Genes

17 pages, 3923 KiB

Open AccessArticle

Sequencing and Description of the Mitochondrial Genome of Orthopodomyia fascipes (Diptera: Culicidae)

by Fábio Silva da Silva, Bruna Laís Sena do Nascimento, Ana Cecília Ribeiro Cruz, Sandro Patroca da Silva, Carine Fortes Aragão, Daniel Damous Dias, Lucas Henrique da Silva e Silva, Lúcia Aline Moura Reis, Hanna Carolina Farias Reis, Liliane Leal das Chagas, José Wilson Rosa Jr., Durval Bertram Rodrigues Vieira, Roberto Carlos Feitosa Brandão, Daniele Barbosa de Almeida Medeiros and Joaquim Pinto Nunes Neto

Genes 2024, 15(7), 874; https://doi.org/10.3390/genes15070874 (registering DOI) - 3 Jul 2024

Abstract

The genus Orthopodomyia Theobald, 1904 (Diptera: Culicidae) comprises 36 wild mosquito species, with distribution largely restricted to tropical and temperate areas, most of which are not recognized as vectors of epidemiological importance due to the lack of information related to their bionomy and [...] Read more.

The genus Orthopodomyia Theobald, 1904 (Diptera: Culicidae) comprises 36 wild mosquito species, with distribution largely restricted to tropical and temperate areas, most of which are not recognized as vectors of epidemiological importance due to the lack of information related to their bionomy and involvement in the cycle transmission of infectious agents. Furthermore, their evolutionary relationships are not completely understood, reflecting the scarcity of genetic information about the genus. Therefore, in this study, we report the first complete description of the mitochondrial genome of a Neotropical species representing the genus, Orthopodomyia fascipes Coquillet, 1906, collected in the Brazilian Amazon region. Using High Throughput Sequencing, we obtained a mitochondrial sequence of 15,598 bp, with an average coverage of 418.5×, comprising 37 functional subunits and a final portion rich in A + T, corresponding to the control region. The phylogenetic analysis, using Maximum Likelihood and Bayesian Inference based on the 13 protein-coding genes, corroborated the monophyly of Culicidae and its two subfamilies, supporting the proximity between the tribes Orthopodomyiini and Mansoniini, partially disagreeing with previous studies based on the use of molecular and morphological markers. The information generated in this study contributes to a better understanding of the taxonomy and evolutionary history of the genus and other groups of Culicidae. Full article

(This article belongs to the Special Issue Genetics, Phylogeny, and Evolution of Insects)

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11 pages, 1032 KiB

Open AccessArticle

Chronic Adolescent Restraint Stress Downregulates miRNA-200a Expression in Male and Female C57BL/6J and BALB/cJ Mice

by Helen M. Kamens, Emma K. Anziano, William J. Horton and Sonia A. Cavigelli

Genes 2024, 15(7), 873; https://doi.org/10.3390/genes15070873 (registering DOI) - 3 Jul 2024

Abstract

Adolescence is a critical developmental period when the brain is plastic, and stress exposure can have lasting physiological consequences. One mechanism through which adolescent stress may have lasting effects is by altering microRNAs (miRNAs), leading to wide-scale gene expression changes. Three prior independent [...] Read more.

Adolescence is a critical developmental period when the brain is plastic, and stress exposure can have lasting physiological consequences. One mechanism through which adolescent stress may have lasting effects is by altering microRNAs (miRNAs), leading to wide-scale gene expression changes. Three prior independent studies used unbiased approaches (RNA sequencing or microarray) to identify miRNAs differentially expressed by chronic variable stress in male rodents. In all three studies, miRNA-200a was differentially expressed in areas of the brain associated with emotion regulation. The current study extends this research to determine if chronic non-variable adolescent stress downregulates miRNA-200a expression by looking at two strains (BALB/cJ and C57BL/6J) of male and female mice. We utilized a 14-day (2 h/day) restraint stress protocol and verified stress effects on adolescent body weight gain and circulating corticosterone concentrations relative to non-restraint controls. Mice were then left undisturbed until they were euthanized in adulthood, at which time brains were collected to measure miRNA-200a in the ventral hippocampus. Three weeks after adolescent stress ended, differences in body weight between groups were no longer significant; however, animals exposed to stress had less miRNA-200a expression in the ventral hippocampus than control animals. These data implicate miRNA-200a expression as a potential mechanism by which adolescent stress can have persistent impacts on multiple outcomes in both male and female mice. Full article

(This article belongs to the Section Neurogenomics)

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28 pages, 1833 KiB

Open AccessReview

Congenital Heart Disease and Genetic Changes in Folate/Methionine Cycles

by Nataša Karas Kuželički and Bojan Doljak

Genes 2024, 15(7), 872; https://doi.org/10.3390/genes15070872 (registering DOI) - 2 Jul 2024

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Abstract

Congenital heart disease is one of the most common congenital malformations and thus represents a considerable public health burden. Hence, the identification of individuals and families with an increased genetic predisposition to congenital heart disease (CHD) and its possible prevention is important. Even [...] Read more.

Congenital heart disease is one of the most common congenital malformations and thus represents a considerable public health burden. Hence, the identification of individuals and families with an increased genetic predisposition to congenital heart disease (CHD) and its possible prevention is important. Even though CHD is associated with the lack of folate during early pregnancy, the genetic background of folate and methionine metabolism perturbations and their influence on CHD risk is not clear. While some genes, such as those coding for cytosolic enzymes of folate/methionine cycles, have been extensively studied, genetic studies of folate transporters (de)glutamation enzymes and mitochondrial enzymes of the folate cycle are lacking. Among genes coding for cytoplasmic enzymes of the folate cycle, MTHFR, MTHFD1, MTR, and MTRR have the strongest association with CHD, while among genes for enzymes of the methionine cycle BHMT and BHMT2 are the most prominent. Among mitochondrial folate cycle enzymes, MTHFD2 plays the most important role in CHD formation, while FPGS was identified as important in the group of (de)glutamation enzymes. Among transporters, the strongest association with CHD was demonstrated for SLC19A1. Full article

(This article belongs to the Special Issue Genetics, Genomics and Precision Medicine in Heart Diseases)

12 pages, 255 KiB

Open AccessArticle

PON1 rs662, rs854560 and TRIB1 rs17321515, rs2954029 Gene Polymorphisms Are Associated with Lipid Parameters in Patients with Unstable Angina

by Damian Malinowski, Krzysztof Safranow and Andrzej Pawlik

Genes 2024, 15(7), 871; https://doi.org/10.3390/genes15070871 (registering DOI) - 2 Jul 2024

Viewed by 124

Abstract

Acute coronary heart disease (CHD) is mainly caused by the rupture of an unstable atherosclerotic plaque. Many different factors can cause stenosis or even occlusion of the coronary artery lumen, such as vasculitis and platelet aggregation. Our study was performed to assess the [...] Read more.

Acute coronary heart disease (CHD) is mainly caused by the rupture of an unstable atherosclerotic plaque. Many different factors can cause stenosis or even occlusion of the coronary artery lumen, such as vasculitis and platelet aggregation. Our study was performed to assess the association between PON1 rs662, rs854560 and TRIB1 rs17321515, rs2954029 polymorphisms and the risk of CHD, as well as the association between studied polymorphisms and selected clinical parameters affecting the risk of develo** ischemic heart disease. A total of 232 patients with unstable angina were enrolled in this study. There were no statistically significant differences in the PON1 rs662, rs854560 and TRIB1 rs17321515, rs2954029 polymorphism distributions between the total study and control groups. Total cholesterol plasma levels were significantly higher in patients with the PON1 rs662 TT genotype compared to those with the CC+TC genotypes, as well as in patients with the PON1 rs854560 TT genotype compared to those with the AA+AT genotypes. LDL plasma levels were significantly increased in patients with the PON1 rs854560 TT genotype compared to those with the AA+AT genotypes. Plasma levels of HDL were significantly decreased in patients with the TRIB1 rs17321515 AA+AG genotypes compared to those with the GG genotype, as well as in patients with the TRIB1 rs2954029 AA+AT genotypes compared to those with the TT genotype. Our results suggest that the analysed polymorphisms are not risk factors for unstable angina in the Polish population. However, the results of this study indicate an association between the PON1 rs662, rs854560 and TRIB1 rs17321515, rs2954029 polymorphisms with lipid parameters in patients with coronary artery disease. Full article

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

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15 pages, 6926 KiB

Open AccessArticle

Identification and Expression Analysis of UPS Gene Family in Potato

by Wenyue Huang, Yifei Lu, Bi Ren, Fuchun Zeng, Yongjian Liu, Liming Lu and Liqin Li

Genes 2024, 15(7), 870; https://doi.org/10.3390/genes15070870 (registering DOI) - 2 Jul 2024

Viewed by 102

Abstract

Ureide permeases (UPSs) mediate the transport of ureides, including allantoin and allantoate, which act as nitrogen-transporting compounds in plants and have recently been found to play a role in cellular signaling. To date, UPSs have not been reported in potato, and their identification [...] Read more.

Ureide permeases (UPSs) mediate the transport of ureides, including allantoin and allantoate, which act as nitrogen-transporting compounds in plants and have recently been found to play a role in cellular signaling. To date, UPSs have not been reported in potato, and their identification is important for further function studies and for understanding molecular mechanisms of plant adverse responses. Based on potato genomic data, we identified 10 StUPS genes in potato (Solanum tuberosum L.). Then, we conducted a comprehensive study of the identified StUPS genes using bioinformatics methods. Genome phylogenetic and genomic localization analyses revealed that StUPSs can be classified into four categories, are highly homologous to Arabidopsis thaliana UPS members, and are distributed on three chromosomes. The six StUPS genes were investigated by RT–qPCR, and the findings indicated that all of these genes are involved in the response to several stresses, including low nitrogen, cold, ABA, salt, H₂O_2, and drought. This study establishes a strong theoretical framework for investigating the function of potato UPS genes, as well as the molecular mechanisms underlying the responses of these genes to various environmental stresses. Full article

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

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15 pages, 620 KiB

Open AccessArticle

Objective Assessments of Smoking and Drinking Outperform Clinical Phenotypes in Predicting Variance in Epigenetic Aging

by Robert Philibert, Man-Kit Lei, Mei Ling Ong and Steven R. H. Beach

Genes 2024, 15(7), 869; https://doi.org/10.3390/genes15070869 (registering DOI) - 2 Jul 2024

Viewed by 169

Abstract

The reliability of the associations of the acceleration of epigenetic aging (EA) indices with clinical phenotypes other than for smoking and drinking is poorly understood. Furthermore, the majority of clinical phenoty** studies have been conducted using data from subjects of European ancestry. In [...] Read more.

The reliability of the associations of the acceleration of epigenetic aging (EA) indices with clinical phenotypes other than for smoking and drinking is poorly understood. Furthermore, the majority of clinical phenoty** studies have been conducted using data from subjects of European ancestry. In order to address these limitations, we conducted clinical, physiologic, and epigenetic assessments of a cohort of 278 middle-aged African American adults and analyzed the associations with the recently described principal-components-trained version of GrimAge (i.e., PC-GrimAge) and with the DunedinPACE (PACE) index using regression analyses. We found that 74% of PC-GrimAge accelerated aging could be predicted by a simple baseline model consisting of age, sex, and methylation-sensitive digital PCR (MSdPCR) assessments of smoking and drinking. The addition of other serological, demographic, and medical history variables or PACE values did not meaningfully improve the prediction, although some variables did significantly improve the model fit. In contrast, clinical variables map** to cardiometabolic syndrome did independently contribute to the prediction of PACE values beyond the baseline model. The PACE values were poorly correlated with the GrimAge values (r = 0.2), with little overlap in variance explained other than that conveyed by smoking and drinking. The results suggest that EA indices may differ in the clinical information that they provide and may have significant limitations as screening tools to guide patient care. Full article

(This article belongs to the Section Epigenomics)

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14 pages, 1960 KiB

Open AccessArticle

Genome-Wide Association Analysis Identified Quantitative Trait Loci (QTLs) Underlying Drought-Related Traits in Cultivated Peanut (Arachis hypogaea L.)

by Phat Dang, **esh Patel, Ron Sorensen, Marshall Lamb and Charles Y. Chen

Genes 2024, 15(7), 868; https://doi.org/10.3390/genes15070868 (registering DOI) - 2 Jul 2024

Viewed by 134

Abstract

Drought is a destructive abiotic stress that affects all critical stages of peanut growth such as emergence, flowering, pegging, and pod filling. The development of a drought-tolerant variety is a sustainable strategy for long-term peanut production. The U.S. mini-core peanut germplasm collection was [...] Read more.

Drought is a destructive abiotic stress that affects all critical stages of peanut growth such as emergence, flowering, pegging, and pod filling. The development of a drought-tolerant variety is a sustainable strategy for long-term peanut production. The U.S. mini-core peanut germplasm collection was evaluated for drought tolerance to the middle-season drought treatment phenoty** for pod weight, pod count, relative water content (RWC), specific leaf area (SLA), leaf dry matter content (LDMC), and drought rating. A genome-wide association study (GWAS) was performed to identify minor and major QTLs. A total of 144 QTLs were identified, including 18 significant QTLs in proximity to 317 candidate genes. Ten significant QTLs on linkage groups (LGs) A03, A05, A06, A07, A08, B04, B05, B06, B09, and B10 were associated with pod weight and pod count. RWC stages 1 and 2 were correlated with pod weight, pod count, and drought rating. Six significant QTLs on LGs A04, A07, B03, and B04 were associated with RWC stages 1 and 2. Drought rating was negatively correlated with pod yield and pod count and was associated with a significant QTL on LG A06. Many QTLs identified in this research are novel for the evaluated traits, with verification that the pod weight shared a significant QTL on chromosome B06 identified in other research. Identified SNP markers and the associated candidate genes provide a resource for molecular marker development. Verification of candidate genes surrounding significant QTLs will facilitate the application of marker-assisted peanut breeding for drought tolerance. Full article

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

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11 pages, 3049 KiB

Open AccessArticle

Expanding Genetic Counselor Roles: A Model for Global Research Development

by Colleen C. Muraresku, Elizabeth M. McCormick, Lydia Rockart, T. Blaine Crowley, Stephanie Asher, Amanda Back, Sarah M. Baldino, Emma Bedoukian, Allison D. Britt, Natalie Burrill, Cara Cacioppo, Dana Farengo Clark, Mary Egan Clark, Laura Conway, Laynie Dratch, Holly A. Dubbs, Nicole M. Engelhardt, Natalie Ginn, Christopher Gray, Tiff Hartman, Evan R. Hathaway, Katherine L. Helbig, Lily Hoffman-Andrews, Stefanie Kasperski, Beth A. Keena, Kierstin N. Keller, Jessica M. Long, Lauren Lulis, Laina Lusk, Daniel E. McGinn, Rebecca Mueller, Rache A. Paul, Lisa Pilchman, Jacquelyn Powers, Sarah E. Raible, Sara Reichert, Alyssa L. Rippert, Angela G. Arnold, Sarah M. Ruggiero, Erica Schindewolf, Katie Rose Sullivan, Shannon Terek, Bekah Wang, McKenzie Wells, Natalia Wisniewski, Renee Wright, Elisabeth McCarty Wood, Stacy Woyciechowski, Kristin Zelley, Kathleen D. Valverde and Donna M. McDonald-McGinn Show full author list Hide full author list

Genes 2024, 15(7), 867; https://doi.org/10.3390/genes15070867 (registering DOI) - 1 Jul 2024

Viewed by 202

Abstract

Purpose: Genetic counselors (GCs) increasingly play key roles in advancing genomic medicine through innovative research. Here, we examine one large cohort of GCs’ evolving contributions to the literature, with the goal of facilitating worldwide professional development for GCs through scholarly activities. Methods: Publications [...] Read more.

Purpose: Genetic counselors (GCs) increasingly play key roles in advancing genomic medicine through innovative research. Here, we examine one large cohort of GCs’ evolving contributions to the literature, with the goal of facilitating worldwide professional development for GCs through scholarly activities. Methods: Publications were cataloged by members of the Section of Genetic Counseling (Section), established at the Children’s Hospital of Philadelphia and the University of Pennsylvania in 2014, including publication year, journal, impact factor, and author position. Data were organized using the “My Bibliography” tool on the National Center for Biotechnology Information website and a Research Electronic Data Capture database created to initially collect manuscripts published through 30 June 2020. A subsequent survey captured publications through 5 February 2024. Results: An amount of 52 of 120 (43%) GCs shared their curriculum vitae/papers. 992 unique publications were identified from 1986 to 2024. Since 2013, no less than 32 papers were published annually by Section members and no less than 10 GCs contributed to publications yearly. Impact factors typically averaged >5.0 per year. Areas of foci diversified considerably since 2015. Conclusions: Here, we establish that GCs indeed contribute to scholarly work as evidenced by the number of publications alone. The establishment of an academic home may have contributed, given publications increased concurrent to launching the Section, providing a model for organizing GCs at institutions nationally and internationally. Highlighting such achievements will foster the expansion of GC roles in the era of precision genomic medicine and therapy. Considering ways to support GCs towards expanding these activities is equally important. Full article

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

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13 pages, 4120 KiB

Open AccessArticle

Genetic Insights into the Historical Attribution of Variety Names of Sweet Chestnut (Castanea sativa Mill.) in Northern Italy

by Marta Cavallini, Gianluca Lombardo, Claudio Cantini, Mauro Gerosa and Giorgio Binelli

Genes 2024, 15(7), 866; https://doi.org/10.3390/genes15070866 (registering DOI) - 1 Jul 2024

Viewed by 222

Abstract

The sweet chestnut (Castanea sativa Mill.) is subject to the progressive disappearance of its traditional chestnut groves. In the northern part of Italy, where distribution of the sweet chestnut is fragmented, many local varieties continue to be identified mostly by oral tradition. [...] Read more.

The sweet chestnut (Castanea sativa Mill.) is subject to the progressive disappearance of its traditional chestnut groves. In the northern part of Italy, where distribution of the sweet chestnut is fragmented, many local varieties continue to be identified mostly by oral tradition. We characterised by SSRs eleven historically recognised varieties of sweet chestnut in the area surrounding Lake Como, with the goal of giving a genetic basis to the traditional classification. We performed classical analysis about differentiation and used Bayesian approaches to detect population structure and to reconstruct demography. The results revealed that historical and genetic classifications are loosely linked when chestnut fruits are just “castagne”, that is, normal fruits, but increasingly overlap where “marroni” (the most prized fruits) are concerned. Bayesian classification allowed us to identify a homogeneous gene cluster not recognised in the traditional assessment of the varieties and to reconstruct possible routes used for the propagation of sweet chestnut. We also reconstructed ancestral relationships between the different gene pools involved and dated ancestral lineages whose results fit with palynological data. We suggest that conservation strategies based on a genetic evaluation of the resource should also rely on traditional cultural heritage, which could reveal new sources of germplasm. Full article

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

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22 pages, 2894 KiB

Open AccessArticle

Genotypic Identification of Trees Using DNA Barcodes and Microbiome Analysis of Rhizosphere Microbial Communities

by Liliana Hopkins, Kayla Yim, Ana Rumora, Melissa F. Baykus, Luisa Martinez and Luis Jimenez

Genes 2024, 15(7), 865; https://doi.org/10.3390/genes15070865 (registering DOI) - 1 Jul 2024

Viewed by 172

Abstract

DNA barcodes can provide accurate identification of plants. We used previously reported DNA primers targeting the internal transcribed spacer (ITS1) region of the nuclear ribosomal cistron, internal transcribed spacer (ITS2), and chloroplast trnL (UAA) intron to identify four trees at Bergen Community College. [...] Read more.

DNA barcodes can provide accurate identification of plants. We used previously reported DNA primers targeting the internal transcribed spacer (ITS1) region of the nuclear ribosomal cistron, internal transcribed spacer (ITS2), and chloroplast trnL (UAA) intron to identify four trees at Bergen Community College. Two of the four trees were identified as Acer rubrum and Fagus sylvatica. However, Quercus was only identified at the genus level, and the fourth tree did not show similar identification between barcodes. Next-generation sequencing of 16S rRNA genes showed that the predominant bacterial communities in the rhizosphere mainly consisted of the Pseudomonadota, Actinomycetota, Bacteroidota, and Acidobacteriota. A. rubrum showed the most diverse bacterial community while F. sylvatica was less diverse. The genus Rhodoplanes showed the highest relative bacterial abundance in all trees. Fungal ITS sequence analysis demonstrated that the communities predominantly consisted of the Ascomycota and Basidiomycota. Quercus showed the highest fungi diversity while F. sylvatica showed the lowest. Russula showed the highest abundance of fungi genera. Average similarity values in the rhizosphere for fungi communities at the phylum level were higher than for bacteria. However, at the genus level, bacterial communities showed higher similarities than fungi. Similarity values decreased at lower taxonomical levels for both bacteria and fungi, indicating each tree has selected for specific bacterial and fungal communities. This study confirmed the distinctiveness of the microbial communities in the rhizosphere of each tree and their importance in sustaining and supporting viability and growth but also demonstrating the limitations of DNA barcoding with the primers used in this study to identify genus and species for some of the trees. The optimization of DNA barcoding will require additional DNA sequences to enhance the resolution and identification of trees at the study site. Full article

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

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17 pages, 2179 KiB

Open AccessArticle

A-to-I Editing Is Subtype-Specific in Non-Hodgkin Lymphomas

by Cai Chen and Ralf Bundschuh

Genes 2024, 15(7), 864; https://doi.org/10.3390/genes15070864 (registering DOI) - 1 Jul 2024

Viewed by 197

Abstract

Cancer is a complex and heterogeneous disease, in which a number of genetic and epigenetic changes occur in tumor onset and progression. Recent studies indicate that changes at the RNA level are also involved in tumorigenesis, such as adenosine-to-inosine (A-to-I) RNA editing. Here, [...] Read more.

Cancer is a complex and heterogeneous disease, in which a number of genetic and epigenetic changes occur in tumor onset and progression. Recent studies indicate that changes at the RNA level are also involved in tumorigenesis, such as adenosine-to-inosine (A-to-I) RNA editing. Here, we systematically investigate transcriptome-wide A-to-I editing events in a large number of samples from Non-Hodgkin lymphomas (NHLs). Using a computational pipeline that determines significant differences in editing level between NHL and normal samples at known A-to-I editing sites, we identify a number of differentially edited editing sites between NHL subtypes and normal samples. Most of the differentially edited sites are located in non-coding regions, and many such sites show a strong correlation between gene expression level and editing efficiency, indicating that RNA editing might have direct consequences for the cancer cell’s aberrant gene regulation status in these cases. Moreover, we establish a strong link between RNA editing and NHL by demonstrating that NHL and normal samples and even NHL subtypes can be distinguished based on genome-wide RNA editing profiles alone. Our study establishes a strong link between RNA editing, cancer and aberrant gene regulation in NHL. Full article

(This article belongs to the Section RNA)

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27 pages, 460 KiB

Open AccessReview

The CRISPR-Cas System and Clinical Applications of CRISPR-Based Gene Editing in Hematology with a Focus on Inherited Germline Predisposition to Hematologic Malignancies

by Rina Kansal

Genes 2024, 15(7), 863; https://doi.org/10.3390/genes15070863 (registering DOI) - 1 Jul 2024

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Abstract

Clustered regularly interspaced short palindromic repeats (CRISPR)-based gene editing has begun to transform the treatment landscape of genetic diseases. The history of the discovery of CRISPR/CRISPR-associated (Cas) proteins/single-guide RNA (sgRNA)-based gene editing since the first report of repetitive sequences of unknown significance in [...] Read more.

Clustered regularly interspaced short palindromic repeats (CRISPR)-based gene editing has begun to transform the treatment landscape of genetic diseases. The history of the discovery of CRISPR/CRISPR-associated (Cas) proteins/single-guide RNA (sgRNA)-based gene editing since the first report of repetitive sequences of unknown significance in 1987 is fascinating, highly instructive, and inspiring for future advances in medicine. The recent approval of CRISPR-Cas9-based gene therapy to treat patients with severe sickle cell anemia and transfusion-dependent β thalassemia has renewed hope for treating other hematologic diseases, including patients with a germline predisposition to hematologic malignancies, who would benefit greatly from the development of CRISPR-inspired gene therapies. The purpose of this paper is three-fold: first, a chronological description of the history of CRISPR-Cas9-sgRNA-based gene editing; second, a brief description of the current state of clinical research in hematologic diseases, including selected applications in treating hematologic diseases with CRISPR-based gene therapy, preceded by a brief description of the current tools being used in clinical genome editing; and third, a presentation of the current progress in gene therapies in inherited hematologic diseases and bone marrow failure syndromes, to hopefully stimulate efforts towards develo** these therapies for patients with inherited bone marrow failure syndromes and other inherited conditions with a germline predisposition to hematologic malignancies. Full article

(This article belongs to the Special Issue Research Progress in Hematological Malignancies: A Molecular Genetics Perspective)

17 pages, 571 KiB

Open AccessArticle

Overcoming Barriers: Strategies for Implementing Pharmacist-Led Pharmacogenetic Services in Swiss Clinical Practice

by Florine M. Wiss, Deborah Jakober, Markus L. Lampert and Samuel S. Allemann

Genes 2024, 15(7), 862; https://doi.org/10.3390/genes15070862 (registering DOI) - 1 Jul 2024

Viewed by 210

Abstract

There is growing evidence that pharmacogenetic analysis can improve drug therapy for individual patients. In Switzerland, pharmacists are legally authorized to initiate pharmacogenetic tests. However, pharmacogenetic tests are rarely conducted in Swiss pharmacies. Therefore, we aimed to identify implementation strategies that facilitate the [...] Read more.

There is growing evidence that pharmacogenetic analysis can improve drug therapy for individual patients. In Switzerland, pharmacists are legally authorized to initiate pharmacogenetic tests. However, pharmacogenetic tests are rarely conducted in Swiss pharmacies. Therefore, we aimed to identify implementation strategies that facilitate the integration of a pharmacist-led pharmacogenetic service into clinical practice. To achieve this, we conducted semi-structured interviews with pharmacists and physicians regarding the implementation process of a pharmacist-led pharmacogenetic service. We utilized the Consolidated Framework for Implementation Research (CFIR) to identify potential facilitators and barriers in the implementation process. Additionally, we employed Expert Recommendations for Implementing Change (ERIC) to identify strategies mentioned in the interviews and used the CFIR-ERIC matching tool to identify additional strategies. We obtained interview responses from nine pharmacists and nine physicians. From these responses, we identified 7 CFIR constructs as facilitators and 12 as barriers. Some of the most commonly mentioned barriers included unclear procedures, lack of cost coverage by health care insurance, insufficient pharmacogenetics knowledge, lack of interprofessional collaboration, communication with the patient, and inadequate e-health technologies. Additionally, we identified 23 implementation strategies mentioned by interviewees using ERIC and 45 potential strategies using the CFIR-ERIC matching tool. In summary, we found that significant barriers hinder the implementation process of this new service. We hope that by highlighting potential implementation strategies, we can advance the integration of a pharmacist-led pharmacogenetic service in Switzerland. Full article

(This article belongs to the Special Issue Advances in Genetic Counseling and Genetic Testing in Precision Medicine)

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23 pages, 4160 KiB

Open AccessArticle

Intermolecular Gene Conversion for the Equalization of Genome Copies in the Polyploid Haloarchaeon Haloferax volcanii: Identification of Important Proteins

by Hanna Özer, Daniel Wasser, Lara Sandner and Jörg Soppa

Genes 2024, 15(7), 861; https://doi.org/10.3390/genes15070861 (registering DOI) - 1 Jul 2024

Viewed by 195

Abstract

The model haloarchaeon Haloferax volcanii is polyploid with about 20 copies of its major chromosome. Recently it has been described that highly efficient intermolecular gene conversion operates in H. volcanii to equalize the chromosomal copies. In the current study, 24 genes were selected [...] Read more.

The model haloarchaeon Haloferax volcanii is polyploid with about 20 copies of its major chromosome. Recently it has been described that highly efficient intermolecular gene conversion operates in H. volcanii to equalize the chromosomal copies. In the current study, 24 genes were selected that encode proteins with orthologs involved in gene conversion or homologous recombination in archaea, bacteria, or eukaryotes. Single gene deletion strains of 22 genes and a control gene were constructed in two parent strains for a gene conversion assay; only radA and radB were shown to be essential. Protoplast fusions were used to generate strains that were heterozygous for the gene HVO_2528, encoding an enzyme for carotinoid biosynthesis. It was revealed that a lack of six of the proteins did not influence the efficiency of gene conversion, while sixteen mutants had severe gene conversion defects. Notably, lack of paralogous proteins of gene families had very different effects, e.g., mutant Δrad25b had no phenotype, while mutants Δrad25a, Δrad25c, and Δrad25d were highly compromised. Generation of a quadruple rad25 and a triple sph deletion strain also indicated that the paralogs have different functions, in contrast to sph2 and sph4, which cannot be deleted simultaneously. There was no correlation between the severity of the phenotypes and the respective transcript levels under non-stressed conditions, indicating that gene expression has to be induced at the onset of gene conversion. Phylogenetic trees of the protein families Rad3/25, MutL/S, and Sph/SMC/Rad50 were generated to unravel the history of the paralogous proteins of H. volcanii. Taken together, unselected intermolecular gene conversion in H. volcanii involves at least 16 different proteins, the molecular roles of which can be studied in detail in future projects. Full article

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

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18 pages, 2410 KiB

Open AccessArticle

Gene Expression Profiling and Qualitative Characteristics in Delaying Flesh Softening of Avocado Fruits

by Ourania Anagnostopoulou, Georgios Tsaniklidis, Konstantinos Paschalidis and Filippos Ververidis

Genes 2024, 15(7), 860; https://doi.org/10.3390/genes15070860 (registering DOI) - 1 Jul 2024

Viewed by 247

Abstract

In this research, qualitative characteristics were studied under different post-harvest treatments in Hass and Fuerte cultivars of avocado (Persea americana) fruits. The post-harvest treatments performed in fruits of these cultivars comprised Ethrel application and plastic film (membrane) covering. The measurements of [...] Read more.

In this research, qualitative characteristics were studied under different post-harvest treatments in Hass and Fuerte cultivars of avocado (Persea americana) fruits. The post-harvest treatments performed in fruits of these cultivars comprised Ethrel application and plastic film (membrane) covering. The measurements of qualitative characteristics were related to color; flesh consistency; measurements of titratable acidity, total soluble solids, percentage of total phenolic contents, and ascorbic peroxidase activity; and the real-time (quantitative) polymerase chain reaction (qPCR) of gene expression and enzyme activities of phenylalanine ammonia-lyase (PAL) and beta-galactosidase (β-gal). The experiments found that the application of plastic film has excellent results in retaining qualitative characteristics and enzyme activities via maintaining firmness in higher levels. The plastic film covering appeared to delay ripening without the use of chemicals and, therefore, it has the potential to extend the duration of the post-harvest life of the avocado fruit. Variations between the two cultivars were found in the measurements of total soluble solids (Fuerte cultivar showed an increase of 22%, whereas Hass cultivar showed an increase of 120% in Brix values) and total phenolic contents (Fuerte cultivar showed a decrease of 16% and Hass cultivar showed an increase of 29%). It is worth noting that PAL’s activity increased significantly (over 44%), as compared to other treatments, and β-galactosidase’s activity decreased, as compared to other treatments. In conclusion, plastic film covering results in a decrease in the activity of β-galactosidase, as shown by the reaction of hydrolysis (enzyme activity) but also from the expression of the related genes. Full article

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

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8 pages, 548 KiB

Open AccessArticle

Lynch Syndrome and Thyroid Nodules: A Single Center Experience

by Irene Spinelli, Simona Moffa, Francesca Fianchi, Teresa Mezza, Francesca Cinti, Gianfranco Di Giuseppe, Clelia Marmo, Gianluca Ianiro, Francesca Romana Ponziani, Annalisa Tortora, Maria Elena Riccioni, Andrea Giaccari and Antonio Gasbarrini

Genes 2024, 15(7), 859; https://doi.org/10.3390/genes15070859 (registering DOI) - 30 Jun 2024

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Abstract

Background: Lynch syndrome (LS) is a genetic disease with increased risk of colorectal cancer and other malignancies. There are few reported cases of thyroid cancer in LS patients. The aim of this study is to investigate the presence of thyroid nodules in LS [...] Read more.

Background: Lynch syndrome (LS) is a genetic disease with increased risk of colorectal cancer and other malignancies. There are few reported cases of thyroid cancer in LS patients. The aim of this study is to investigate the presence of thyroid nodules in LS patients and to explore their association with the genetic features of the disease. Methods: A retrospective and descriptive analysis was conducted to include all LS patients followed at the CEMAD (Centro Malattie Apparato Digerente) of Fondazione Policlinico Universitario A. Gemelli IRCCS. The characteristics of LS disease, gene mutations, and previous history of thyroid disease were evaluated. Majority of patients underwent thyroid ultrasound (US), and nodule cytology was performed when needed. Results: Of a total of 139 patients with LS, 110 patients were included in the study. A total of 103 patients (74%) underwent thyroid ultrasound examinations, and 7 patients (5%) had a previous history of thyroid disease (cancer or multinodular goiter). The mean age was 51.9 years. Thyroid nodules were found in 62 patients (60%) who underwent US, and 9 of them (14%) had suspicious features of malignancy, inducing a fine-needle aspiration biopsy. A cytologic analysis classified 7 of 9 cases (78%) as TIR2 and 2 (22%) as TIR3a. Between patients with nodular thyroid disease (single nodule, multinodular goiter, and cancer), most of them (25 patients, 36% of total) were carriers of the MSH6 mutation, while 22 (32%), 17 (24%), and 5 (7%) had MSH2, MLH1, and PMS2 mutations, respectively. Conclusions: A high prevalence of thyroid nodules was found in patients with LS, especially in MSH6-carrying patients. Performing at least one thyroid ultrasound examination is suggested for the detection of nodular thyroid disease in LS patients. Systematic investigations are needed to estimate their prevalence, features, and risk of malignant transformation. Full article

(This article belongs to the Section Genetic Diagnosis)

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23 pages, 1206 KiB

Open AccessPerspective

Integrated Approaches and Practical Recommendations in Patient Care Identified with 5q Spinal Muscular Atrophy through Newborn Screening

by Vanessa L. Romanelli Tavares, Rodrigo Holanda Mendonça, Maytê S. Toledo, Sônia M. Hadachi, Carmela M. Grindler, Edmar Zanoteli, Wilson Marques, Jr., Acary S. B. Oliveira, Paulo Breinis, Maria da P. A. Morita and Marcondes C. França, Jr.

Genes 2024, 15(7), 858; https://doi.org/10.3390/genes15070858 (registering DOI) - 29 Jun 2024

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Abstract

In recent years, significant progress has been made in 5q Spinal Muscular Atrophy therapeutics, emphasizing the importance of early diagnosis and intervention for better clinical outcomes. Characterized by spinal cord motor neuron degeneration, 5q-SMA leads to muscle weakness, swallowing difficulties, respiratory insufficiency, and [...] Read more.

In recent years, significant progress has been made in 5q Spinal Muscular Atrophy therapeutics, emphasizing the importance of early diagnosis and intervention for better clinical outcomes. Characterized by spinal cord motor neuron degeneration, 5q-SMA leads to muscle weakness, swallowing difficulties, respiratory insufficiency, and skeletal deformities. Recognizing the pre-symptomatic phases supported by screening and confirmatory genetic tests is crucial for early diagnosis. This work addresses key considerations in implementing 5q-SMA screening within the Brazilian National Newborn Screening Program and explores Brazil’s unique challenges and opportunities, including genetic tests, time-to-patient referral to specialized centers, program follow-up, and treatment algorithms. We aim to guide healthcare professionals and policymakers, facilitating global discussions, including Latin American countries, and knowledge-sharing on this critical subject to improve the care for newborns identified with 5q SMA. Full article

(This article belongs to the Special Issue Genetic Newborn Screening)

13 pages, 3332 KiB

Open AccessArticle

Leonurine Exerts Anti-Inflammatory Effects in Lipopolysaccharide (LPS)-Induced Endometritis by Modulating Mouse JAK-STAT/PI3K-Akt/PPAR Signaling Pathways

by Yongbin Shao, Yan Luo, Yaoqiang Sun, **gbo Jiang, Zhiyuan Li, Zhen Wang, Mengmeng Wang and **nli Gu

Genes 2024, 15(7), 857; https://doi.org/10.3390/genes15070857 (registering DOI) - 29 Jun 2024

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Abstract

Endometritis is a common disease in postpartum cows, characterized by delayed uterine recovery due to endometrial inflammation. Although antibiotics and hormones are commonly used, they have certain limitations. One potential alternative is using motherwort extract, specifically leonurine, which exhibits anti-inflammatory properties. However, leonurine’s [...] Read more.

Endometritis is a common disease in postpartum cows, characterized by delayed uterine recovery due to endometrial inflammation. Although antibiotics and hormones are commonly used, they have certain limitations. One potential alternative is using motherwort extract, specifically leonurine, which exhibits anti-inflammatory properties. However, leonurine’s exact molecular mechanism of action remains unclear. In this study, 40 mice were randomly divided into four groups: a control group, endometritis model group, LPS + leonurine group (30 mg/kg), and LPS + dexamethasone group (5 mg/kg). Transcriptomic analysis revealed that leonurine modulates multiple signaling pathways, including JAK-STAT/PI3K-Akt, and influences the expression of key genes, such as Prlr, Socs2, Col1a1, and Akt1. Furthermore, leonurine effectively reduces levels of inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, and IL-1β (p < 0.01), which play a crucial role in regulating acute endometritis. Additionally, leonurine helps maintain cholesterol homeostasis and attenuates inflammation through the peroxisome proliferator-activated receptor (PPAR) signaling pathway by modulating genes such as Cyp27a1, Hmgcs1, and Scd2. These findings suggest that leonurine has a protective effect against LPS-induced endometritis and that its anti-inflammatory properties involve multiple pathways and targets, which are potentially mediated by regulating signaling pathways such as JAK-STAT/PI3K-Akt and PPAR. Full article

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

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11 pages, 733 KiB

Open AccessArticle

Variation of the 3’RR1 HS1.2 Enhancer and Its Genomic Context

by Carla Jodice, Patrizia Malaspina, Bianca Maria Ciminelli, Cristina Martinez-Labarga, Michela Biancolella, Giuseppe Novelli and Andrea Novelletto

Genes 2024, 15(7), 856; https://doi.org/10.3390/genes15070856 (registering DOI) - 29 Jun 2024

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Abstract

In humans, the HS1.2 enhancer in the Ig heavy-chain locus is modular, with length polymorphism. Previous studies have shown the following features for this variation: (i) strong population structuring; (ii) association with autoimmune diseases; and (iii) association with developmental changes in Ig expression. [...] Read more.

In humans, the HS1.2 enhancer in the Ig heavy-chain locus is modular, with length polymorphism. Previous studies have shown the following features for this variation: (i) strong population structuring; (ii) association with autoimmune diseases; and (iii) association with developmental changes in Ig expression. The HS1.2 region could then be considered as a contributor to inter-individual diversity in humoral response in adaptive immunity. We experimentally determined the HS1.2-length class genotype in 72 of the 1000 Genomes CEU cell lines and assigned the HS1.2 alleles to haplotypes defined by 18 landmark SNPs. We also sequenced the variable portion and ~200 bp of the flanking DNA of 34 HS1.2 alleles. Furthermore, we computationally explored the ability of different allelic arrangements to bind transcription factors. Non-random association between HS1.2 and Gm allotypes in the European population clearly emerged. We show a wealth of variation in the modular composition of HS1.2, with five SNPs further contributing to diversity. Longer alleles offer more potential sites for binding but, for same-length alleles, SNP variation creates/destroys potential binding sites. Altogether, the arrangements of modules and SNP alleles both inside and outside HS1.2 denote an organization of diversity far from randomness. In the context of the strong divergence of human populations for this genomic region and the reported disease associations, our results suggest that selective forces shaped the pattern of its diversity. Full article

(This article belongs to the Special Issue Evolution of Non-coding Elements in Genome Biology)

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19 pages, 963 KiB

Open AccessArticle

New Observations of the Effects of the Cytoplasm of Aegilops kotschyi Boiss. in Bread Wheat Triticum aestivum L

by Chaolan Fan, Joanna Melonek and Adam J. Lukaszewski

Genes 2024, 15(7), 855; https://doi.org/10.3390/genes15070855 (registering DOI) - 28 Jun 2024

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Abstract

The cytoplasm of Aegilops kotschyi is known for the induction of male sterility and haploidy in wheat. Both systems originally appeared rather simple, but manipulation of the standard chromosome constitution of the nuclear genome revealed additional interactions. This study shows that while there [...] Read more.

The cytoplasm of Aegilops kotschyi is known for the induction of male sterility and haploidy in wheat. Both systems originally appeared rather simple, but manipulation of the standard chromosome constitution of the nuclear genome revealed additional interactions. This study shows that while there is little or no allelic variation at the main fertility restorer locus Rf^multi on chromosome arm 1BS, additional genes may also be involved in the nuclear–mitochondrial genome interactions, affecting not only male fertility but also the growth rate, from pollen competition for fertilization and early endosperm divisions all the way to seed size and plant maturity. Some of these effects appear to be of a sporophytic nature; others are gametophytic. Induction of parthenogenesis by a rye inducer in conjunction with the Ae. kotschyi cytoplasm is well known. However, here we show that the cytoplasmic-nuclear interactions affect all aspects of double fertilization: producing maternal haploids from unfertilized eggs, diploids from fertilized eggs or synergids, embryo-less kernels, and fertilized eggs without fertilization of the double nucleus in the embryo sack. It is unclear how frequent the inducers of parthenogenesis are, as variation, if any, is obscured by suppressors present in the wheat genome. Genetic dissection of a single wheat accession revealed five distinct loci affecting the rate of maternal haploid production: four acting as suppressors and one as an enhancer. Only when the suppressing haplotypes are confirmed may it be possible to the identify genetic variation of haploidy inducers, map their position(s), and determine their nature and the mode of action. Full article

(This article belongs to the Special Issue Genetics and Breeding of Polyploid Plants)

10 pages, 2790 KiB

Open AccessCase Report

EDA Missense Variant in a Cat with X-Linked Hypohidrotic Ectodermal Dysplasia

by Stefan J. Rietmann, Noëlle Cochet-Faivre, Helene Dropsy, Vidhya Jagannathan, Lucie Chevallier and Tosso Leeb

Genes 2024, 15(7), 854; https://doi.org/10.3390/genes15070854 (registering DOI) - 28 Jun 2024

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Abstract

Hypohidrotic ectodermal dysplasia is a developmental defect characterized by sparse or absent hair, missing or malformed teeth and defects in eccrine glands. Loss-of-function variants in the X-chromosomal EDA gene have been reported to cause hypohidrotic ectodermal dysplasia in humans, mice, dogs and cattle. [...] Read more.

Hypohidrotic ectodermal dysplasia is a developmental defect characterized by sparse or absent hair, missing or malformed teeth and defects in eccrine glands. Loss-of-function variants in the X-chromosomal EDA gene have been reported to cause hypohidrotic ectodermal dysplasia in humans, mice, dogs and cattle. We investigated a male cat exhibiting diffuse truncal alopecia with a completely absent undercoat. The cat lacked several teeth, and the remaining teeth had an abnormal conical shape. Whole-genome sequencing revealed a hemizygous missense variant in the EDA gene, XM_011291781.3:c.1042G>A or XP_011290083.1:p.(Ala348Thr). The predicted amino acid exchange is located in the C-terminal TNF signaling domain of the encoded ectodysplasin. The corresponding missense variant in the human EDA gene, p.Ala349Thr, has been reported as a recurring pathogenic variant in several human patients with X-linked hypohidrotic ectodermal dysplasia. The identified feline variant therefore represents the likely cause of the hypohidrotic ectodermal dysplasia in the investigated cat, and the genetic investigation confirmed the suspected clinical diagnosis. This is the first report of an EDA-related hypohidrotic ectodermal dysplasia in cats. Full article

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

12 pages, 5286 KiB

Open AccessArticle

Potential Involvement of MnCYP710A11 in Botrytis cinerea Resistance in Arabidopsis thaliana and Morus notabilis

by Hui An, Donghao Wang, Lin Yu, Hongshun Wu, Yue Qin, Shihao Zhang, **anling Ji, Youchao **n and **aodong Li

Genes 2024, 15(7), 853; https://doi.org/10.3390/genes15070853 - 28 Jun 2024

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Abstract

Cytochrome P450 (CYP) is a crucial oxidoreductase enzyme that plays a significant role in plant defense mechanisms. In this study, a specific cytochrome P450 gene (MnCYP710A11) was discovered in mulberry (Morus notabilis). Bioinformatic analysis and expression pattern analysis were [...] Read more.

Cytochrome P450 (CYP) is a crucial oxidoreductase enzyme that plays a significant role in plant defense mechanisms. In this study, a specific cytochrome P450 gene (MnCYP710A11) was discovered in mulberry (Morus notabilis). Bioinformatic analysis and expression pattern analysis were conducted to elucidate the involvement of MnCYP710A11 in combating Botrytis cinerea infection. After the infection of B. cinerea, there was a notable increase in the expression of MnCYP710A11. MnCYP710A11 is overexpressed in Arabidopsis and mulberry and strongly reacts to B. cinerea. The overexpression of the MnCYP710A11 gene in Arabidopsis and mulberry led to a substantial enhancement in resistance against B. cinerea, elevated catalase (CAT) activity, increased proline content, and reduced malondialdehyde (MDA) levels. At the same time, H₂O₂ and O₂⁻ levels in MnCYP710A11 transgenic Arabidopsis were decreased, which reduced the damage of ROS accumulation to plants. Furthermore, our research indicates the potential involvement of MnCYP710A11 in B. cinerea resistance through the modulation of other resistance-related genes. These findings establish a crucial foundation for gaining deeper insights into the role of cytochrome P450 in mulberry plants. Full article

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

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10 pages, 466 KiB

Open AccessArticle

Association of LPP and ZMIZ1 Gene Polymorphism with Celiac Disease in Subjects from Punjab, Pakistan

by Sumaira Zulfiqar, Amna Fiaz, Waqas Ahmed Khan, Misbah Hussain, Ansar Ali, Nadeem Ahmed, Basharat Ali and Muhammad Adnan Masood

Genes 2024, 15(7), 852; https://doi.org/10.3390/genes15070852 - 27 Jun 2024

Viewed by 231

Abstract

Celiac disease (CD) is a complicated autoimmune disease that is caused by gluten sensitivity. It was commonly believed that CD only affected white Europeans, but recent findings show that it is also prevailing in some other racial groups, like South Asians, Caucasians, Africans, [...] Read more.

Celiac disease (CD) is a complicated autoimmune disease that is caused by gluten sensitivity. It was commonly believed that CD only affected white Europeans, but recent findings show that it is also prevailing in some other racial groups, like South Asians, Caucasians, Africans, and Arabs. Genetics plays a profound role in increasing the risk of develo** CD. Genetic Variations in non-HLA genes such as LPP, ZMIZ1, CCR3, and many more influence the risk of CD in various populations. This study aimed to explore the association between LPP rs1464510 and ZMIZ1 rs1250552 and CD in the Punjabi Pakistani population. For this, a total of 70 human subjects were selected and divided into healthy controls and patients. Genoty** was performed using an in-house-developed tetra-amplification refractory mutation system polymerase chain reaction. Statistical analysis revealed a significant association between LPP rs1464510 (χ² = 4.421, p = 0.035) and ZMIZ1 rs1250552 (χ2 = 3.867, p = 0.049) and CD. Multinomial regression analysis showed that LPP rs1464510 A allele reduces the risk of CD by ~52% (OR 0.48, CI: 0.24–0.96, 0.037), while C allele-carrying subjects are at ~2.6 fold increased risk of CD (OR 3.65, CI: 1.25–10.63, 0.017). Similarly, the ZMIZ1 rs1250552 AG genotype significantly reduces the risk of CD by 73% (OR 0.26, CI: 0.077–0.867, p = 0.028). In summary, Genetic Variations in the LPP and ZMIZ1 genes influence the risk of CD in Punjabi Pakistani subjects. LPP rs1464510 A allele and ZMIZ1 AG genotype play a protective role and reduce the risk of CD. Full article

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

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19 pages, 1874 KiB

Open AccessArticle

Studies on Human Cultured Fibroblasts and Cutaneous Squamous Cell Carcinomas Suggest That Overexpression of Histone Variant H2A.J Promotes Radioresistance and Oncogenic Transformation

by Benjamin M. Freyter, Mutaz A. Abd Al-razaq, Markus Hecht, Christian Rübe and Claudia E. Rübe

Genes 2024, 15(7), 851; https://doi.org/10.3390/genes15070851 - 27 Jun 2024

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Abstract

Background: Cellular senescence in response to ionizing radiation (IR) limits the replication of damaged cells by causing permanent cell cycle arrest. However, IR can induce pro-survival signaling pathways that reduce the extent of radiation-induced cytotoxicity and promote the development of radioresistance. The differential [...] Read more.

Background: Cellular senescence in response to ionizing radiation (IR) limits the replication of damaged cells by causing permanent cell cycle arrest. However, IR can induce pro-survival signaling pathways that reduce the extent of radiation-induced cytotoxicity and promote the development of radioresistance. The differential incorporation of histone variant H2A.J has profound effects on higher-order chromatin organization and on establishing the epigenetic state of radiation-induced senescence. However, the precise epigenetic mechanism and function of H2A.J overexpression in response to IR exposure still needs to be elucidated. Methods: Primary (no target, NT) and genetically modified fibroblasts overexpressing H2A.J (H2A.J-OE) were exposed to 20 Gy and analyzed 2 weeks post-IR for radiation-induced senescence by immunohistochemistry and immunofluorescence microscopy. Transcriptome signatures were analyzed in (non-)irradiated NT and H2A.J-OE fibroblasts by RNA sequencing. Since H2A.J plays an important role in the epidermal homeostasis of human skin, the oncogenic potential of H2A.J was investigated in cutaneous squamous cell carcinoma (cSCC). The tissue microarrays of cSCC were analyzed for H2A.J protein expression pattern by automated image analysis. Results: In response to radiation-induced DNA damage, the overexpression of H2A.J impairs the formation of senescence-associated heterochromatin foci (SAHF), thereby inhibiting the SAHF-mediated silencing of proliferation-promoting genes. The dysregulated activation of cyclins and cyclin-dependent kinases disturbs cell cycle arrest in irradiated H2A.J-OE fibroblasts, thereby overcoming radiation-induced senescence. Comparative transcriptome analysis revealed significantly increased WNT16 signaling in H2A.J OE fibroblasts after IR exposure, promoting the fundamental mechanisms of tumor development and progression, including the activation of the epithelial–mesenchymal transition. The quantitative analysis of cSCCs revealed that undifferentiated tumors are associated with high nuclear H2A.J expression, related with greater oncogenic potential. Conclusion: H2A.J overexpression induces radioresistance and promotes oncogenic transformation through the activation of WNT16 signaling pathway functions. H2A.J-associated signatures may improve risk stratification by identifying patients with more aggressive cSCC who may require radiotherapy with increased doses. Full article

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

13 pages, 1095 KiB

Open AccessArticle

Sinuous Is a Claudin Required for Locust Molt in Locusta migratoria

by Yichao Zhang, Hong**g Li, Qiuyan Lan, **aoman Liu, Haihua Wu, Jianzhen Zhang, **aoming Zhao and Yanli Wang

Genes 2024, 15(7), 850; https://doi.org/10.3390/genes15070850 - 27 Jun 2024

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Abstract

The epidermal cells of insects are polarized epithelial cells that play a pivotal role in the insect’s molting process. Sinuous, a pivotal structural protein involved in the formation of septate junctions among epithelial cells, is essential for its physiological function. In this study, [...] Read more.

The epidermal cells of insects are polarized epithelial cells that play a pivotal role in the insect’s molting process. Sinuous, a pivotal structural protein involved in the formation of septate junctions among epithelial cells, is essential for its physiological function. In this study, to determine whether sinuous participates in the regulation of insect molting, we identified the sinuous gene, Lmsinu, in Locusta migratoria, which encodes a protein belonging to the claudin family and shares 62.6% identity with Drosophila’s sinuous protein. Lmsinu is expressed in multiple tissues, and its expression level in the integument significantly increases prior to molting. Knockdown of Lmsinu in L. migratoria results in larval mortality during molting. Furthermore, hematoxylin and eosin and chitin staining demonstrate that the downregulation of Lmsinu led to a prolonged degradation process of the old cuticle during the molting process. Electron microscopy analysis further revealed that knockdown of Lmsinu disrupts the formation of septate junctions among epidermal cells, which are a monolayer of polarized epithelial cells, which may hinder the functionality of epidermal cells during the process of molting. In summary, these findings suggest that Lmsinu plays a role in nymph molting by regulating the formation of septate junctions among epidermal cells. Full article

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

13 pages, 532 KiB

Open AccessArticle

Swine Influenza Viruses Isolated from 2019 to 2022 in Shandong Province, China, Exemplify the Dominant Genotype

by Yuzhong Zhao, Lebin Han, Haotian Sang, Sidang Liu, **** Yang, Yanmeng Hou and Yihong **ao

Genes 2024, 15(7), 849; https://doi.org/10.3390/genes15070849 - 27 Jun 2024

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Abstract

Swine influenza viruses (SIVs) have been circulating in swine globally and are potential threats to human health. During the surveillance of SIVs in Shandong Province, China, from 2019 to 2022, 21 reassortant G4 genotype Eurasian avian-like (EA) H1N1 subtypes containing genes from the [...] Read more.

Swine influenza viruses (SIVs) have been circulating in swine globally and are potential threats to human health. During the surveillance of SIVs in Shandong Province, China, from 2019 to 2022, 21 reassortant G4 genotype Eurasian avian-like (EA) H1N1 subtypes containing genes from the EA H1N1 (HA and NA), 2009 pandemic (pdm/09) H1N1 virus (PB2, PB1, PA, NP, and M), and classical swine (CS) H1N1 (NS) lineages were isolated. The analysis of the key functional amino acid sites in the isolated viruses showed that two mutation sites (190D and 225E) that preferentially bind to the human α2-6 sialic acid receptor were found in HA. In PB2, three mutation sites (271A, 590S, and 591R) that may increase mammalian fitness and a mutation site (431M) that increases pathogenicity in mice were found. A typical human signature marker that may promote infection in humans, 357K, was found in NP. The viruses could replicate efficiently in mouse lungs and turbinates, and one of the H1N1 isolates could replicate in mouse kidneys and brains without prior adaption, which indicates that the viruses potentially pose a threat to human health. Histopathological results showed that the isolated viruses caused typical bronchopneumonia and encephalitis in mice. The results indicate that G4 genotype H1N1 has potential transmissibility to humans, and surveillance should be enhanced, which could provide important information for assessing the pandemic potential of the viruses. Full article

(This article belongs to the Special Issue The Diversity and Evolution of the Animal Virome)

9 pages, 239 KiB

Open AccessArticle

by Raffaele Falsaperla, Vincenzo Sortino, Marina Antonietta Schinocca, Gaia Fusto, Roberta Rizzo, Chiara Barberi, Martino Ruggieri and Xena Giada Pappalardo

Genes 2024, 15(7), 848; https://doi.org/10.3390/genes15070848 - 27 Jun 2024

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Abstract

PURA syndrome is a congenital developmental disorder caused by de novo mutations in the PURA gene, which encodes a DNA/RNA-binding protein essential for transcriptional and translational regulation. We present the case of an 11-year-old patient with a de novo frameshift variant in the [...] Read more.

PURA syndrome is a congenital developmental disorder caused by de novo mutations in the PURA gene, which encodes a DNA/RNA-binding protein essential for transcriptional and translational regulation. We present the case of an 11-year-old patient with a de novo frameshift variant in the PURA gene, identified through whole exome sequencing (WES). In addition to the classical PURA deficiency phenotype, our patient exhibited pronounced sialorrhea and seizures, which were effectively treated with the ketogenic diet (KD). Our integrative approach, combining a literature review and bioinformatics data, has led to the first documented clinical case showing improvement in both sialorrhea and seizures with KD treatment, a phenomenon not previously reported. Although a direct relationship between the de novo PURA mutation and the KD was not established, we identified a novel frameshift deletion associated with a new clinical phenotype. Full article

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

14 pages, 821 KiB

Open AccessArticle

Structural Differences between the Genomes of Deinococcus radiodurans Strains from Different Laboratories

by Ksenija Zahradka, Davor Zahradka and Jelena Repar

Genes 2024, 15(7), 847; https://doi.org/10.3390/genes15070847 - 27 Jun 2024

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Abstract

The bacterium Deinococcus radiodurans is known to efficiently and accurately reassemble its genome after hundreds of DNA double-strand breaks (DSBs). Only at very large amounts of radiation-induced DSBs is this accuracy affected in the wild-type D. radiodurans, causing rearrangements in its genome [...] Read more.

The bacterium Deinococcus radiodurans is known to efficiently and accurately reassemble its genome after hundreds of DNA double-strand breaks (DSBs). Only at very large amounts of radiation-induced DSBs is this accuracy affected in the wild-type D. radiodurans, causing rearrangements in its genome structure. However, changes in its genome structure may also be possible during the propagation and storage of cell cultures. We investigate this possibility by listing structural differences between three completely sequenced genomes of D. radiodurans strains with a recent common ancestor—the type strain stored and sequenced in two different laboratories (of the ATCC 13939 lineage) and the first sequenced strain historically used as the reference (ATCC BAA-816). We detected a number of structural differences and found the most likely mechanisms behind them: (i) transposition/copy number change in mobile interspersed repeats—insertion sequences and small non-coding repeats, (ii) variable number of monomers within tandem repeats, (iii) deletions between long direct DNA repeats, and (iv) deletions between short (4–10 bp) direct DNA repeats. The most surprising finding was the deletions between short repeats because it indicates the utilization of a less accurate DSB repair mechanism in conditions in which a more accurate one should be both available and preferred. The detected structural differences, as well as SNPs and short indels, while being important footprints of deinococcal DNA metabolism and repair, are also a valuable resource for researchers using these D. radiodurans strains. Full article

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

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14 pages, 1740 KiB

Open AccessArticle

Genomic Regions Associated with Resistance to Gastrointestinal Parasites in Australian Merino Sheep

by Brenda Vera, Elly A. Navajas, Pablo Peraza, Beatriz Carracelas, Elize Van Lier and Gabriel Ciappesoni

Genes 2024, 15(7), 846; https://doi.org/10.3390/genes15070846 - 27 Jun 2024

Viewed by 241

Abstract

The objective of this study was to identify genomic regions and genes associated with resistance to gastrointestinal nematodes in Australian Merino sheep in Uruguay, using the single-step GWAS methodology (ssGWAS), which is based on genomic estimated breeding values (GEBVs) obtained from a combination [...] Read more.

The objective of this study was to identify genomic regions and genes associated with resistance to gastrointestinal nematodes in Australian Merino sheep in Uruguay, using the single-step GWAS methodology (ssGWAS), which is based on genomic estimated breeding values (GEBVs) obtained from a combination of pedigree, genomic, and phenotypic data. This methodology converts GEBVs into SNP effects. The analysis included 26,638 animals with fecal egg count (FEC) records obtained in two independent parasitic cycles (FEC1 and FEC2) and 1700 50K SNP genotypes. The comparison of genomic regions was based on genetic variances (gVar(%)) explained by non-overlap** regions of 20 SNPs. For FEC1 and FEC2, 18 and 22 genomic windows exceeded the significance threshold (gVar(%) ≥ 0.22%), respectively. The genomic regions with strong associations with FEC1 were located on chromosomes OAR 2, 6, 11, 21, and 25, and for FEC2 on OAR 5, 6, and 11. The proportion of genetic variance attributed to the top windows was 0.83% and 1.9% for FEC1 and FEC2, respectively. The 33 candidate genes shared between the two traits were subjected to enrichment analysis, revealing a marked enrichment in biological processes related to immune system functions. These results contribute to the understanding of the genetics underlying gastrointestinal parasite resistance and its implications for other productive and welfare traits in animal breeding programs. Full article

(This article belongs to the Special Issue Advances in Cattle, Sheep, and Goats Molecular Genetics and Breeding)

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15 pages, 1980 KiB

Open AccessArticle

Deafness DFNB128 Associated with a Recessive Variant of Human MAP3K1 Recapitulates Hearing Loss of Map3k1-Deficient Mice

by Rabia Faridi, Rizwan Yousaf, Sayaka Inagaki, Rafal Olszewski, Shoujun Gu, Robert J. Morell, Elizabeth Wilson, Ying **a, Tanveer Ahmed Qaiser, Muhammad Rashid, Cristina Fenollar-Ferrer, Michael Hoa, Sheikh Riazuddin and Thomas B. Friedman

Genes 2024, 15(7), 845; https://doi.org/10.3390/genes15070845 - 27 Jun 2024

Viewed by 326

Abstract

Deafness in vertebrates is associated with variants of hundreds of genes. Yet, many mutant genes causing rare forms of deafness remain to be discovered. A consanguineous Pakistani family segregating nonsyndromic deafness in two sibships were studied using microarrays and exome sequencing. A 1.2 [...] Read more.

Deafness in vertebrates is associated with variants of hundreds of genes. Yet, many mutant genes causing rare forms of deafness remain to be discovered. A consanguineous Pakistani family segregating nonsyndromic deafness in two sibships were studied using microarrays and exome sequencing. A 1.2 Mb locus (DFNB128) on chromosome 5q11.2 encompassing six genes was identified. In one of the two sibships of this family, a novel homozygous recessive variant NM_005921.2:c.4460G>A p.(Arg1487His) in the kinase domain of MAP3K1 co-segregated with nonsyndromic deafness. There are two previously reported Map3k1-kinase-deficient mouse models that are associated with recessively inherited syndromic deafness. MAP3K1 phosphorylates serine and threonine and functions in a signaling pathway where pathogenic variants of HGF, MET, and GAB1 were previously reported to be associated with human deafness DFNB39, DFNB97, and DFNB26, respectively. Our single-cell transcriptome data of mouse cochlea mRNA show expression of Map3k1 and its signaling partners in several inner ear cell types suggesting a requirement of wild-type MAP3K1 for normal hearing. In contrast to dominant variants of MAP3K1 associated with Disorders of Sex Development 46,XY sex-reversal, our computational modeling of the recessive substitution p.(Arg1487His) predicts a subtle structural alteration in MAP3K1, consistent with the limited phenotype of nonsyndromic deafness. Full article

(This article belongs to the Special Issue Molecular Basis of Rare Genetic Diseases)

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Genes, Volume 15, Issue 7 (July 2024) – 55 articles

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