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Genes

Genes is a peer-reviewed, open access journal of genetics and genomics published monthly online by MDPI. The Spanish Society for Biochemistry and Molecular Biology (SEBBM) is affiliated with Genes and their members receive discounts on the article processing charges.

Open Access— free for readers, with article processing charges (APC) paid by authors or their institutions.
High Visibility: indexed within Scopus, SCIE (Web of Science), PubMed, MEDLINE, PMC, Embase, PubAg, and other databases.
Journal Rank: JCR - Q2 (Genetics and Heredity) / CiteScore - Q2 (Genetics (clinical))
Rapid Publication: manuscripts are peer-reviewed and a first decision is provided to authors approximately 14.9 days after submission; acceptance to publication is undertaken in 2.6 days (median values for papers published in this journal in the second half of 2024).
Recognition of Reviewers: Reviewers who provide timely, thorough peer-review reports receive vouchers entitling them to a discount on the APC of their next publication in any MDPI journal, in appreciation of the work done.

Impact Factor: 2.8 (2023); 5-Year Impact Factor: 3.3 (2023)

Imprint Information Journal Flyer Open Access ISSN: 2073-4425

Latest Articles

14 pages, 1523 KiB

Open AccessReview

The p12 Subunit Choreographs the Regulation and Functions of Two Forms of DNA Polymerase δ in Mammalian Cells

by Dazhong Xu, Selvaraj Ayyamperumal, Sufang Zhang, Jinjin Chen, Ernest Y. C. Lee and Marietta Y. W. T. Lee

Genes 2025, 16(2), 188; https://doi.org/10.3390/genes16020188 - 3 Feb 2025

There are two forms of DNA polymerase δ in human cells, Pol δ4 and Pol δ3, which differ based on their possession of the p12 subunit. The degradation of p12 has emerged as an important regulatory mechanism that controls the generation of Pol [...] Read more.

There are two forms of DNA polymerase δ in human cells, Pol δ4 and Pol δ3, which differ based on their possession of the p12 subunit. The degradation of p12 has emerged as an important regulatory mechanism that controls the generation of Pol δ3. The underlying importance of this system lies in the altered enzymatic properties of the two forms of Pol δ engendered by the influence of p12. We briefly review how the balance of these two forms is regulated through the degradation of p12. We focus on the roles of Pol δ4, whose cellular functions are less well known. This is significant because recent studies show that this is the form engaged in the homology-dependent repair of double-strand breaks. We consider new horizons for future research into this system and their potential involvement in tumorigenesis. Full article

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15 pages, 2865 KiB

Open AccessArticle

Transcriptomic Analysis Reveals Patterns of Expression of Stage-Specific Genes in Early Apis cerana Embryos

by Runlang Su, Yuhui Chen, Rui Zhu, Guiling Ding, Kun Dong, Mao Feng and Jiaxing Huang

Genes 2025, 16(2), 187; https://doi.org/10.3390/genes16020187 - 3 Feb 2025

Background/Objectives: Apis cerana development is described as comprising four stages: embryo, larva, pupa, and adult. There are significant differences between workers and drones in terms of physiological functions and social roles, and the formation of the organ primordia occurs during the embryonic stage. [...] Read more.

Background/Objectives: Apis cerana development is described as comprising four stages: embryo, larva, pupa, and adult. There are significant differences between workers and drones in terms of physiological functions and social roles, and the formation of the organ primordia occurs during the embryonic stage. Therefore, the objective of this study is to investigate the differential expression of and alternative splicing of genes in worker and drone embryos and to explain their unique developmental patterns. Methods: Long-read sequencing (PacBio Iso-Seq) and short-read sequencing (Illumina RNA-Seq) were used to investigate worker and drone embryo gene expression differences in A. cerana across five developmental points (12, 24, 36, 48, and 60 h). Results: The study identified 59,254 common isoforms, with 5744 and 5106 isoforms specific to worker and drone embryos, respectively. Additionally, a new transcript of the csd gene was identified. The number of differentially expressed genes (3391) and differential splicing events (470 genes) peaked at the 24-h embryonic stage. Differential splicing events of csd, dsx, and Y-y were observed in the worker and drone embryos. Conclusions: The gene expression results indicated that the 24-h embryonic point is a critical period for the expression of genes related to developmental and behavioral differences between workers and drones. The findings provide a theoretical basis for future research on the developmental differences between workers and drones. Full article

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

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16 pages, 5136 KiB

Open AccessArticle

Analysis of the Codon Usage Bias Pattern in the Chloroplast Genomes of Chloranthus Species (Chloranthaceae)

by Jisi Zhang and Miao Feng

Genes 2025, 16(2), 186; https://doi.org/10.3390/genes16020186 - 2 Feb 2025

Background: The codon preference of chloroplast genomes not only reflects mutation patterns during the evolutionary processes of species but also significantly affects the efficiency of gene expression. This characteristic holds significant scientific importance in the application of chloroplast genetic engineering and the genetic [...] Read more.

Background: The codon preference of chloroplast genomes not only reflects mutation patterns during the evolutionary processes of species but also significantly affects the efficiency of gene expression. This characteristic holds significant scientific importance in the application of chloroplast genetic engineering and the genetic improvement of species. Chloranthus, an ancestral angiosperm with significant economic, medicinal, and ornamental value, belongs to the basal angiosperms. However, the codon usage patterns among Chloranthus species have remained unclear. Methods: To investigate codon usage bias and its influencing factors in Chloranthus chloroplast genomes, we utilized CodonW, CUSP, and SPSS software to analyze the chloroplast genomes of seven Chloranthus species. Results: In this study, we reported and characterized the complete chloroplast genome of the Chinese endemic species Chloranthus angustifolius. The phylogenetic tree based on the whole chloroplast genomes showed that C. angustifolius is sister to Chloranthus fortunei, and the genus Chloranthus is divided into two major clades, consistent with previous studies. Our results revealed that the GC content at different codon positions across all seven Chloranthus species was less than 50%, with GC1 > GC2 > GC3. Additionally, the average effective number of codons (ENC) values exceeded 45. A total of 10 shared optimal codons were identified, nine of which end with A or U. PR2-plot, ENC-plot, and neutrality plot analyses indicated that natural selection primarily influenced codon usage bias in the chloroplast genomes of Chloranthus. Conclusions: We newly obtained the chloroplast genome of C. angustifolius and proposed that natural selection played a key role in codon usage patterns in Chloranthus species. These findings contribute to our understanding of evolutionary history and genetic diversity within this genus. Full article

(This article belongs to the Special Issue Molecular Adaptation and Evolutionary Genetics in Plants)

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18 pages, 878 KiB

Open AccessReview

Integrating Machine Learning-Based Approaches into the Design of ASO Therapies

by Jamie Leckie and Toshifumi Yokota

Genes 2025, 16(2), 185; https://doi.org/10.3390/genes16020185 - 2 Feb 2025

Rare diseases impose a significant burden on affected individuals, caregivers, and healthcare systems worldwide. Developing effective therapeutics for these small patient populations presents substantial challenges. Antisense oligonucleotides (ASOs) have emerged as a promising therapeutic approach that targets the underlying genetic cause of disease [...] Read more.

Rare diseases impose a significant burden on affected individuals, caregivers, and healthcare systems worldwide. Developing effective therapeutics for these small patient populations presents substantial challenges. Antisense oligonucleotides (ASOs) have emerged as a promising therapeutic approach that targets the underlying genetic cause of disease at the RNA level. Several ASOs have gained FDA approval for the treatment of genetic conditions, including use in personalized N-of-1 trials. However, despite their potential, ASOs often exhibit limited clinical efficacy, and optimizing their design is a complex process influenced by numerous factors. Machine learning-based platforms, including eSkip-Finder and ASOptimizer, have been developed to address these challenges by predicting optimal ASO sequences and chemical modifications to enhance efficacy. eSkip-Finder focuses on exon-skipping applications, while ASOptimizer aims to optimize ASOs for RNA degradation. Preliminary in vitro results have demonstrated the promising predictive power of these platforms. However, limitations remain, including their generalizability to alternative targets and gaps in their consideration of all factors influencing ASO efficacy and safety. Continued advancements in machine learning models, alongside efforts to incorporate additional features affecting ASO efficacy and safety, hold significant promise for the field. These platforms have the potential to streamline ASO development, reduce associated costs, and improve clinical outcomes, positioning machine learning as a key tool in the future of ASO therapeutics. Full article

(This article belongs to the Special Issue Feature Papers in Human Genomics and Genetic Diseases 2024)

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17 pages, 8146 KiB

Open AccessArticle

Characterization and Expression Analysis of the bHLH Gene Family During Developmental Stages and Under Various Abiotic Stresses in Sanghuangporus baumii

by Ruipeng Liu, Tingting Sun, Pengyu Du, Zengcai Liu, Yawei Li, Xinyu Tong and Li Zou

Genes 2025, 16(2), 184; https://doi.org/10.3390/genes16020184 - 2 Feb 2025

Background: Basic helix–loop–helix (bHLH) transcription factors (TFs) widely exist in eukaryotic organisms and play a key role in plant growth and development in response to environmental stresses. Sanghuangporus baumii, an important medicinal mushroom known for its anticancer properties, has limited research on [...] Read more.

Background: Basic helix–loop–helix (bHLH) transcription factors (TFs) widely exist in eukaryotic organisms and play a key role in plant growth and development in response to environmental stresses. Sanghuangporus baumii, an important medicinal mushroom known for its anticancer properties, has limited research on the bHLH gene family. Methods: This research utilized the genomic data from S. baumii to identify bHLH family members, and their gene structure, conserved motifs, and phylogenetic relationship were characterized. Additionally, we conducted an analysis of promoter cis-elements and predicted protein interaction networks. We also examined the expression profiles of bHLH genes during different developmental stages and in response to four abiotic stresses: heat, cold, oxidative stress, and heavy metal exposure. Finally, we overexpressed the candidate gene SbbHLH3 in yeast to assess its tolerance to these different stress conditions. Results: A total of 12 SbbHLH genes were identified in S. baumii, and the members of the bHLH gene family displayed a variety of physicochemical characteristics, reflecting their diverse array of functions. Based on homology, the SbbHLH proteins are more closely related to those found in Lentinula edodes and Pleurotus ostreatus. The analysis of promoter cis-elements showed that SbbHLHs contain several elements associated with abiotic stress response, and a network prediction identified 28 bHLH-interacting proteins. Expression pattern analysis revealed that most SbbHLH genes exhibited a positive response to different developmental stages and abiotic stresses. Notably, the overexpression of SbbHLH3 significantly enhanced stress tolerance in yeast. Conclusions: This study provides a comprehensive assessment of the bHLH family in S. baumii, delivering new genetic resources for breeding resistant varieties. Full article

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

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17 pages, 3776 KiB

Open AccessArticle

Molecular Markers Specific for the Pseudomonadaceae Genera Provide Novel and Reliable Means for the Identification of Other Pseudomonas Strains/spp. Related to These Genera

by Bashudev Rudra and Radhey S. Gupta

Genes 2025, 16(2), 183; https://doi.org/10.3390/genes16020183 - 2 Feb 2025

Background/Objectives: Taxon-specific conserved signature indels (CSIs) exhibit a strong predictive ability of being found in other members of specific taxa/genera. Recently, multiple exclusively shared CSIs were identified for several newly described Pseudomonadaceae genera (viz. Aquipseudomonas, Atopomonas, Caenipseudomonas, Chryseomonas Ectopseudomonas, [...] Read more.

Background/Objectives: Taxon-specific conserved signature indels (CSIs) exhibit a strong predictive ability of being found in other members of specific taxa/genera. Recently, multiple exclusively shared CSIs were identified for several newly described Pseudomonadaceae genera (viz. Aquipseudomonas, Atopomonas, Caenipseudomonas, Chryseomonas Ectopseudomonas, Geopseudomonas, Halopseudomonas, Metapseudomonas, Phytopseudomonas, Serpens, Stutzerimonas, Thiopseudomonas, and Zestomonas). This study examines the potential applications of these CSIs for identifying other Pseudomonas spp. (strains) related to these genera. Methods: This work utilized the AppIndels.com server, which uses information regarding the presence of known taxon-specific CSIs in a genome for predicting its taxonomic affiliation. For this purpose, sequence information for different CSIs specific for the Pseudomonadaceae species/genera were added to the server’s database. Results: The AppIndels server was used to predict the taxonomic affiliation of 1972 genomes of unclassified Pseudomonas spp. (strains/isolates). Based upon finding a significant number of CSIs matching a specific taxon, the AppIndels server made positive predictions regarding the taxonomic affiliation of 299 examined genomes into the following clades/genera: Pseudomonas sensu stricto clade (46), Pseudomonas aeruginosa (64), Ectopseudomonas (46), Chryseomonas (32), Stutzerimonas (31), Metapseudomonas (22), Aquipseudomonas (21), Phytopseudomonas (17), Halopseudomonas (9), Geopseudomonas (4), Thiopseudomonas (3), Serpens (2), and Caenipseudomonas and Zestomonas (1 each). Phylogenetic studies confirmed that the taxonomic predictions by the server were 100% accurate. Conclusions: Our results demonstrate that the CSIs specific for Pseudomonadaceae species/genera, in conjunction with the AppIndels server, provides a novel and useful tool for identifying other species/strains affiliated with these species/genera. Phylogenetic studies suggest that many examined Pseudomonas strains constitute novel species in the indicated genera. Full article

(This article belongs to the Special Issue Feature Papers in Microbial Genetics and Genomics)

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10 pages, 923 KiB

Open AccessArticle

MLH1 Methylation Status and Microsatellite Instability in Patients with Colorectal Cancer

by Manuel Alejandro Rico-Méndez, Miguel Angel Trujillo-Rojas, María de la Luz Ayala-Madrigal, Jesús Arturo Hernández-Sandoval, Anahí González-Mercado, Melva Gutiérrez-Angulo, José Geovanni Romero-Quintana, Jesús Alonso Valenzuela-Pérez, Ruth Ramírez-Ramírez, Beatriz Armida Flores-López and José Miguel Moreno-Ortiz

Genes 2025, 16(2), 182; https://doi.org/10.3390/genes16020182 - 2 Feb 2025

Background/Objectives: The purpose of the current study was to compare the methylation of five regions of the CpG island of MLH1 with the presence of microsatellite instability (MSI) in colorectal cancer (CRC) patients. Methods: The study analyzed 138 CRC tumor samples. DNA extraction [...] Read more.

Background/Objectives: The purpose of the current study was to compare the methylation of five regions of the CpG island of MLH1 with the presence of microsatellite instability (MSI) in colorectal cancer (CRC) patients. Methods: The study analyzed 138 CRC tumor samples. DNA extraction was performed, followed by bisulfite conversion. MLH1 gene methylation was assessed by methylation-specific PCR (MS-PCR), and the resulting fragments were analyzed using polyacrylamide gels. MSI was evaluated using multiplex PCR, and the fragments were run through capillary electrophoresis. R studio (v4.4.1) and SPSS (v29.0) software were used for the statistical analysis, and values of p < 0.05 were considered statistically significant. Results: The study showed 75.4% unmethylated, 21% partially methylated, and 3.6% fully methylated samples, with region A frequently methylated. MSI was observed in 7.2% of cases (MSI-H: 5.8%, MSI-L: 1.4%). BAT-26 was the most unstable marker. A significant difference between MLH1 methylation and MSI-H (p < 0.01) was identified, but there was no relationship with specific MLH1 regions. Conclusions: No differences were identified when analyzing specific methylation regions in relation to MSI. This study is the first to describe MSI frequency in Mexican patients regardless of age. Full article

(This article belongs to the Special Issue Genetic and Genomic Research on Colorectal Cancer)

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13 pages, 47260 KiB

Open AccessArticle

Transcriptome Analysis Reveals Equine Endometrium’s Gene Expression Profile Around Embryo Fixation

by Tseweendolmaa Ulaangerel, Siqin Mu, Jolanqiqige Sodyelalt, Minna Yi, Bilig Zhao, Asiya Hao, Xin Wen, Baoxiang Han and Gerelchimeg Bou

Genes 2025, 16(2), 181; https://doi.org/10.3390/genes16020181 - 1 Feb 2025

Background/Objectives: The success or failure of embryo fixation is crucial for embryo attachment and later development. As an epithelial chorioallantoic placenta-type animal, the horse has a special process of embryo implantation, and the mechanism of embryo fixation in horses is still unclear. Methods: [...] Read more.

Background/Objectives: The success or failure of embryo fixation is crucial for embryo attachment and later development. As an epithelial chorioallantoic placenta-type animal, the horse has a special process of embryo implantation, and the mechanism of embryo fixation in horses is still unclear. Methods: In this study, the structural and transcriptomic characteristics of endometrial tissue from the fixed and nonfixed sides of 20-day gestation embryos in Mongolian horses were investigated to search for important genes and potential molecular markers associated with the fixation phase of equine embryos. Results: A comparison of the structures of the endometrial tissues of the two sides revealed that the endometrium on the fixed side presented distinctive features, which were characterized mainly by the development of glands on the fixed side compared with those on the nonfixed side. A total of 3987 differentially expressed genes were identified in the transcriptome, among which 1931 genes were highly expressed on the fixed side of the embryo, including CDH1, DRA, DQB, CLND2, BOLA-DQB, CLDN10, PTGER2, and PTGFR. The differentially expressed genes were enriched in biological processes such as cell adhesion, morphogenesis, NOD signaling, and vitamin uptake, as well as prostatic hormones. Conclusions: These results suggest that equine embryo fixation may depend at least on the regulation of prostaglandins and the establishment of cellular connections. This provides a foundation for exploring the molecular mechanisms of key genes and pathways related to equine embryo fixation and offers new insights into feeding management and the monitoring of mares in the early stages of pregnancy. Full article

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

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20 pages, 3701 KiB

Open AccessArticle

miRNA Signatures as Predictors of Therapy Response in Castration-Resistant Prostate Cancer: Insights from Clinical Liquid Biopsies and 3D Culture Models

by Jonathan Puente-Rivera, Stephanie I. Nuñez-Olvera, Verónica Fernández-Sánchez, Monica Alethia Cureño-Díaz, Erika Gómez-Zamora, Estibeyesbo Said Plascencia-Nieto, Elisa Elvira Figueroa-Angulo and María Elizbeth Alvarez-Sánchez

Genes 2025, 16(2), 180; https://doi.org/10.3390/genes16020180 - 1 Feb 2025

Background/Objectives: Prostate cancer (PCa) patients who do not respond to androgen deprivation therapy (ADT), referred to as castration-resistant prostate cancer (CRPC), remain a clinical challenge due to confirm the aggressive nature of CRPC and its resistance to conventional therapies. This study aims to [...] Read more.

Background/Objectives: Prostate cancer (PCa) patients who do not respond to androgen deprivation therapy (ADT), referred to as castration-resistant prostate cancer (CRPC), remain a clinical challenge due to confirm the aggressive nature of CRPC and its resistance to conventional therapies. This study aims to investigate the potential of microRNAs (miRNAs) as biomarkers for predicting therapeutic response in CRPC patients. Methods: We performed miRNA and mRNA expression analyses using publicly available datasets and applied 3D cell culture models to replicate more physiologically relevant tumor conditions. Genetic analysis techniques were employed on publicly available data, and expression profiles from 3D cell culture models were examined. Results: Eighteen miRNAs with differential expression were identified between patients who responded favorably to abiraterone therapy (responders) and those with advanced CRPC (non-responders). Specifically, miRNAs such as hsa-miR-152-3p and hsa-miR-34a-3p were found to be associated with critical pathways, including TGF-β signaling and P53, which are linked to therapeutic resistance. Several miRNAs were identified as potential predictors of treatment efficacy, including therapies like abiraterone. Conclusions: These results indicate that miRNAs could serve as non-invasive biomarkers for predicting therapeutic outcomes, facilitating a more personalized approach to CRPC treatment. This study provides a novel perspective on treatment strategies for CRPC, emphasizing the role of miRNAs in improving therapeutic precision and efficacy in this complex disease. Full article

(This article belongs to the Special Issue MicroRNA in Cancers)

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18 pages, 2989 KiB

Open AccessArticle

Genetic Diversity Analysis and Comprehensive Evaluation of “M82” in EMS-Mutagenized Tomato

by Yanchao Yang, Zhanming Tan, Shuang Liang, Wei Cheng, Yihuan Sun, Yunxia Cheng, Yu Song, Yongming Wang, Jialong Wu and Qi Wang

Genes 2025, 16(2), 179; https://doi.org/10.3390/genes16020179 - 1 Feb 2025

Background: Ethyl methyl sulfonate (EMS) mutagenesis is widely used because of its advantages of inducing point mutations and no need for genetic transformation. To identify germplasm resources of processed tomatoes with superior comprehensive traits suitable for cultivation in Xinjiang. Methods: In this study, [...] Read more.

Background: Ethyl methyl sulfonate (EMS) mutagenesis is widely used because of its advantages of inducing point mutations and no need for genetic transformation. To identify germplasm resources of processed tomatoes with superior comprehensive traits suitable for cultivation in Xinjiang. Methods: In this study, tomato seeds were treated with 2% EMS reagent for 12 h, 21 quality traits and 20 quantitative traits of 33 processed tomatoes derived from EMS-mutagenized“M82”were evaluated. Results: The results indicated that for traits such as hypocotyl color, growth habit, plant type, leaf type, and leaf shape, the range of quantitative trait variation was 8.45–37.25%, with a genetic diversity index ranging from 1.25 to 2.07. Conclusions: Cluster analysis of quantitative traits categorized the 33 EMS-mutagenized “M82” processed tomato resources into five groups: Group I contained 22 robust germplasm samples; Group II consisted of a single potential high-quality germplasm; Group III comprised five germplasm with a small and extreme plant type; Group IV included four high-yield germplasm; and Group V represented one moderate, conventional germplasm. Raw data from 15 quantitative traits across the 33 accessions were standardized using the “extreme method” to extract six comprehensive factors. The top 10 germplasm resources based on the comprehensive score were 76, 137, 97, 102, 19, 104, 21, 108, 17, and 147. It provides some theoretical basis for realizing the high-yield and high-quality cultivation and variety breeding of processed tomatoes in Xinjiang. Full article

(This article belongs to the Special Issue Genes and Genomics of Plants Under Abiotic Stresses)

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18 pages, 4427 KiB

Open AccessArticle

An Actively Homing Insertion Element in a Phage Methylase Contains a Hidden HNH Endonuclease

by Danielle Arsenault, Sophia P. Gosselin and Johann Peter Gogarten

Genes 2025, 16(2), 178; https://doi.org/10.3390/genes16020178 - 1 Feb 2025

Background/Objectives: The ShiLan domain was previously identified as an insertion sequence in a phage DNA methylase gene that exhibited similar evolutionary patterns to that of an active intein or self-splicing intron but could not be identified as either. It produces no internal [...] Read more.

Background/Objectives: The ShiLan domain was previously identified as an insertion sequence in a phage DNA methylase gene that exhibited similar evolutionary patterns to that of an active intein or self-splicing intron but could not be identified as either. It produces no internal stop codons when read in frame with its host methylase gene, leading to the thought that it may not be an intron and rather be an abnormal type of intein. However, the sequence has no detectable self-splicing domains, which are essential for intein persistence, as preventing an intein from successfully splicing is often detrimental to proper host protein function. Methods: The analysis of alternate open reading frames for the full nucleotide sequence of this insertion element revealed the insertion to be an out-of-frame histidine-asparagine-histidine (HNH) endonuclease. A GTG start codon is located 18 bp into the insertion, and a TAA stop codon within the last four bases of the insertion (TAAC). When this frame is read, an HNH endonuclease is revealed. In-depth computational analysis could not retrieve support for this element being any known type of self-splicing element, neither intein nor intron. When read in-frame with the methylase gene, this insertion is predicted to take on a looping structure that may be able to avoid interference with the DNA methylase activity. We performed searches for sequences similar in nature to the inserted out-of-frame HNH and found several in other phages and prokaryotes. We present our survey of these out-of-frame endonuclease insertion elements as well as some speculation on how these endonucleases are getting translated to facilitate their homing activity. Conclusions: These findings expand our understanding of the possible arrangements for and prevalence of unorthodox mobile genetic elements and overlapping open reading frames in phages. Full article

(This article belongs to the Section Viral Genomics)

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19 pages, 1210 KiB

Open AccessReview

Understanding Heritable Variation Among Hosts in Infectious Diseases Through the Lens of Twin Studies

by Maria K. Smatti, Hadi M. Yassine, Hamdi Mbarek and Dorret I. Boomsma

Genes 2025, 16(2), 177; https://doi.org/10.3390/genes16020177 - 1 Feb 2025

Genetic factors have been hypothesized to contribute to the heterogeneity in the response to infectious diseases (IDs). The classical twin design provides a powerful tool to estimate the role of genetic contributions to variation in infection outcomes. With this design, the impact of [...] Read more.

Genetic factors have been hypothesized to contribute to the heterogeneity in the response to infectious diseases (IDs). The classical twin design provides a powerful tool to estimate the role of genetic contributions to variation in infection outcomes. With this design, the impact of heritability on the proneness as well as infection- and vaccine-induced immune responses have been documented for multiple infections, including tuberculosis, malaria, leprosy, otitis media, polio, mumps, measles, rubella, influenza, hepatitis B, and human papillomavirus infections, and recently, SARS-CoV-2. The current data show the heritable aspect in nearly all infections considered. In this contribution, we review and discuss human twin studies on the heritability of host characteristics in liability and response to IDs. This review emphasizes the importance of considering factors such as sex, disease stages, and disease presentation when assessing heritability and argues that the classical twin design provides a unique circumstance for exploring the genetic contribution as twins share levels of maternal antibodies, ancestral background, often the dates and number of vaccine doses, differences in vaccines’ manufacturing and storage, age, family environment, and other exposures. Additionally, we highlight the value of twin studies and the usefulness of combining the twin model with contemporary genomics technologies and advanced statistical tools to grasp a comprehensive and nuanced understanding of heritability in IDs. Full article

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

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12 pages, 635 KiB

Open AccessCase Report

The Arg99Gln Substitution in HNRNPC Is Associated with a Distinctive Clinical Phenotype Characterized by Facial Dysmorphism and Ocular and Cochlear Anomalies

by Luigi Chiriatti, Manuela Priolo, Roberta Onesimo, Mattia Carvetta, Chiara Leoni, Alessandro Bruselles, Francesca Clementina Radio, Camilla Cappelletti, Marco Ferilli, Daniela Ricci, Marcello Niceta, Viviana Cordeddu, Andrea Ciolfi, Cecilia Mancini, Giuseppe Zampino and Marco Tartaglia

Genes 2025, 16(2), 176; https://doi.org/10.3390/genes16020176 - 1 Feb 2025

Background/Objectives: Heterozygous variants in the heterogeneous nuclear ribonucleoprotein C gene (HNRNPC) have recently been reported to cause intellectual developmental disorder-74 (MRD74), a neurodevelopmental disorder with no recurrent diagnostic handles. Affected individuals show variable, non-specific, and subtle dysmorphic features. The degree of [...] Read more.

Background/Objectives: Heterozygous variants in the heterogeneous nuclear ribonucleoprotein C gene (HNRNPC) have recently been reported to cause intellectual developmental disorder-74 (MRD74), a neurodevelopmental disorder with no recurrent diagnostic handles. Affected individuals show variable, non-specific, and subtle dysmorphic features. The degree of developmental delay (DD)/intellectual disability (ID) is also wide, ranging from mild to severe. The mutational spectrum is relatively broad with exon deletions and splice site and frameshift variants distributed along the entire length of the gene leading to HNRNPC loss of function. Only two missense changes located within the RNA-binding motif (RBM) and adjacent linker region of the more abundant isoform (Arg64Trp and Arg99Gln) have been described. Notably, the Arg99Gln amino acid substitution was reported in a subject presenting with a more complex and unique clinical phenotype characterized by distinctive facial features, DD/ID, cochlear aplasia, and bilateral colobomatous microphthalmia, suggesting the possible occurrence of phenotypic heterogeneity. Results: Here, we report the second individual carrying the Arg99Gln change in HNRNPC and having clinical features with a significant overlap with the peculiar phenotype of the previously described subject, supporting the occurrence of a genotype–phenotype correlation. Conclusions: Due to the concomitant occurrence of ocular and cochlear involvement as recognizable diagnostic handles, we propose that the HNRNPC^Arg99Gln-related phenotype should be considered as a potential differential diagnosis in subjects with ID and major signs of CHARGE syndrome not fulfilling the minimum criteria for a clinical diagnosis. Full article

(This article belongs to the Special Issue Feature Papers in Human Genomics and Genetic Diseases 2024)

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13 pages, 4519 KiB

Open AccessArticle

Transcriptional Regulatory Network of the Embryonic Diapause Termination Process in Artemia

by Bin Wang, Zhen He, Mingzhi Zhang, Ruiqi Zhang, Zhentao Song, Anqi Li and Tong Hao

Genes 2025, 16(2), 175; https://doi.org/10.3390/genes16020175 - 1 Feb 2025

Artemia is a typical animal used for the study of the diapause mechanism. The research on the regulation mechanism of diapause mainly focuses on the occurrence and maintenance of diapause. There are few studies on the mechanism of embryonic pause termination (EDT), especially [...] Read more.

Artemia is a typical animal used for the study of the diapause mechanism. The research on the regulation mechanism of diapause mainly focuses on the occurrence and maintenance of diapause. There are few studies on the mechanism of embryonic pause termination (EDT), especially for its transcriptional regulation mechanism. This study integrated transcriptional regulatory data from ATAC-seq and gene expression data from RNA-seq to explore the transcriptional regulatory mechanisms involved in the EDT process. Through integrated analysis, four important transcription factors (TFs), SVP, MYC, RXR, and SMAD6, were found to play a role in the EDT process, in which SVP, MYC, and RXR were upregulated, while SMAD6 was downregulated in the EDT stage. Through co-expression analysis, a transcription regulatory network for these four TFs was constructed and the functions of the TFs were analyzed. The expression of the TFs was further verified by RT-qPCR. Through functional analysis, SVP was found to be predominantly involved in cell adhesion and signal transduction. MYC probably played a role in protein binding. RXR may function in the process of RNA binding and the transfer of phosphorus-containing groups. Smad6 regulated the signal transduction, cell adhesion, and oxidation–reduction processes. The expression of the key TFs was verified by RT-qPCR. The results of this work provide important clues for the mechanism of transcriptional regulation in the EDT process of Artemia. Full article

(This article belongs to the Special Issue Genetic and Genomic Studies of Marine Animals)

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15 pages, 23444 KiB

Open AccessArticle

Construction of the Red Swamp Crayfish (Procambarus clarkii) Family Selection Population and Whole Genome Sequencing to Screen WIPFI Candidate Genes Related to Growth

by Xing Tian, Xiudan Yuan, Zhigang He, Weiguo Li, Jinlong Li, Yong He, Shiming Deng, Jiarong Guo, Miaoquan Fang and Dongwu Wang

Genes 2025, 16(2), 174; https://doi.org/10.3390/genes16020174 - 31 Jan 2025

Background/Objectives: Procambarus clarkii is an important freshwater aquaculture species in China which has the characteristics of rich nutrition and delicious taste. However, the expansion of aquaculture scale, germplasm degradation, and other problems that have become increasingly prominent seriously restrict the sustainable development [...] Read more.

Background/Objectives: Procambarus clarkii is an important freshwater aquaculture species in China which has the characteristics of rich nutrition and delicious taste. However, the expansion of aquaculture scale, germplasm degradation, and other problems that have become increasingly prominent seriously restrict the sustainable development of the crayfish industry. Genetic improvement is an urgent need for the crayfish aquaculture industry, and selective breeding is an important way to improve the crayfish varieties. Methods: We established full-sibling family populations of the red swamp crayfish and performed whole-genome resequencing of the F3 family-selected red swamp crayfish population and wild red swamp crayfish populations from four regions of Hunan Province (Nanx, Mil, Caish, and Wangc). Results: The results showed that there was a clear separation between the wild population and the family population, and the decline rate was slightly faster in the wild population than that of the family breeding population. There was local gene flow between family populations, as well as gene flow between Mil, Caish, and families. In addition, 52 SNP loci related to body weight traits were identified by genome-wide association analysis, and the candidate gene WIPF1 related to growth was screened out. Conclusions: We established a line selection population of red swamp crayfish and obtained more stable candidate lines. In addition, this study identified Wiskott–Aldrich syndrome protein-interacting protein family member 1 (WIPF1) as a candidate gene related to body weight for the first time. The results provide a theoretical basis for exploring the growth mechanism of P. clarkii and carrying out in-depth genetic improvement. Full article

(This article belongs to the Special Issue Genetics and Genomics Applied to Aquatic Animal Science—2nd Edition)

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18 pages, 17704 KiB

Open AccessArticle

Terrestrial Adaptation in Chelonoidis vicina as Revealed Based on Analysis of the Complete Mitochondrial Genome

by Yao Chen, Xibao Wang, Xiaoyang Wu, Yongquan Shang, Qinguo Wei, Haotian Cai, Weilai Sha, Yan Qi, Shuli Liu and Honghai Zhang

Genes 2025, 16(2), 173; https://doi.org/10.3390/genes16020173 - 30 Jan 2025

Background/Objectives: Mitochondrial genomes are widely used in phylogenetics and evolutionary and ecological research. Methods: In this study, the newest mitochondrial genome of Chelonoidis vicina was assembled and annotated. The comparative mitochondrial genome and selection pressure analyses were used to examine the terrestrial adaptive [...] Read more.

Background/Objectives: Mitochondrial genomes are widely used in phylogenetics and evolutionary and ecological research. Methods: In this study, the newest mitochondrial genome of Chelonoidis vicina was assembled and annotated. The comparative mitochondrial genome and selection pressure analyses were used to examine the terrestrial adaptive evolution characteristics of C. vicina and other terrestrial reptiles. Results: The results reveal that the mitochondrial genome of the tortoise C. vicina is consistent with that of other tortoise species, comprising 13 protein-coding genes (PCGs), 2 rRNAs, 22 tRNAs, and 1 noncoding control region (CR). The analysis of selection pressure reveals the presence of positive selection sites in the COX2, COX3, Cytb, ND3, ND4, ND4L, ND5, and ND6 genes of terrestrial reptiles. Of these, the COX2 and ND3 genes exhibited faster evolutionary rates. The mitochondrial genome structure of C. vicina is consistent with that of different terrestrial reptiles. The positive selection sites of COX2 and ND3 in terrestrial reptiles are closely related to a change in mitochondrial energy metabolism, which is possibly related to terrestrial adaptability. Conclusions: The results of this study provide new insights into the adaptive evolution of C. vicina to terrestrial niches from a mitogenomic perspective, as well as genetic resources for the protection of C. vicina. Full article

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

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19 pages, 3451 KiB

Open AccessArticle

Type 1 Diabetes Risk Variants Reduce Beta Cell Function

by Wiktoria Ratajczak, Angus G. Jones, Sarah D. Atkinson and Catriona Kelly

Genes 2025, 16(2), 172; https://doi.org/10.3390/genes16020172 - 29 Jan 2025

Introduction: The variants rs10517086 and rs1534422 are predictive of type 1 diabetes mellitus (T1DM) development and poor residual β cell function within the first year of diagnosis. However, the mechanism by which risk is conferred is unknown. We explored the impact of both [...] Read more.

Introduction: The variants rs10517086 and rs1534422 are predictive of type 1 diabetes mellitus (T1DM) development and poor residual β cell function within the first year of diagnosis. However, the mechanism by which risk is conferred is unknown. We explored the impact of both variants on β cell function in vitro and assessed their relationship with C-peptide in people with T1DM and type 2 diabetes mellitus (T2DM). Methods: Using CRISPR/Cas9, the variants were introduced into a β cell line (BRIN-BD11) and a T cell line (Jurkat cells) from which the conditioned media was applied to otherwise healthy β cells to model the inflammatory environment associated with these variants. Results: Both variants significantly reduced glucose-stimulated insulin secretion, increased production of pro-inflammatory cytokines and reduced expression of several β cell markers and transcription factors (KCNJ11, KCNQ1, SCL2A2, GCK, NKX6.1, Pdx1 NGN3). However, HNF1A was significantly upregulated in the presence of both variants. We subsequently silenced HNF1A in variant expressing BRIN-BD11 cells using siRNA and found that gene expression profiles were normalised. Induction of each variant significantly increased expression of the lncRNAs they encode, which was normalised upon HNF1A silencing. Analysis of the DARE (Diabetes Alliance for Research in England) study revealed an association of rs10517086_A genotype with C-peptide in 153 individuals with T1DM, but not in 417 people with T2DM. Conclusions: These data suggest that rs1534422 and rs10517086 exert multiple insults on the β cell through excessive upregulation of HNF1A and induction of pro-inflammatory cytokines, and highlight their utility as prognostic markers of β cell function. Full article

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

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11 pages, 466 KiB

Open AccessArticle

The Relationship of the Pathogenic Variant rs721048 in the Intron of the EHBP1 Gene with the Development of Prostate Cancer and Colorectal Cancer in the Kazakh Population

by Marina Romanova, Saltanat Abdikerim, Kaisar Dauyey, Ziyo Gassanov, Nurlan Baltayev, Shyngys Satymbayev, Aigul Zhunussova, Dilyara Kaidarova and Gulnur Zhunussova

Genes 2025, 16(2), 171; https://doi.org/10.3390/genes16020171 - 28 Jan 2025

Background: Prostate cancer (PC) is one of the most common oncological diseases among men. Up to 20% of PC cases are associated with hereditary risks or syndromes. The impact of common variants, particularly EHBP1 c.1185+30064G>A rs721048, on developing PC and other malignancies remains [...] Read more.

Background: Prostate cancer (PC) is one of the most common oncological diseases among men. Up to 20% of PC cases are associated with hereditary risks or syndromes. The impact of common variants, particularly EHBP1 c.1185+30064G>A rs721048, on developing PC and other malignancies remains unclear. There are also no data on the frequency of this variant in the Kazakh population or its association with PC, nor its potential connection with other malignancies, particularly colorectal cancer (CRC). Methods: We utilized the TruSight Cancer Sequencing Panel to assess pathological genomic variants in 72 male patients with histologically verified aggressive PC and 119 patients of Kazakh nationality with histologically confirmed CRC compared to the control group. Results: A variant in the intron of the EHBP1 gene c.1185+30064G>A rs721048 was identified in 18 patients (25%) out of 72 with PC, while in the control group of 41 healthy males, the rs721048 variant was found in only 4 (9.8%) individuals. In the CRC group, rs721048 was detected in 17 cases (14.2%) and eight control individuals (10%). Conclusions: The frequency of the EHBP1 c.1185+30064G>A rs721048 variant in the PC group was significantly higher (p < 0.05) than in healthy males of Kazakh nationality. Identifying EHBP1 c.1185+30064G>A among the male population of Kazakhstan will help form the high-risk groups for PC to prevent the development of malignant neoplasms. The presence of rs721048 was not significantly associated with the risk of developing CRC in our study. Full article

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

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14 pages, 1803 KiB

Open AccessArticle

Long Noncoding RNAs Responding to Ethanol Stress in Yeast Seem Associated with Protein Synthesis and Membrane Integrity

by Amanda Piveta Schnepper, Agatha M. S. Kubo, Camila Moreira Pinto, Ramon Hernany Martins Gomes, Matheus Naia Fioretto, Luís Antonio Justulin, Aline M. M. Braz, Marjorie de Assis Golim, Rejane M. T. Grotto and Guilherme Targino Valente

Genes 2025, 16(2), 170; https://doi.org/10.3390/genes16020170 - 28 Jan 2025

Background/Objectives: Translation and the formation of membraneless organelles are linked mechanisms to promote cell stress surveillance. LncRNAs responsive to ethanol stress transcr_9136 of the SEY6210 strain and transcr_10027 of the BY4742 strain appear to act on tolerance to ethanol in these strains. Here, [...] Read more.

Background/Objectives: Translation and the formation of membraneless organelles are linked mechanisms to promote cell stress surveillance. LncRNAs responsive to ethanol stress transcr_9136 of the SEY6210 strain and transcr_10027 of the BY4742 strain appear to act on tolerance to ethanol in these strains. Here, we investigate whether the ethanol responsiveness of transcr_9136 and transcr_10027 and their role in ethanol stress are associated with protein biogenesis and membraneless organelle assembly. Methods: SEY6210 transcr_9136∆ and BY4742 transcr_10027∆ and their wild-type counterparts were subjected to their maximum ethanol-tolerant stress. The expression of the transcr_9136, transcr_10027, ILT1, RRP1, 27S, 25S, TIR3, and FAA3 genes was accessed by qPCR. The level of DCP1a, PABP, and eIF4E proteins was evaluated by Western blotting. Bioinformatics analyses allowed us to check whether transcr_9136 may regulate the expression of RRP1 and predict the interaction between transcr_10027 and Tel1p. The cell death rate of SEY6210 strains under control and ethanol stress conditions was assessed by flow cytometry. Finally, we evaluated the total protein yield of all strains analyzed. Results: The results demonstrated that transcr_9136 of SEY6210 seems to control the expression of RRP1 and 27S rRNA and reduce the general translation. Furthermore, transcr_9136 seems to act on cell membrane integrity. Transcr_10027 of BY4742 appears to inhibit processing body formation and induce a general translation level. Conclusions: This is the first report on the effect of lncRNAs on yeast protein synthesis and new mechanisms of stress-responsive lncRNAs in yeast, with potential industrial applications such as ethanol production. Full article

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

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12 pages, 4045 KiB

Open AccessArticle

Analysis of Short Tandem Repeat Expansions in a Cohort of 12,496 Exomes from Patients with Neurological Diseases Reveals Variable Genotyping Rate Dependent on Exome Capture Kits

by Clarissa Rocca, David Murphy, Chris Clarkson, Matteo Zanovello, Delia Gagliardi, Queen Square Genomics, Rauan Kaiyrzhanov, Javeria Alvi, Reza Maroofian, Stephanie Efthymiou, Tipu Sultan, Jana Vandrovcova, James Polke, Robyn Labrum, Henry Houlden and Arianna Tucci

Genes 2025, 16(2), 169; https://doi.org/10.3390/genes16020169 - 28 Jan 2025

Background/Objectives: Short tandem repeat expansions are the most common cause of inherited neurological diseases. These disorders are clinically and genetically heterogeneous, such as in myotonic dystrophy and spinocerebellar ataxia, and they are caused by different repeat motifs in different genomic locations. Major advances [...] Read more.

Background/Objectives: Short tandem repeat expansions are the most common cause of inherited neurological diseases. These disorders are clinically and genetically heterogeneous, such as in myotonic dystrophy and spinocerebellar ataxia, and they are caused by different repeat motifs in different genomic locations. Major advances in bioinformatic tools used to detect repeat expansions from short read sequencing data in the last few years have led to the implementation of these workflows into next generation sequencing pipelines in healthcare. Here, we aimed to evaluate the clinical utility of analysing repeat expansions through exome sequencing in a large cohort of genetically undiagnosed patients with neurological disorders. Methods: We here analyse 27 disease-causing DNA repeats found in the coding, intronic and untranslated regions in 12,496 exomes in patients with a range of neurogenetic conditions. Results: We identified—and validated by polymerase chain reaction—29 repeat expansions across a range of loci, 48% (n = 14) of which were diagnostic. We then analysed the genotyping performance across all repeat loci and found that, despite high coverage in most repeats in coding regions, some loci had low genotyping rates, such as those that cause spinocerebellar ataxia 2 (ATXN2, 0.1–8.4%) and Huntington disease (HTT, 0.2–58.2%), depending on the capture kit. Conversely, while most intronic repeats were not genotyped, we found a high genotyping rate in the intronic locus that causes spinocerebellar ataxia 36 (NOP56, 30.1–98.3%) and in the one that causes myotonic dystrophy type 1 (DMPK, myotonic dystrophy type 1). Conclusions: We show that the key factors that influence the genotyping rate of repeat expansion loci analysis are the sequencing read length and exome capture kit. These results provide important information about the performance of exome sequencing as a genetic test for repeat expansion disorders. Full article

(This article belongs to the Special Issue Molecular Genetics of Neurodegenerative Diseases and Neuromuscular Diseases)

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