Genes

23 pages, 2251 KiB

Open AccessEditor’s ChoiceReview

Transfer RNA Modification Enzymes with a Thiouridine Synthetase, Methyltransferase and Pseudouridine Synthase (THUMP) Domain and the Nucleosides They Produce in tRNA

by Hiroyuki Hori

Genes 2023, 14(2), 382; https://doi.org/10.3390/genes14020382 - 31 Jan 2023

Cited by 8 | Viewed by 3397

Abstract

The existence of the thiouridine synthetase, methyltransferase and pseudouridine synthase (THUMP) domain was originally predicted by a bioinformatic study. Since the prediction of the THUMP domain more than two decades ago, many tRNA modification enzymes containing the THUMP domain have been identified. According [...] Read more.

The existence of the thiouridine synthetase, methyltransferase and pseudouridine synthase (THUMP) domain was originally predicted by a bioinformatic study. Since the prediction of the THUMP domain more than two decades ago, many tRNA modification enzymes containing the THUMP domain have been identified. According to their enzymatic activity, THUMP-related tRNA modification enzymes can be classified into five types, namely 4-thiouridine synthetase, deaminase, methyltransferase, a partner protein of acetyltransferase and pseudouridine synthase. In this review, I focus on the functions and structures of these tRNA modification enzymes and the modified nucleosides they produce. Biochemical, biophysical and structural studies of tRNA 4-thiouridine synthetase, tRNA methyltransferases and tRNA deaminase have established the concept that the THUMP domain captures the 3′-end of RNA (in the case of tRNA, the CCA-terminus). However, in some cases, this concept is not simply applicable given the modification patterns observed in tRNA. Furthermore, THUMP-related proteins are involved in the maturation of other RNAs as well as tRNA. Moreover, the modified nucleosides, which are produced by the THUMP-related tRNA modification enzymes, are involved in numerous biological phenomena, and the defects of genes for human THUMP-related proteins are implicated in genetic diseases. In this review, these biological phenomena are also introduced. Full article

(This article belongs to the Special Issue Transfer RNA Modification)

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19 pages, 2999 KiB

Open AccessEditor’s ChoiceReview

Nonsense-Mediated mRNA Decay as a Mediator of Tumorigenesis

by Preeti Nagar, Md Rafikul Islam and Mohammad Alinoor Rahman

Genes 2023, 14(2), 357; https://doi.org/10.3390/genes14020357 - 30 Jan 2023

Cited by 16 | Viewed by 6905

Abstract

Nonsense-mediated mRNA decay (NMD) is an evolutionarily conserved and well-characterized biological mechanism that ensures the fidelity and regulation of gene expression. Initially, NMD was described as a cellular surveillance or quality control process to promote selective recognition and rapid degradation of erroneous transcripts [...] Read more.

Nonsense-mediated mRNA decay (NMD) is an evolutionarily conserved and well-characterized biological mechanism that ensures the fidelity and regulation of gene expression. Initially, NMD was described as a cellular surveillance or quality control process to promote selective recognition and rapid degradation of erroneous transcripts harboring a premature translation-termination codon (PTC). As estimated, one-third of mutated and disease-causing mRNAs were reported to be targeted and degraded by NMD, suggesting the significance of this intricate mechanism in maintaining cellular integrity. It was later revealed that NMD also elicits down-regulation of many endogenous mRNAs without mutations (~10% of the human transcriptome). Therefore, NMD modulates gene expression to evade the generation of aberrant truncated proteins with detrimental functions, compromised activities, or dominant-negative effects, as well as by controlling the abundance of endogenous mRNAs. By regulating gene expression, NMD promotes diverse biological functions during development and differentiation, and facilitates cellular responses to adaptation, physiological changes, stresses, environmental insults, etc. Mutations or alterations (such as abnormal expression, degradation, post-translational modification, etc.) that impair the function or expression of proteins associated with the NMD pathway can be deleterious to cells and may cause pathological consequences, as implicated in developmental and intellectual disabilities, genetic defects, and cancer. Growing evidence in past decades has highlighted NMD as a critical driver of tumorigenesis. Advances in sequencing technologies provided the opportunity to identify many NMD substrate mRNAs in tumor samples compared to matched normal tissues. Interestingly, many of these changes are tumor-specific and are often fine-tuned in a tumor-specific manner, suggesting the complex regulation of NMD in cancer. Tumor cells differentially exploit NMD for survival benefits. Some tumors promote NMD to degrade a subset of mRNAs, such as those encoding tumor suppressors, stress response proteins, signaling proteins, RNA binding proteins, splicing factors, and immunogenic neoantigens. In contrast, some tumors suppress NMD to facilitate the expression of oncoproteins or other proteins beneficial for tumor growth and progression. In this review, we discuss how NMD is regulated as a critical mediator of oncogenesis to promote the development and progression of tumor cells. Understanding how NMD affects tumorigenesis differentially will pave the way for the development of more effective and less toxic, targeted therapeutic opportunities in the era of personalized medicine. Full article

(This article belongs to the Special Issue RNA Splicing in Cancer and Targeted Therapies)

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14 pages, 3081 KiB

Open AccessEditor’s ChoiceArticle

Competition for Light Interception in Different Plant Canopy Characteristics of Diverse Cotton Cultivars

by Fahmida Sultana, Washu Dev, Minghua Xin, Yingchun Han, Lu Feng, Yaping Lei, Beifang Yang, Guoping Wang, Xiaofei Li, Zhanbiao Wang, Fangfang Xing, Shiwu Xiong and Yabing Li

Genes 2023, 14(2), 364; https://doi.org/10.3390/genes14020364 - 30 Jan 2023

Cited by 12 | Viewed by 2931

Abstract

Identifying the ideal plant nature and canopy structure is of great importance for improving photosynthetic production and the potential action of plants. To address this challenge, an investigation was accomplished in 2018 and 2019 at the Institute of Cotton Research (ICR) of the [...] Read more.

Identifying the ideal plant nature and canopy structure is of great importance for improving photosynthetic production and the potential action of plants. To address this challenge, an investigation was accomplished in 2018 and 2019 at the Institute of Cotton Research (ICR) of the Chinese Academy of Agricultural Science (CAAS), Henan Province, China. Six cotton varieties with diverse maturities and plant canopy structures were used to evaluate the light interception (LI) in cotton, the leaf area index (LAI), the biomass, and the yield throughout the two years of study. The light spatial distribution in the plant canopy was evaluated using a geographic statistical method, following the increasing quantity of radiation intercepted, which was determined using the rules of Simpson. Compared to the cotton plants with a compact structure, varieties with both a loose and tower design captured a comparatively higher amount of light (average 31.3%) and achieved a higher LAI (average 32.4%), eventually achieving a high yield (average 10.1%). Furthermore, the polynomial correlation revealed a positive relationship between the biomass accumulation in the reproductive parts and canopy-accrued light interception (LI), signifying that light interception is critical for the yield development of cotton. Furthermore, when the leaf area index (LAI) was peaked, radiation interception and biomass reached the highest during the boll-forming stage. These findings will provide guidance on the light distribution in cotton cultivars with an ideal plant structure for light capture development, providing an important foundation for researchers to better manage light and canopies. Full article

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

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16 pages, 2842 KiB

Open AccessEditor’s ChoiceArticle

DNA Methylation as a Biomarker for Monitoring Disease Outcome in Patients with Hypovitaminosis and Neurological Disorders

by Olaia Martínez-Iglesias, Vinogran Naidoo, Lola Corzo, Rocío Pego, Silvia Seoane, Susana Rodríguez, Margarita Alcaraz, Adriana Muñiz, Natalia Cacabelos and Ramón Cacabelos

Genes 2023, 14(2), 365; https://doi.org/10.3390/genes14020365 - 30 Jan 2023

Cited by 10 | Viewed by 2695

Abstract

DNA methylation remains an under-recognized diagnostic biomarker for several diseases, including neurodegenerative disorders. In this study, we examined differences in global DNA methylation (5mC) levels in serum samples from patients during the initial- and the follow-up visits. Each patient underwent a blood analysis [...] Read more.

DNA methylation remains an under-recognized diagnostic biomarker for several diseases, including neurodegenerative disorders. In this study, we examined differences in global DNA methylation (5mC) levels in serum samples from patients during the initial- and the follow-up visits. Each patient underwent a blood analysis and neuropsychological assessments. The analysis of 5mC levels revealed two categories of patients; Group A who, during the follow-up, had increased 5mC levels, and Group B who had decreased 5mC levels. Patients with low Fe-, folate-, and vitamin B12- levels during the initial visit showed increased levels of 5mC after treatment when assessed during the follow-up. During the follow-up, 5mC levels in Group A patients increased after treatment for hypovitaminosis with the nutraceutical compounds Animon Complex and MineraXin Plus. 5mC levels were maintained during the follow-up in Group A patients treated for neurological disorders with the bioproducts AtreMorine and NeoBrainine. There was a positive correlation between 5mC levels and MMSE scores, and an inverse correlation between 5mC and ADAS-Cog scores. This expected correlation was observed in Group A patients only. Our study appears to indicate that 5mC has a diagnostic value as a biomarker across different pathologies. Full article

(This article belongs to the Special Issue Pharmacogenomics: Challenges and Future)

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18 pages, 1254 KiB

Open AccessEditor’s ChoiceReview

Histone Modifications in Alzheimer’s Disease

by Dalileia Aparecida Santana, Marilia de Arruda Cardoso Smith and Elizabeth Suchi Chen

Genes 2023, 14(2), 347; https://doi.org/10.3390/genes14020347 - 29 Jan 2023

Cited by 61 | Viewed by 6225

Abstract

Since Late-onset Alzheimer’s disease (LOAD) derives from a combination of genetic variants and environmental factors, epigenetic modifications have been predicted to play a role in the etiopathology of LOAD. Along with DNA methylation, histone modifications have been proposed as the main epigenetic modifications [...] Read more.

Since Late-onset Alzheimer’s disease (LOAD) derives from a combination of genetic variants and environmental factors, epigenetic modifications have been predicted to play a role in the etiopathology of LOAD. Along with DNA methylation, histone modifications have been proposed as the main epigenetic modifications that contribute to the pathologic mechanisms of LOAD; however, little is known about how these mechanisms contribute to the disease’s onset or progression. In this review, we highlighted the main histone modifications and their functional role, including histone acetylation, histone methylation, and histone phosphorylation, as well as changes in such histone modifications that occur in the aging process and mainly in Alzheimer’s disease (AD). Furthermore, we pointed out the main epigenetic drugs tested for AD treatment, such as those based on histone deacetylase (HDAC) inhibitors. Finally, we remarked on the perspectives around the use of such epigenetics drugs for treating AD. Full article

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

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11 pages, 1725 KiB

Open AccessEditor’s ChoiceArticle

Response Surface Methodology for Optimization of Multiplex-PCR Protocols for Detection of TYLCV, TSWV and Fol Molecular Markers: Analytical Performance Evaluation

by Richecarde Lafrance, José Benigno Valdez-Torres, Claudia Villicaña, Raymundo Saúl García-Estrada, Mayra Janeth Esparza-Araiza and Josefina León-Félix

Genes 2023, 14(2), 337; https://doi.org/10.3390/genes14020337 - 28 Jan 2023

Cited by 3 | Viewed by 3664

Abstract

Molecular markers linked to disease resistance genes which affect economically important crops are of great interest. In the case of tomato, a major focus on resistance breeding to multiple fungal and viral pathogens such as Tomato yellow leaf curl virus (TYLCV), Tomato spotted [...] Read more.

Molecular markers linked to disease resistance genes which affect economically important crops are of great interest. In the case of tomato, a major focus on resistance breeding to multiple fungal and viral pathogens such as Tomato yellow leaf curl virus (TYLCV), Tomato spotted wilt virus (TSWV) and Fusarium oxysporum f. sp. lycopersici (Fol), have led to the introgression of several resistance genes; therefore, molecular markers have become important in molecular-assisted selection (MAS) of tomato varieties resistant to those pathogens. However, assays that allow simultaneous evaluation of resistant genotypes, such as multiplex PCR, need to be optimized and evaluated to demonstrate their analytical performance, as many factors can affect them. This work aimed to generate multiplex PCR protocols for the joint detection of the molecular markers associated with pathogen resistance genes in tomato plants that are sensitive, specific and repeatable. For the optimization a central composite design of a response surface methodology (RSM-CCD) was used. For analytical performance evaluation, specificity/selectivity and sensibility (limit of detection and dynamic range) were analyzed. Two protocols were optimized: the first one with a desirability of 1.00, contained two markers (At-2 and P7-43) linked to I- and I-3-resistant genes. The second one with a desirability of 0.99, contained markers (SSR-67, SW5 and P6-25) linked to I-, Sw-5-, and Ty-3-resistant genes. For protocol 1, all the commercial hybrids (7/7) were resistant to Fol, and for protocol 2, two hybrids were resistant to Fol, one to TSWV and one to TYLCV with good analytical performance. In both protocols, the varieties considered susceptible to the pathogens, no-amplicon or susceptible amplicons, were observed. The optimized multiplex PCR protocols showed dynamic ranges from 5.97 up to 161.3 ng DNA. The limit of detection was 17.92 ng and 53.76 ng DNA for protocols 1 and 2, respectively, giving 100% positive results in the test replicates. This method allowed to develop optimized multiplex PCR protocols with few assays which translates into less time and resources, without sacrificing method performance. Full article

(This article belongs to the Section Genes & Environments)

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13 pages, 957 KiB

Open AccessEditor’s ChoiceArticle

The Genetic Background of Hearing Loss in Patients with EVA and Cochlear Malformation

by Natalia Bałdyga, Dominika Oziębło, Nina Gan, Mariusz Furmanek, Marcin L. Leja, Henryk Skarżyński and Monika Ołdak

Genes 2023, 14(2), 335; https://doi.org/10.3390/genes14020335 - 28 Jan 2023

Cited by 5 | Viewed by 2538

Abstract

The most frequently observed congenital inner ear malformation is enlarged vestibular aqueduct (EVA). It is often accompanied with incomplete partition type 2 (IP2) of the cochlea and a dilated vestibule, which together constitute Mondini malformation. Pathogenic SLC26A4 variants are considered the major cause [...] Read more.

The most frequently observed congenital inner ear malformation is enlarged vestibular aqueduct (EVA). It is often accompanied with incomplete partition type 2 (IP2) of the cochlea and a dilated vestibule, which together constitute Mondini malformation. Pathogenic SLC26A4 variants are considered the major cause of inner ear malformation but the genetics still needs clarification. The aim of this study was to identify the cause of EVA in patients with hearing loss (HL). Genomic DNA was isolated from HL patients with radiologically confirmed bilateral EVA (n = 23) and analyzed by next generation sequencing using a custom HL gene panel encompassing 237 HL-related genes or a clinical exome. The presence and segregation of selected variants and the CEVA haplotype (in the 5′ region of SLC26A4) was verified by Sanger sequencing. Minigene assay was used to evaluate the impact of novel synonymous variant on splicing. Genetic testing identified the cause of EVA in 17/23 individuals (74%). Two pathogenic variants in the SLC26A4 gene were identified as the cause of EVA in 8 of them (35%), and a CEVA haplotype was regarded as the cause of EVA in 6 of 7 patients (86%) who carried only one SLC26A4 genetic variant. In two individuals with a phenotype matching branchio-oto-renal (BOR) spectrum disorder, cochlear hypoplasia resulted from EYA1 pathogenic variants. In one patient, a novel variant in CHD7 was detected. Our study shows that SLC26A4, together with the CEVA haplotype, accounts for more than half of EVA cases. Syndromic forms of HL should also be considered in patients with EVA. We conclude that to better understand inner ear development and the pathogenesis of its malformations, there is a need to look for pathogenic variants in noncoding regions of known HL genes or to link them with novel candidate HL genes. Full article

(This article belongs to the Special Issue Genetics of Ear Development and Hearing Loss)

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11 pages, 752 KiB

Open AccessEditor’s ChoiceArticle

Identification of Germline Variants in Patients with Hereditary Cancer Syndromes in Northeast Mexico

by Diana Cristina Pérez-Ibave, María Lourdes Garza-Rodríguez, María Fernanda Noriega-Iriondo, Sonia María Flores-Moreno, Manuel Ismael González-Geroniz, Absalon Espinoza-Velazco, Ana Lilia Castruita-Ávila, Fernando Alcorta-Núñez, Omar Alejandro Zayas-Villanueva, Juan Francisco González-Guerrero, Adelina Alcorta-Garza, Oscar Vidal-Gutiérrez and Carlos Horacio Burciaga-Flores

Genes 2023, 14(2), 341; https://doi.org/10.3390/genes14020341 - 28 Jan 2023

Cited by 8 | Viewed by 2909

Abstract

Hereditary cancer syndromes (HCS) are genetic diseases with an increased risk of developing cancer. This research describes the implementation of a cancer prevention model, genetic counseling, and germline variants testing in an oncologic center in Mexico. A total of 315 patients received genetic [...] Read more.

Hereditary cancer syndromes (HCS) are genetic diseases with an increased risk of developing cancer. This research describes the implementation of a cancer prevention model, genetic counseling, and germline variants testing in an oncologic center in Mexico. A total of 315 patients received genetic counseling, genetic testing was offered, and 205 individuals were tested for HCS. In 6 years, 131 (63.90%) probands and 74 (36.09%) relatives were tested. Among the probands, we found that 85 (63.9%) had at least one germline variant. We identified founder mutations in BRCA1 and a novel variant in APC that led to the creation of an in-house detection process for the whole family. The most frequent syndrome was hereditary breast and ovarian cancer syndrome (HBOC) (41 cases with BRCA1 germline variants in most of the cases), followed by eight cases of hereditary non-polyposic cancer syndrome (HNPCC or Lynch syndrome) (with MLH1 as the primarily responsible gene), and other high cancer risk syndromes. Genetic counseling in HCS is still a global challenge. Multigene panels are an essential tool to detect the variants frequency. Our program has a high detection rate of probands with HCS and pathogenic variants (40%), compared with other reports that detect 10% in other populations. Full article

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

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14 pages, 2201 KiB

Open AccessEditor’s ChoiceArticle

High Levels of Diversity in Anopheles Subgenus Kerteszia Revealed by Species Delimitation Analyses

by Brian P. Bourke, Richard C. Wilkerson, Fredy Ruiz-Lopez, Silvia A. Justi, David B. Pecor, Martha L. Quinones, Juan-Carlos Navarro, Joubert Alarcón Ormaza, Joubert Alarcón Ormaza, Jr., Ranulfo González, Carmen Flores-Mendoza, Fanny Castro, Jesús E. Escovar and Yvonne-Marie Linton

Genes 2023, 14(2), 344; https://doi.org/10.3390/genes14020344 - 28 Jan 2023

Cited by 5 | Viewed by 2680

Abstract

The Anopheles subgenus Kerteszia is a poorly understood group of mosquitoes that includes several species of medical importance. Although there are currently twelve recognized species in the subgenus, previous studies have shown that this is likely to be an underestimate of species diversity. [...] Read more.

The Anopheles subgenus Kerteszia is a poorly understood group of mosquitoes that includes several species of medical importance. Although there are currently twelve recognized species in the subgenus, previous studies have shown that this is likely to be an underestimate of species diversity. Here, we undertake a baseline study of species delimitation using the barcode region of the mtDNA COI gene to explore species diversity among a geographically and taxonomically diverse range of Kerteszia specimens. Beginning with 10 of 12 morphologically identified Kerteszia species spanning eight countries, species delimitation analyses indicated a high degree of cryptic diversity. Overall, our analyses found support for at least 28 species clusters within the subgenus Kerteszia. The most diverse taxon was Anopheles neivai, a known malaria vector, with eight species clusters. Five other species taxa showed strong signatures of species complex structure, among them Anopheles bellator, which is also considered a malaria vector. There was some evidence for species structure within An. homunculus, although the results were equivocal across delimitation analyses. The current study, therefore, suggests that species diversity within the subgenus Kerteszia has been grossly underestimated. Further work will be required to build on this molecular characterization of species diversity and will rely on genomic level approaches and additional morphological data to test these species hypotheses. Full article

(This article belongs to the Special Issue Advances in Evolutionary Genetics and Phylogenetics of Mosquito Species)

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16 pages, 741 KiB

Open AccessEditor’s ChoiceArticle

Tumor Androgen Receptor Protein Level Is Positively Associated with a Better Overall Survival in Melanoma Patients

by Nupur Singh, Jude Khatib, Chi-Yang Chiu, Jianjian Lin, Tejesh Surender Patel and Feng Liu-Smith

Genes 2023, 14(2), 345; https://doi.org/10.3390/genes14020345 - 28 Jan 2023

Cited by 2 | Viewed by 2650

Abstract

Androgen receptor (AR) is expressed in numerous tissues and serves important biologic functions in skin, prostate, immune, cardiovascular, and neural systems, alongside sexual development. Several studies have associated AR expression and patient survival in various cancers, yet there are limited studies examining the [...] Read more.

Androgen receptor (AR) is expressed in numerous tissues and serves important biologic functions in skin, prostate, immune, cardiovascular, and neural systems, alongside sexual development. Several studies have associated AR expression and patient survival in various cancers, yet there are limited studies examining the relationship between AR expression and cutaneous melanoma. This study used genomics and proteomics data from The Cancer Proteome Atlas (TCPA) and The Cancer Genome Atlas (TCGA), with 470 cutaneous melanoma patient data points. Cox regression analyses evaluated the association between AR protein level with overall survival and revealed that a higher level of AR protein was positively associated with a better overall survival (OS) (p = 0.003). When stratified by sex, the AR association with OS was only significant for both sexes. The multivariate Cox models with justifications of sex, age of diagnosis, stage of disease, and Breslow depth of the tumor confirmed the AR-OS association in all patients. However, the significance of AR was lost when ulceration was included in the model. When stratified by sex, the multivariate Cox models indicated significant role of AR in OS of female patients but not in males. AR-associated genes were identified and enrichment analysis revealed shared and distinct gene network in male and female patients. Furthermore, AR was found significantly associated with OS in RAS mutant subtypes of melanoma but not in BRAF, NF1, or triple-wild type subtypes of melanoma. Our study may provide insight into the well-known female survival advantage in melanoma patients. Full article

(This article belongs to the Special Issue Feature Papers: Molecular Genetics and Genomics 2023)

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10 pages, 262 KiB

Open AccessEditor’s ChoiceCommunication

Use of Next-Generation Sequencing to Support the Diagnosis of Familial Interstitial Pneumonia

by Ana Rita Gigante, Eduarda Milheiro Tinoco, Ana Fonseca, Inês Marques, Agostinho Sanches, Natália Salgueiro, Carla Nogueira, Sérgio Campainha and Sofia Neves

Genes 2023, 14(2), 326; https://doi.org/10.3390/genes14020326 - 27 Jan 2023

Viewed by 1855

Abstract

Familial interstitial pneumonia (FIP) is defined as idiopathic interstitial lung disease (ILD) in two or more relatives. Genetic studies on familial ILD discovered variants in several genes or associations with genetic polymorphisms. The aim of this study was to describe the clinical features [...] Read more.

Familial interstitial pneumonia (FIP) is defined as idiopathic interstitial lung disease (ILD) in two or more relatives. Genetic studies on familial ILD discovered variants in several genes or associations with genetic polymorphisms. The aim of this study was to describe the clinical features of patients with suspected FIP and to analyze the genetic variants detected through next-generation sequencing (NGS) genetic testing. A retrospective analysis was conducted in patients followed in an ILD outpatient clinic who had ILD and a family history of ILD in at least one first- or second-degree relative and who underwent NGS between 2017 and 2021. Only patients with at least one genetic variant were included. Genetic testing was performed on 20 patients; of these, 13 patients had a variant in at least one gene with a known association with familial ILD. Variants in genes implicated in telomere and surfactant homeostasis and MUC5B variants were detected. Most variants were classified with uncertain clinical significance. Probable usual interstitial pneumonia radiological and histological patterns were the most frequently identified. The most prevalent phenotype was idiopathic pulmonary fibrosis. Pulmonologists should be aware of familial forms of ILD and genetic diagnosis. Full article

(This article belongs to the Section Genetic Diagnosis)

14 pages, 562 KiB

Open AccessEditor’s ChoiceArticle

Public Health Genetics: Surveying Preparedness for the Next Generation of Public Health Professionals

by Anastasia M. Jacko, Andrea L. Durst, Karen L. Niemchick, Stephen M. Modell and Amy H. Ponte

Genes 2023, 14(2), 317; https://doi.org/10.3390/genes14020317 - 26 Jan 2023

Cited by 1 | Viewed by 2300

Abstract

Since the Human Genome Project’s completion in 2003, the need for increased population genetic literacy has grown exponentially. To address this need, public health professionals must be educated appropriately to serve the public best. This study examines the current state of public health [...] Read more.

Since the Human Genome Project’s completion in 2003, the need for increased population genetic literacy has grown exponentially. To address this need, public health professionals must be educated appropriately to serve the public best. This study examines the current state of public health genetics education within existing master of public health (MPH) programs. A total of 171 MPH Council on Education for Public Health Accreditation (CEPH)-accredited programs across the nation were identified via a preliminary internet search. The American Public Health Association (APHA) Genomics Forum Policy Committee created 14 survey questions to assess the current status of incorporating genetics/genomics education within MPH programs. Using the Qualtrics survey system through the University of Pittsburgh, a link to the anonymous survey was sent to each director’s email address obtained from their program’s website. There were 41 survey responses, with 37 finished to completion, for a response rate of 21.6% (37/171). A total of 75.7% (28/37) of respondents reported having courses containing genetics/genomics information in their programs’ coursework. Only 12.6% reported such coursework to be required for program completion. Commonly listed barriers to incorporating genetics/genomics include limited faculty knowledge and lack of space in existing courses and programs. Survey results revealed the incongruous and limited incorporation of genetics/genomics within the context of graduate-level public health education. While most recorded programs report offering public health genetics coursework, the extent and requirement of such instruction are not considered necessary for program completion, thereby potentially limiting the genetic literacy of the current pool of public health professionals. Full article

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

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10 pages, 2295 KiB

Open AccessEditor’s ChoiceArticle

Evidence for Strand Asymmetry in Different Plastid Genomes

by Cindy Ruan and Brian R. Morton

Genes 2023, 14(2), 320; https://doi.org/10.3390/genes14020320 - 26 Jan 2023

Cited by 1 | Viewed by 1688

Abstract

A common genome composition pattern in eubacteria is an asymmetry between the leading and lagging strands resulting in opposite skew patterns in the two replichores that lie between the origin and terminus of replication. Although this pattern has been reported for a couple [...] Read more.

A common genome composition pattern in eubacteria is an asymmetry between the leading and lagging strands resulting in opposite skew patterns in the two replichores that lie between the origin and terminus of replication. Although this pattern has been reported for a couple of isolated plastid genomes, it is not clear how widespread it is overall in this chromosome. Using a random walk approach, we examine plastid genomes outside of the land plants, which are excluded since they are known not to initiate replication at a single site, for such a pattern of asymmetry. Although it is not a common feature, we find that it is detectable in the plastid genome of species from several diverse lineages. The euglenozoa in particular show a strong skew pattern as do several rhodophytes. There is a weaker pattern in some chlorophytes but it is not apparent in other lineages. The ramifications of this for analyses of plastid evolution are discussed. Full article

(This article belongs to the Special Issue Plant Plastid Genome)

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17 pages, 4116 KiB

Open AccessEditor’s ChoiceArticle

The Adaptive Evolution in the Fall Armyworm Spodoptera frugiperda (Lepidoptera: Noctuidae) Revealed by the Diversity of Larval Gut Bacteria

by Yan-Ping Wang, Xu Liu, Chun-Yan Yi, Xing-Yu Chen, Chang-Hua Liu, Cui-Cui Zhang, Qing-Dong Chen, Song Chen, Hong-Ling Liu and De-Qiang Pu

Genes 2023, 14(2), 321; https://doi.org/10.3390/genes14020321 - 26 Jan 2023

Cited by 14 | Viewed by 2798

Abstract

Insect gut microbes have important roles in host feeding, digestion, immunity, development, and coevolution with pests. The fall armyworm, Spodoptera frugiperda (Smith, 1797), is a major migratory agricultural pest worldwide. The effects of host plant on the pest’s gut bacteria remain to be [...] Read more.

Insect gut microbes have important roles in host feeding, digestion, immunity, development, and coevolution with pests. The fall armyworm, Spodoptera frugiperda (Smith, 1797), is a major migratory agricultural pest worldwide. The effects of host plant on the pest’s gut bacteria remain to be investigated to better understand their coevolution. In this study, differences in the gut bacterial communities were examined for the fifth and sixth instar larvae of S. frugiperda fed on leaves of different host plants (corn, sorghum, highland barley, and citrus). The 16S rDNA full-length amplification and sequencing method was used to determine the abundance and diversity of gut bacteria in larval intestines. The highest richness and diversity of gut bacteria were in corn-fed fifth instar larvae, whereas in sixth instar larvae, the richness and diversity were higher when larvae were fed by other crops. Firmicutes and Proteobacteria were dominant phyla in gut bacterial communities of fifth and sixth instar larvae. According to the LDA Effect Size (LEfSe) analysis, the host plants had important effects on the structure of gut bacterial communities in S. frugiperda. In the PICRUSt2 analysis, most predicted functional categories were associated with metabolism. Thus, the host plant species attacked by S. frugiperda larvae can affect their gut bacterial communities, and such changes are likely important in the adaptive evolution of S. frugiperda to host plants. Full article

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

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15 pages, 21866 KiB

Open AccessEditor’s ChoiceArticle

A Founder Intronic Variant in P3H1 Likely Results in Aberrant Splicing and Protein Truncation in Patients of Karen Descent with Osteogenesis Imperfecta Type VIII

by Piranit Nik Kantaputra, Salita Angkurawaranon, Worrachet Intachai, Chumpol Ngamphiw, Bjorn Olsen, Sissades Tongsima, Timothy C. Cox and James R. Ketudat Cairns

Genes 2023, 14(2), 322; https://doi.org/10.3390/genes14020322 - 26 Jan 2023

Cited by 2 | Viewed by 2427

Abstract

One of the most important steps in post-translational modifications of collagen type I chains is the hydroxylation of carbon-3 of proline residues by prolyl-3-hydroxylase-1 (P3H1). Genetic variants in P3H1 have been reported to cause autosomal recessive osteogenesis imperfecta (OI) type VIII. Clinical and [...] Read more.

One of the most important steps in post-translational modifications of collagen type I chains is the hydroxylation of carbon-3 of proline residues by prolyl-3-hydroxylase-1 (P3H1). Genetic variants in P3H1 have been reported to cause autosomal recessive osteogenesis imperfecta (OI) type VIII. Clinical and radiographic examinations, whole-exome sequencing (WES), and bioinformatic analysis were performed in 11 Thai children of Karen descent affected by multiple bone fractures. Clinical and radiographic findings in these patients fit OI type VIII. Phenotypic variability is evident. WES identified an intronic homozygous variant (chr1:43212857A > G; NM_022356.4:c.2055 + 86A > G) in P3H1 in all patients, with parents in each patient being heterozygous for the variant. This variant is predicted to generate a new “CAG” splice acceptor sequence, resulting in the incorporation of an extra exon that leads to a frameshift in the final exon and subsequent non-functional P3H1 isoform a. Alternative splicing of P3H1 resulting in the absence of functional P3H1 caused OI type VIII in 11 Thai children of Karen descent. This variant appears to be specific to the Karen population. Our study emphasizes the significance of considering intronic variants. Full article

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

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10 pages, 2284 KiB

Open AccessEditor’s ChoiceHypothesis

Microsatellite Instability and Aberrant Pre-mRNA Splicing: How Intimate Is It?

by Laurent Corcos, Enora Le Scanf, Gaël Quéré, Danielle Arzur, Gwennina Cueff, Catherine Le Jossic-Corcos and Cédric Le Maréchal

Genes 2023, 14(2), 311; https://doi.org/10.3390/genes14020311 - 25 Jan 2023

Cited by 1 | Viewed by 2319

Abstract

Cancers that belong to the microsatellite instability (MSI) class can account for up to 15% of all cancers of the digestive tract. These cancers are characterized by inactivation, through the mutation or epigenetic silencing of one or several genes from the DNA MisMatch [...] Read more.

Cancers that belong to the microsatellite instability (MSI) class can account for up to 15% of all cancers of the digestive tract. These cancers are characterized by inactivation, through the mutation or epigenetic silencing of one or several genes from the DNA MisMatch Repair (MMR) machinery, including MLH1, MLH3, MSH2, MSH3, MSH6, PMS1, PMS2 and Exo1. The unrepaired DNA replication errors turn into mutations at several thousand sites that contain repetitive sequences, mainly mono- or dinucleotides, and some of them are related to Lynch syndrome, a predisposition condition linked to a germline mutation in one of these genes. In addition, some mutations shortening the microsatellite (MS) stretch could occur in the 3′-intronic regions, i.e., in the ATM (ATM serine/threonine kinase), MRE11 (MRE11 homolog) or the HSP110 (Heat shock protein family H) genes. In these three cases, aberrant pre-mRNA splicing was observed, and it was characterized by the occurrence of selective exon skipping in mature mRNAs. Because both the ATM and MRE11 genes, which as act as players in the MNR (MRE11/NBS1 (Nibrin)/RAD50 (RAD50 double strand break repair protein) DNA damage repair system, participate in double strand breaks (DSB) repair, their frequent splicing alterations in MSI cancers lead to impaired activity. This reveals the existence of a functional link between the MMR/DSB repair systems and the pre-mRNA splicing machinery, the diverted function of which is the consequence of mutations in the MS sequences. Full article

(This article belongs to the Special Issue Reciprocal Links between RNA Metabolism and DNA Damage)

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14 pages, 834 KiB

Open AccessEditor’s ChoiceReview

miRNAs: The Road from Bench to Bedside

by Giuseppe Iacomino

Genes 2023, 14(2), 314; https://doi.org/10.3390/genes14020314 - 25 Jan 2023

Cited by 55 | Viewed by 9676

Abstract

miRNAs are small noncoding RNAs that control gene expression at the posttranscriptional level. It has been recognised that miRNA dysregulation reflects the state and function of cells and tissues, contributing to their dysfunction. The identification of hundreds of extracellular miRNAs in biological fluids [...] Read more.

miRNAs are small noncoding RNAs that control gene expression at the posttranscriptional level. It has been recognised that miRNA dysregulation reflects the state and function of cells and tissues, contributing to their dysfunction. The identification of hundreds of extracellular miRNAs in biological fluids has underscored their potential in the field of biomarker research. In addition, the therapeutic potential of miRNAs is receiving increasing attention in numerous conditions. On the other hand, many operative problems including stability, delivery systems, and bioavailability, still need to be solved. In this dynamic field, biopharmaceutical companies are increasingly engaged, and ongoing clinical trials point to anti-miR and miR-mimic molecules as an innovative class of molecules for upcoming therapeutic applications. This article aims to provide a comprehensive overview of current knowledge on several pending issues and new opportunities offered by miRNAs in the treatment of diseases and as early diagnostic tools in next-generation medicine. Full article

(This article belongs to the Special Issue The Ins and Outs of miRNAs as Biomarkers)

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23 pages, 4069 KiB

Open AccessEditor’s ChoiceArticle

ABCB1 Amplicon Contains Cyclic AMP Response Element-Driven TRIP6 Gene in Taxane-Resistant MCF-7 Breast Cancer Sublines

by Petr Daniel, Kamila Balušíková, Radka Václavíková, Karolína Šeborová, Šárka Ransdorfová, Marie Valeriánová, Longfei Wei, Michael Jelínek, Tereza Tlapáková, Thomas Fleischer, Vessela N. Kristensen, Pavel Souček, Iwao Ojima and Jan Kovář

Genes 2023, 14(2), 296; https://doi.org/10.3390/genes14020296 - 23 Jan 2023

Cited by 1 | Viewed by 2685

Abstract

A limited number of studies are devoted to regulating TRIP6 expression in cancer. Hence, we aimed to unveil the regulation of TRIP6 expression in MCF-7 breast cancer cells (with high TRIP6 expression) and taxane-resistant MCF-7 sublines (manifesting even higher TRIP6 expression). We found [...] Read more.

A limited number of studies are devoted to regulating TRIP6 expression in cancer. Hence, we aimed to unveil the regulation of TRIP6 expression in MCF-7 breast cancer cells (with high TRIP6 expression) and taxane-resistant MCF-7 sublines (manifesting even higher TRIP6 expression). We found that TRIP6 transcription is regulated primarily by the cyclic AMP response element (CRE) in hypomethylated proximal promoters in both taxane-sensitive and taxane-resistant MCF-7 cells. Furthermore, in taxane-resistant MCF-7 sublines, TRIP6 co-amplification with the neighboring ABCB1 gene, as witnessed by fluorescence in situ hybridization (FISH), led to TRIP6 overexpression. Ultimately, we found high TRIP6 mRNA levels in progesterone receptor-positive breast cancer and samples resected from premenopausal women. Full article

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

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20 pages, 475 KiB

Open AccessEditor’s ChoiceSystematic Review

Status Epilepticus in Chromosomal Disorders Associated with Epilepsy: A Systematic Review

by Luca Bergonzini, Jacopo Pruccoli, Ilaria Pettenuzzo, Rosa Pugliano, Luca Soliani, Anna Fetta and Duccio Maria Cordelli

Genes 2023, 14(2), 299; https://doi.org/10.3390/genes14020299 - 23 Jan 2023

Cited by 1 | Viewed by 2961

Abstract

Status Epilepticus (SE) is a neurological emergency resulting from the failure of mechanisms of seizure termination or from the initiation of mechanisms that lead to prolonged seizures. The International League Against Epilepsy (ILAE) identified 13 chromosomal disorders associated with epilepsy (CDAE); data regarding [...] Read more.

Status Epilepticus (SE) is a neurological emergency resulting from the failure of mechanisms of seizure termination or from the initiation of mechanisms that lead to prolonged seizures. The International League Against Epilepsy (ILAE) identified 13 chromosomal disorders associated with epilepsy (CDAE); data regarding SE occurrence in these patients is lacking. A systematic scoping review was conducted to outline current literature evidence about clinical features, treatments, and outcomes of SE in pediatric and adult patients with CDAE. A total of 373 studies were identified with the initial search; 65 of these were selected and regarded as SE in Angelman Syndrome (AS, n = 20), Ring 20 Syndrome (R20, n = 24), and other syndromes (n = 21). Non-convulsive status epilepticus (NCSE) is frequently observed in AS and R20. No specific, targeted therapies for SE in CDAE are available to date; anecdotal reports about SE treatment are described in the text, as well as various brief- and long-term outcomes. Further evidence is needed to precisely portray the clinical features, treatment options, and outcomes of SE in these patients. Full article

(This article belongs to the Collection Study on Genotypes and Phenotypes of Pediatric Clinical Rare Diseases)

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8 pages, 413 KiB

Open AccessEditor’s ChoiceCommunication

RADX Gene Variant May Predispose to Familial Asperger Syndrome

by Alessia Azzarà, Roberto Rumore, Fulvia Brugnoletti, Elisabetta Tabolacci, Irene Bottillo, Eugenio Sangiorgi and Fiorella Gurrieri

Genes 2023, 14(2), 301; https://doi.org/10.3390/genes14020301 - 23 Jan 2023

Viewed by 2630

Abstract

Asperger syndrome (AS) is a pervasive developmental disorder characterized by general impairment in socialization, stereotypical behavior, defective adaptation to the social context usually without intellectual disability, and some high functioning areas related to memory and mathematics. Clinical criteria are not well defined and [...] Read more.

Asperger syndrome (AS) is a pervasive developmental disorder characterized by general impairment in socialization, stereotypical behavior, defective adaptation to the social context usually without intellectual disability, and some high functioning areas related to memory and mathematics. Clinical criteria are not well defined and the etiology is heterogeneous and mostly unknown. Like in typical autism spectrum disorders (ASD), the genetic background plays a crucial role in AS, and often an almost mendelian segregation can be observed in some families. We performed a whole exome sequencing (WES) in three relatives of a family with vertical transmission of AS-ASD to identify variants in candidate genes segregating with the phenotype. Variant p.(Cys834Ser) in the RADX gene was the only one segregating among all the affected family members. This gene encodes a single-strand DNA binding factor, which mediates the recruitment of genome maintenance proteins to sites of replication stress. Replication stress and genome instability have been reported recently in neural progenitor cells derived from ASD patients, leading to a disruption of long neural genes involved in cell–cell adhesion and migration. We propose RADX as a new gene that when mutated could represent a predisposing factor to AS-ASD. Full article

(This article belongs to the Section Technologies and Resources for Genetics)

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19 pages, 3296 KiB

Open AccessEditor’s ChoiceArticle

A Network-Based Approach for Improving Annotation of Transcription Factor Functions and Binding Sites in Arabidopsis thaliana

by Tanzira Najnin, Sakhawat Hossain Saimon, Garry Sunter and Jianhua Ruan

Genes 2023, 14(2), 282; https://doi.org/10.3390/genes14020282 - 21 Jan 2023

Viewed by 2155

Abstract

Transcription factors are an integral component of the cellular machinery responsible for regulating many biological processes, and they recognize distinct DNA sequence patterns as well as internal/external signals to mediate target gene expression. The functional roles of an individual transcription factor can be [...] Read more.

Transcription factors are an integral component of the cellular machinery responsible for regulating many biological processes, and they recognize distinct DNA sequence patterns as well as internal/external signals to mediate target gene expression. The functional roles of an individual transcription factor can be traced back to the functions of its target genes. While such functional associations can be inferred through the use of binding evidence from high-throughput sequencing technologies available today, including chromatin immunoprecipitation sequencing, such experiments can be resource-consuming. On the other hand, exploratory analysis driven by computational techniques can alleviate this burden by narrowing the search scope, but the results are often deemed low-quality or non-specific by biologists. In this paper, we introduce a data-driven, statistics-based strategy to predict novel functional associations for transcription factors in the model plant Arabidopsis thaliana. To achieve this, we leverage one of the largest available gene expression compendia to build a genome-wide transcriptional regulatory network and infer regulatory relationships among transcription factors and their targets. We then use this network to build a pool of likely downstream targets for each transcription factor and query each target pool for functionally enriched gene ontology terms. The results exhibited sufficient statistical significance to annotate most of the transcription factors in Arabidopsis with highly specific biological processes. We also perform DNA binding motif discovery for transcription factors based on their target pool. We show that the predicted functions and motifs strongly agree with curated databases constructed from experimental evidence. In addition, statistical analysis of the network revealed interesting patterns and connections between network topology and system-level transcriptional regulation properties. We believe that the methods demonstrated in this work can be extended to other species to improve the annotation of transcription factors and understand transcriptional regulation on a system level. Full article

(This article belongs to the Section Bioinformatics)

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17 pages, 3022 KiB

Open AccessEditor’s ChoiceArticle

Ablation of Gabra5 Influences Corticosterone Levels and Anxiety-like Behavior in Mice

by Linn Amanda Syding, Agnieszka Kubik-Zahorodna, David Pajuelo Reguera, Petr Nickl, Bohdana Hruskova, Michaela Kralikova, Jana Kopkanova, Vendula Novosadova, Petr Kasparek, Jan Prochazka, Jan Rozman, Rostislav Turecek and Radislav Sedlacek

Genes 2023, 14(2), 285; https://doi.org/10.3390/genes14020285 - 21 Jan 2023

Cited by 1 | Viewed by 2591

Abstract

Stress responses are activated by the hypothalamic-pituitary-adrenal axis (HPA axis), culminating in the release of glucocorticoids. During prolonged periods of secretion of glucocorticoids or inappropriate behavioral responses to a stressor, pathologic conditions may occur. Increased glucocorticoid concentration is linked to generalized anxiety, and [...] Read more.

Stress responses are activated by the hypothalamic-pituitary-adrenal axis (HPA axis), culminating in the release of glucocorticoids. During prolonged periods of secretion of glucocorticoids or inappropriate behavioral responses to a stressor, pathologic conditions may occur. Increased glucocorticoid concentration is linked to generalized anxiety, and there are knowledge gaps regarding its regulation. It is known that the HPA axis is under GABAergic control, but the contribution of the individual subunits of the GABA receptor is largely unknown. In this study, we investigated the relationship between the α5 subunit and corticosterone levels in a new mouse model deficient for Gabra5, which is known to be linked to anxiety disorders in humans and phenologs observed in mice. We observed decreased rearing behavior, suggesting lower anxiety in the Gabra5^−/− animals; however, such a phenotype was absent in the open field and elevated plus maze tests. In addition to decreased rearing behavior, we also found decreased levels of fecal corticosterone metabolites in Gabra5^−/− mice indicating a lowered stress response. Moreover, based on the electrophysiological recordings where we observed a hyperpolarized state of hippocampal neurons, we hypothesize that the constitutive ablation of the Gabra5 gene leads to functional compensation with other channels or GABA receptor subunits in this model. Full article

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

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15 pages, 8115 KiB

Open AccessEditor’s ChoiceArticle

The Evolutionary History of a DNA Methylase Reveals Frequent Horizontal Transfer and Within-Gene Recombination

by Sophia P. Gosselin, Danielle R. Arsenault, Catherine A. Jennings and Johann Peter Gogarten

Genes 2023, 14(2), 288; https://doi.org/10.3390/genes14020288 - 21 Jan 2023

Cited by 2 | Viewed by 2304

Abstract

Inteins, often referred to as protein introns, are highly mobile genetic elements that invade conserved genes throughout the tree of life. Inteins have been found to invade a wide variety of key genes within actinophages. While in the process of conducting a survey [...] Read more.

Inteins, often referred to as protein introns, are highly mobile genetic elements that invade conserved genes throughout the tree of life. Inteins have been found to invade a wide variety of key genes within actinophages. While in the process of conducting a survey of these inteins in actinophages, we discovered that one protein family of methylases contained a putative intein, and two other unique insertion elements. These methylases are known to occur commonly in phages as orphan methylases (possibly as a form of resistance to restriction–modification systems). We found that the methylase family is not conserved within phage clusters and has a disparate distribution across divergent phage groups. We determined that two of the three insertion elements have a patchy distribution within the methylase protein family. Additionally, we found that the third insertion element is likely a second homing endonuclease, and that all three elements (the intein, the homing endonuclease, and what we refer to as the ShiLan domain) have different insertion sites that are conserved in the methylase gene family. Furthermore, we find strong evidence that both the intein and ShiLan domain are partaking in long-distance horizontal gene transfer events between divergent methylases in disparate phage hosts within the already dispersed methylase distribution. The reticulate evolutionary history of methylases and their insertion elements reveals high rates of gene transfer and within-gene recombination in actinophages. Full article

(This article belongs to the Special Issue Feature Papers: Molecular Genetics and Genomics 2023)

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15 pages, 3272 KiB

Open AccessEditor’s ChoiceArticle

Stage-Specific Transcriptomes of the Mussel Mytilus coruscus Reveals the Developmental Program for the Planktonic to Benthic Transition

by Yu-Qing Wang, Qi Liu, Yan Zhou, Lizhi Chen, Yue-Ming Yang, Xue Shi, Deborah M. Power and Yi-Feng Li

Genes 2023, 14(2), 287; https://doi.org/10.3390/genes14020287 - 21 Jan 2023

Cited by 14 | Viewed by 3151

Abstract

Many marine invertebrate larvae undergo complex morphological and physiological changes during the planktonic—benthic transition (a.k.a. metamorphosis). In this study, transcriptome analysis of different developmental stages was used to uncover the molecular mechanisms underpinning larval settlement and metamorphosis of the mussel, Mytilus coruscus. [...] Read more.

Many marine invertebrate larvae undergo complex morphological and physiological changes during the planktonic—benthic transition (a.k.a. metamorphosis). In this study, transcriptome analysis of different developmental stages was used to uncover the molecular mechanisms underpinning larval settlement and metamorphosis of the mussel, Mytilus coruscus. Analysis of highly upregulated differentially expressed genes (DEGs) at the pediveliger stage revealed enrichment of immune-related genes. The results may indicate that larvae co-opt molecules of the immune system to sense and respond to external chemical cues and neuroendocrine signaling pathways forecast and trigger the response. The upregulation of adhesive protein genes linked to byssal thread secretion indicates the anchoring capacity required for larval settlement arises prior to metamorphosis. The results of gene expression support a role for the immune and neuroendocrine systems in mussel metamorphosis and provide the basis for future studies to disentangle gene networks and the biology of this important lifecycle transformation. Full article

(This article belongs to the Special Issue Genetic Breeding and Genomics of Marine Shellfish)

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20 pages, 1341 KiB

Open AccessEditor’s ChoiceReview

Effect of the Rho-Kinase/ROCK Signaling Pathway on Cytoskeleton Components

by Guangzhao Guan, Richard D. Cannon, Dawn E. Coates and Li Mei

Genes 2023, 14(2), 272; https://doi.org/10.3390/genes14020272 - 20 Jan 2023

Cited by 59 | Viewed by 9079

Abstract

The mechanical properties of cells are important in tissue homeostasis and enable cell growth, division, migration and the epithelial-mesenchymal transition. Mechanical properties are determined to a large extent by the cytoskeleton. The cytoskeleton is a complex and dynamic network composed of microfilaments, intermediate [...] Read more.

The mechanical properties of cells are important in tissue homeostasis and enable cell growth, division, migration and the epithelial-mesenchymal transition. Mechanical properties are determined to a large extent by the cytoskeleton. The cytoskeleton is a complex and dynamic network composed of microfilaments, intermediate filaments and microtubules. These cellular structures confer both cell shape and mechanical properties. The architecture of the networks formed by the cytoskeleton is regulated by several pathways, a key one being the Rho-kinase/ROCK signaling pathway. This review describes the role of ROCK (Rho-associated coiled-coil forming kinase) and how it mediates effects on the key components of the cytoskeleton that are critical for cell behaviour. Full article

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

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20 pages, 5005 KiB

Open AccessEditor’s ChoiceArticle

Functional Assessment of a New PBX1 Variant in a 46,XY Fetus with Severe Syndromic Difference of Sexual Development through CRISPR-Cas9 Gene Editing

by Laura Mary, Delphine Leclerc, Audrey Labalme, Pascale Bellaud, Séverine Mazaud-Guittot, Stéphane Dréano, Bertrand Evrard, Antoine Bigand, Aurélie Cauchoix, Philippe Loget, Anna Lokchine, Laurence Cluzeau, David Gilot, Marc-Antoine Belaud-Rotureau and Sylvie Jaillard

Genes 2023, 14(2), 273; https://doi.org/10.3390/genes14020273 - 20 Jan 2023

Cited by 1 | Viewed by 2720

Abstract

Sexual development is a complex process relying on numerous genes. Disruptions in some of these genes are known to cause differences of sexual development (DSDs). Advances in genome sequencing allowed the discovery of new genes implicated in sexual development, such as PBX1. We [...] Read more.

Sexual development is a complex process relying on numerous genes. Disruptions in some of these genes are known to cause differences of sexual development (DSDs). Advances in genome sequencing allowed the discovery of new genes implicated in sexual development, such as PBX1. We present here a fetus with a new PBX1 NM_002585.3: c.320G>A,p.(Arg107Gln) variant, presenting with severe DSD along with renal and lung malformations. Using CRISPR-Cas9 gene editing on HEK293T cells, we generated a KD cell line for PBX1. The KD cell line showed reduced proliferation and adhesion properties compared with HEK293T cells. HEK293T and KD cells were then transfected plasmids coding either PBX1 WT or PBX1-320G>A (mutant). WT or mutant PBX1 overexpression rescued cell proliferation in both cell lines. RNA-seq analyses showed less than 30 differentially expressed genes, in ectopic mutant-PBX1-expressing cells compared with WT-PBX1. Among them, U2AF1, encoding a splicing factor subunit, is an interesting candidate. Overall, mutant PBX1 seems to have modest effects compared with WT PBX1 in our model. However, the recurrence of PBX1 Arg107 substitution in patients with closely related phenotypes calls for its impact in human diseases. Further functional studies are needed to explore its effects on cellular metabolism. Full article

(This article belongs to the Special Issue Molecular Genetics of Infertility)

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15 pages, 9432 KiB

Open AccessEditor’s ChoiceArticle

SERPINB3, Adult-Onset Immunodeficiency, and Generalized Pustular Psoriasis

by Piranit Kantaputra, Teerada Daroontum, Mati Chuamanochan, Suteeraporn Chaowattanapanit, Salin Kiratikanon, Charoen Choonhakarn, Worrachet Intachai, Bjorn Olsen, Sissades Tongsima, Chumpol Ngamphiw, Patrizia Pontisso, Timothy C. Cox and Puey Ounjai

Genes 2023, 14(2), 266; https://doi.org/10.3390/genes14020266 - 19 Jan 2023

Cited by 12 | Viewed by 3339

Abstract

Background: Generalized pustular psoriasis (GPP; MIM 614204) is a rare and severe pustular autoinflammatory skin disease in which acute generalized erythema and scaling develop with numerous sterile pustules. GPP shares skin manifestations, especially pustular skin reaction, with adult-onset immunodeficiency (AOID) with anti-interferon-γ autoantibodies, [...] Read more.

Background: Generalized pustular psoriasis (GPP; MIM 614204) is a rare and severe pustular autoinflammatory skin disease in which acute generalized erythema and scaling develop with numerous sterile pustules. GPP shares skin manifestations, especially pustular skin reaction, with adult-onset immunodeficiency (AOID) with anti-interferon-γ autoantibodies, an autoimmune disease. Methods: Clinical examinations and whole-exome sequencing (WES) were performed on 32 patients with pustular psoriasis phenotypes and 21 patients with AOID with pustular skin reaction. Immunohistochemical and histopathological studies were performed. Results: WES identified three Thai patients presenting with similar pustular phenotypes—two with a diagnosis of AOID and the other with GPP. A heterozygous missense variant chr18:g.61325778C>A NM_006919.2: c.438G>T; NP_008850.1: p.Lys146Asn; rs193238900 in SERPINB3 was identified in two patients: one with GPP and the other with AOID. The other patient who had AOID carried a heterozygous missense variant chr18:g.61323147T>C NM_006919.2: c.917A>G; NP_008850.1: p.Asp306Gly in SERPINB3. Immunohistochemical studies showed overexpression of SERPINA1 and SERPINB3, a hallmark of psoriatic skin lesions. Conclusions: Genetic variants in SERPINB3 are associated with GPP and AOID with pustular skin reaction. The skin of patients with GPP and AOID carrying SERPINB3 mutations showed overexpression of SERPINB3 and SERPINA1. Clinically and genetically, GPP and AOID appear to share pathogenetic mechanisms. Full article

(This article belongs to the Special Issue Autoimmune Disease Genetics Volume II)

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20 pages, 2837 KiB

Open AccessEditor’s ChoiceArticle

Client Applications and Server-Side Docker for Management of RNASeq and/or VariantSeq Workflows and Pipelines of the GPRO Suite

by Ahmed Ibrahem Hafez, Beatriz Soriano, Aya Allah Elsayed, Ricardo Futami, Raquel Ceprian, Ricardo Ramos-Ruiz, Genis Martinez, Francisco Jose Roig, Miguel Angel Torres-Font, Fernando Naya-Catala, Josep Alvar Calduch-Giner, Lucia Trilla-Fuertes, Angelo Gamez-Pozo, Vicente Arnau, Jose Maria Sempere-Luna, Jaume Perez-Sanchez, Toni Gabaldon and Carlos Llorens

Genes 2023, 14(2), 267; https://doi.org/10.3390/genes14020267 - 19 Jan 2023

Cited by 2 | Viewed by 3736

Abstract

The GPRO suite is an in-progress bioinformatic project for -omics data analysis. As part of the continued growth of this project, we introduce a client- and server-side solution for comparative transcriptomics and analysis of variants. The client-side consists of two Java applications called [...] Read more.

The GPRO suite is an in-progress bioinformatic project for -omics data analysis. As part of the continued growth of this project, we introduce a client- and server-side solution for comparative transcriptomics and analysis of variants. The client-side consists of two Java applications called “RNASeq” and “VariantSeq” to manage pipelines and workflows based on the most common command line interface tools for RNA-seq and Variant-seq analysis, respectively. As such, “RNASeq” and “VariantSeq” are coupled with a Linux server infrastructure (named GPRO Server-Side) that hosts all dependencies of each application (scripts, databases, and command line interface software). Implementation of the Server-Side requires a Linux operating system, PHP, SQL, Python, bash scripting, and third-party software. The GPRO Server-Side can be installed, via a Docker container, in the user’s PC under any operating system or on remote servers, as a cloud solution. “RNASeq” and “VariantSeq” are both available as desktop (RCP compilation) and web (RAP compilation) applications. Each application has two execution modes: a step-by-step mode enables each step of the workflow to be executed independently, and a pipeline mode allows all steps to be run sequentially. “RNASeq” and “VariantSeq” also feature an experimental, online support system called GENIE that consists of a virtual (chatbot) assistant and a pipeline jobs panel coupled with an expert system. The chatbot can troubleshoot issues with the usage of each tool, the pipeline jobs panel provides information about the status of each computational job executed in the GPRO Server-Side, while the expert system provides the user with a potential recommendation to identify or fix failed analyses. Our solution is a ready-to-use topic specific platform that combines the user-friendliness, robustness, and security of desktop software, with the efficiency of cloud/web applications to manage pipelines and workflows based on command line interface software. Full article

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

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15 pages, 688 KiB

Open AccessEditor’s ChoiceReview

Gene Expression and Epigenetic Regulation in the Prefrontal Cortex of Schizophrenia

by Wiktor Bilecki and Marzena Maćkowiak

Genes 2023, 14(2), 243; https://doi.org/10.3390/genes14020243 - 18 Jan 2023

Cited by 11 | Viewed by 5763

Abstract

Schizophrenia pathogenesis remains challenging to define; however, there is strong evidence that the interaction of genetic and environmental factors causes the disorder. This paper focuses on transcriptional abnormalities in the prefrontal cortex (PFC), a key anatomical structure that determines functional outcomes in schizophrenia. [...] Read more.

Schizophrenia pathogenesis remains challenging to define; however, there is strong evidence that the interaction of genetic and environmental factors causes the disorder. This paper focuses on transcriptional abnormalities in the prefrontal cortex (PFC), a key anatomical structure that determines functional outcomes in schizophrenia. This review summarises genetic and epigenetic data from human studies to understand the etiological and clinical heterogeneity of schizophrenia. Gene expression studies using microarray and sequencing technologies reported the aberrant transcription of numerous genes in the PFC in patients with schizophrenia. Altered gene expression in schizophrenia is related to several biological pathways and networks (synaptic function, neurotransmission, signalling, myelination, immune/inflammatory mechanisms, energy production and response to oxidative stress). Studies investigating mechanisms driving these transcriptional abnormalities focused on alternations in transcription factors, gene promoter elements, DNA methylation, posttranslational histone modifications or posttranscriptional regulation of gene expression mediated by non-coding RNAs. Full article

(This article belongs to the Special Issue Epigenetics in the Central Nervous System)

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14 pages, 1067 KiB

Open AccessEditor’s ChoiceArticle

Framework of the Alu Subfamily Evolution in the Platyrrhine Three-Family Clade of Cebidae, Callithrichidae, and Aotidae

by Jessica M. Storer, Jerilyn A. Walker, Jasmine N. Baker, Shifat Hossain, Christian Roos, Travis J. Wheeler and Mark A. Batzer

Genes 2023, 14(2), 249; https://doi.org/10.3390/genes14020249 - 18 Jan 2023

Cited by 2 | Viewed by 2103

Abstract

The history of Alu retroposons has been choreographed by the systematic accumulation of inherited diagnostic nucleotide substitutions to form discrete subfamilies, each having a distinct nucleotide consensus sequence. The oldest subfamily, AluJ, gave rise to AluS after the split between Strepsirrhini [...] Read more.

The history of Alu retroposons has been choreographed by the systematic accumulation of inherited diagnostic nucleotide substitutions to form discrete subfamilies, each having a distinct nucleotide consensus sequence. The oldest subfamily, AluJ, gave rise to AluS after the split between Strepsirrhini and what would become Catarrhini and Platyrrhini. The AluS lineage gave rise to AluY in catarrhines and to AluTa in platyrrhines. Platyrrhine Alu subfamilies Ta7, Ta10, and Ta15 were assigned names based on a standardized nomenclature. However, with the subsequent intensification of whole genome sequencing (WGS), large scale analyses to characterize Alu subfamilies using the program COSEG identified entire lineages of subfamilies simultaneously. The first platyrrhine genome with WGS, the common marmoset (Callithrix jacchus; [caljac3]), resulted in Alu subfamily names sf0 to sf94 in an arbitrary order. Although easily resolved by alignment of the consensus sequences, this naming convention can become increasingly confusing as more genomes are independently analyzed. In this study, we reported Alu subfamily characterization for the platyrrhine three-family clade of Cebidae, Callithrichidae, and Aotidae. We investigated one species/genome from each recognized family of Callithrichidae and Aotidae and of both subfamilies (Cebinae and Saimiriinae) of the family Cebidae. Furthermore, we constructed a comprehensive network of Alu subfamily evolution within the three-family clade of platyrrhines to provide a working framework for future research. Alu expansion in the three-family clade has been dominated by AluTa15 and its derivatives. Full article

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

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13 pages, 1202 KiB

Open AccessEditor’s ChoiceArticle

KIF6 Trp719Arg Genetic Variant Increases Risk for Thoracic Aortic Dissection

by Juan J. Velasco, Yupeng Li, Bulat A. Ziganshin, Mohammad A. Zafar, John A. Rizzo, Deqiong Ma, Hui Zang, Asanish Kalyanasundaram and John A. Elefteriades

Genes 2023, 14(2), 252; https://doi.org/10.3390/genes14020252 - 18 Jan 2023

Cited by 1 | Viewed by 2485

Abstract

Background: KIF6 (kinesin family member 6), a protein coded by the KIF6 gene, serves an important intracellular function to transport organelles along microtubules. In a pilot study, we found that a common KIF6 Trp719Arg variant increased the propensity of thoracic aortic aneurysms (TAA) [...] Read more.

Background: KIF6 (kinesin family member 6), a protein coded by the KIF6 gene, serves an important intracellular function to transport organelles along microtubules. In a pilot study, we found that a common KIF6 Trp719Arg variant increased the propensity of thoracic aortic aneurysms (TAA) to suffer dissection (AD). The present study aims for a definite investigation of the predictive ability of KIF6 719Arg vis à vis AD. Confirmatory findings would enhance natural history prediction in TAA. Methods: 1108 subjects (899 aneurysm and 209 dissection patients) had KIF6 719Arg variant status determined. Results: The 719Arg variant in the KIF6 gene correlated strongly with occurrence of AD. Specifically, KIF6 719Arg positivity (homozygous or heterozygous) was substantially more common in dissectors (69.8%) than non-dissectors (58.5%) (p = 0.003). Odds ratios (OR) for suffering aortic dissection ranged from 1.77 to 1.94 for Arg carriers in various dissection categories. These high OR associations were noted for both ascending and descending aneurysms and for homozygous and heterozygous Arg variant patients. The rate of aortic dissection over time was significantly higher for carriers of the Arg allele (p = 0.004). Additionally, Arg allele carriers were more likely to reach the combined endpoint of dissection or death (p = 0.03). Conclusions: We demonstrate the marked adverse impact of the 719Arg variant of the KIF6 gene on the likelihood that a TAA patient will suffer aortic dissection. Clinical assessment of the variant status of this molecularly important gene may provide a valuable “non-size” criterion to enhance surgical decision making above and beyond the currently used metric of aortic size (diameter). Full article

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

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9 pages, 3542 KiB

Open AccessEditor’s ChoiceCase Report

Identification of a Small Supernumerary Marker Chromosome in a Turner Syndrome Patient with Karyotype mos 46,X,+mar/45,X

by María Teresa Alejandra González-Rodríguez, Sinhue Alejandro Brukman-Jiménez, Idalid Cuero-Quezada, Jorge Román Corona-Rivera, Alfredo Corona-Rivera, Graciela Serafín-Saucedo, Liuba M. Aguirre-Salas and Lucina Bobadilla-Morales

Genes 2023, 14(2), 253; https://doi.org/10.3390/genes14020253 - 18 Jan 2023

Cited by 1 | Viewed by 9804

Abstract

Turner Syndrome is characterized by a normal X chromosome and the partial or complete absence of a second sexual chromosome. Small supernumerary marker chromosomes are present in 6.6% of these patients. Because of the wide range of Turner syndrome karyotypes, it is difficult [...] Read more.

Turner Syndrome is characterized by a normal X chromosome and the partial or complete absence of a second sexual chromosome. Small supernumerary marker chromosomes are present in 6.6% of these patients. Because of the wide range of Turner syndrome karyotypes, it is difficult to establish a relationship with the phenotype of the patients. We present the case of a female patient with Turner syndrome, insulin resistance, type 2 diabetes, and intellectual disability. The karyotype revealed the presence of mosaicism with a monosomy X cell line and a second line with a small marker chromosome. FISH of two different tissues was used to identify the marker chromosome with probes for X and Y centromeres. Both tissues presented mosaicism for a two X chromosome signal, differing in the percentage of the monosomy X cell percentage. Comparative genomic hybridization with the CytoScan^TMHD assay was performed in genomic DNA from peripheral blood, allowing us to determine the size and breakage points of the small marker chromosome. The patient presents a phenotype that combines classic Turner syndrome features and unlikely ones as intellectual disability. The size, implicated genes, and degree of inactivation of the X chromosome influence the broad spectrum of phenotypes resulting from these chromosomes. Full article

(This article belongs to the Section Genetic Diagnosis)

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7 pages, 1005 KiB

Open AccessEditor’s ChoiceBrief Report

Genome Survey Sequencing of the Mole Cricket Gryllotalpa orientalis

by Kuo Sun, De-Long Guan, Hua-Teng Huang and Sheng-Quan Xu

Genes 2023, 14(2), 255; https://doi.org/10.3390/genes14020255 - 18 Jan 2023

Cited by 1 | Viewed by 2570

Abstract

The mole cricket Gryllotalpa orientalis is an evolutionarily, medicinal, and agriculturally significant insect that inhabits underground environments and is distributed globally. This study measured genome size by flow cytometry and k-mer based on low-coverage sequencing, and nuclear repetitive elements were also identified. The [...] Read more.

The mole cricket Gryllotalpa orientalis is an evolutionarily, medicinal, and agriculturally significant insect that inhabits underground environments and is distributed globally. This study measured genome size by flow cytometry and k-mer based on low-coverage sequencing, and nuclear repetitive elements were also identified. The haploid genome size estimate is 3.14 Gb by flow cytometry, 3.17 Gb, and 3.77 Gb-based two k-mer methods, respectively, which is well within the range previously reported for other species of the suborder Ensifera. 56% of repetitive elements were found in G. orientalis, similar to 56.83% in Locusta migratoria. However, the great size of repetitive sequences could not be annotated to specific repeat element families. For the repetitive elements that were annotated, Class I-LINE retrotransposon elements were the most common families and more abundant than satellite and Class I-LTR. These results based on the newly developed genome survey could be used in the taxonomic study and whole genome sequencing to improve the understanding of the biology of G. orientalis. Full article

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

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9 pages, 267 KiB

Open AccessEditor’s ChoiceCommunication

Selected SNPs of FCN2 Associated with Chronic Tonsillitis in the Polish Adult Population

by Jadwiga Gaździcka, Karolina Gołąbek, Dorota Hudy, Katarzyna Miśkiewicz-Orczyk, Natalia Zięba, Wojciech Tynior, Marek Asman, Maciej Misiołek and Joanna Katarzyna Strzelczyk

Genes 2023, 14(2), 242; https://doi.org/10.3390/genes14020242 - 17 Jan 2023

Cited by 2 | Viewed by 1696

Abstract

Chronic tonsillitis is a problem related to bacterial and viral infections. Ficolins play a key role in the defence against various pathogens. In the present study, we investigated the associations between the selected single nucleotide polymorphisms (SNPs) of the FCN2 gene and chronic [...] Read more.

Chronic tonsillitis is a problem related to bacterial and viral infections. Ficolins play a key role in the defence against various pathogens. In the present study, we investigated the associations between the selected single nucleotide polymorphisms (SNPs) of the FCN2 gene and chronic tonsillitis in the Polish population. The study included 101 patients with chronic tonsillitis and 101 healthy individuals. The selected SNPs of FCN2 (rs3124953, rs17514136 and rs3124954) were genotyped using TaqMan SNP Genotyping Assays (Applied Biosystem, Foster City, CA, USA). The analysis of rs17514136 and rs3124953 showed no significant differences in genotype frequencies between the chronic tonsillitis patients and controls (p > 0.01). The CT genotype of rs3124954 was significantly more frequent, while the CC genotype was less frequent in chronic tonsillitis patients (p = 0.003 and p = 0.001, respectively). The frequency of the A/G/T haplotype (rs17514136/rs3124953/rs3124954) was significantly more common in chronic tonsillitis patients (p = 0.0011). Moreover, the FCN2 CT genotype of rs3124954 was associated with a higher risk of chronic tonsillitis, while the CC genotype of rs3124954 decreased this risk. Our findings demonstrate that FCN2 rs3124954 may be associated with chronic tonsillitis in the Polish adult population. Full article

(This article belongs to the Special Issue Head and Neck Genetics)

12 pages, 10327 KiB

Open AccessEditor’s ChoiceArticle

Linear Diagnostic Procedure Elicited by Clinical Genetics and Validated by mRNA Analysis in Neuronal Ceroid Lipofuscinosis 7 Associated with a Novel Non-Canonical Splice Site Variant in MFSD8

by Domizia Pasquetti, Giuseppe Marangi, Daniela Orteschi, Marina Carapelle, Federica Francesca L’Erario, Romina Venditti, Sabrina Maietta, Domenica Immacolata Battaglia, Ilaria Contaldo, Chiara Veredice and Marcella Zollino

Genes 2023, 14(2), 245; https://doi.org/10.3390/genes14020245 - 17 Jan 2023

Cited by 3 | Viewed by 2624

Abstract

Neuronal ceroid lipofuscinoses (CNL) are lysosomal storage diseases that represent the most common cause of dementia in children. To date, 13 autosomal recessive (AR) and 1 autosomal dominant (AD) gene have been characterized. Biallelic variants in MFSD8 cause CLN7 type, with nearly 50 [...] Read more.

Neuronal ceroid lipofuscinoses (CNL) are lysosomal storage diseases that represent the most common cause of dementia in children. To date, 13 autosomal recessive (AR) and 1 autosomal dominant (AD) gene have been characterized. Biallelic variants in MFSD8 cause CLN7 type, with nearly 50 pathogenic variants, mainly truncating and missense, reported so far. Splice site variants require functional validation. We detected a novel homozygous non-canonical splice-site variant in MFSD8 in a 5-year-old girl who presented with progressive neurocognitive impairment and microcephaly. The diagnostic procedure was elicited by clinical genetics first, and then confirmed by cDNA sequencing and brain imaging. Inferred by the common geographic origin of the parents, an autosomal recessive inheritance was hypothesized, and SNP-array was performed as the first-line genetic test. Only three AR genes lying within the observed 24 Mb regions of homozygosity were consistent with the clinical phenotype, including EXOSC9, SPATA5 and MFSD8. The cerebral and cerebellar atrophy detected in the meantime by MRI, along with the suspicion of accumulation of ceroid lipopigment in neurons, prompted us to perform targeted MFSD8 sequencing. Following the detection of a splice site variant of uncertain significance, skipping of exon 8 was demonstrated by cDNA sequencing, and the variant was redefined as pathogenic. Full article

(This article belongs to the Section RNA)

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10 pages, 14946 KiB

Open AccessEditor’s ChoiceBrief Report

Involvement of Mitochondrial Dysfunction in FOXG1 Syndrome

by Victoria A. Bjerregaard, Amanda M. Levy, Mille S. Batz, Ravina Salehi, Mathis Hildonen, Trine B. Hammer, Rikke S. Møller, Claus Desler and Zeynep Tümer

Genes 2023, 14(2), 246; https://doi.org/10.3390/genes14020246 - 17 Jan 2023

Viewed by 2753

Abstract

FOXG1 (Forkhead box g1) syndrome is a neurodevelopmental disorder caused by a defective transcription factor, FOXG1, important for normal brain development and function. As FOXG1 syndrome and mitochondrial disorders have shared symptoms and FOXG1 regulates mitochondrial function, we investigated whether defective FOXG1 leads [...] Read more.

FOXG1 (Forkhead box g1) syndrome is a neurodevelopmental disorder caused by a defective transcription factor, FOXG1, important for normal brain development and function. As FOXG1 syndrome and mitochondrial disorders have shared symptoms and FOXG1 regulates mitochondrial function, we investigated whether defective FOXG1 leads to mitochondrial dysfunction in five individuals with FOXG1 variants compared to controls (n = 6). We observed a significant decrease in mitochondrial content and adenosine triphosphate (ATP) levels and morphological changes in mitochondrial network in the fibroblasts of affected individuals, indicating involvement of mitochondrial dysfunction in FOXG1 syndrome pathogenesis. Further investigations are warranted to elucidate how FOXG1 deficiency impairs mitochondrial homeostasis. Full article

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

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9 pages, 2646 KiB

Open AccessEditor’s ChoiceCommunication

The Mitochondrial Genomes of Two Parasitoid Wasps Protapanteles immunis and Parapanteles hyposidrae (Hymenoptera: Braconidae) with Phylogenetic Implications and Novel Gene Rearrangements

by Dandan Xiao, Ziqi Wang, Jiachen Zhu, Xiaogui Zhou, Pu Tang and Xuexin Chen

Genes 2023, 14(1), 230; https://doi.org/10.3390/genes14010230 - 16 Jan 2023

Cited by 1 | Viewed by 2197

Abstract

Parapanteles hypsidrae (Wilkinson, 1928) and Protapanteles immunis (Haliday, 1834) are the most important parasitic wasps of Ectropis grisescens Warren and Ectropis obliqua (Prout). We sequenced and annotated the mitochondrial genomes of Pa. hyposidrae and Pr. immunis, which are 17,063 bp and 16,397 [...] Read more.

Parapanteles hypsidrae (Wilkinson, 1928) and Protapanteles immunis (Haliday, 1834) are the most important parasitic wasps of Ectropis grisescens Warren and Ectropis obliqua (Prout). We sequenced and annotated the mitochondrial genomes of Pa. hyposidrae and Pr. immunis, which are 17,063 bp and 16,397 bp in length, respectively, and possess 37 mitochondrial genes. We discovered two novel types of gene rearrangement, the local inversion of nad4L in Pa. hyposidrae and the remote inversion of the block cox3-nad3-nad5-nad4 in Pr. immunis, within the mitogenomes of Braconidae. The phylogenetic analysis supported the subfamily Microgastrinae is a monophyletic group, but the tribes Apantelini and Cotesiini within this subfamily are paraphyletic groups. Full article

(This article belongs to the Special Issue Advanced Research on Mitochondrial Genome)

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13 pages, 1381 KiB

Open AccessEditor’s ChoiceArticle

Genetic and Morphological Variation in Hypodontia of Maxillary Lateral Incisors

by Bernadette Kerekes-Máthé, Krisztina Mártha, Claudia Bănescu, Matthew Brook O’Donnell and Alan H. Brook

Genes 2023, 14(1), 231; https://doi.org/10.3390/genes14010231 - 16 Jan 2023

Cited by 9 | Viewed by 3672

Abstract

(1) Background: Hypodontia has a multifactorial aetiology, in which genetic factors are a major component. Associated with this congenital absence, the formed teeth may show differences in size and shape, which may vary with the specific genetic variants and with the location of [...] Read more.

(1) Background: Hypodontia has a multifactorial aetiology, in which genetic factors are a major component. Associated with this congenital absence, the formed teeth may show differences in size and shape, which may vary with the specific genetic variants and with the location of the missing teeth. The aims of the present study were to investigate a specific variant of MSX1, derive morphometric tooth measurements in a sample of patients with isolated maxillary lateral incisor agenesis and matched controls, and model the findings. (2) Methods: Genotyping of the MSX1 rs8670 genetic variant and morphometric measurements with a 2D image analysis method were performed for 26 hypodontia patients and 26 matched controls. (3) Results: The risk of upper lateral incisor agenesis was 6.9 times higher when the T allele was present. The morphometric parameters showed significant differences between hypodontia patients and controls and between the unilateral and bilateral agenesis cases. The most affected crown dimension in the hypodontia patients was the bucco-lingual dimension. In crown shape there was significant variation the Carabelli trait in upper first molars. (4) Conclusions: The MSX1 rs8670 variant was associated with variations in morphological outcomes. The new findings for compensatory interactions between the maxillary incisors indicate that epigenetic and environmental factors interact with this genetic variant. A single-level directional complex interactive network model incorporates the variations seen in this study. Full article

(This article belongs to the Special Issue Genetic, Epigenetic and Environmental Factors in Dental Development and Pathologies: Genes, Interactions and Dental Development)

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13 pages, 3956 KiB

Open AccessEditor’s ChoiceArticle

Peanut AhmTERF1 Regulates Root Growth by Modulating Mitochondrial Abundance

by Limei Li, Xiaoyun Li, Chen Yang and Ling Li

Genes 2023, 14(1), 209; https://doi.org/10.3390/genes14010209 - 13 Jan 2023

Cited by 3 | Viewed by 2112

Abstract

Mitochondria are responsible for energy generation, as well as key metabolic and signaling pathways, and thus affect the entire developmental process of plants as well as their responses to stress. In metazoans, mitochondrial transcription termination factors (mTERFs) are known to regulate mitochondrial transcription. [...] Read more.

Mitochondria are responsible for energy generation, as well as key metabolic and signaling pathways, and thus affect the entire developmental process of plants as well as their responses to stress. In metazoans, mitochondrial transcription termination factors (mTERFs) are known to regulate mitochondrial transcription. mTERFs have also been discovered in plants, but only a few of these proteins have been explored for their biological functions. Here, we report a role in root growth for mitochondria-associated protein AhmTERF1 in peanut (Arachis hypogaea L.). Overexpressing AhmTERF1 significantly stimulated the growth of peanut hairy roots and transgenic Arabidopsis. Surprisingly, AhmTERF1 is predominantly expressed in the root meristem where it increases mitochondrial abundance. AhmTERF1 binding to mtDNA was enriched in the RRN18 and RRN26 regions, suggesting it is related to the accumulation of mitochondrial ribosomes. Peanut is one of the main oil crops and the important source of edible oil and AhmTERF1 likely affects agronomic traits related to root growth in different peanut cultivars. We propose that peanut AhmTERF1 is an important protein for root growth due to its role in regulating mitochondrial abundance. Full article

(This article belongs to the Special Issue Genomics and Breeding of Oil Crops)

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12 pages, 3623 KiB

Open AccessEditor’s ChoiceArticle

The Complete Mitochondrial Genome and Gene Arrangement of the Enigmatic Scaphopod Pictodentalium vernedei

by Tianzhe Zhang, Yunan Wang and Hao Song

Genes 2023, 14(1), 210; https://doi.org/10.3390/genes14010210 - 13 Jan 2023

Cited by 1 | Viewed by 3008

Abstract

The enigmatic scaphopods, or tusk shells, are a small and rare group of molluscs whose phylogenomic position among the Conchifera is undetermined, and the taxonomy within this class also needs revision. Such work is hindered by there only being a very few mitochondrial [...] Read more.

The enigmatic scaphopods, or tusk shells, are a small and rare group of molluscs whose phylogenomic position among the Conchifera is undetermined, and the taxonomy within this class also needs revision. Such work is hindered by there only being a very few mitochondrial genomes in this group that are currently available. Here, we present the assembly and annotation of the complete mitochondrial genome from Dentaliida Pictodentalium vernedei, whose mitochondrial genome is 14,519 bp in size, containing 13 protein-coding genes, 22 tRNA genes and two rRNA genes. The nucleotide composition was skewed toward A-T, with a 71.91% proportion of AT content. Due to the mitogenome-based phylogenetic analysis, we defined P. vernedei as a sister to Graptacme eborea in Dentaliida. Although a few re-arrangements occurred, the mitochondrial gene order showed deep conservation within Dentaliida. Yet, such a gene order in Dentaliida largely diverges from Gadilida and other molluscan classes, suggesting that scaphopods have the highest degree of mitogenome arrangement compared to other molluscs. Full article

(This article belongs to the Special Issue Genetic Evolution of Marine Shellfish)

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12 pages, 373 KiB

Open AccessEditor’s ChoiceArticle

Support Interval for Two-Sample Summary Data-Based Mendelian Randomization

by Kai Wang

Genes 2023, 14(1), 211; https://doi.org/10.3390/genes14010211 - 13 Jan 2023

Cited by 3 | Viewed by 2832

Abstract

The summary-data-based Mendelian randomization (SMR) method is gaining popularity in estimating the causal effect of an exposure on an outcome. In practice, the instrument SNP is often selected from the genome-wide association study (GWAS) on the exposure but no correction is made for [...] Read more.

The summary-data-based Mendelian randomization (SMR) method is gaining popularity in estimating the causal effect of an exposure on an outcome. In practice, the instrument SNP is often selected from the genome-wide association study (GWAS) on the exposure but no correction is made for such selection in downstream analysis, leading to a biased estimate of the effect size and invalid inference. We address this issue by using the likelihood derived from the sampling distribution of the estimated SNP effects in the exposure GWAS and the outcome GWAS. This likelihood takes into account how the instrument SNPs are selected. Since the effective sample size is 1, the asymptotic theory does not apply. We use a support for a profile likelihood as an interval estimate of the causal effect. Simulation studies indicate that this support has robust coverage while the confidence interval implied by the SMR method has lower-than-nominal coverage. Furthermore, the variance of the two-stage least squares estimate of the causal effect is shown to be the same as the variance used for SMR for one-sample data when there is no selection. Full article

(This article belongs to the Topic Big Data in Healthcare, Bioinformatics and Precision Medicine)
(This article belongs to the Section Bioinformatics)

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22 pages, 4274 KiB

Open AccessEditor’s ChoiceArticle

Changes in Hox Gene Chromatin Organization during Odontogenic Lineage Specification

by Gokul Gopinathan, Xinmin Zhang, Xianghong Luan and Thomas G. H. Diekwisch

Genes 2023, 14(1), 198; https://doi.org/10.3390/genes14010198 - 12 Jan 2023

Cited by 2 | Viewed by 2696

Abstract

Craniofacial tissues comprise highly evolved organs characterized by a relative lack of expression in the HOX family transcription factors. In the present study, we sought to define the epigenetic events that limit HOX gene expression from undifferentiated neural crest cells to semi-differentiated odontogenic [...] Read more.

Craniofacial tissues comprise highly evolved organs characterized by a relative lack of expression in the HOX family transcription factors. In the present study, we sought to define the epigenetic events that limit HOX gene expression from undifferentiated neural crest cells to semi-differentiated odontogenic progenitors and to explore the effects of elevated levels of HOX. The ChIP-chip data demonstrated high levels of repressive H3K27me3 marks on the HOX gene promoters in ES and cranial neural crest cells when compared to the H3K4me3 marks, while the K4/K27 ratio was less repressive in the odontogenic progenitors, dental follicle, dental pulp, periodontal ligament fibroblasts, alveolar bone osteoblasts, and cementoblasts. The gene expression of multiple HOX genes, especially those from the HOXA and HOXB clusters, was significantly elevated and many times higher in alveolar bone cells than in the dental follicle cells. In addition, the HOX levels in the skeletal osteoblasts were many times higher in the trunk osteoblasts compared to the alveolar bone osteoblasts, and the repressive mark H3K27me3 promoter occupancy was substantially and significantly elevated in the alveolar bone osteoblasts when compared to the trunk osteoblasts. To explore the effect of elevated HOX levels in craniofacial neural crest cells, HOX expression was induced by transfecting cells with the Cdx4 transcription factor, resulting in a significant decrease in the mineralization markers, RUNX2, OSX, and OCN upon HOX elevation. Promoting HOX gene expression in developing teeth using the small molecule EZH2 inhibitor GSK126 resulted in an increased number of patterning events, supernumerary cusp formation, and increased Hoxa4 and Hoxb6 gene expression when compared to the controls. Together, these studies illustrate the profound effects of epigenetic regulatory events at all stages of the differentiation of craniofacial peripheral tissues from the neural crest, including lineage specification, tissue differentiation, and patterning. Full article

(This article belongs to the Special Issue Chromatin Organization in Cell Differentiation)

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10 pages, 1476 KiB

Open AccessEditor’s ChoiceHypothesis

How Can CpG Methylations, and Pair-to-Pair Correlations between the Main (Gene) and the Opposite Strands, Suggest a Bending DNA Loop: Insights into the 5′-UTR of DAT1

by Vincenza Di Paola, Martina Morrone, Valentina Poli, Andrea Fuso, Esterina Pascale and Walter Adriani

Genes 2023, 14(1), 190; https://doi.org/10.3390/genes14010190 - 11 Jan 2023

Cited by 1 | Viewed by 1921

Abstract

A working hypothesis issues from patterns of methylation in the 5′-UTR of the DAT1 gene. We considered relationships between pairs of CpGs, of which one on the main-gene strand and another on the complementary opposite strand (COS). We elaborated on data from ADHD [...] Read more.

A working hypothesis issues from patterns of methylation in the 5′-UTR of the DAT1 gene. We considered relationships between pairs of CpGs, of which one on the main-gene strand and another on the complementary opposite strand (COS). We elaborated on data from ADHD children: we calculated all possible combinations of probabilities (estimated by multiplying two raw values of methylation) in pairs of CpGs from either strand. We analyzed all correlations between any given pair and all other pairs. For pairs correlating with M6-M6COS, some pairs had cytosines positioning to the reciprocal right (e.g., M3-M2COS and M6-M5COS), other pairs had cytosines positioning to the reciprocal left (e.g., M2-M3COS; M5-M6COS). Significant pair-to-pair correlations emerged between main-strand and COS CpG pairs. Through graphic representations, we hypothesized that DNA folded to looping conformations: the C¹GG C²GG C³GG and C⁵G C⁶G motifs would become close enough to allow cytosines 1-2-3 to interact with cytosines 5-6 (on both strands). Data further suggest a sliding, with left- and right-ward oscillations of DNA strands. While thorough empirical verification is needed, we hypothesize simultaneous methylation of main-strand and COS DNA (“methylation dynamics”) to serve as a promising biomarker. Full article

(This article belongs to the Special Issue Genetic Basis of Stress-Related Neuropsychiatric Disorders)

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12 pages, 2225 KiB

Open AccessEditor’s ChoiceArticle

Small Body, Large Chromosomes: Centric Fusions Shaped the Karyotype of the Amazonian Miniature Fish Nannostomus anduzei (Characiformes, Lebiasinidae)

by Renata Luiza Rosa de Moraes, Francisco de Menezes Cavalcante Sassi, Manoela Maria Ferreira Marinho, Petr Ráb, Jorge Ivan Rebelo Porto, Eliana Feldberg and Marcelo de Bello Cioffi

Genes 2023, 14(1), 192; https://doi.org/10.3390/genes14010192 - 11 Jan 2023

Cited by 2 | Viewed by 2374

Abstract

Miniature refers to species with extraordinarily small adult body size when adult and can be found within all major metazoan groups. It is considered that miniature species have experienced severe alteration of numerous morphological traits during evolution. For a variety of reasons, including [...] Read more.

Miniature refers to species with extraordinarily small adult body size when adult and can be found within all major metazoan groups. It is considered that miniature species have experienced severe alteration of numerous morphological traits during evolution. For a variety of reasons, including severe labor concerns during collecting, chromosomal acquisition, and taxonomic issues, miniature fishes are neglected and understudied. Since some available studies indicate possible relationship between diploid chromosome number (2n) and body size in fishes, we aimed to study one of the smallest Neotropical fish Nannostomus anduzei (Teleostei, Characiformes, Lebiasinidae), using both conventional (Giemsa staining, C-banding) and molecular cytogenetic methods (FISH mapping of rDNAs, microsatellites, and telomeric sequences). Our research revealed that N. anduzei possesses one of the lowest diploid chromosome numbers (2n = 22) among teleost fishes, and its karyotype is entirely composed of large metacentric chromosomes. All chromosomes, except for pair number 11, showed an 18S rDNA signal in the pericentromeric region. 5S rDNA signals were detected in the pericentromeric regions of chromosome pair number 1 and 6, displaying synteny to 18S rDNA signals. Interstitial telomeric sites (ITS) were identified in the centromeric region of pairs 6 and 8, indicating that centric fusions played a significant role in karyotype evolution of studied species. Our study provides further evidence supporting the trend of diploid chromosome number reduction along with miniaturization of adult body size in fishes. Full article

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

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18 pages, 341 KiB

Open AccessEditor’s ChoiceArticle

Vitamin D Receptor Gene Polymorphisms Affect Osteoporosis-Related Traits and Response to Antiresorptive Therapy

by Vladimira Mondockova, Veronika Kovacova, Nina Zemanova, Martina Babikova, Monika Martiniakova, Drahomir Galbavy and Radoslav Omelka

Genes 2023, 14(1), 193; https://doi.org/10.3390/genes14010193 - 11 Jan 2023

Cited by 13 | Viewed by 3009

Abstract

The present study analyzed the effect of vitamin D receptor (VDR) gene polymorphisms (ApaI, TaqI, BsmI, FokI, and Cdx2) on bone mineral density (BMD), biochemical parameters and bone turnover markers, fracture prevalence, and response to three types of antiresorptive therapy (estrogen-progesterone, [...] Read more.

The present study analyzed the effect of vitamin D receptor (VDR) gene polymorphisms (ApaI, TaqI, BsmI, FokI, and Cdx2) on bone mineral density (BMD), biochemical parameters and bone turnover markers, fracture prevalence, and response to three types of antiresorptive therapy (estrogen-progesterone, raloxifene, and ibandronate) in 356 postmenopausal women from Slovakia. Association analysis revealed a significant effect of BsmI polymorphism on lumbar spine BMD, serum osteocalcin (OC), and β-CrossLaps levels. While ApaI and Cdx2 polymorphisms were associated with OC and alkaline phosphatase, TaqI polymorphism affected all turnover markers. ApaI, TaqI, and BsmI genotypes increased the risk of spinal, radial, or total fractures with odds ratios ranging from 2.03 to 3.17. Each of therapy types evaluated had a beneficial effect on all osteoporosis-related traits; however, the VDR gene affected only ibandronate and raloxifene treatment. ApaI/aa, TaqI/TT, and BsmI/bb genotypes showed a weaker or no response to ibandronate therapy in femoral and spinal BMD. The impact of aforementioned polymorphisms on turnover markers was also genotype dependent. On the contrary, only TaqI and BsmI polymorphisms influenced raloxifene therapy, even only in lumbar spine BMD. These results point to the potential of using the VDR gene in personalized pharmacotherapy of osteoporosis. Full article

(This article belongs to the Special Issue Genetics of Complex Human Disease)

21 pages, 3807 KiB

Open AccessEditor’s ChoiceArticle

A Genome-Wide View of the Transcriptome Dynamics of Fresh-Cut Potato Tubers

by Li Wang, Wanxing Wang, Jianwei Shan, Chengchen Li, Haicui Suo, Jitao Liu, Kang An, Xiaobo Li and Xingyao Xiong

Genes 2023, 14(1), 181; https://doi.org/10.3390/genes14010181 - 10 Jan 2023

Cited by 8 | Viewed by 2594

Abstract

Fresh fruits and vegetable products are easily perishable during postharvest handling due to enzymatic browning reactions. This phenomenon has contributed to a significant loss of food. To reveal the physiological changes in fresh-cut potato tubers at the molecular level, a transcriptome analysis of [...] Read more.

Fresh fruits and vegetable products are easily perishable during postharvest handling due to enzymatic browning reactions. This phenomenon has contributed to a significant loss of food. To reveal the physiological changes in fresh-cut potato tubers at the molecular level, a transcriptome analysis of potato tubers after cutting was carried out. A total of 10,872, 10,449, and 11,880 differentially expressed genes (DEGs) were identified at 4 h, 12 h and 24 h after cutting, respectively. More than 87.5% of these DEGs were classified into the categories of biological process (BP) and molecular function (MF) based on Gene Ontology (GO) analysis. There was a difference in the response to cutting at different stages after the cutting of potato tubers. The genes related to the phenol and fatty biosynthesis pathways, which are responsible for enzymatic browning and wound healing in potato tubers, were significantly enriched at 0–24 h after cutting. Most genes related to the enzymatic browning of potato tubers were up-regulated in response to cut-wounding. Plant hormone biosynthesis, signal molecular biosynthesis and transduction-related genes, such as gibberelin (GA), cytokinin (CK), ethylene (ET), auxin (IAA), jasmonic acid (JA), salicylic (SA), and Respiratory burst oxidase (Rboh) significantly changed at the early stage after cutting. In addition, the transcription factors involved in the wound response were the most abundant at the early stage after cutting. The transcription factor with the greatest response to injury was MYB, followed by AP2-EREBP, C3H and WRKY. This study revealed the physiological changes at the molecular level of fresh-cut potato tubers after cutting. This information is needed for developing a better approach to enhancing the postharvest shelf life of fresh processed potato and the breeding of potato plants that are resistant to enzymatic browning. Full article

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

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11 pages, 298 KiB

Open AccessEditor’s ChoiceArticle

Generating Minimal Models of H1N1 NS1 Gene Sequences Using Alignment-Based and Alignment-Free Algorithms

by Meng Fang, Jiawei Xu, Nan Sun and Stephen S.-T. Yau

Genes 2023, 14(1), 186; https://doi.org/10.3390/genes14010186 - 10 Jan 2023

Cited by 1 | Viewed by 1608

Abstract

For virus classification and tracing, one idea is to generate minimal models from the gene sequences of each virus group for comparative analysis within and between classes, as well as classification and tracing of new sequences. The starting point of defining a minimal [...] Read more.

For virus classification and tracing, one idea is to generate minimal models from the gene sequences of each virus group for comparative analysis within and between classes, as well as classification and tracing of new sequences. The starting point of defining a minimal model for a group of gene sequences is to find their longest common sequence (LCS), but this is a non-deterministic polynomial-time hard (NP-hard) problem. Therefore, we applied some heuristic approaches of finding LCS, as well as some of the newer methods of treating gene sequences, including multiple sequence alignment (MSA) and k-mer natural vector (NV) encoding. To evaluate our algorithms, a five-fold cross validation classification scheme on a dataset of H1N1 virus non-structural protein 1 (NS1) gene was analyzed. The results indicate that the MSA-based algorithm has the best performance measured by classification accuracy, while the NV-based algorithm exhibits advantages in the time complexity of generating minimal models. Full article

(This article belongs to the Special Issue Statistical Methods for Genetic Epidemiology)

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20 pages, 980 KiB

Open AccessEditor’s ChoiceReview

Genetic Diversity, Conservation, and Utilization of Plant Genetic Resources

by Romesh Kumar Salgotra and Bhagirath Singh Chauhan

Genes 2023, 14(1), 174; https://doi.org/10.3390/genes14010174 - 9 Jan 2023

Cited by 257 | Viewed by 37742

Abstract

Plant genetic resources (PGRs) are the total hereditary material, which includes all the alleles of various genes, present in a crop species and its wild relatives. They are a major resource that humans depend on to increase farming resilience and profit. Hence, the [...] Read more.

Plant genetic resources (PGRs) are the total hereditary material, which includes all the alleles of various genes, present in a crop species and its wild relatives. They are a major resource that humans depend on to increase farming resilience and profit. Hence, the demand for genetic resources will increase as the world population increases. There is a need to conserve and maintain the genetic diversity of these valuable resources for sustainable food security. Due to environmental changes and genetic erosion, some valuable genetic resources have already become extinct. The landraces, wild relatives, wild species, genetic stock, advanced breeding material, and modern varieties are some of the important plant genetic resources. These diverse resources have contributed to maintaining sustainable biodiversity. New crop varieties with desirable traits have been developed using these resources. Novel genes/alleles linked to the trait of interest are transferred into the commercially cultivated varieties using biotechnological tools. Diversity should be maintained as a genetic resource for the sustainable development of new crop varieties. Additionally, advances in biotechnological tools, such as next-generation sequencing, molecular markers, in vitro culture technology, cryopreservation, and gene banks, help in the precise characterization and conservation of rare and endangered species. Genomic tools help in the identification of quantitative trait loci (QTLs) and novel genes in plants that can be transferred through marker-assisted selection and marker-assisted backcrossing breeding approaches. This article focuses on the recent development in maintaining the diversity of genetic resources, their conservation, and their sustainable utilization to secure global food security. Full article

(This article belongs to the Special Issue Genetic Diversity, Conservation and Utilization of Plant Genetic Resources)

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13 pages, 294 KiB

Open AccessEditor’s ChoiceArticle

Association between Genetic Variants and Peripheral Neuropathy in Patients with NSCLC Treated with First-Line Platinum-Based Therapy

by Corine de Jong, Gerarda J. M. Herder, Simone W. A. van Haarlem, Femke S. van der Meer, Anne S. R. van Lindert, Alexandra ten Heuvel, Jan Brouwer, Toine C. G. Egberts and Vera H. M. Deneer

Genes 2023, 14(1), 170; https://doi.org/10.3390/genes14010170 - 7 Jan 2023

Cited by 5 | Viewed by 2550

Abstract

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common, disabling side effect in non-small cell lung cancer (NSCLC) patients treated with platinum-based therapy. There is increasing evidence for associations between genetic variants and susceptibility to CIPN. The aim of this study was to further [...] Read more.

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common, disabling side effect in non-small cell lung cancer (NSCLC) patients treated with platinum-based therapy. There is increasing evidence for associations between genetic variants and susceptibility to CIPN. The aim of this study was to further explore genetic risk factors for CIPN by investigating previously reported genetic associations. Methods: A multicenter prospective follow-up study (PGxLUNG, NTR NL5373610015) in NSCLC patients (stage II-IV) treated with first-line platinum-based (cisplatin or carboplatin) chemotherapy was conducted. Clinical evaluation of neuropathy (CTCAE v4.03) was performed at baseline and before each cycle (four cycles, every three weeks) of chemotherapy and at three and six months after treatment initiation. The relationship between 34 single nucleotide polymorphisms (SNPs) in 26 genes and any grade (grade ≥ 1) and severe (grade ≥ 2) CIPN was assessed by using univariate and multivariate logistic regression modelling. Results: In total, 320 patients were included of which 26.3% (n = 84) and 8.1% (n = 26) experienced any grade and severe CIPN, respectively. The GG-genotype (rs879207, A > G) of TRPV1, a gene expressed in peripheral sensory neurons, was observed in 11.3% (n = 36) of the patients and associated with an increased risk of severe neuropathy (OR 5.2, 95%CI 2.1–12.8, adjusted p-value 0.012). A quarter (25%, n = 9/36) of the patients with the GG-genotype developed severe neuropathy compared to 6% (n = 17/282) of the patients with the AG- or AA-genotype. Multivariate logistic regression analysis showed statistically significant associations between the GG-genotype (ORadj 4.7, 95%CI 1.8–12.3) and between concomitant use of paclitaxel (ORadj 7.2, 95%CI 2.5–21.1) and severe CIPN. Conclusions: Patients with the GG-genotype (rs879207) of TRPV1 have an almost 5-fold higher risk of developing severe neuropathy when treated with platinum-based therapy. Future studies should aim to validate these findings in an independent cohort and to further investigated the individualization of platinum-based chemotherapy in clinical practice. Full article

(This article belongs to the Section Pharmacogenetics)

13 pages, 2503 KiB

Open AccessEditor’s ChoiceArticle

Gathering the Stakeholder’s Perspective: Experiences and Opportunities in Rare Genetic Disease Research

by Lauren K. White, T. Blaine Crowley, Brenda Finucane, Emily J. McClellan, Sarah Donoghue, Sixto Garcia-Minaur, Gabriela M. Repetto, Matthias Fischer, Sebastien Jacquemont, Raquel E. Gur, Anne M. Maillard, Kirsten A. Donald, Anne S. Bassett, Ann Swillen and Donna M. McDonald-McGinn

Genes 2023, 14(1), 169; https://doi.org/10.3390/genes14010169 - 7 Jan 2023

Cited by 3 | Viewed by 2375

Abstract

Background: Research participant feedback is rarely collected; therefore, investigators have limited understanding regarding stakeholders’ (affected individuals/caregivers) motivation to participate. Members of the Genes to Mental Health Network (G2MH) surveyed stakeholders affected by copy number variants (CNVs) regarding perceived incentives for study participation, opinions [...] Read more.

Background: Research participant feedback is rarely collected; therefore, investigators have limited understanding regarding stakeholders’ (affected individuals/caregivers) motivation to participate. Members of the Genes to Mental Health Network (G2MH) surveyed stakeholders affected by copy number variants (CNVs) regarding perceived incentives for study participation, opinions concerning research priorities, and the necessity for future funding. Respondents were also asked about feelings of preparedness, research burden, and satisfaction with research study participation. Methods: Modified validated surveys were used to assess stakeholders´ views across three domains: (1) Research Study Enrollment, Retainment, Withdrawal, and Future Participation; (2) Overall Research Experience, Burden, and Preparedness; (3) Research Priorities and Obstacles. Top box score analyses were performed. Results: A total of 704 stakeholders´ responded from 29 countries representing 55 CNVs. The top reasons for initial participation in the research included reasons related to education and altruism. The top reasons for leaving a research study included treatment risks and side effects. The importance of sharing research findings and laboratory results with stakeholders was underscored by participants. Most stakeholders reported positive research experiences. Conclusions: This study provides important insight into how individuals and families affected with a rare CNV feel toward research participation and their overall experience in rare disease research. There are clear targets for areas of improvement for study teams, although many stakeholders reported positive research experiences. Key findings from this international survey may help advance collaborative research and improve the experience of participants, investigators, and other stakeholders moving forward. Full article

(This article belongs to the Special Issue 22q11.2 Deletion Syndrome)

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