. The two BPI/LBPs showed significant antibacterial activity against Gram-negative Escherichia coli and Gram-positive S. agalactiae and Streptococcus iniae. In contrast, the antibacterial activity against Staphylococcus aureus, Corynebacterium glutamicum, Vibrio parahaemolyticus, V. alginolyticus and Vibrio harveyi was low and decreased with time. The membrane permeability of bacteria treated with recombinant ToBPI1/LBP and ToBPI2/LBP was significantly enhanced. These results suggest that ToBPI1/LBP and ToBPI2/LBP may play important immunological roles in the immune response of the golden pompano to bacteria. This study will provide basic information and new insights into the immune response mechanism of the golden pompano to bacteria and the function of BPI/LBP. Full article

(This article belongs to the Section Animal Genetics and Genomics)

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15 pages, 5397 KiB

Open AccessEditor’s ChoiceArticle

Genome-Wide Analysis of DREB Family Genes and Characterization of Cold Stress Responses in the Woody Plant Prunus nana

by Cheng Qian, Lulu Li, Huanhuan Guo, Gaopu Zhu, Ning Yang, Xiaoyan Tan and Han Zhao

Genes 2023, 14(4), 811; https://doi.org/10.3390/genes14040811 - 28 Mar 2023

Cited by 4 | Viewed by 2595

Abstract

Dehydration response element binding factor (DREB) is a family of plant-specific transcription factors, whose members participate in the regulation of plant responses to various abiotic stresses. Prunus nana, also known as the wild almond, is a member of the Rosaceae family that [...] Read more.

Dehydration response element binding factor (DREB) is a family of plant-specific transcription factors, whose members participate in the regulation of plant responses to various abiotic stresses. Prunus nana, also known as the wild almond, is a member of the Rosaceae family that is rare and found to grow in the wild in China. These wild almond trees are found in hilly regions in northern Xinjiang, and exhibit greater drought and cold stress resistance than cultivated almond varieties. However, the response of P. nana DREBs (PnaDREBs) under low temperature stress is still unclear. In this study, 46 DREB genes were identified in the wild almond genome, with this number being slightly lower than that in the sweet almond (Prunus dulcis cultivar ‘Nonpareil’). These DREB genes in wild almond were separated into two classes. All PnaDREB genes were located on six chromosomes. PnaDREB proteins that were classified in the same groups contained specific shared motifs, and promoter analyses revealed that PnaDREB genes harbored a range of stress-responsive elements associated with drought, low-temperature stress, light responsivity, and hormone-responsive cis-regulatory elements within their promoter regions. MicroRNA target site prediction analyses also suggested that 79 miRNAs may regulate the expression of 40 of these PnaDREB genes, with PnaDREB2. To examine if these identified PnaDREB genes responded to low temperature stress, 15 of these genes were selected including seven homologous to Arabidopsis C-repeat binding factor (CBFs), and their expression was assessed following incubation for 2 h at 25 °C, 5 °C, 0 °C, −5 °C, or −10 °C. In summary, this analysis provides an overview of the P. nana PnaDREB gene family and provides a foundation for further studies of the ability of different PnaDREB genes to regulate cold stress responses in almond plants. Full article

(This article belongs to the Special Issue Genetic Studies of Ornamental Horticulture and Floriculture)

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19 pages, 2954 KiB

Open AccessEditor’s ChoiceArticle

Transcriptomic and Chromatin Landscape Analysis Reveals That Involvement of Pituitary Level Transcription Factors Modulate Incubation Behaviors of Magang Geese

by Jianye Chang, Di Fan, Jiaxin Liu, Yanglong Xu, Xuefei Huang, Yunbo Tian, Jin Xu, Yunmao Huang, Jue Ruan and Xu Shen

Genes 2023, 14(4), 815; https://doi.org/10.3390/genes14040815 - 28 Mar 2023

Cited by 2 | Viewed by 2702

Abstract

The incubation behavior of geese seriously affects their egg production performance. Studies on incubation behavior have identified functional genes, but the regulatory architecture relationship between functional genes and chromatin accessibility remains poorly understood. Here, we present an integrated analysis of open chromatin profiles [...] Read more.

The incubation behavior of geese seriously affects their egg production performance. Studies on incubation behavior have identified functional genes, but the regulatory architecture relationship between functional genes and chromatin accessibility remains poorly understood. Here, we present an integrated analysis of open chromatin profiles and transcriptome to identify the cis-regulatory element and their potential transcription factors involved in regulating incubation behavior in goose pituitary. Assay for transposase-accessible chromatin sequencing (ATAC-seq) revealed that open chromatin regions increased in the pituitary during the transition from incubation behavior to laying. We identified 920 significant differential accessible regions (DARs) in the pituitary. Compared to the laying stage, most DARs had higher chromatin accessibility in the brooding stage. Motif analysis of open DARs showed that the most significant transcription factor (TF) occupied sites predominantly enriched in motifs binding to the RFX family (RFX5, RFX2, and RFX1). While the majority of TF motifs enriched under sites of the nuclear receptor (NR) family (ARE, GRE, and PGR) in closed DARs at the incubation behavior stage. Footprint analysis indicated that the transcription factor RFX family exhibited higher binding on chromatin at the brooding stage. To further elucidate the effect of changes in chromatin accessibility on gene expression levels, a comparison of the transcriptome revealed 279 differentially expressed genes (DEGs). The transcriptome changes were associated with processes of steroid biosynthesis. By integrating ATAC-seq and RNA-seq, few DARs directly affect incubation behavior by regulating the transcription levels of genes. Five DAR-related DEGs were found to be closely related to maintaining the incubation behavior in geese. Footprinting analysis revealed a set of transcription factors (RFX1, RFX2, RFX3, RFX5, BHLHA15, SIX1, and DUX) which displayed the highest activity at the brooding stage. SREBF2 was predicted to be the unique differentially expressed transcription factor whose mRNA level was down-regulated and enriched in hyper-accessible regions of PRL in the broody stage. In the present study, we comprehensively profiled the transcriptome and chromatin accessibility in the pituitary related to incubation behavior. Our findings provided insight into the identification and analysis of regulatory elements in goose incubation behavior. The epigenetic alterations profiled here can help decipher the epigenetic mechanisms that contribute to the regulation of incubation behavior in birds. Full article

(This article belongs to the Special Issue Poultry Breeding: Genetics and Genomics)

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15 pages, 1845 KiB

Open AccessEditor’s ChoiceArticle

Molecular Design-Based Breeding: A Kinship Index-Based Selection Method for Complex Traits in Small Livestock Populations

by Jiamin Gu, Jianwei Guo, Zhenyang Zhang, Yuejin Xu, Qamar Raza Qadri, Zhe Zhang, Zhen Wang, Qishan Wang and Yuchun Pan

Genes 2023, 14(4), 807; https://doi.org/10.3390/genes14040807 - 27 Mar 2023

Cited by 1 | Viewed by 3332

Abstract

Genomic selection (GS) techniques have improved animal breeding by enhancing the prediction accuracy of breeding values, particularly for traits that are difficult to measure and have low heritability, as well as reducing generation intervals. However, the requirement to establish genetic reference populations can [...] Read more.

Genomic selection (GS) techniques have improved animal breeding by enhancing the prediction accuracy of breeding values, particularly for traits that are difficult to measure and have low heritability, as well as reducing generation intervals. However, the requirement to establish genetic reference populations can limit the application of GS in pig breeds with small populations, especially when small populations make up most of the pig breeds worldwide. We aimed to propose a kinship index based selection (KIS) method, which defines an ideal individual with information on the beneficial genotypes for the target trait. Herein, the metric for assessing selection decisions is a beneficial genotypic similarity between the candidate and the ideal individual; thus, the KIS method can overcome the need for establishing genetic reference groups and continuous phenotype determination. We also performed a robustness test to make the method more aligned with reality. Simulation results revealed that compared to conventional genomic selection methods, the KIS method is feasible, particularly, when the population size is relatively small. Full article

(This article belongs to the Special Issue Advances in Pig Breeding and Genetics)

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45 pages, 1211 KiB

Open AccessEditor’s ChoiceReview

Microsatellites as Molecular Markers with Applications in Exploitation and Conservation of Aquatic Animal Populations

by Roman Wenne

Genes 2023, 14(4), 808; https://doi.org/10.3390/genes14040808 - 27 Mar 2023

Cited by 23 | Viewed by 8226

Abstract

A large number of species and taxa have been studied for genetic polymorphism. Microsatellites have been known as hypervariable neutral molecular markers with the highest resolution power in comparison with any other markers. However, the discovery of a new type of molecular marker—single [...] Read more.

A large number of species and taxa have been studied for genetic polymorphism. Microsatellites have been known as hypervariable neutral molecular markers with the highest resolution power in comparison with any other markers. However, the discovery of a new type of molecular marker—single nucleotide polymorphism (SNP) has put the existing applications of microsatellites to the test. To ensure good resolution power in studies of populations and individuals, a number of microsatellite loci from 14 to 20 was often used, which corresponds to about 200 independent alleles. Recently, these numbers have tended to be increased by the application of genomic sequencing of expressed sequence tags (ESTs) and the choice of the most informative loci for genotyping depends on the aims of research. Examples of successful applications of microsatellite molecular markers in aquaculture, fisheries, and conservation genetics in comparison to SNPs are summarized in this review. Microsatellites can be considered superior markers in such topics as kinship and parentage analysis in cultured and natural populations, the assessment of gynogenesis, androgenesis and ploidization. Microsatellites can be coupled with SNPs for mapping QTL. Microsatellites will continue to be used in research of genetic diversity in cultured stocks, and also in natural populations as an economically advantageous genotyping technique. Full article

(This article belongs to the Section Population and Evolutionary Genetics and Genomics)

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17 pages, 2991 KiB

Open AccessEditor’s ChoiceArticle

An Attempt to Identify the Medaka Receptor for Somatolactin Alpha Using a Reverse Genetics Approach

by Yuko Moroki, Mamiko Komori, Yuko Ogawa, Erina Nagumo, Haruna Ohno and Shoji Fukamachi

Genes 2023, 14(4), 796; https://doi.org/10.3390/genes14040796 - 26 Mar 2023

Cited by 2 | Viewed by 2280

Abstract

Somatolactin alpha (SLα) is a fish-specific hormone involved in body color regulation. The growth hormone (GH) is another hormone that is expressed in all vertebrates and promotes growth. These peptide hormones act by binding to receptors (SLα receptor (SLR) and GH receptor (GHR)); [...] Read more.

Somatolactin alpha (SLα) is a fish-specific hormone involved in body color regulation. The growth hormone (GH) is another hormone that is expressed in all vertebrates and promotes growth. These peptide hormones act by binding to receptors (SLα receptor (SLR) and GH receptor (GHR)); however, the relationships between these ligands and their receptors vary among species. Here, we first performed phylogenetic tree reconstruction by collecting the amino-acid sequences classified as SLR, GHR, or GHR-like from bony fish. Second, we impaired SLR or GHR functions in medaka (Oryzias sakaizumii) using CRISPR/Cas9. Lastly, we analyzed SLR and GHR mutants for phenotypes to deduce their functions. Phylogenetic tree reconstruction was performed using a total of 222 amino-acid sequences from 136 species, which revealed that many GHRa and GHRb are vaguely termed as GHR or GHR-like, while showing no orthologous/paralogous relationships. SLR and GHR mutants were successfully established for phenotyping. SLR mutants exhibited premature lethality after hatching, indicating an essential role for SLR in normal growth. GHR mutations did not affect viability, body length, or body color. These results provide no evidence that either SLR or GHR functions as a receptor for SLα; rather, phylogenetically and functionally, they seem to be receptors for GH, although their (subfunctionalized) roles warrant further investigation. Full article

(This article belongs to the Special Issue Genetic Studies of Fish)

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19 pages, 793 KiB

Open AccessEditor’s ChoiceArticle

Adaptively Integrative Association between Multivariate Phenotypes and Transcriptomic Data for Complex Diseases

by Yujia Li, Yusi Fang, Hung-Ching Chang, Michael Gorczyca, Peng Liu and George C. Tseng

Genes 2023, 14(4), 798; https://doi.org/10.3390/genes14040798 - 26 Mar 2023

Viewed by 1916

Abstract

Phenotype–gene association studies can uncover disease mechanisms for translational research. Association with multiple phenotypes or clinical variables in complex diseases has the advantage of increasing statistical power and offering a holistic view. Existing multi-variate association methods mostly focus on SNP-based genetic associations. In [...] Read more.

Phenotype–gene association studies can uncover disease mechanisms for translational research. Association with multiple phenotypes or clinical variables in complex diseases has the advantage of increasing statistical power and offering a holistic view. Existing multi-variate association methods mostly focus on SNP-based genetic associations. In this paper, we extend and evaluate two adaptive Fisher’s methods, namely AFp and AFz, from the p-value combination perspective for phenotype–mRNA association analysis. The proposed method effectively aggregates heterogeneous phenotype–gene effects, allows association with different data types of phenotypes, and performs the selection of the associated phenotypes. Variability indices of the phenotype–gene effect selection are calculated by bootstrap analysis, and the resulting co-membership matrix identifies gene modules clustered by phenotype–gene effect. Extensive simulations demonstrate the superior performance of AFp compared to existing methods in terms of type I error control, statistical power and biological interpretation. Finally, the method is separately applied to three sets of transcriptomic and clinical datasets from lung disease, breast cancer, and brain aging and generates intriguing biological findings. Full article

(This article belongs to the Special Issue Feature Papers in Technologies and Resources for Genetics)

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20 pages, 1802 KiB

Open AccessEditor’s ChoiceReview

Computational Biology Helps Understand How Polyploid Giant Cancer Cells Drive Tumor Success

by Matheus Correia Casotti, Débora Dummer Meira, Aléxia Stefani Siqueira Zetum, Bruno Cancian de Araújo, Danielle Ribeiro Campos da Silva, Eldamária de Vargas Wolfgramm dos Santos, Fernanda Mariano Garcia, Flávia de Paula, Gabriel Mendonça Santana, Luana Santos Louro, Lyvia Neves Rebello Alves, Raquel Furlani Rocon Braga, Raquel Silva dos Reis Trabach, Sara Santos Bernardes, Thomas Erik Santos Louro, Eduardo Cremonese Filippi Chiela, Guido Lenz, Elizeu Fagundes de Carvalho and Iúri Drumond Louro

Genes 2023, 14(4), 801; https://doi.org/10.3390/genes14040801 - 26 Mar 2023

Cited by 16 | Viewed by 5501

Abstract

Precision and organization govern the cell cycle, ensuring normal proliferation. However, some cells may undergo abnormal cell divisions (neosis) or variations of mitotic cycles (endopolyploidy). Consequently, the formation of polyploid giant cancer cells (PGCCs), critical for tumor survival, resistance, and immortalization, can occur. [...] Read more.

Precision and organization govern the cell cycle, ensuring normal proliferation. However, some cells may undergo abnormal cell divisions (neosis) or variations of mitotic cycles (endopolyploidy). Consequently, the formation of polyploid giant cancer cells (PGCCs), critical for tumor survival, resistance, and immortalization, can occur. Newly formed cells end up accessing numerous multicellular and unicellular programs that enable metastasis, drug resistance, tumor recurrence, and self-renewal or diverse clone formation. An integrative literature review was carried out, searching articles in several sites, including: PUBMED, NCBI-PMC, and Google Academic, published in English, indexed in referenced databases and without a publication time filter, but prioritizing articles from the last 3 years, to answer the following questions: (i) “What is the current knowledge about polyploidy in tumors?”; (ii) “What are the applications of computational studies for the understanding of cancer polyploidy?”; and (iii) “How do PGCCs contribute to tumorigenesis?” Full article

(This article belongs to the Collection Feature Papers in Bioinformatics)

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11 pages, 850 KiB

Open AccessEditor’s ChoiceCommunication

The Role of Genetic Testing in Children Requiring Surgery for Ectopia Lentis

by Mohammud Musleh, Adam Bull, Emma Linton, Jingshu Liu, Sarah Waller, Claire Hardcastle, Jill Clayton-Smith, Vinod Sharma, Graeme C. Black, Susmito Biswas, Jane L. Ashworth and Panagiotis I. Sergouniotis

Genes 2023, 14(4), 791; https://doi.org/10.3390/genes14040791 - 25 Mar 2023

Cited by 2 | Viewed by 2283

Abstract

Non-traumatic ectopia lentis can be isolated or herald an underlying multisystemic disorder. Technological advances have revolutionized genetic testing for many ophthalmic disorders, and this study aims to provide insights into the clinical utility of genetic analysis in paediatric ectopia lentis. Children that underwent [...] Read more.

Non-traumatic ectopia lentis can be isolated or herald an underlying multisystemic disorder. Technological advances have revolutionized genetic testing for many ophthalmic disorders, and this study aims to provide insights into the clinical utility of genetic analysis in paediatric ectopia lentis. Children that underwent lens extraction for ectopia lentis between 2013 and 2017 were identified, and gene panel testing findings and surgical outcomes were collected. Overall, 10/11 cases received a probable molecular diagnosis. Genetic variants were identified in four genes: FBN1 (associated with Marfan syndrome and cardiovascular complications; n = 6), ADAMTSL4 (associated with non-syndromic ectopia lentis; n = 2), LTBP2 (n = 1) and ASPH (n = 1). Parents appeared unaffected in 6/11 cases; the initial presentation of all six of these children was to an ophthalmologist, and only 2/6 had FBN1 variants. Notably, 4/11 cases required surgery before the age of 4 years, and only one of these children carried an FBN1 variant. In summary, in this retrospective cohort study, panel-based genetic testing pointed to a molecular diagnosis in >90% of paediatric ectopia lentis cases requiring surgery. In a subset of study participants, genetic analysis revealed changes in genes that have not been linked to extraocular manifestations and highlighted that extensive systemic investigations were not required in these individuals. We propose the introduction of genetic testing early in the diagnostic pathway in children with ectopia lentis. Full article

(This article belongs to the Special Issue Molecular Diagnosis and Disease Mechanisms in Eye Disorders)

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12 pages, 1501 KiB

Open AccessEditor’s ChoiceArticle

T-Cell Receptor Repertoire Characteristics Associated with Prognostic Significance in High-Grade Serous Ovarian Carcinoma

by Ju-Won Kim, Sewha Kim, So-Yun Yang, Je-Gun Joung and Sohyun Hwang

Genes 2023, 14(4), 785; https://doi.org/10.3390/genes14040785 - 24 Mar 2023

Cited by 1 | Viewed by 2146

Abstract

High-grade serous ovarian carcinoma (HGSOC) is a fatal gynecological malignancy. Somatic recombination occurring during T-cell receptor (TCR) development results in TCR diversity, and the TCR repertoire, thus produced, is associated with immune response. This study analyzed the difference in the TCR repertoire and [...] Read more.

High-grade serous ovarian carcinoma (HGSOC) is a fatal gynecological malignancy. Somatic recombination occurring during T-cell receptor (TCR) development results in TCR diversity, and the TCR repertoire, thus produced, is associated with immune response. This study analyzed the difference in the TCR repertoire and their prognostic significance in 51 patients with HGSOC. The patient’s clinical characteristics, gene expression pattern, TCR clonotypes, and degree of tumor-infiltrating leukocytes (TILs) were analyzed, and the patients were divided into groups depending on their recurrence pattern, tumor-infiltrating leukocyte (TIL) score, and homologous recombinant repair pathway deficiency (HRD)-associated mutations. The TCR repertoire was low in patients with recurrence and showed the expansion of eight TCR segments. Interestingly, a few genes correlated with the TCRs also showed a difference in expression according to the prognosis. Among them, seven genes were related to immune responses and KIAA1199 was up-regulated in ovarian cancer. Our study shows that the differences in the TCR repertoire in patients with ovarian cancer and their associated immune pathways could affect the prognosis of HGSOC. Full article

(This article belongs to the Special Issue Advances in Genetics and Genomics of Ovarian Cancer)

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25 pages, 7695 KiB

Open AccessEditor’s ChoiceArticle

Unveiling the Impact of Gene Presence/Absence Variation in Driving Inter-Individual Sequence Diversity within the CRP-I Gene Family in Mytilus spp.

by Nicolò Gualandi, Davide Fracarossi, Damiano Riommi, Marco Sollitto, Samuele Greco, Mario Mardirossian, Sabrina Pacor, Tiago Hori, Alberto Pallavicini and Marco Gerdol

Genes 2023, 14(4), 787; https://doi.org/10.3390/genes14040787 - 24 Mar 2023

Cited by 4 | Viewed by 2477

Abstract

Mussels (Mytilus spp.) tolerate infections much better than other species living in the same marine coastal environment thanks to a highly efficient innate immune system, which exploits a remarkable diversification of effector molecules involved in mucosal and humoral responses. Among these, antimicrobial [...] Read more.

Mussels (Mytilus spp.) tolerate infections much better than other species living in the same marine coastal environment thanks to a highly efficient innate immune system, which exploits a remarkable diversification of effector molecules involved in mucosal and humoral responses. Among these, antimicrobial peptides (AMPs) are subjected to massive gene presence/absence variation (PAV), endowing each individual with a potentially unique repertoire of defense molecules. The unavailability of a chromosome-scale assembly has so far prevented a comprehensive evaluation of the genomic arrangement of AMP-encoding loci, preventing an accurate ascertainment of the orthology/paralogy relationships among sequence variants. Here, we characterized the CRP-I gene cluster in the blue mussel Mytilus edulis, which includes about 50 paralogous genes and pseudogenes, mostly packed in a small genomic region within chromosome 5. We further reported the occurrence of widespread PAV within this family in the Mytilus species complex and provided evidence that CRP-I peptides likely adopt a knottin fold. We functionally characterized the synthetic peptide sCRP-I H1, assessing the presence of biological activities consistent with other knottins, revealing that mussel CRP-I peptides are unlikely to act as antimicrobial agents or protease inhibitors, even though they may be used as defense molecules against infections from eukaryotic parasites. Full article

(This article belongs to the Special Issue Aquaculture Genetics: Latest Advances and Prospects)

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13 pages, 1963 KiB

Open AccessEditor’s ChoiceArticle

Correlation between Parental Transcriptome and Field Data for the Characterization of Heterosis in Chinese Cabbage

by Ru Li, Min Tian, Qiong He and Lugang Zhang

Genes 2023, 14(4), 776; https://doi.org/10.3390/genes14040776 - 23 Mar 2023

Cited by 1 | Viewed by 1694

Abstract

In Chinese cabbage breeding, hybrids have made a terrific contribution due to heterosis, the superior performance of offspring compared to their inbred parents. Since the development of new, top-performing hybrids requires a large scale of human and material resources, the prediction of hybrid [...] Read more.

In Chinese cabbage breeding, hybrids have made a terrific contribution due to heterosis, the superior performance of offspring compared to their inbred parents. Since the development of new, top-performing hybrids requires a large scale of human and material resources, the prediction of hybrid performance is of utmost interest to plant breeders. In our research, leaf transcriptome data from eight parents were used to investigate if they might be employed as markers to predict hybrid performance and heterosis. In Chinese cabbage, heterosis of plant growth weight (PGW) and heterosis of head weight (HW) were more obvious than other traits. The number of differential expression genes (DEGs) between parents was related to the PGW, length of the biggest outer leaf (LOL), leaf head height (LHH), leaf head width (LHW), HW, leaf number of head (LNH) and plant height (PH) of hybrids, and up-regulated DEGs number was also associated with these traits. Euclidean and binary distances of parental gene expression levels were significantly correlated with the PGW, LOL, LHH, LHW, HW and PH of hybrids. Additionally, there was a significant correlation between the parental expression levels of multiple genes involved in the ribosomal metabolic pathway and hybrid observations and heterosis in PGW, with the BrRPL23A gene showing the highest correlation with the MPH of PGW(r = 0.75). Therefore, leaf transcriptome data can preliminarily predict the hybrid performance and select parents in Chinese cabbage. Full article

(This article belongs to the Section Plant Genetics and Genomics)

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22 pages, 1790 KiB

Open AccessEditor’s ChoiceReview

Machine Learning-Assisted Approaches in Modernized Plant Breeding Programs

by Mohsen Yoosefzadeh Najafabadi, Mohsen Hesami and Milad Eskandari

Genes 2023, 14(4), 777; https://doi.org/10.3390/genes14040777 - 23 Mar 2023

Cited by 52 | Viewed by 9688

Abstract

In the face of a growing global population, plant breeding is being used as a sustainable tool for increasing food security. A wide range of high-throughput omics technologies have been developed and used in plant breeding to accelerate crop improvement and develop new [...] Read more.

In the face of a growing global population, plant breeding is being used as a sustainable tool for increasing food security. A wide range of high-throughput omics technologies have been developed and used in plant breeding to accelerate crop improvement and develop new varieties with higher yield performance and greater resilience to climate changes, pests, and diseases. With the use of these new advanced technologies, large amounts of data have been generated on the genetic architecture of plants, which can be exploited for manipulating the key characteristics of plants that are important for crop improvement. Therefore, plant breeders have relied on high-performance computing, bioinformatics tools, and artificial intelligence (AI), such as machine-learning (ML) methods, to efficiently analyze this vast amount of complex data. The use of bigdata coupled with ML in plant breeding has the potential to revolutionize the field and increase food security. In this review, some of the challenges of this method along with some of the opportunities it can create will be discussed. In particular, we provide information about the basis of bigdata, AI, ML, and their related sub-groups. In addition, the bases and functions of some learning algorithms that are commonly used in plant breeding, three common data integration strategies for the better integration of different breeding datasets using appropriate learning algorithms, and future prospects for the application of novel algorithms in plant breeding will be discussed. The use of ML algorithms in plant breeding will equip breeders with efficient and effective tools to accelerate the development of new plant varieties and improve the efficiency of the breeding process, which are important for tackling some of the challenges facing agriculture in the era of climate change. Full article

(This article belongs to the Collection Feature Papers: 'Plant Genetics and Genomics' Section)

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13 pages, 4130 KiB

Open AccessEditor’s ChoiceArticle

The Synchronized Progression from Mitosis to Meiosis in Female Primordial Germ Cells between Layers and Broilers

by Yuxiao Ma, Wenhui Wu, Yun Zhang, Xuzhao Wang, Jiahui Wei, Xiaotong Guo, Man Xue and Guiyu Zhu

Genes 2023, 14(4), 781; https://doi.org/10.3390/genes14040781 - 23 Mar 2023

Cited by 3 | Viewed by 2338

Abstract

Layer and broiler hens show a dramatic difference in the volume and frequency of egg production. However, it is unclear whether the intrinsic competency of oocyte generation is also different between the two types of chicken. All oocytes were derived from the primordial [...] Read more.

Layer and broiler hens show a dramatic difference in the volume and frequency of egg production. However, it is unclear whether the intrinsic competency of oocyte generation is also different between the two types of chicken. All oocytes were derived from the primordial germ cells (PGC) in the developing embryo, and female PGC proliferation (mitosis) and the subsequent differentiation (meiosis) determine the ultimate ovarian pool of germ cells available for future ovulation. In this study, we systematically compared the cellular phenotype and gene expression patterns during PGC mitosis (embryonic day 10, E10) and meiosis (E14) between female layers and broilers to determine whether the early germ cell development is also subjected to the selective breeding of egg production traits. We found that PGCs from E10 showed much higher activity in cell propagation and were enriched in cell proliferation signaling pathways than PGCs from E14 in both types of chicken. A common set of genes, namely insulin-like growth factor 2 (IGF2) and E2F transcription factor 4 (E2F4), were identified as the major regulators of cell proliferation in E10 PGCs of both strains. In addition, we found that E14 PGCs from both strains showed an equal ability to initiate meiosis, which was associated with the upregulation of key genes for meiotic initiation. The intrinsic cellular dynamics during the transition from proliferation to differentiation of female germ cells were conserved between layers and broilers. Hence, we surmise that other non-cell autonomous mechanisms involved in germ-somatic cell interactions would contribute to the divergence of egg production performance between layers and broilers. Full article

(This article belongs to the Special Issue Livestock: Genomics, Genetics and Breeding)

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12 pages, 1295 KiB

Open AccessEditor’s ChoiceArticle

Improving Hereditary Hemorrhagic Telangiectasia Molecular Diagnosis: A Referral Center Experience

by Cinthia Aguilera, Ariadna Padró-Miquel, Anna Esteve-Garcia, Pau Cerdà, Raquel Torres-Iglesias, Núria Llecha and Antoni Riera-Mestre

Genes 2023, 14(3), 772; https://doi.org/10.3390/genes14030772 - 22 Mar 2023

Cited by 1 | Viewed by 2442

Abstract

Background: Hereditary hemorrhagic telangiectasia (HHT) is a rare vascular disease inherited in an autosomal dominant manner. Disease-causing variants in endoglin (ENG) and activin A receptor type II-like 1 (ACVRL1) genes are detected in more than 90% of the patients [...] Read more.

Background: Hereditary hemorrhagic telangiectasia (HHT) is a rare vascular disease inherited in an autosomal dominant manner. Disease-causing variants in endoglin (ENG) and activin A receptor type II-like 1 (ACVRL1) genes are detected in more than 90% of the patients undergoing molecular testing. The identification of variants of unknown significance is often seen as a challenge in clinical practice that makes family screening and genetic counseling difficult. Here, we show that the implementation of cDNA analysis to assess the effect of splice site variants on mRNA splicing is a powerful tool. Methods: Gene panel sequencing of genes associated with HHT and other arteriovenous malformation-related syndromes was performed. To evaluate the effect of the splice site variants, cDNA analysis of ENG and ACVRL1 genes was carried out. Results: three novel splice site variants were identified in ENG (c.68-2A > T and c.1311+4_1311+8del) and ACVLR1 (c.526-6C > G) genes correspondingly in three individuals with HHT that met ≥ 3 Curaçao criteria. All three variants led to an aberrant splicing inducing exon skipping (ENG:c.68-2A > T and ACVRL1:c.526-6C > G) or intron retention (ENG:c.1311+4_1311+8del) allowing the confirmation of the predicted effect on splicing and the reclassification from unknown significance to pathogenic/likely pathogenic of two of them. Conclusions: RNA analysis should be performed to assess and/or confirm the impact of variants on splicing. The molecular diagnosis of HHT patients is crucial to allow family screening and accurate genetic counseling. A multidisciplinary approach including clinicians and geneticists is crucial when dealing with patients with rare diseases. Full article

(This article belongs to the Section Human Genomics and Genetic Diseases)

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12 pages, 2610 KiB

Open AccessEditor’s ChoiceArticle

The Expression Patterns of Exogenous Plant miRNAs in Chickens

by Hao Li, Pu Zhang, Diyan Li, Binlong Chen, Jing Li and Tao Wang

Genes 2023, 14(3), 760; https://doi.org/10.3390/genes14030760 - 21 Mar 2023

Cited by 1 | Viewed by 2320

Abstract

(1) Background: MicroRNAs (miRNAs) are involved in a variety of biological processes, such as cell proliferation, cell differentiation, and organ development. Recent studies have shown that plant miRNAs may enter the diet and play physiological and/or pathophysiological roles in human health and disease; [...] Read more.

(1) Background: MicroRNAs (miRNAs) are involved in a variety of biological processes, such as cell proliferation, cell differentiation, and organ development. Recent studies have shown that plant miRNAs may enter the diet and play physiological and/or pathophysiological roles in human health and disease; however, little is known about plant miRNAs in chickens. (2) Methods: Here, we analyzed miRNA sequencing data, with the use of five Chinese native chicken breeds and six different tissues (heart, liver, spleen, lung, kidney, and leg muscle), and used Illumina sequencing to detect the expression of plant miRNAs in the pectoralis muscles at fourteen developmental stages of Tibetan chickens. (3) Results: The results showed that plant miRNAs are detectable in multiple tissues and organs in different chicken breeds. Surprisingly, we found that plant miRNAs, such as tae-miR2018, were detectable in free-range Tibetan chicken embryos at different stages. The results of gavage feeding experiments also showed that synthetic tae-miR2018 was detectable in caged Tibetan chickens after ingestion. The analysis of tae-miR2018 showed that its target genes were related to skeletal muscle organ development, regulation of mesodermal cell fate specification, growth factor activity, negative regulation of the cell cycle, and regulation of growth, indicating that exogenous miRNA may regulate the development of chicken embryos. Further cell cultures and exogenous miRNA uptake assay experiments showed that synthetic wheat miR2018 can be absorbed by chicken myoblasts. (4) Conclusions: Our study found that chickens can absorb and deposit plant miRNAs in various tissues and organs. The plant miRNAs detected in embryos may be involved in the development of chicken embryos. Full article

(This article belongs to the Special Issue Poultry Genetics and Genomics)

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2 pages, 178 KiB

Open AccessEditor’s ChoiceCorrection

Correction: Noguchi et al. PCR-Based Screening of Spinal Muscular Atrophy for Newborn Infants in Hyogo Prefecture, Japan. Genes 2022, 13, 2110

by Yoriko Noguchi, Ryosuke Bo, Hisahide Nishio, Hisayuki Matsumoto, Keiji Matsui, Yoshihiko Yano, Masami Sugawara, Go Ueda, Yogik Onky Silvana Wijaya, Emma Tabe Eko Niba, Masakazu Shinohara, Yoshihiro Bouike, Atsuko Takeuchi, Kentaro Okamoto, Toshio Saito, Hideki Shimomura, Tomoko Lee, Yasuhiro Takeshima, Kazumoto Iijima, Kandai Nozu and Hiroyuki Awano Show full author list Hide full author list

Genes 2023, 14(3), 759; https://doi.org/10.3390/genes14030759 - 21 Mar 2023

Cited by 1 | Viewed by 1606

Abstract

The authors wish to make the following correction to this paper [...] Full article

(This article belongs to the Special Issue Advances in Genetics of Motor Neuron Diseases)

16 pages, 3790 KiB

Open AccessEditor’s ChoiceArticle

Expression of INPP5D Isoforms in Human Brain: Impact of Alzheimer’s Disease Neuropathology and Genetics

by Diana J. Zajac, James Simpson, Eric Zhang, Ishita Parikh and Steven Estus

Genes 2023, 14(3), 763; https://doi.org/10.3390/genes14030763 - 21 Mar 2023

Cited by 12 | Viewed by 3317

Abstract

The single nucleotide polymorphisms rs35349669 and rs10933431 within Inositol Polyphosphate-5-Phosphatase D (INPP5D) are strongly associated with Alzheimer’s Disease risk. To better understand INPP5D expression in the brain, we investigated INPP5D isoform expression as a function of rs35349669 and rs10933431, as well [...] Read more.

The single nucleotide polymorphisms rs35349669 and rs10933431 within Inositol Polyphosphate-5-Phosphatase D (INPP5D) are strongly associated with Alzheimer’s Disease risk. To better understand INPP5D expression in the brain, we investigated INPP5D isoform expression as a function of rs35349669 and rs10933431, as well as Alzheimer’s disease neuropathology, by qPCR and isoform-specific primers. In addition, INPP5D allelic expression imbalance was evaluated relative to rs1141328 within exon 1. Expression of INPP5D isoforms associated with transcription start sites in exon 1 and intron 14 was increased in individuals with high Alzheimer’s disease neuropathology. In addition, a novel variant with 47bp lacking from exon 12 increased expression in Alzheimer’s Disease brains, accounting for 13% of total INPP5D expression, and was found to undergo nonsense-mediated decay. Although inter-individual variation obscured a possible polymorphism effect on INPP5D isoform expression as measured by qPCR, rs35349669 was associated with rs1141328 allelic expression imbalance, suggesting that rs35349669 is significantly associated with full-length INPP5D isoform expression. In summary, expression of INPP5D isoforms with start sites in exon 1 and intron 14 are increased in brains with high Alzheimer’s Disease neuropathology, a novel isoform lacking the phosphatase domain was significantly increased with the disease, and the polymorphism rs35349669 correlates with allele-specific full-length INPP5D expression. Full article

(This article belongs to the Special Issue Genetics: Insights into Alzheimer’s Disease)

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12 pages, 875 KiB

Open AccessEditor’s ChoiceArticle

Association of Single Nucleotide Polymorphism in the DGAT1 Gene with the Fatty Acid Composition of Cows Milked Once and Twice a Day

by Inthujaa Sanjayaranj, Alastair K. H. MacGibbon, Stephen E. Holroyd, Patrick W. M. Janssen, Hugh T. Blair and Nicolas Lopez-Villalobos

Genes 2023, 14(3), 767; https://doi.org/10.3390/genes14030767 - 21 Mar 2023

Cited by 2 | Viewed by 2236

Abstract

A single nucleotide polymorphism (SNP) rs109421300 of the diacylglycerol acyltransferase 1 (DGAT1) on bovine chromosome 14 is associated with fat yield, fat percentage, and protein percentage. This study aimed to investigate the effect of SNP rs109421300 on production traits and the [...] Read more.

A single nucleotide polymorphism (SNP) rs109421300 of the diacylglycerol acyltransferase 1 (DGAT1) on bovine chromosome 14 is associated with fat yield, fat percentage, and protein percentage. This study aimed to investigate the effect of SNP rs109421300 on production traits and the fatty acid composition of milk from cows milked once a day (OAD) and twice a day (TAD) under New Zealand grazing conditions. Between September 2020 and March 2021, 232 cows from a OAD herd and 182 cows from a TAD herd were genotyped. The CC genotype of SNP rs109421300 was associated with significantly (p < 0.05) higher fat yield, fat percentage, and protein percentage, and lower milk and protein yields in both milking frequencies. The CC genotype was also associated with significantly (p < 0.05) higher proportions of C16:0 and C18:0, higher predicted solid fat content at 10 °C (SFC₁₀), and lower proportions of C4:0 and C18:1 cis-9 in both milking frequencies. The association of SNP with fatty acids was similar in both milking frequencies, with differences in magnitudes. The SFC₁₀ of cows milked OAD was lower than cows milked TAD for all three SNP genotypes suggesting the suitability of OAD milk for producing easily spreadable butter. These results demonstrate that selecting cows with the CC genotype is beneficial for New Zealand dairy farmers with the current payment system, however, this would likely result in less spreadable butter. Full article

(This article belongs to the Section Animal Genetics and Genomics)

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11 pages, 704 KiB

Open AccessEditor’s ChoiceArticle

Therapeutic Targeting of P53: A Comparative Analysis of APR-246 and COTI-2 in Human Tumor Primary Culture 3-D Explants

by Adam J. Nagourney, Joshua B. Gipoor, Steven S. Evans, Paulo D’Amora, Max S. Duesberg, Paula J. Bernard, Federico Francisco and Robert A. Nagourney

Genes 2023, 14(3), 747; https://doi.org/10.3390/genes14030747 - 19 Mar 2023

Cited by 4 | Viewed by 3262

Abstract

Background: TP53 is the most commonly mutated gene in human cancer with loss of function mutations largely concentrated in “hotspots” affecting DNA binding. APR-246 and COTI-2 are small molecules under investigation in P53 mutated cancers. APR binds to P53 cysteine residues, altering [...] Read more.

Background: TP53 is the most commonly mutated gene in human cancer with loss of function mutations largely concentrated in “hotspots” affecting DNA binding. APR-246 and COTI-2 are small molecules under investigation in P53 mutated cancers. APR binds to P53 cysteine residues, altering conformation, while COTI-2 showed activity in P53 mutant tumors by a computational platform. We compared APR-246 and COTI-2 activity in human tumor explants from 247 surgical specimens. Methods: Ex vivo analyses of programmed cell death measured drug-induced cell death by delayed-loss-of-membrane integrity and ATP content. The LC50s were compared by Z-Score. Synergy was conducted by the method of Chou and Talalay, and correlations were performed by Pearson moment. Results: APR-246 and COTI-2 activity favored hematologic neoplasms, but solid tumor activity varied by diagnosis. COTI-2 and APR-246 activity did not correlate (R = 0.1028) (NS). COTI-2 activity correlated with nitrogen mustard, cisplatin and gemcitabine, doxorubicin and selumetinib, with a trend for APR-246 with doxorubicin. For ovarian cancer, COTI-2 showed synergy with cisplatin at 25%. Conclusions: COTI-2 and APR-246 activity differ by diagnosis. A lack of correlation supports distinct modes of action. Cisplatin synergy is consistent with P53’s role in DNA damage. Different mechanisms of action may underlie disease specificity and offer better disease targeting. Full article

(This article belongs to the Topic Advances in Genetics and Precision Medicine in Human Diseases)

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4 pages, 198 KiB

Open AccessEditor’s ChoiceEditorial

Special Issue “Parkinson’s Disease: Genetics and Pathogenesis”

by Suzanne Lesage and Joanne Trinh

Genes 2023, 14(3), 737; https://doi.org/10.3390/genes14030737 - 17 Mar 2023

Cited by 2 | Viewed by 2147

Abstract

Parkinson’s disease (PD) is a common and incurable neurodegenerative disease, affecting 1% of the population over the age of 65 [...] Full article

(This article belongs to the Special Issue Parkinson's Disease: Genetics and Pathogenesis)

9 pages, 676 KiB

Open AccessEditor’s ChoiceBrief Report

Comparing Gene Panels for Non-Retinal Indications: A Systematic Review

by Rebecca Procopio, Jose S. Pulido, Kammi B. Gunton, Zeba A. Syed, Daniel Lee, Mark L. Moster, Robert Sergott, Julie A. Neidich and Margaret M. Reynolds

Genes 2023, 14(3), 738; https://doi.org/10.3390/genes14030738 - 17 Mar 2023

Viewed by 1956

Abstract

Importance: The options for genetic testing continue to grow for ocular conditions, including optic atrophy, anterior segment dysgenesis, cataracts, corneal dystrophy, nystagmus, and glaucoma. Gene panels can vary in content and coverage, as we and others have evaluated in inherited retinal disease (IRD). [...] Read more.

Importance: The options for genetic testing continue to grow for ocular conditions, including optic atrophy, anterior segment dysgenesis, cataracts, corneal dystrophy, nystagmus, and glaucoma. Gene panels can vary in content and coverage, as we and others have evaluated in inherited retinal disease (IRD). Objective: To describe gene panel testing options for inherited eye disease phenotypes and their differences. This review is important for making diagnostic decisions. Evidence review: A licensed, certified genetic counselor (RP) used Concert Genetics and the search terms optic atrophy, corneal dystrophy, cataract, glaucoma, anterior segment dysgenesis, microphthalmia/anophthalmia, and nystagmus to identify available testing options performed by CLIA-certified commercial genetic testing laboratories. Other co-authors were surveyed with respect to genetic panels used for the indications of interest. Ophthalmic panels were then compared using Concert Genetics in addition to their own websites. Findings: Panels from each clinical category were included and summarized. This comparison highlighted the differences and similarities between panels so that clinicians can make informed decisions. Conclusions: Access to genetic testing is increasing. The diagnostic yield of genetic testing is increasing. Each panel is different, so phenotyping or characterizing clinical characteristics that may help predict a specific genotype, as well as pre-test hypotheses regarding a genotype, should shape the choice of panels. Full article

(This article belongs to the Section Human Genomics and Genetic Diseases)

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22 pages, 1064 KiB

Open AccessEditor’s ChoiceReview

Satellite DNAs—From Localized to Highly Dispersed Genome Components

by Eva Šatović-Vukšić and Miroslav Plohl

Genes 2023, 14(3), 742; https://doi.org/10.3390/genes14030742 - 17 Mar 2023

Cited by 52 | Viewed by 4868

Abstract

According to the established classical view, satellite DNAs are defined as abundant non-coding DNA sequences repeated in tandem that build long arrays located in heterochromatin. Advances in sequencing methodologies and development of specialized bioinformatics tools enabled defining a collection of all repetitive DNAs [...] Read more.

According to the established classical view, satellite DNAs are defined as abundant non-coding DNA sequences repeated in tandem that build long arrays located in heterochromatin. Advances in sequencing methodologies and development of specialized bioinformatics tools enabled defining a collection of all repetitive DNAs and satellite DNAs in a genome, the repeatome and the satellitome, respectively, as well as their reliable annotation on sequenced genomes. Supported by various non-model species included in recent studies, the patterns of satellite DNAs and satellitomes as a whole showed much more diversity and complexity than initially thought. Differences are not only in number and abundance of satellite DNAs but also in their distribution across the genome, array length, interspersion patterns, association with transposable elements, localization in heterochromatin and/or in euchromatin. In this review, we compare characteristic organizational features of satellite DNAs and satellitomes across different animal and plant species in order to summarize organizational forms and evolutionary processes that may lead to satellitomes’ diversity and revisit some basic notions regarding repetitive DNA landscapes in genomes. Full article

(This article belongs to the Special Issue Satellite DNA Genomics)

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2 pages, 571 KiB

Open AccessEditor’s ChoiceCorrection

Correction: Leske, B.A.; Biddulph, T.B. Estimating Effects of Radiation Frost on Wheat Using a Field-Based Frost Control Treatment to Stop Freezing Damage. Genes 2022, 13, 578

by Brenton A. Leske and Thomas Ben Biddulph

Genes 2023, 14(3), 728; https://doi.org/10.3390/genes14030728 - 16 Mar 2023

Cited by 1 | Viewed by 1075

Abstract

In the original publication [...] Full article

(This article belongs to the Special Issue Genetic Diversity of Plant Tolerance to Environmental Restraints)

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12 pages, 4097 KiB

Open AccessEditor’s ChoiceArticle

Internal Transcribed Spacer and 16S Amplicon Sequencing Identifies Microbial Species Associated with Asbestos in New Zealand

by Erin Doyle, Dan Blanchon, Sarah Wells, Peter de Lange, Pete Lockhart, Nick Waipara, Michael Manefield, Shannon Wallis and Terri-Ann Berry

Genes 2023, 14(3), 729; https://doi.org/10.3390/genes14030729 - 16 Mar 2023

Cited by 3 | Viewed by 2699

Abstract

Inhalation of asbestos fibres can cause lung inflammation and the later development of asbestosis, lung cancer, and mesothelioma, and the use of asbestos is banned in many countries. In most countries, large amounts of asbestos exists within building stock, buried in landfills, and [...] Read more.

Inhalation of asbestos fibres can cause lung inflammation and the later development of asbestosis, lung cancer, and mesothelioma, and the use of asbestos is banned in many countries. In most countries, large amounts of asbestos exists within building stock, buried in landfills, and in contaminated soil. Mechanical, thermal, and chemical treatment options do exist, but these are expensive, and they are not effective for contaminated soil, where only small numbers of asbestos fibres may be present in a large volume of soil. Research has been underway for the last 20 years into the potential use of microbial action to remove iron and other metal cations from the surface of asbestos fibres to reduce their toxicity. To access sufficient iron for metabolism, many bacteria and fungi produce organic acids, or iron-chelating siderophores, and in a growing number of experiments these have been found to degrade asbestos fibres in vitro. This paper uses the internal transcribed spacer (ITS) and 16S amplicon sequencing to investigate the fungal and bacterial diversity found on naturally-occurring asbestos minerals, asbestos-containing building materials, and asbestos-contaminated soils with a view to later selectively culturing promising species, screening them for siderophore production, and testing them with asbestos fibres in vitro. After filtering, 895 ITS and 1265 16S amplicon sequencing variants (ASVs) were detected across the 38 samples, corresponding to a range of fungal, bacteria, cyanobacterial, and lichenized fungal species. Samples from Auckland (North Island, New Zealand) asbestos cement, Auckland asbestos-contaminated soils, and raw asbestos rocks from Kahurangi National Park (South Island, New Zealand) were comprised of very different microbial communities. Five of the fungal species detected in this study are known to produce siderophores. Full article

(This article belongs to the Section Microbial Genetics and Genomics)

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10 pages, 640 KiB

Open AccessEditor’s ChoiceArticle

SCN9A rs6746030 Polymorphism and Pain Perception in Combat Athletes and Non-Athletes

by Katarzyna Leźnicka, Maciej Pawlak, Marek Sawczuk, Agata Gasiorowska and Agata Leońska-Duniec

Genes 2023, 14(3), 733; https://doi.org/10.3390/genes14030733 - 16 Mar 2023

Cited by 4 | Viewed by 2489

Abstract

One of the genes associated with pain perception is SCN9A, which encodes an α-subunit of the voltage gated sodium channel, NaV1.7, a crucial player in peripheral pain sensation. It has been suggested that a common missense polymorphism within SCN9A (rs6746030; G>A; R1150W) [...] Read more.

One of the genes associated with pain perception is SCN9A, which encodes an α-subunit of the voltage gated sodium channel, NaV1.7, a crucial player in peripheral pain sensation. It has been suggested that a common missense polymorphism within SCN9A (rs6746030; G>A; R1150W) may affect nociception in the general population, but its effects of pain perception in athletes remain unknown. Therefore, the aim of the study was to investigate the association between a polymorphism within SCN9A (rs6746030) and pain perception (pain threshold and pain tolerance) in the group of combat athletes (n = 214) and students (n = 92) who did not participate in sports at a professional level. Genotyping was carried out using TaqMan Real-Time PCR method. No significant differences were found between the SCN9A genotype distributions with respect to the pain threshold. However, the probability of having a high pain threshold was higher in the combat sports group than in the control group. The probability of having a decreased pain tolerance was higher in the carriers of the GA and AA genotype than in the homozygotes of the GG genotype. Moreover, the possibility of having a high pain threshold was higher in the combat athlete group than in the control group. The results of our study suggest that the SCN9A rs6746030 polymorphism may affect pain perception. However, the additional effect of the experimental group may suggest that pain tolerance is significantly modulated by other factors, such as the systematic exposure of the athletes’ bodies to short-term high-intensity stimuli during training sessions. Full article

(This article belongs to the Section Molecular Genetics and Genomics)

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20 pages, 14568 KiB

Open AccessEditor’s ChoiceArticle

FERMT1 Is a Prognostic Marker Involved in Immune Infiltration of Pancreatic Adenocarcinoma Correlating with m⁶A Modification and Necroptosis

by Qian Wu, Jin Li, Pei Wang, Qihang Peng, Zhongcui Kang, Yiting Deng, Jiayi Li, Dehong Yan, Feng Ge and Ying Chen

Genes 2023, 14(3), 734; https://doi.org/10.3390/genes14030734 - 16 Mar 2023

Cited by 5 | Viewed by 2545

Abstract

As an important member of the kindlin family, fermitin family member 1 (FERMT1) can interact with integrin and its aberrant expression involves multiple tumors. However, there are few systematic studies on FERMT1 in pancreatic carcinoma (PAAD). We used several public databases to analyze [...] Read more.

As an important member of the kindlin family, fermitin family member 1 (FERMT1) can interact with integrin and its aberrant expression involves multiple tumors. However, there are few systematic studies on FERMT1 in pancreatic carcinoma (PAAD). We used several public databases to analyze the expression level and clinicopathological characteristics of FERMT1 in PAAD. Meanwhile, the correlation between FERMT1 expression and diagnostic and prognostic value, methylation, potential biological function, immune infiltration, and sensitivity to chemotherapy drugs in PAAD patients were investigated. FERMT1 was significantly up-regulated in PAAD and correlated with T stage, and histologic grade. High FERMT1 expression was closely connected with poor prognosis and can be used to diagnose PAAD. Moreover, the methylation of six CpG sites of FERMT1 was linked to prognosis, and FERMT1 expression was significantly related to N6-methyladenosine (m⁶A) modification. Functional enrichment analysis revealed that FERMT1 co-expression genes participated in diverse biological functions including necroptosis. In addition, the expression of FERMT1 was associated with immune cell infiltration and the expression of immune checkpoint molecules. Finally, FERMT1 overexpression may be sensitive to chemotherapy drugs such as Palbociclib, AM-5992 and TAE-226. FERMT1 can serve as a diagnostic and prognostic marker of PAAD, which is connected with immune cell infiltration and the modulation of m⁶A and necroptosis. Full article

(This article belongs to the Section Bioinformatics)

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14 pages, 1406 KiB

Open AccessEditor’s ChoiceArticle

Mutational Spectrum of the ABCA12 Gene and Genotype–Phenotype Correlation in a Cohort of 64 Patients with Autosomal Recessive Congenital Ichthyosis

by Alrun Hotz, Julia Kopp, Emmanuelle Bourrat, Vinzenz Oji, Kira Süßmuth, Katalin Komlosi, Bakar Bouadjar, Iliana Tantcheva-Poór, Maritta Hellström Pigg, Regina C. Betz, Kathrin Giehl, Fiona Schedel, Lisa Weibel, Solveig Schulz, Dora V. Stölzl, Gianluca Tadini, Emine Demiral, Karin Berggard, Andreas D. Zimmer, Svenja Alter and Judith Fischer Show full author list Hide full author list

Genes 2023, 14(3), 717; https://doi.org/10.3390/genes14030717 - 15 Mar 2023

Cited by 12 | Viewed by 6797

Abstract

Autosomal recessive congenital ichthyosis (ARCI) is a non-syndromic congenital disorder of cornification characterized by abnormal scaling of the skin. The three major phenotypes are lamellar ichthyosis, congenital ichthyosiform erythroderma, and harlequin ichthyosis. ARCI is caused by biallelic mutations in ABCA12, ALOX12B, [...] Read more.

Autosomal recessive congenital ichthyosis (ARCI) is a non-syndromic congenital disorder of cornification characterized by abnormal scaling of the skin. The three major phenotypes are lamellar ichthyosis, congenital ichthyosiform erythroderma, and harlequin ichthyosis. ARCI is caused by biallelic mutations in ABCA12, ALOX12B, ALOXE3, CERS3, CYP4F22, NIPAL4, PNPLA1, SDR9C7, SULT2B1, and TGM1. The most severe form of ARCI, harlequin ichthyosis, is caused by mutations in ABCA12. Mutations in this gene can also lead to congenital ichthyosiform erythroderma or lamellar ichthyosis. We present a large cohort of 64 patients affected with ARCI carrying biallelic mutations in ABCA12. Our study comprises 34 novel mutations in ABCA12, expanding the mutational spectrum of ABCA12-associated ARCI up to 217 mutations. Within these we found the possible mutational hotspots c.4541G>A, p.(Arg1514His) and c.4139A>G, p.(Asn1380Ser). A correlation of the phenotype with the effect of the genetic mutation on protein function is demonstrated. Loss-of-function mutations on both alleles generally result in harlequin ichthyosis, whereas biallelic missense mutations mainly lead to CIE or LI. Full article

(This article belongs to the Special Issue Feature Papers in Human Genomics and Genetic Diseases 2023)

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12 pages, 1173 KiB

Open AccessEditor’s ChoiceArticle

Genome-Wide Scan of Wool Production Traits in Akkaraman Sheep

by Yunus Arzik, Mehmet Kizilaslan, Sedat Behrem, Stephen N. White, Lindsay M. W. Piel and Mehmet Ulas Cinar

Genes 2023, 14(3), 713; https://doi.org/10.3390/genes14030713 - 14 Mar 2023

Cited by 20 | Viewed by 3856

Abstract

The objective of this study was to uncover the genetic background of wool quality, a production trait, by estimating genomic heritability and implementing GWAS in Akkaraman sheep. The wool characteristics measured included fibre diameter (FD) and staple length (SL) at the age of [...] Read more.

The objective of this study was to uncover the genetic background of wool quality, a production trait, by estimating genomic heritability and implementing GWAS in Akkaraman sheep. The wool characteristics measured included fibre diameter (FD) and staple length (SL) at the age of 8 months and yearling fibre diameter (YFD), yearling staple length (YSL) and yearling greasy fleece weight (YGFW) at 18 months of age. Animals were genotyped using the Axiom 50 K Ovine Genotyping Array. Maximum likelihood estimations of a linear mixed model (LMM) were used to estimate genomic heritability, where GWAS was conducted following a score test of each trait. Genomic heritability estimates for the traits ranged between 0.22 and 0.63, indicating that phenotypes have a moderate range of heritability. One genome- and six chromosome-wide significant SNPs were associated with the wool traits in Akkaraman lambs. Accordingly, TRIM2, MND1, TLR2, RNF175, CEP290, TMTC3, RERE, SLC45A1, SOX2, MORN1, SKI, FAAP20, PRKCZ, GABRD, CFAP74, CALML6 and TMEM52 genes as well as nine uncharacterized regions (LOC101118971, LOC105609137, LOC105603067, LOC101122892, LOC106991694, LOC106991467, LOC106991455, LOC105616534 and LOC105609719) were defined as plausible candidates. The findings of this study shed light on the genetics of wool quality and yield for the Akkaraman breed and suggests targets for breeders during systematic breeding programmes. Full article

(This article belongs to the Special Issue Genetics and Breeding of Small Ruminants)

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16 pages, 2248 KiB

Open AccessEditor’s ChoiceArticle

An Investigation into Compound Likelihood Ratios for Forensic DNA Mixtures

by Richard Wivell, Hannah Kelly, Jason Kokoszka, Jace Daniels, Laura Dickson, John Buckleton and Jo-Anne Bright

Genes 2023, 14(3), 714; https://doi.org/10.3390/genes14030714 - 14 Mar 2023

Cited by 1 | Viewed by 2851

Abstract

Simple propositions are defined as those with one POI and the remaining contributors unknown under H_p and all unknown contributors under H_a. Conditional propositions are defined as those with one POI, one or more assumed contributors, and the remaining contributors [...] Read more.

Simple propositions are defined as those with one POI and the remaining contributors unknown under H_p and all unknown contributors under H_a. Conditional propositions are defined as those with one POI, one or more assumed contributors, and the remaining contributors (if any) unknown under H_p, and the assumed contributor(s) and N unknown contributors under H_a. In this study, compound propositions are those with multiple POI and the remaining contributors unknown under H_p and all unknown contributors under Ha. We study the performance of these three proposition sets on thirty-two samples (two laboratories × four NOCs × four mixtures) consisting of four mixtures, each with N = 2, N = 3, N = 4, and N = 5 contributors using the probabilistic genotyping software, STRmix™. In this study, it was found that conditional propositions have a much higher ability to differentiate true from false donors than simple propositions. Compound propositions can misstate the weight of evidence given the propositions strongly in either direction. Full article

(This article belongs to the Special Issue Forensic DNA Mixture Interpretation and Probabilistic Genotyping)

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20 pages, 1252 KiB

Open AccessEditor’s ChoiceReview

Telomere Length Changes in Cancer: Insights on Carcinogenesis and Potential for Non-Invasive Diagnostic Strategies

by Zuzana Holesova, Lucia Krasnicanova, Rami Saade, Ondrej Pös, Jaroslav Budis, Juraj Gazdarica, Vanda Repiska and Tomas Szemes

Genes 2023, 14(3), 715; https://doi.org/10.3390/genes14030715 - 14 Mar 2023

Cited by 19 | Viewed by 6642

Abstract

Telomere dynamics play a crucial role in the maintenance of chromosome integrity; changes in telomere length may thus contribute to the development of various diseases including cancer. Understanding the role of telomeric DNA in carcinogenesis and detecting the presence of cell-free telomeric DNA [...] Read more.

Telomere dynamics play a crucial role in the maintenance of chromosome integrity; changes in telomere length may thus contribute to the development of various diseases including cancer. Understanding the role of telomeric DNA in carcinogenesis and detecting the presence of cell-free telomeric DNA (cf-telDNA) in body fluids offer a potential biomarker for novel cancer screening and diagnostic strategies. Liquid biopsy is becoming increasingly popular due to its undeniable benefits over conventional invasive methods. However, the organization and function of cf-telDNA in the extracellular milieu are understudied. This paper provides a review based on 3,398,017 cancer patients, patients with other conditions, and control individuals with the aim to shed more light on the inconsistent nature of telomere lengthening/shortening in oncological contexts. To gain a better understanding of biological factors (e.g., telomerase activation, alternative lengthening of telomeres) affecting telomere homeostasis across different types of cancer, we summarize mechanisms responsible for telomere length maintenance. In conclusion, we compare tissue- and liquid biopsy-based approaches in cancer assessment and provide a brief outlook on the methodology used for telomere length evaluation, highlighting the advances of state-of-the-art approaches in the field. Full article

(This article belongs to the Special Issue DNA Damage and Repair at the Crossroad with Telomeres)

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12 pages, 444 KiB

Open AccessEditor’s ChoiceArticle

Lack of Association of Polymorphism Located Upstream of ABCA1 (rs2472493), in FNDC3B (rs7636836), and Near ANKRD55–MAP3K1 Genes (rs61275591) in Primary Open-Angle Glaucoma Patients of Saudi Origin

by Altaf A. Kondkar, Tahira Sultan, Taif A. Azad, Essam A. Osman, Faisal A. Almobarak, Glenn P. Lobo and Saleh A. Al-Obeidan

Genes 2023, 14(3), 704; https://doi.org/10.3390/genes14030704 - 13 Mar 2023

Cited by 2 | Viewed by 1889

Abstract

Polymorphisms rs2472493 near ABCA1, rs7636836 in FNDC3B, and rs61275591 near the ANKRD55–MAP3K1 genes were previously reported to exhibit genome-wide significance in primary open-angle glaucoma (POAG). Since these polymorphisms have not been investigated in the Arab population of Saudi Arabia, we examined [...] Read more.

Polymorphisms rs2472493 near ABCA1, rs7636836 in FNDC3B, and rs61275591 near the ANKRD55–MAP3K1 genes were previously reported to exhibit genome-wide significance in primary open-angle glaucoma (POAG). Since these polymorphisms have not been investigated in the Arab population of Saudi Arabia, we examined their association with POAG in a Saudi cohort. Genotyping was performed in 152 POAG cases and 246 controls using Taqman real-time assays and their associations with POAG and clinical markers, such as intraocular pressure, cup/disc ratio, and the number of antiglaucoma medications, were tested by statistical methods. There was no association observed between POAG and the minor allele frequencies of rs2472493[G], rs7636836[T], or rs61275591[A]. None of the genetic models such as co-dominant, dominant, recessive, over-dominant, and log-additive demonstrated any genotype link. The Rs2472493 genotype showed a modest association (p = 0.044) with the number of antiglaucoma medications in the POAG group, but no significant genotype effect on post hoc analysis. In addition, a G-T allelic haplotype of rs2472493 (ABCA1) and rs7636836 (FNDC3B) did show an over two-fold increased risk of POAG (odds ratio = 2.18), albeit non-significantly (p = 0.092). Similarly, no other allelic haplotype of the three variants showed any significant association with POAG. Our study did not replicate the genetic association of rs2472493 (ABCA1), rs763683 (FNDC3B), and rs61275591 (ANKRD55–MAP3K1) in POAG and related clinical phenotypes, suggesting that these polymorphisms are not associated with POAG in a Saudi cohort of Arab ethnicity. However, large population-based multicenter studies are needed to validate these results. Full article

(This article belongs to the Special Issue Single-Nucleotide Polymorphisms: Association, Molecular Function, Application, and Progress)

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11 pages, 4833 KiB

Open AccessEditor’s ChoiceCommunication

The Complete Mitochondrial Genome of Homophyllia bowerbanki (Scleractinia, Lobophylliidae): The First Sequence for the Genus Homophyllia

by Peng Tian, Wei Wang, Ziqing Xu, Bingbing Cao, Zhiyu Jia, Fucheng Sun, Jiaguang Xiao and Wentao Niu

Genes 2023, 14(3), 695; https://doi.org/10.3390/genes14030695 - 11 Mar 2023

Cited by 2 | Viewed by 1762

Abstract

Reef-building coral species of the order Scleractinia play an important role in shallow tropical seas by providing an environmental base for the ecosystem. The molecular data of complete mitochondrial genome have become an important source for evaluating phylogenetic and evolutionary studies of Scleractinia. [...] Read more.

Reef-building coral species of the order Scleractinia play an important role in shallow tropical seas by providing an environmental base for the ecosystem. The molecular data of complete mitochondrial genome have become an important source for evaluating phylogenetic and evolutionary studies of Scleractinia. Here, the complete mitogenome of Homophyllia bowerbanki (Milne Edwards and Haime, 1857), collected from Nansha Islands of the South China Sea, was sequenced for the first time through a next-generation sequencing method. H. bowerbanki is the first species of its genus for which the mitogenome was sequenced. This mitogenome was 18,154 bp in size and included two transfer RNA genes (tRNAs), 13 protein-coding genes (PCGs), and two ribosomal RNA genes (rRNAs). It showed a similar gene structure and gene order to the other typical scleractinians. All 17 genes were encoded on the H strand and the total GC content was 33.86% in mitogenome. Phylogenetic analysis (maximum likelihood tree method) showed that H. bowerbanki belonged to the “Robust” clade and clustered together with other two species in the family Lobophylliidae based on 13 PCGs. The mitogenome can provide significant molecular information to clarify the evolutionary and phylogenetic relationships between stony corals and to facilitate their taxonomic classification; it can also support coral species monitoring and conservation efforts. Full article

(This article belongs to the Section Molecular Genetics and Genomics)

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21 pages, 758 KiB

Open AccessEditor’s ChoiceReview

The Autism Spectrum: Behavioral, Psychiatric and Genetic Associations

by Ann Genovese and Merlin G. Butler

Genes 2023, 14(3), 677; https://doi.org/10.3390/genes14030677 - 9 Mar 2023

Cited by 85 | Viewed by 27304

Abstract

Autism spectrum disorder (ASD) consists of a group of heterogeneous genetic neurobehavioral disorders associated with developmental impairments in social communication skills and stereotypic, rigid or repetitive behaviors. We review common behavioral, psychiatric and genetic associations related to ASD. Autism affects about 2% of [...] Read more.

Autism spectrum disorder (ASD) consists of a group of heterogeneous genetic neurobehavioral disorders associated with developmental impairments in social communication skills and stereotypic, rigid or repetitive behaviors. We review common behavioral, psychiatric and genetic associations related to ASD. Autism affects about 2% of children with 4:1 male-to-female ratio and a heritability estimate between 70 and 90%. The etiology of ASD involves a complex interplay between inheritance and environmental factors influenced by epigenetics. Over 800 genes and dozens of genetic syndromes are associated with ASD. Novel gene–protein interactions with pathway and molecular function analyses have identified at least three functional pathways including chromatin modeling, Wnt, Notch and other signaling pathways and metabolic disturbances involving neuronal growth and dendritic spine profiles. An estimated 50% of individuals with ASD are diagnosed with chromosome deletions or duplications (e.g., 15q11.2, BP1-BP2, 16p11.2 and 15q13.3), identified syndromes (e.g., Williams, Phelan-McDermid and Shprintzen velocardiofacial) or single gene disorders. Behavioral and psychiatric conditions in autism impacted by genetics influence clinical evaluations, counseling, diagnoses, therapeutic interventions and treatment approaches. Pharmacogenetics testing is now possible to help guide the selection of psychotropic medications to treat challenging behaviors or co-occurring psychiatric conditions commonly seen in ASD. In this review of the autism spectrum disorder, behavioral, psychiatric and genetic observations and associations relevant to the evaluation and treatment of individuals with ASD are discussed. Full article

(This article belongs to the Special Issue Genes, Phenotypes and Molecular Mechanisms for Personalized Medicine in Autism)

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15 pages, 2589 KiB

Open AccessEditor’s ChoiceReview

The Role of PRMT5 in Immuno-Oncology

by Yoshinori Abe, Takumi Sano and Nobuyuki Tanaka

Genes 2023, 14(3), 678; https://doi.org/10.3390/genes14030678 - 9 Mar 2023

Cited by 16 | Viewed by 6107

Abstract

Immune checkpoint inhibitor (ICI) therapy has caused a paradigm shift in cancer therapeutic strategy. However, this therapy only benefits a subset of patients. The difference in responses to ICIs is believed to be dependent on cancer type and its tumor microenvironment (TME). The [...] Read more.

Immune checkpoint inhibitor (ICI) therapy has caused a paradigm shift in cancer therapeutic strategy. However, this therapy only benefits a subset of patients. The difference in responses to ICIs is believed to be dependent on cancer type and its tumor microenvironment (TME). The TME is favorable for cancer progression and metastasis and can also help cancer cells to evade immune attacks. To improve the response to ICIs, it is crucial to understand the mechanism of how the TME is maintained. Protein arginine methyltransferase 5 (PRMT5) di-methylates arginine residues in its substrates and has essential roles in the epigenetic regulation of gene expression, signal transduction, and the fidelity of mRNA splicing. Through these functions, PRMT5 can support cancer cell immune evasion. PRMT5 is necessary for regulatory T cell (Treg) functions and promotes cancer stemness and the epithelial–mesenchymal transition. Specific factors in the TME can help recruit Tregs, tumor-associated macrophages, and myeloid-derived suppressor cells into tumors. In addition, PRMT5 suppresses antigen presentation and the production of interferon and chemokines, which are necessary to recruit T cells into tumors. Overall, PRMT5 supports an immunosuppressive TME. Therefore, PRMT5 inhibition would help recover the immune cycle and enable the immune system-mediated elimination of cancer cells. Full article

(This article belongs to the Section Molecular Genetics and Genomics)

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15 pages, 1846 KiB

Open AccessEditor’s ChoiceArticle

Optical Genome Mapping Reveals and Characterizes Recurrent Aberrations and New Fusion Genes in Adult ALL

by Lisa-Marie Vieler, Verena Nilius-Eliliwi, Roland Schroers, Deepak Ben Vangala, Huu Phuc Nguyen and Wanda Maria Gerding

Genes 2023, 14(3), 686; https://doi.org/10.3390/genes14030686 - 9 Mar 2023

Cited by 13 | Viewed by 3330

Abstract

(1) Background: In acute lymphoblastic leukemia (ALL) the genetic characterization remains challenging. Due to the genetic heterogeneity of mutations in adult patients, only a small proportion of aberrations can be analyzed with standard routine diagnostics. Optical genome mapping (OGM) has recently opened up [...] Read more.

(1) Background: In acute lymphoblastic leukemia (ALL) the genetic characterization remains challenging. Due to the genetic heterogeneity of mutations in adult patients, only a small proportion of aberrations can be analyzed with standard routine diagnostics. Optical genome mapping (OGM) has recently opened up new possibilities for the characterization of structural variants on a genome-wide level, thus enabling simultaneous analysis for a broad spectrum of genetic aberrations. (2) Methods: 11 adult ALL patients were examined using OGM. (3) Results: Genetic results obtained by karyotyping and FISH were confirmed by OGM for all patients. Karyotype was redefined, and additional genetic information was obtained in 82% (9/11) of samples by OGM, previously not diagnosed by standard of care. Besides gross-structural chromosome rearrangements, e.g., ring chromosome 9 and putative isodicentric chromosome 8q, deletions in CDKN2A/2B were detected in 7/11 patients, defining an approx. 20 kb minimum region of overlap, including an alternative exon 1 of the CDKN2A gene. The results further confirm recurrent ALL aberrations (e.g., PAX5, ETV6, VPREB1, IKZF1). (4) Conclusions: Genome-wide OGM analysis enables a broad genetic characterization in adult ALL patients in one single workup compared to standard clinical testing, facilitating a detailed genetic diagnosis, risk-stratification, and target-directed treatment strategies. Full article

(This article belongs to the Special Issue Commemorating the Launch of the Section "Cytogenomics")

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14 pages, 2634 KiB

Open AccessEditor’s ChoiceArticle

Molecular Heterogeneity of Pediatric AML with Atypical Promyelocytes Accumulation in Children—A Single Center Experience

by Aleksandra Borkovskaia, Sofia Bogacheva, Tatiana Konyukhova, Elina Dadakhanova, Marina Gaskova, Olga Soldatkina, Maria Dubrovina, Alexander Popov, Ekaterina Mikhailova, Evgenia Inushkina, Marat Kazanov, Evgeniy Matveev, Galina Novichkova, Michael Maschan, Alexey Maschan, Yulia Olshanskaya and Elena Zerkalenkova

Genes 2023, 14(3), 675; https://doi.org/10.3390/genes14030675 - 8 Mar 2023

Cited by 2 | Viewed by 2873

Abstract

Acute promyelocytic leukemia (APL) pathogenesis is based on RARA gene translocations, which are of high importance in the diagnosis of and proper therapy selection for APL. However, in some cases acute myeloid leukemia (AML) demonstrates APL-like morphological features such as atypical promyelocytes accumulation. [...] Read more.

Acute promyelocytic leukemia (APL) pathogenesis is based on RARA gene translocations, which are of high importance in the diagnosis of and proper therapy selection for APL. However, in some cases acute myeloid leukemia (AML) demonstrates APL-like morphological features such as atypical promyelocytes accumulation. This type of AML is characterized by the involvement of other RAR family members or completely different genes. In the present study, we used conventional karyotyping, FISH and high-throughput sequencing in a group of 271 de novo AML with atypical promyelocytes accumulation. Of those, 255 cases were shown to carry a typical chromosomal translocation t(15;17)(q24;q21) with PML::RARA chimeric gene formation (94.1%). Other RARA-positive cases exhibited cryptic PML::RARA fusion without t(15;17)(q24;q21) (1.8%, n = 5) and variant t(5;17)(q35;q21) translocation with NPM1::RARA chimeric gene formation (1.5%, n = 4). However, 7 RARA-negative AMLs with atypical promyelocytes accumulation were also discovered. These cases exhibited TBL1XR1::RARB and KMT2A::SEPT6 fusions as well as mutations, e.g., NPM1 insertion and non-recurrent chromosomal aberrations. Our findings demonstrate the genetic diversity of AML with APL-like morphological features, which is of high importance for successful therapy implementation. Full article

(This article belongs to the Special Issue Genetics of Blood Disorders)

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19 pages, 1302 KiB

Open AccessEditor’s ChoiceArticle

Genome Analysis Using Whole-Exome Sequencing of Non-Syndromic Cleft Lip and/or Palate from Malagasy Trios Identifies Variants Associated with Cilium-Related Pathways and Asian Genetic Ancestry

by Zarko Manojlovic, Allyn Auslander, Yuxin Jin, Ryan J. Schmidt, Yili Xu, Sharon Chang, Ruocen Song, Sue A. Ingles, Alana Nunes, KC Vavra, Devin Feigelson, Sylvia Rakotoarison, Melissa DiBona, Kathy Magee, Operation Smile, Anjaramamy Ramamonjisoa and William Magee III

Genes 2023, 14(3), 665; https://doi.org/10.3390/genes14030665 - 7 Mar 2023

Cited by 3 | Viewed by 3299

Abstract

Background: Orofacial clefts (OFCs) are common congenital disabilities that can occur as isolated non-syndromic events or as part of Mendelian syndromes. OFC risk factors vary due to differences in regional environmental exposures, genetic variants, and ethnicities. In recent years, significant progress has been [...] Read more.

Background: Orofacial clefts (OFCs) are common congenital disabilities that can occur as isolated non-syndromic events or as part of Mendelian syndromes. OFC risk factors vary due to differences in regional environmental exposures, genetic variants, and ethnicities. In recent years, significant progress has been made in understanding OFCs, due to advances in sequencing and genotyping technologies. Despite these advances, very little is known about the genetic interplay in the Malagasy population. Methods: Here, we performed high-resolution whole-exome sequencing (WES) on non-syndromic cleft lip with or without palate (nCL/P) trios in the Malagasy population (78 individuals from 26 families (trios)). To integrate the impact of genetic ancestry admixture, we computed both global and local ancestries. Results: Participants demonstrated a high percentage of both African and Asian admixture. We identified damaging variants in primary cilium-mediated pathway genes WNT5B (one family), GPC4 (one family), co-occurrence in MSX1 (five families), WDR11 (one family), and tubulin stabilizer SEPTIN9 (one family). Furthermore, we identified an autosomal homozygous damaging variant in PHGDH (one family) gene that may impact metabiotic activity. Lastly, all variants were predicted to reside on local Asian genetic ancestry admixed alleles. Conclusion: Our results from examining the Malagasy genome provide limited support for the hypothesis that germline variants in primary cilia may be risk factors for nCL/P, and outline the importance of integrating local ancestry components better to understand the multi-ethnic impact on nCL/P. Full article

(This article belongs to the Section Human Genomics and Genetic Diseases)

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12 pages, 3750 KiB

Open AccessEditor’s ChoiceCase Report

A Case Report of a Feto-Placental Mosaicism Involving a Segmental Aneuploidy: A Challenge for Genome Wide Screening by Non-Invasive Prenatal Testing of Cell-Free DNA in Maternal Plasma

by Luigia De Falco, Giuseppina Vitiello, Giovanni Savarese, Teresa Suero, Raffaella Ruggiero, Pasquale Savarese, Monica Ianniello, Nadia Petrillo, Mariasole Bruno, Antonietta Legnante, Francesco Fioravanti Passaretti, Carmela Ardisia, Attilio Di Spiezio Sardo and Antonio Fico

Genes 2023, 14(3), 668; https://doi.org/10.3390/genes14030668 - 7 Mar 2023

Cited by 2 | Viewed by 2964

Abstract

Non-invasive prenatal testing (NIPT) using cell-free DNA can detect fetal chromosomal anomalies with high clinical sensitivity and specificity. In approximately 0.1% of clinical cases, the NIPT result and a subsequent diagnostic karyotype are discordant. Here we report a case of a 32-year-old pregnant [...] Read more.

Non-invasive prenatal testing (NIPT) using cell-free DNA can detect fetal chromosomal anomalies with high clinical sensitivity and specificity. In approximately 0.1% of clinical cases, the NIPT result and a subsequent diagnostic karyotype are discordant. Here we report a case of a 32-year-old pregnant patient with a 44.1 Mb duplication on the short arm of chromosome 4 detected by NIPT at 12 weeks’ gestation. Amniocentesis was carried out at 18 weeks’ gestation, followed by conventional and molecular cytogenetic analysis on cells from the amniotic fluid. SNP array analysis found a de novo deletion of 1.2 Mb at chromosome 4, and this deletion was found to be near the critical region of the Wolf-Hirschhorn syndrome. A normal 46,XY karyotype was identified by G-banding analysis. The patient underwent an elective termination and molecular investigations on tissues from the fetus, and the placenta confirmed the presence of type VI true fetal mosaicism. It is important that a patient receives counselling following a high-risk call on NIPT, with appropriate diagnostic analysis advised before any decisions regarding the pregnancy are taken. This case highlights the importance of genetic counselling following a high-risk call on NIPT, especially in light of the increasing capabilities of NIPT detection of sub-chromosomal deletions and duplications. Full article

(This article belongs to the Special Issue Genetics and Genomics of Prenatal Testing)

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14 pages, 1804 KiB

Open AccessEditor’s ChoiceArticle

Identification of Two Homozygous Variants in MYBPC3 and SMYD1 Genes Associated with Severe Infantile Cardiomyopathy

by Marta W. Szulik, Miguel Reyes-Múgica, Daniel F. Marker, Ana M. Gomez, Matthew D. Zinn, Leslie K. Walsh, Juan Pablo Ochoa, Sarah Franklin and Lina Ghaloul-Gonzalez

Genes 2023, 14(3), 659; https://doi.org/10.3390/genes14030659 - 6 Mar 2023

Cited by 2 | Viewed by 3478

Abstract

Mutations in cardiac genes are one of the primary causes of infantile cardiomyopathy. In this study, we report the genetic findings of two siblings carrying variations in the MYBPC3 and SMYD1 genes. The first patient is a female proband exhibiting hypertrophic cardiomyopathy (HCM) [...] Read more.

Mutations in cardiac genes are one of the primary causes of infantile cardiomyopathy. In this study, we report the genetic findings of two siblings carrying variations in the MYBPC3 and SMYD1 genes. The first patient is a female proband exhibiting hypertrophic cardiomyopathy (HCM) and biventricular heart failure carrying a truncating homozygous MYBPC3 variant c.1224-52G>A (IVS13-52G>A) and a novel homozygous variant (c.302A>G; p.Asn101Ser) in the SMYD1 gene. The second patient, the proband’s sibling, is a male infant diagnosed with hypertrophic cardiomyopathy and carries the same homozygous MYBPC3 variant. While this specific MYBPC3 variant (c.1224-52G>A, IVS13-52G>A) has been previously reported to be associated with adult-onset hypertrophic cardiomyopathy, this is the first report linking it to infantile cardiomyopathy. In addition, this work describes, for the first time, a novel SMYD1 variant (c.302A>G; p.Asn101Ser) that has never been reported. We performed a histopathological evaluation of tissues collected from both probands and show that these variants lead to myofibrillar disarray, reduced and irregular mitochondrial cristae and cardiac fibrosis. Together, these results provide critical insight into the molecular functionality of these genes in human cardiac physiology. Full article

(This article belongs to the Section Human Genomics and Genetic Diseases)

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11 pages, 1299 KiB

Open AccessEditor’s ChoiceArticle

Exome-Wide Association Study of Competitive Performance in Elite Athletes

by Celal Bulgay, Anıl Kasakolu, Hasan Hüseyin Kazan, Raluca Mijaica, Erdal Zorba, Onur Akman, Isık Bayraktar, Rıdvan Ekmekci, Seyrani Koncagul, Korkut Ulucan, Ekaterina A. Semenova, Andrey K. Larin, Nikolay A. Kulemin, Edward V. Generozov, Lorand Balint, Georgian Badicu, Ildus I. Ahmetov and Mehmet Ali Ergun

Genes 2023, 14(3), 660; https://doi.org/10.3390/genes14030660 - 6 Mar 2023

Cited by 17 | Viewed by 4740

Abstract

The aim of the study was to identify genetic variants associated with personal best scores in Turkish track and field athletes and to compare allelic frequencies between sprint/power and endurance athletes and controls using a whole-exome sequencing (WES) approach, followed by replication studies [...] Read more.

The aim of the study was to identify genetic variants associated with personal best scores in Turkish track and field athletes and to compare allelic frequencies between sprint/power and endurance athletes and controls using a whole-exome sequencing (WES) approach, followed by replication studies in independent cohorts. The discovery phase involved 60 elite Turkish athletes (31 sprint/power and 29 endurance) and 20 ethnically matched controls. The replication phase involved 1132 individuals (115 elite Russian sprinters, 373 elite Russian endurance athletes (of which 75 athletes were with VO_2max measurements), 209 controls, 148 Russian and 287 Finnish individuals with muscle fiber composition and cross-sectional area (CSA) data). None of the single nucleotide polymorphisms (SNPs) reached an exome-wide significance level (p < 2.3 × 10⁻⁷) in genotype–phenotype and case–control studies of Turkish athletes. However, of the 53 nominally (p < 0.05) associated SNPs, four functional variants were replicated. The SIRT1 rs41299232 G allele was significantly over-represented in Turkish (p = 0.047) and Russian (p = 0.018) endurance athletes compared to sprint/power athletes and was associated with increased VO_2max (p = 0.037) and a greater proportion of slow-twitch muscle fibers (p = 0.035). The NUP210 rs2280084 A allele was significantly over-represented in Turkish (p = 0.044) and Russian (p = 0.012) endurance athletes compared to sprint/power athletes. The TRPM2 rs1785440 G allele was significantly over-represented in Turkish endurance athletes compared to sprint/power athletes (p = 0.034) and was associated with increased VO_2max (p = 0.008). The AGRN rs4074992 C allele was significantly over-represented in Turkish sprint/power athletes compared to endurance athletes (p = 0.037) and was associated with a greater CSA of fast-twitch muscle fibers (p = 0.024). In conclusion, we present the first WES study of athletes showing that this approach can be used to identify novel genetic markers associated with exercise- and sport-related phenotypes. Full article

(This article belongs to the Special Issue Genetics, Sports and Training)

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