Genes

Article

12 pages, 734 KiB

Open AccessEditor’s ChoiceArticle

LncRNA-SNPs in a Brazilian Breast Cancer Cohort: A Case-Control Study

by Carolina Mathias, Anelis Maria Marin, Ana Flávia Kohler, Heloisa Bruna Soligo Sanchuki, Natalie Sukow, Marcia Holsbach Beltrame, Suelen Cristina Soares Baal, Ana Paula Martins Sebastião, Enilze Maria de Souza Fonseca Ribeiro, Daniela Fiori Gradia, Mateus Nóbrega Aoki and Jaqueline Carvalho de Oliveira

Genes 2023, 14(5), 971; https://doi.org/10.3390/genes14050971 - 25 Apr 2023

Cited by 2 | Viewed by 2207

Abstract

Long noncoding RNAs (lncRNAs) are a class of non-coding RNAs that contain more than 200 nucleotides and exhibit a versatile regulatory capacity. Genomic alterations in lncRNAs have already been investigated in several complex diseases, including breast cancer (BC). BC is a highly heterogeneous [...] Read more.

Long noncoding RNAs (lncRNAs) are a class of non-coding RNAs that contain more than 200 nucleotides and exhibit a versatile regulatory capacity. Genomic alterations in lncRNAs have already been investigated in several complex diseases, including breast cancer (BC). BC is a highly heterogeneous disease and is the most prevalent cancer type among women worldwide. Single nucleotide polymorphisms (SNPs) in lncRNA regions appear to have an important role in BC susceptibility; however, little is known about lncRNA-SNPs in the Brazilian population. This study used Brazilian tumor samples to identify lncRNA-SNPs with a biological role in BC development. We applied a bioinformatic approach intersecting lncRNAs that are differentially expressed in BC tumor samples using The Cancer Genome Atlas (TCGA) cohort data and looked for lncRNAs with SNPs associated with BC in the Genome Wide Association Studies (GWAS) catalog. We highlight four lncRNA-SNPs—rs3803662, rs4415084, rs4784227, and rs7716600—which were genotyped in Brazilian BC samples in a case-control study. The SNPs rs4415084 and rs7716600 were associated with BC development at higher risk. These SNPs were also associated with progesterone status and lymph node status, respectively. The rs3803662/rs4784227 haplotype GT was associated with BC risk. These genomic alterations were also evaluated in light of the lncRNA’s secondary structure and gain/loss of miRNA binding sites to better understand its biological functions. We emphasize that our bioinformatics approach could find lncRNA-SNPs with a potential biological role in BC development and that lncRNA-SNPs should be more deeply investigated in a highly heterogeneous disease population. Full article

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

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16 pages, 263 KiB

Open AccessEditor’s ChoiceArticle

Expanding the Knowledge of KIF1A-Dependent Disorders to a Group of Polish Patients

by Justyna Paprocka, Aleksandra Jezela-Stanek, Robert Śmigiel, Anna Walczak, Hanna Mierzewska, Anna Kutkowska-Kaźmierczak, Rafał Płoski, Ewa Emich-Widera and Barbara Steinborn

Genes 2023, 14(5), 972; https://doi.org/10.3390/genes14050972 - 25 Apr 2023

Cited by 6 | Viewed by 2854

Abstract

Background: KIF1A (kinesin family member 1A)-related disorders encompass a variety of diseases. KIF1A variants are responsible for autosomal recessive and dominant spastic paraplegia 30 (SPG, OMIM610357), autosomal recessive hereditary sensory and autonomic neuropathy type 2 (HSN2C, OMIM614213), and autosomal dominant neurodegeneration and spasticity [...] Read more.

Background: KIF1A (kinesin family member 1A)-related disorders encompass a variety of diseases. KIF1A variants are responsible for autosomal recessive and dominant spastic paraplegia 30 (SPG, OMIM610357), autosomal recessive hereditary sensory and autonomic neuropathy type 2 (HSN2C, OMIM614213), and autosomal dominant neurodegeneration and spasticity with or without cerebellar atrophy or cortical visual impairment (NESCAV syndrome), formerly named mental retardation type 9 (MRD9) (OMIM614255). KIF1A variants have also been occasionally linked with progressive encephalopathy with brain atrophy, progressive neurodegeneration, PEHO-like syndrome (progressive encephalopathy with edema, hypsarrhythmia, optic atrophy), and Rett-like syndrome. Materials and Methods: The first Polish patients with confirmed heterozygous pathogenic and potentially pathogenic KIF1A variants were analyzed. All the patients were of Caucasian origin. Five patients were females, and four were males (female-to-male ratio = 1.25). The age of onset of the disease ranged from 6 weeks to 2 years. Results: Exome sequencing identified three novel variants. Variant c.442G>A was described in the ClinVar database as likely pathogenic. The other two novel variants, c.609G>C; p.(Arg203Ser) and c.218T>G, p.(Val73Gly), were not recorded in ClinVar. Conclusions: The authors underlined the difficulties in classifying particular syndromes due to non-specific and overlapping signs and symptoms, sometimes observed only temporarily. Full article

(This article belongs to the Special Issue Genetics and Genomics of Heritable Pediatric Disorders)

14 pages, 2161 KiB

Open AccessEditor’s ChoiceArticle

Identification of LncRNAs and Functional Analysis of ceRNA Related to Fatty Acid Synthesis during Flax Seed Development

by Xinsen Yang, Caiyue Liu, Qiaoling Tang, Tianbao Zhang, Limin Wang, Lida Han, Jianping Zhang and Xinwu Pei

Genes 2023, 14(5), 967; https://doi.org/10.3390/genes14050967 - 24 Apr 2023

Cited by 3 | Viewed by 1838

Abstract

Flax is a flowering plant cultivated for its oil and contains various unsaturated fatty acids. Linseed oil is known as the “deep-sea fish oil” of plants, and is beneficial to brain and blood lipids, among other positive effects. Long non-coding RNAs (lncRNAs) play [...] Read more.

Flax is a flowering plant cultivated for its oil and contains various unsaturated fatty acids. Linseed oil is known as the “deep-sea fish oil” of plants, and is beneficial to brain and blood lipids, among other positive effects. Long non-coding RNAs (lncRNAs) play an important role in plant growth and development. There are not many studies assessing how lncRNAs are related to the fatty acid synthesis of flax. The relative oil contents of the seeds of the variety Heiya NO.14 (for fiber) and the variety Macbeth (for oil) were determined at 5 day, 10 day, 20 day, and 30 day after flowering. We found that 10–20 day is an important period for ALA accumulation in the Macbeth variety. The strand-specific transcriptome data were analyzed at these four time points, and a series of lncRNAs related to flax seed development were screened. A competing endogenous RNA (ceRNA) network was constructed and the accuracy of the network was verified using qRT-PCR. MSTRG.20631.1 could act with miR156 on the same target, squamosa promoter-binding-like protein (SPL), to influence fatty acid biosynthesis through a gluconeogenesis-related pathway during flax seed development. This study provides a theoretical basis for future studies assessing the potential functions of lncRNAs during seed development. Full article

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

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14 pages, 637 KiB

Open AccessEditor’s ChoiceArticle

Prognostic Values of Gene Copy Number Alterations in Prostate Cancer

by Abdulaziz Alfahed, Henry Okuchukwu Ebili, Nasser Eissa Almoammar, Glowi Alasiri, Osama A. AlKhamees, Jehad A. Aldali, Ayoub Al Othaim, Zaki H. Hakami, Abdulhadi M. Abdulwahed and Hisham Ali Waggiallah

Genes 2023, 14(5), 956; https://doi.org/10.3390/genes14050956 - 22 Apr 2023

Cited by 7 | Viewed by 3025

Abstract

Whilst risk prediction for individual prostate cancer (PCa) cases is of a high priority, the current risk stratification indices for PCa management have severe limitations. This study aimed to identify gene copy number alterations (CNAs) with prognostic values and to determine if any [...] Read more.

Whilst risk prediction for individual prostate cancer (PCa) cases is of a high priority, the current risk stratification indices for PCa management have severe limitations. This study aimed to identify gene copy number alterations (CNAs) with prognostic values and to determine if any combination of gene CNAs could have risk stratification potentials. Clinical and genomic data of 500 PCa cases from the Cancer Genome Atlas stable were retrieved from the Genomic Data Commons and cBioPortal databases. The CNA statuses of a total of 52 genetic markers, including 21 novel markers and 31 previously identified potential prognostic markers, were tested for prognostic significance. The CNA statuses of a total of 51/52 genetic markers were significantly associated with advanced disease at an odds ratio threshold of ≥1.5 or ≤0.667. Moreover, a Kaplan–Meier test identified 27/52 marker CNAs which correlated with disease progression. A Cox Regression analysis showed that the amplification of MIR602 and deletions of MIR602, ZNF267, MROH1, PARP8, and HCN1 correlated with a progression-free survival independent of the disease stage and Gleason prognostic group grade. Furthermore, a binary logistic regression analysis identified twenty-two panels of markers with risk stratification potentials. The best model of 7/52 genetic CNAs, which included the SPOP alteration, SPP1 alteration, CCND1 amplification, PTEN deletion, CDKN1B deletion, PARP8 deletion, and NKX3.1 deletion, stratified the PCa cases into a localised and advanced disease with an accuracy of 70.0%, sensitivity of 85.4%, specificity of 44.9%, positive predictive value of 71.67%, and negative predictive value of 65.35%. This study validated prognostic gene level CNAs identified in previous studies, as well as identified new genetic markers with CNAs that could potentially impact risk stratification in PCa. Full article

(This article belongs to the Special Issue Bioinformatics of Disease Genes)

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12 pages, 1531 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

Japanese Flounder pol-miR-155 Is Involved in Edwardsiella tarda Infection via ATG3

by Zhanwei Zhang and Xiaolu Guan

Genes 2023, 14(5), 958; https://doi.org/10.3390/genes14050958 - 22 Apr 2023

Cited by 5 | Viewed by 2002

Abstract

MicroRNAs (miRNAs) are small RNA molecules that function in the post-transcriptionally regulation of the expression of diverse genes, including those involved in immune defense. Edwardsiella tarda can infect a broad range of hosts and cause severe disease in aquatic species, including Japanese flounder [...] Read more.

MicroRNAs (miRNAs) are small RNA molecules that function in the post-transcriptionally regulation of the expression of diverse genes, including those involved in immune defense. Edwardsiella tarda can infect a broad range of hosts and cause severe disease in aquatic species, including Japanese flounder (Paralichthys olivaceus). In this study, we examined the regulation mechanism of a flounder miRNA, pol-miR-155, during the infection of E. tarda. Pol-miR-155 was identified to target flounder ATG3. Overexpression of pol-miR-155 or knockdown of ATG3 expression suppressed autophagy and promoted the intracellular replication of E. tarda in flounder cells. Overexpression of pol-miR-155 activated the NF-κB signaling pathway and further promoted the expression of downstream immune related genes of interleukin (IL)-6 and IL-8. These results unraveled the regulatory effect of pol-miR-155 in autophagy and in E. tarda infection. Full article

(This article belongs to the Special Issue Advances in Genes and Genomics of Aquatic Animals and Pathogens)

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15 pages, 3736 KiB

Open AccessEditor’s ChoiceArticle

Intrafollicular Retinoic Acid Signaling Is Important for Luteinizing Hormone-Induced Oocyte Meiotic Resumption

by Fupeng Wang, Yawen Tang, Yijie Cai, Ran Yang, Zongyu Wang, Xiaodong Wang, Qianying Yang, Wenjing Wang, Jianhui Tian and Lei An

Genes 2023, 14(4), 946; https://doi.org/10.3390/genes14040946 - 20 Apr 2023

Cited by 4 | Viewed by 2369

Abstract

It has been clear that retinoic acid (RA), the most active vitamin A (VA) derivative, plays a central role in governing oocyte meiosis initiation. However, it has not been functionally determined if RA participates in luteinizing hormone (LH)-induced resumption from long-lasting oocyte meiotic [...] Read more.

It has been clear that retinoic acid (RA), the most active vitamin A (VA) derivative, plays a central role in governing oocyte meiosis initiation. However, it has not been functionally determined if RA participates in luteinizing hormone (LH)-induced resumption from long-lasting oocyte meiotic arrest, which is essential for haploid oocyte formation. In the present study, using well-established in vivo and in vitro models, we identified that intrafollicular RA signaling is important for normal oocyte meiotic resumption. A mechanistic study indicated that mural granulosa cells (MGCs) are the indispensable follicular compartment for RA-prompted meiotic resumption. Moreover, retinoic acid receptor (RAR) is essential for mediating RA signaling to regulate meiotic resumption. Furthermore, we found zinc finger protein 36 (ZFP36) is the transcriptional target of RAR. Both RA signaling and epidermal growth factor (EGF) signaling were activated in MGCs in response to LH surge, and two intrafollicular signalings cooperate to induce rapid Zfp36 upregulation and Nppc mRNA decrease, which is critical to LH-induced meiotic resumption. These findings extend our understanding of the role of RA in oocyte meiosis: RA not only governs meiotic initiation but also regulates LH-induced meiotic resumption. We also emphasize the importance of LH-induced metabolic changes in MGCs in this process. Full article

(This article belongs to the Special Issue Genetic Regulation of Animal Reproduction)

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12 pages, 1060 KiB

Open AccessEditor’s ChoiceArticle

Comprehensive Genetic Analysis of Druze Provides Insights into Carrier Screening

by Eden Avnat, Guy Shapira, Shelly Shoval, Ifat Israel-Elgali, Anna Alkelai, Alan R. Shuldiner, Claudia Gonzaga-Jauregui, Jamal Zidan, Taiseer Maray, Noam Shomron and Eitan Friedman

Genes 2023, 14(4), 937; https://doi.org/10.3390/genes14040937 - 18 Apr 2023

Cited by 1 | Viewed by 2703

Abstract

Background: Druze individuals, like many genetically homogeneous and isolated populations, harbor recurring pathogenic variants (PV) in autosomal recessive (AR) disorders. Methods: Variant calling of whole-genome sequencing (WGS) of 40 Druze from the Human Genome Diversity Project (HGDP) was performed (HGDP-cohort). Additionally, we performed [...] Read more.

Background: Druze individuals, like many genetically homogeneous and isolated populations, harbor recurring pathogenic variants (PV) in autosomal recessive (AR) disorders. Methods: Variant calling of whole-genome sequencing (WGS) of 40 Druze from the Human Genome Diversity Project (HGDP) was performed (HGDP-cohort). Additionally, we performed whole exome sequencing (WES) of 118 Druze individuals: 38 trios and 2 couples, representing geographically distinct clans (WES-cohort). Rates of validated PV were compared with rates in worldwide and Middle Eastern populations, from the gnomAD and dbSNP datasets. Results: Overall, 34 PVs were identified: 30 PVs in genes underlying AR disorders, 3 additional PVs were associated with autosomal dominant (AD) disorders, and 1 PV with X-linked-dominant inherited disorder in the WES cohort. Conclusions: The newly identified PVs associated with AR conditions should be considered for incorporation into prenatal-screening options offered to Druze individuals after an extension and validation of the results in a larger study. Full article

(This article belongs to the Special Issue Genetic Variants in Human Population and Diseases)

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14 pages, 5790 KiB

Open AccessEditor’s ChoiceArticle

Deep-Learning-Based Hepatic Ploidy Quantification Using H&E Histopathology Images

by Zhuoyu Wen, Yu-Hsuan Lin, Shidan Wang, Naoto Fujiwara, Ruichen Rong, Kevin W. Jin, Donghan M. Yang, Bo Yao, Shengjie Yang, Tao Wang, Yang Xie, Yujin Hoshida, Hao Zhu and Guanghua Xiao

Genes 2023, 14(4), 921; https://doi.org/10.3390/genes14040921 - 16 Apr 2023

Cited by 4 | Viewed by 3236

Abstract

Polyploidy, the duplication of the entire genome within a single cell, is a significant characteristic of cells in many tissues, including the liver. The quantification of hepatic ploidy typically relies on flow cytometry and immunofluorescence (IF) imaging, which are not widely available in [...] Read more.

Polyploidy, the duplication of the entire genome within a single cell, is a significant characteristic of cells in many tissues, including the liver. The quantification of hepatic ploidy typically relies on flow cytometry and immunofluorescence (IF) imaging, which are not widely available in clinical settings due to high financial and time costs. To improve accessibility for clinical samples, we developed a computational algorithm to quantify hepatic ploidy using hematoxylin-eosin (H&E) histopathology images, which are commonly obtained during routine clinical practice. Our algorithm uses a deep learning model to first segment and classify different types of cell nuclei in H&E images. It then determines cellular ploidy based on the relative distance between identified hepatocyte nuclei and determines nuclear ploidy using a fitted Gaussian mixture model. The algorithm can establish the total number of hepatocytes and their detailed ploidy information in a region of interest (ROI) on H&E images. This is the first successful attempt to automate ploidy analysis on H&E images. Our algorithm is expected to serve as an important tool for studying the role of polyploidy in human liver disease. Full article

(This article belongs to the Special Issue Feature Papers in Technologies and Resources for Genetics 2023)

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17 pages, 1243 KiB

Open AccessEditor’s ChoiceArticle

Interaction between KLOTHO-VS Heterozygosity and APOE ε4 Allele Predicts Rate of Cognitive Decline in Late-Onset Alzheimer’s Disease

by Xi Richard Chen, Yongzhao Shao, Martin J. Sadowski and on behalf of the Alzheimer’s Disease Neuroimaging Initiative

Genes 2023, 14(4), 917; https://doi.org/10.3390/genes14040917 - 15 Apr 2023

Cited by 2 | Viewed by 3177

Abstract

KLOTHO-VS heterozygosity (KL-VS^het+) promotes longevity and protects against cognitive decline in aging. To determine whether KL-VS^het+ mitigates Alzheimer’s disease (AD) progression, we used longitudinal linear-mixed models to compare the rate of change in multiple cognitive measures [...] Read more.

KLOTHO-VS heterozygosity (KL-VS^het+) promotes longevity and protects against cognitive decline in aging. To determine whether KL-VS^het+ mitigates Alzheimer’s disease (AD) progression, we used longitudinal linear-mixed models to compare the rate of change in multiple cognitive measures in AD patients stratified by APOE ε4 carrier status. We aggregated data on 665 participants (208 KL-VS^het−/ε4−, 307 KL-VS^het−/ε4+, 66 KL-VS^het+/ε4−, and 84 KL-VS^het+/ε4+) from two prospective cohorts, the National Alzheimer’s Coordinating Center and the Alzheimer’s Disease Neuroimaging Initiative. All participants were initially diagnosed with mild cognitive impairment, later developed AD dementia during the study, and had at least three subsequent visits. KL-VS^het+ conferred slower cognitive decline in ε4 non-carriers (+0.287 MMSE points/year, p = 0.001; −0.104 CDR-SB points/year, p = 0.026; −0.042 ADCOMS points/year, p < 0.001) but not in ε4 carriers who generally had faster rates of decline than non-carriers. Stratified analyses showed that the protective effect of KL-VS^het+ was particularly prominent in male participants, those who were older than the median baseline age of 76 years, or those who had an education level of at least 16 years. For the first time, our study provides evidence that KL-VS^het+ status has a protective effect on AD progression and interacts with the ε4 allele. Full article

(This article belongs to the Special Issue Molecular Biomarkers in Alzheimer’s Disease)

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15 pages, 3467 KiB

Open AccessEditor’s ChoiceArticle

The Potential Regulation of A-to-I RNA Editing on Genes in Parkinson’s Disease

by Sijia Wu, Qiuping Xue, Xinyu Qin, Xiaoming Wu, Pora Kim, Jacqueline Chyr, Xiaobo Zhou and Liyu Huang

Genes 2023, 14(4), 919; https://doi.org/10.3390/genes14040919 - 15 Apr 2023

Cited by 3 | Viewed by 2576

Abstract

Parkinson’s disease (PD) is characterized by dopaminergic neurodegeneration and an abnormal accumulation of α-synuclein aggregates. A number of genetic factors have been shown to increase the risk of PD. Exploring the underlying molecular mechanisms that mediate PD’s transcriptomic diversity can help us understand [...] Read more.

Parkinson’s disease (PD) is characterized by dopaminergic neurodegeneration and an abnormal accumulation of α-synuclein aggregates. A number of genetic factors have been shown to increase the risk of PD. Exploring the underlying molecular mechanisms that mediate PD’s transcriptomic diversity can help us understand neurodegenerative pathogenesis. In this study, we identified 9897 A-to-I RNA editing events associated with 6286 genes across 372 PD patients. Of them, 72 RNA editing events altered miRNA binding sites and this may directly affect miRNA regulations of their host genes. However, RNA editing effects on the miRNA regulation of genes are more complex. They can (1) abolish existing miRNA binding sites, which allows miRNAs to regulate other genes; (2) create new miRNA binding sites that may sequester miRNAs from regulating other genes; or (3) occur in the miRNA seed regions and change their targets. The first two processes are also referred to as miRNA competitive binding. In our study, we found 8 RNA editing events that may alter the expression of 1146 other genes via miRNA competition. We also found one RNA editing event that modified a miRNA seed region, which was predicted to disturb the regulation of four genes. Considering the PD-related functions of the affected genes, 25 A-to-I RNA editing biomarkers for PD are proposed, including the 3 editing events in the EIF2AK2, APOL6, and miR-4477b seed regions. These biomarkers may alter the miRNA regulation of 133 PD-related genes. All these analyses reveal the potential mechanisms and regulations of RNA editing in PD pathogenesis. Full article

(This article belongs to the Special Issue Transcriptomics and Bioinformatics in Precision Medicine)

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23 pages, 2815 KiB

Open AccessEditor’s ChoiceArticle

Whole Mitochondrial Genome Detection and Analysis of Two- to Four-Generation Maternal Pedigrees Using a New Massively Parallel Sequencing Panel

by Dan Peng, Jiaojiao Geng, Jingyi Yang, Jiajun Liu, Nana Wang, Riga Wu and Hongyu Sun

Genes 2023, 14(4), 912; https://doi.org/10.3390/genes14040912 - 14 Apr 2023

Cited by 7 | Viewed by 2632

Abstract

Mitochondrial DNA (mtDNA) is an effective genetic marker in forensic practice, especially for aged bones and hair shafts. Detection of the whole mitochondrial genome (mtGenome) using traditional Sanger-type sequencing is laborious and time-consuming. Additionally, its ability to distinguish point heteroplasmy (PHP) and length [...] Read more.

Mitochondrial DNA (mtDNA) is an effective genetic marker in forensic practice, especially for aged bones and hair shafts. Detection of the whole mitochondrial genome (mtGenome) using traditional Sanger-type sequencing is laborious and time-consuming. Additionally, its ability to distinguish point heteroplasmy (PHP) and length heteroplasmy (LHP) is limited. The application of massively parallel sequencing in mtDNA detection helps researchers to study the mtGenome in-depth. The ForenSeq mtDNA Whole Genome Kit, which contains a total of 245 short amplicons, is one of the multiplex library preparation kits for the mtGenome. We used this system to detect the mtGenome in the blood samples and hair shafts of thirty-three individuals from eight two-generation pedigrees, one three-generation pedigree, and one four-generation pedigree. High-quality sequencing results were obtained. Ten unique mtGenome haplotypes were observed in the mothers from the ten pedigrees. A total of 26 PHPs were observed using the interpretation threshold of 6%. Eleven types of LHPs in six regions were evaluated in detail. When considering homoplasmic variants only, consistent mtGenome haplotypes were observed between the twice-sequenced libraries and between the blood and hair shafts from the same individual and among maternal relatives in the pedigrees. Four inherited PHPs were observed, and the remainder were de novo/disappearing PHPs in the pedigrees. Our results demonstrate the effective capability of the ForenSeq mtDNA Whole Genome Kit to generate the complete mtGenome in blood and hair shafts, as well as the complexity of mtDNA haplotype comparisons between different types of maternal relatives when heteroplasmy is considered. Full article

(This article belongs to the Special Issue Advances in Forensic Molecular Genetics)

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16 pages, 326 KiB

Open AccessEditor’s ChoiceArticle

Molecular and Sociodemographic Colorectal Cancer Disparities in Latinos Living in Puerto Rico

by Julyann Perez-Mayoral, Maria Gonzalez-Pons, Hilmaris Centeno-Girona, Ingrid M. Montes-Rodríguez, Marievelisse Soto-Salgado, Belisa Suárez, Natalia Rodríguez, Giancarlo Colón, Javier Sevilla, Daphne Jorge, Xavier Llor, Rosa M. Xicola, Doris H. Toro, Luis Tous-López, Marla Torres-Torres, José S. Reyes, Nicolas López-Acevedo, Ajay Goel, Segundo Rodríguez-Quilichini and Marcia Cruz-Correa

Genes 2023, 14(4), 894; https://doi.org/10.3390/genes14040894 - 11 Apr 2023

Cited by 5 | Viewed by 2937

Abstract

Background: The incidence of sporadic colorectal cancer (CRC) among individuals <50 years (early-onset CRC) has been increasing in the United States (U.S.) and Puerto Rico. CRC is currently the leading cause of cancer death among Hispanic men and women living in Puerto Rico [...] Read more.

Background: The incidence of sporadic colorectal cancer (CRC) among individuals <50 years (early-onset CRC) has been increasing in the United States (U.S.) and Puerto Rico. CRC is currently the leading cause of cancer death among Hispanic men and women living in Puerto Rico (PRH). The objective of this study was to characterize the molecular markers and clinicopathologic features of colorectal tumors from PRH to better understand the molecular pathways leading to CRC in this Hispanic subpopulation. Methods: Microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and KRAS and BRAF mutation status were analyzed. Sociodemographic and clinicopathological characteristics were evaluated using Chi-squared and Fisher’s exact tests. Results: Of the 718 tumors analyzed, 34.2% (n = 245) were early-onset CRC, and 51.7% were males. Among the tumors with molecular data available (n = 192), 3.2% had MSI, 9.7% had BRAF, and 31.9% had KRAS mutations. The most common KRAS mutations observed were G12D (26.6%) and G13D (20.0%); G12C was present in 4.4% of tumors. A higher percentage of Amerindian admixture was significantly associated with early-onset CRC. Conclusions: The differences observed in the prevalence of the molecular markers among PRH tumors compared to other racial/ethnic groups suggest a distinct molecular carcinogenic pathway among Hispanics. Additional studies are warranted. Full article

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

27 pages, 13999 KiB

Open AccessEditor’s ChoiceArticle

Chromosome-Level Genome Assembly of the Blue Mussel Mytilus chilensis Reveals Molecular Signatures Facing the Marine Environment

by Cristian Gallardo-Escárate, Valentina Valenzuela-Muñoz, Gustavo Nuñez-Acuña, Diego Valenzuela-Miranda, Fabian J. Tapia, Marco Yévenes, Gonzalo Gajardo, Jorge E. Toro, Pablo A. Oyarzún, Gloria Arriagada, Beatriz Novoa, Antonio Figueras, Steven Roberts and Marco Gerdol

Genes 2023, 14(4), 876; https://doi.org/10.3390/genes14040876 - 7 Apr 2023

Cited by 16 | Viewed by 4756

Abstract

The blue mussel Mytilus chilensis is an endemic and key socioeconomic species inhabiting the southern coast of Chile. This bivalve species supports a booming aquaculture industry, which entirely relies on artificially collected seeds from natural beds that are translocated to diverse physical–chemical ocean [...] Read more.

The blue mussel Mytilus chilensis is an endemic and key socioeconomic species inhabiting the southern coast of Chile. This bivalve species supports a booming aquaculture industry, which entirely relies on artificially collected seeds from natural beds that are translocated to diverse physical–chemical ocean farming conditions. Furthermore, mussel production is threatened by a broad range of microorganisms, pollution, and environmental stressors that eventually impact its survival and growth. Herein, understanding the genomic basis of the local adaption is pivotal to developing sustainable shellfish aquaculture. We present a high-quality reference genome of M. chilensis, which is the first chromosome-level genome for a Mytilidae member in South America. The assembled genome size was 1.93 Gb, with a contig N50 of 134 Mb. Through Hi-C proximity ligation, 11,868 contigs were clustered, ordered, and assembled into 14 chromosomes in congruence with the karyological evidence. The M. chilensis genome comprises 34,530 genes and 4795 non-coding RNAs. A total of 57% of the genome contains repetitive sequences with predominancy of LTR-retrotransposons and unknown elements. Comparative genome analysis of M. chilensis and M. coruscus was conducted, revealing genic rearrangements distributed into the whole genome. Notably, transposable Steamer-like elements associated with horizontal transmissible cancer were explored in reference genomes, suggesting putative relationships at the chromosome level in Bivalvia. Genome expression analysis was also conducted, showing putative genomic differences between two ecologically different mussel populations. The evidence suggests that local genome adaptation and physiological plasticity can be analyzed to develop sustainable mussel production. The genome of M. chilensis provides pivotal molecular knowledge for the Mytilus complex. Full article

(This article belongs to the Special Issue Genetics and Genomics in Aquatic Animals)

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12 pages, 1337 KiB

Open AccessEditor’s ChoiceArticle

Leri–Weill Dyschondrosteosis Caused by a Leaky Homozygous SHOX Splice-Site Variant

by Julia Vodopiutz, Lisa-Maria Steurer, Florentina Haufler, Franco Laccone, Dorota Garczarczyk-Asim, Matthias Hilkenmeier, Philipp Steinbauer and Andreas R. Janecke

Genes 2023, 14(4), 877; https://doi.org/10.3390/genes14040877 - 7 Apr 2023

Cited by 2 | Viewed by 2359

Abstract

SHOX deficiency is a common genetic cause of short stature of variable degree. SHOX haploinsufficiency causes Leri–Weill dyschondrosteosis (LWD) as well as nonspecific short stature. SHOX haploinsufficiency is known to result from heterozygous loss-of-function variants with pseudo-autosomal dominant inheritance, while biallelic SHOX loss-of-function [...] Read more.

SHOX deficiency is a common genetic cause of short stature of variable degree. SHOX haploinsufficiency causes Leri–Weill dyschondrosteosis (LWD) as well as nonspecific short stature. SHOX haploinsufficiency is known to result from heterozygous loss-of-function variants with pseudo-autosomal dominant inheritance, while biallelic SHOX loss-of-function variants cause the more severe skeletal dysplasia, Langer mesomelic dyschondrosteosis (LMD). Here we report for the first time the pseudo-autosomal recessive inheritance of LWD in two siblings caused by a novel homozygous non-canonical, leaky splice-site variant in intron 3 of SHOX: c.544+5G>C. Transcript analyses in patient-derived fibroblasts showed homozygous patients to produce approximately equal amounts of normally spliced mRNA and mRNA with the abnormal retention of intron 3 and containing a premature stop codon (p.Val183Glyfs*31). The aberrant transcript was shown to undergo nonsense-mediated mRNA decay, and thus resulting in SHOX haploinsufficiency in the homozygous patient. Six healthy relatives who are of normal height are heterozygous for this variant and fibroblasts from a heterozygote for the c.544+5G>C variant produced wild-type transcript amounts comparable to healthy control. The unique situation reported here highlights the fact that the dosage of SHOX determines the clinical phenotype rather than the Mendelian inheritance pattern of SHOX variants. This study extends the molecular and inheritance spectrum of SHOX deficiency disorder and highlights the importance of functional testing of SHOX variants of unknown significance in order to allow appropriate counseling and precision medicine for each family individual. Full article

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

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17 pages, 2051 KiB

Open AccessEditor’s ChoiceArticle

Leishmania infantum (JPCM5) Transcriptome, Gene Models and Resources for an Active Curation of Gene Annotations

by Esther Camacho, Sandra González-de la Fuente, Jose Carlos Solana, Laura Tabera, Fernando Carrasco-Ramiro, Begoña Aguado and Jose M. Requena

Genes 2023, 14(4), 866; https://doi.org/10.3390/genes14040866 - 4 Apr 2023

Cited by 3 | Viewed by 2612

Abstract

Leishmania infantum is one of the causative agents of visceral leishmaniases, the most severe form of leishmaniasis. An improved assembly for the L. infantum genome was published five years ago, yet delineation of its transcriptome remained to be accomplished. In this work, the [...] Read more.

Leishmania infantum is one of the causative agents of visceral leishmaniases, the most severe form of leishmaniasis. An improved assembly for the L. infantum genome was published five years ago, yet delineation of its transcriptome remained to be accomplished. In this work, the transcriptome annotation was attained by a combination of both short and long RNA-seq reads. The good agreement between the results derived from both methodologies confirmed that transcript assembly based on Illumina RNA-seq and further delimitation according to the positions of spliced leader (SAS) and poly-A (PAS) addition sites is an adequate strategy to annotate the transcriptomes of Leishmania, a procedure previously used for transcriptome annotation in other Leishmania species and related trypanosomatids. These analyses also confirmed that the Leishmania transcripts boundaries are relatively slippery, showing extensive heterogeneity at the 5′- and 3′-ends. However, the use of RNA-seq reads derived from the PacBio technology (referred to as Iso-Seq) allowed the authors to uncover some complex transcription patterns occurring at particular loci that would be unnoticed by the use of short RNA-seq reads alone. Thus, Iso-Seq analysis provided evidence that transcript processing at particular loci would be more dynamic than expected. Another noticeable finding was the observation of a case of allelic heterozygosity based on the existence of chimeric Iso-Seq reads that might be generated by an event of intrachromosomal recombination. In addition, we are providing the L. infantum gene models, including both UTRs and CDS regions, that would be helpful for undertaking whole-genome expression studies. Moreover, we have built the foundations of a communal database for the active curation of both gene/transcript models and functional annotations for genes and proteins. Full article

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

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13 pages, 4343 KiB

Open AccessEditor’s ChoiceArticle

Molecular Characterization of the Acyl-CoA-Binding Protein Genes Reveals Their Significant Roles in Oil Accumulation and Abiotic Stress Response in Cotton

by Yizhen Chen, Mingchuan Fu, Hao Li, Liguo Wang, Renzhong Liu and Zhanji Liu

Genes 2023, 14(4), 859; https://doi.org/10.3390/genes14040859 - 1 Apr 2023

Cited by 3 | Viewed by 1889

Abstract

Members of the acyl-CoA-binding protein (ACBP) gene family play vital roles in diverse processes related to lipid metabolism, growth and development, and environmental response. Plant ACBP genes have been well-studied in a variety of species including Arabidopsis, soybean, rice and maize. However, the [...] Read more.

Members of the acyl-CoA-binding protein (ACBP) gene family play vital roles in diverse processes related to lipid metabolism, growth and development, and environmental response. Plant ACBP genes have been well-studied in a variety of species including Arabidopsis, soybean, rice and maize. However, the identification and functions of ACBP genes in cotton remain to be elucidated. In this study, a total of 11 GaACBP, 12 GrACBP, 20 GbACBP, and 19 GhACBP genes were identified in the genomes of Gossypium arboreum, Gossypium raimondii, Gossypium babardense, and Gossypium hirsutum, respectively, and grouped into four clades. Forty-nine duplicated gene pairs were identified in Gossypium ACBP genes, and almost all of which have undergone purifying selection during the long evolutionary process. In addition, expression analyses showed that most of the GhACBP genes were highly expressed in the developing embryos. Furthermore, GhACBP1 and GhACBP2 were induced by salt and drought stress based on a real-time quantitative PCR (RT-qPCR) assay, indicating that these genes may play an important role in salt- and drought-stress tolerance. This study will provide a basic resource for further functional analysis of the ACBP gene family in cotton. Full article

(This article belongs to the Special Issue Cotton Genes, Genetics, and Genomics)

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15 pages, 4754 KiB

Open AccessEditor’s ChoiceArticle

Stable Isotope Tracing Reveals an Altered Fate of Glucose in N-Acetyltransferase 1 Knockout Breast Cancer Cells

by James T. F. Wise, Xinmin Yin, Xipeng Ma, Xiang Zhang and David W. Hein

Genes 2023, 14(4), 843; https://doi.org/10.3390/genes14040843 - 31 Mar 2023

Cited by 2 | Viewed by 2570

Abstract

Breast cancer is one of the leading causes of cancer death. Recent studies found that arylamine N-acetyltransferase 1 (NAT1) is frequently upregulated in breast cancer, further suggesting NAT1 could be a potential therapeutic target for breast cancer. Previous publications have established that [...] Read more.

Breast cancer is one of the leading causes of cancer death. Recent studies found that arylamine N-acetyltransferase 1 (NAT1) is frequently upregulated in breast cancer, further suggesting NAT1 could be a potential therapeutic target for breast cancer. Previous publications have established that NAT1 knockout (KO) in breast cancer cell lines leads to growth reduction both in vitro and in vivo and metabolic changes. These reports suggest that NAT1 contributes to the energy metabolism of breast cancer cells. Proteomic analysis and non-targeted metabolomics suggested that NAT1 KO may change the fate of glucose as it relates to the TCA/KREB cycle of the mitochondria of breast cancer cells. In this current study, we used [U-¹³C]-glucose stable isotope resolved metabolomics to determine the effect of NAT1 KO on the metabolic profile of MDA-MB-231 breast cancer cells. We incubated breast cancer cells (MDA-MB-231 cells) and NAT1 Crispr KO cells (KO#2 and KO#5) with [U-¹³C]-glucose for 24 h. Tracer incubation polar metabolites from the cells were extracted and analyzed by 2DLC-MS, and metabolite differences were compared between the parental and NAT1 KO cells. Differences consistent between the two KO cells were considered changes due to the loss of NAT1. The data revealed decreases in the ¹³C enrichment of TCA/Krebs cycle intermediates in NAT1 KO cells compared to the MDA-MB-231 cells. Specifically, ¹³C-labeled citrate, isocitrate, a-ketoglutarate, fumarate, and malate were all decreased in NAT1 KO cells. We also detected increased ¹³C-labeled L-lactate levels in the NAT1 KO cells and decreased ¹³C enrichment in some nucleotides. Pathway analysis showed that arginine biosynthesis, alanine, aspartate and glutamate metabolism, and the TCA cycle were most affected. These data provide additional evidence supporting the impacts of NAT1 knockout on cellular energy metabolism. The data suggest that NAT1 expression is important for the proper functioning of mitochondria and the flux of glucose through the TCA/Krebs cycle in breast cancer cells. The metabolism changes in the fate of glucose in NAT1 KO breast cancer cells offer more insight into the role of NAT1 in energy metabolism and the growth of breast cancer cells. These data provide additional evidence that NAT1 may be a useful therapeutic target for breast cancer. Full article

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

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21 pages, 5897 KiB

Open AccessEditor’s ChoiceArticle

Sequencing of the Pituitary Transcriptome after GnRH Treatment Uncovers the Involvement of lncRNA-m23b/miR-23b-3p/CAMK2D in FSH Synthesis and Secretion

by Tian Wang, Guokun Zhao, Song Yu, Yi Zheng, Haixiang Guo, Haoqi Wang, Peisen Zhao, Wenyin Xie, Wenzhi Ren and Bao Yuan

Genes 2023, 14(4), 846; https://doi.org/10.3390/genes14040846 - 31 Mar 2023

Cited by 2 | Viewed by 2251

Abstract

The pituitary gland is a key participant in the hypothalamic–pituitary–gonadal axis, as it secretes a variety of hormones and plays an important role in mammalian reproduction. Gonadotrophin-releasing hormone(GnRH) signaling molecules can bind to GnRH receptors on the surfaces of adenohypophysis gonadotropin cells and [...] Read more.

The pituitary gland is a key participant in the hypothalamic–pituitary–gonadal axis, as it secretes a variety of hormones and plays an important role in mammalian reproduction. Gonadotrophin-releasing hormone(GnRH) signaling molecules can bind to GnRH receptors on the surfaces of adenohypophysis gonadotropin cells and regulate the expression of follicle-stimulating hormone(FSH) and luteinizing hormone(LH) through various pathways. An increasing number of studies have shown that noncoding RNAs mediate the regulation of GnRH signaling molecules in the adenohypophysis. However, the expression changes and underlying mechanisms of genes and noncoding RNAs in the adenohypophysis under the action of GnRH remain unclear. In the present study, we performed RNA sequencing (RNA-seq) of the rat adenohypophysis before and after GnRH treatment to identify differentially expressed mRNAs, lncRNAs, and miRNAs. We found 385 mRNAs, 704 lncRNAs, and 20 miRNAs that were significantly differentially expressed in the rat adenohypophysis. Then, we used a software to predict the regulatory roles of lncRNAs as molecular sponges that compete with mRNAs to bind miRNAs, and construct a GnRH-mediated ceRNA regulatory network. Finally, we enriched the differentially expressed mRNAs, lncRNA target genes, and ceRNA regulatory networks to analyze their potential roles. Based on the sequencing results, we verified that GnRH could affect FSH synthesis and secretion by promoting the competitive binding of lncRNA-m23b to miR-23b-3p to regulate the expression of Calcium/Calmodulin Dependent Protein Kinase II Delta(CAMK2D). Our findings provide strong data to support exploration of the physiological processes in the rat adenohypophysis under the action of GnRH. Furthermore, our profile of lncRNA expression in the rat adenohypophysis provides a theoretical basis for research on the roles of lncRNAs in the adenohypophysis. Full article

(This article belongs to the Special Issue Genetic Regulation of Animal Reproduction)

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11 pages, 1442 KiB

Open AccessEditor’s ChoiceCommunication

Retinal Phenotyping of a Murine Model of Lafora Disease

by Ajoy Vincent, Kashif Ahmed, Rowaida Hussein, Zorana Berberovic, Anupreet Tumber, Xiaochu Zhao and Berge A. Minassian

Genes 2023, 14(4), 854; https://doi.org/10.3390/genes14040854 - 31 Mar 2023

Cited by 1 | Viewed by 2445

Abstract

Lafora disease (LD) is a progressive neurologic disorder caused by biallelic pathogenic variants in EPM2A or EPM2B, leading to tissue accumulation of polyglucosan aggregates termed Lafora bodies (LBs). This study aimed to characterize the retinal phenotype in Epm2a^−/− mice by examining [...] Read more.

Lafora disease (LD) is a progressive neurologic disorder caused by biallelic pathogenic variants in EPM2A or EPM2B, leading to tissue accumulation of polyglucosan aggregates termed Lafora bodies (LBs). This study aimed to characterize the retinal phenotype in Epm2a^−/− mice by examining knockout (KO; Epm2a^−/−) and control (WT) littermates at two time points (10 and 14 months, respectively). In vivo exams included electroretinogram (ERG) testing, optical coherence tomography (OCT) and retinal photography. Ex vivo retinal testing included Periodic acid Schiff Diastase (PASD) staining, followed by imaging to assess and quantify LB deposition. There was no significant difference in any dark-adapted or light-adapted ERG parameters between KO and WT mice. The total retinal thickness was comparable between the groups and the retinal appearance was normal in both groups. On PASD staining, LBs were observed in KO mice within the inner and outer plexiform layers and in the inner nuclear layer. The average number of LBs within the inner plexiform layer in KO mice were 1743 ± 533 and 2615 ± 915 per mm², at 10 and 14 months, respectively. This is the first study to characterize the retinal phenotype in an Epm2a^−/− mouse model, demonstrating significant LB deposition in the bipolar cell nuclear layer and its synapses. This finding may be used to monitor the efficacy of experimental treatments in mouse models. Full article

(This article belongs to the Topic Animal Models of Human Disease)

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15 pages, 3298 KiB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 2 | Viewed by 2871

Abstract

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

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

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

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13 pages, 2893 KiB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 2 | Viewed by 2491

Abstract

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

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

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

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16 pages, 788 KiB

Open AccessEditor’s ChoiceArticle

Rare Coding Variants in Patients with Non-Syndromic Vestibular Dysfunction

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

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

Cited by 3 | Viewed by 3238

Abstract

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

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

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

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32 pages, 1390 KiB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 1 | Viewed by 1784

Abstract

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

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

(This article belongs to the Section Bioinformatics)

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15 pages, 6799 KiB

Open AccessEditor’s ChoiceArticle

vwa1 Knockout in Zebrafish Causes Abnormal Craniofacial Chondrogenesis by Regulating FGF Pathway

by Xiaomin Niu, Fuyu Zhang, Lu Ping, Yibei Wang, Bo Zhang, Jian Wang and Xiaowei Chen

Genes 2023, 14(4), 838; https://doi.org/10.3390/genes14040838 - 30 Mar 2023

Cited by 9 | Viewed by 2859

Abstract

Hemifacial microsomia (HFM), a rare disorder of first- and second-pharyngeal arch development, has been linked to a point mutation in VWA1 (von Willebrand factor A domain containing 1), encoding the protein WARP in a five-generation pedigree. However, how the VWA1 mutation relates to [...] Read more.

Hemifacial microsomia (HFM), a rare disorder of first- and second-pharyngeal arch development, has been linked to a point mutation in VWA1 (von Willebrand factor A domain containing 1), encoding the protein WARP in a five-generation pedigree. However, how the VWA1 mutation relates to the pathogenesis of HFM is largely unknown. Here, we sought to elucidate the effects of the VWA1 mutation at the molecular level by generating a vwa1-knockout zebrafish line using CRISPR/Cas9. Mutants and crispants showed cartilage dysmorphologies, including hypoplastic Meckel’s cartilage and palatoquadrate cartilage, malformed ceratohyal with widened angle, and deformed or absent ceratobranchial cartilages. Chondrocytes exhibited a smaller size and aspect ratio and were aligned irregularly. In situ hybridization and RT-qPCR showed a decrease in barx1 and col2a1a expression, indicating abnormal cranial neural crest cell (CNCC) condensation and differentiation. CNCC proliferation and survival were also impaired in the mutants. Expression of FGF pathway components, including fgf8a, fgfr1, fgfr2, fgfr3, fgfr4, and runx2a, was decreased, implying a role for VWA1 in regulating FGF signaling. Our results demonstrate that VWA1 is essential for zebrafish chondrogenesis through effects on condensation, differentiation, proliferation, and apoptosis of CNCCs, and likely impacts chondrogenesis through regulation of the FGF pathway. Full article

(This article belongs to the Special Issue Zebrafish Models for Human Genetic Disease Studies)

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12 pages, 1854 KiB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 1 | Viewed by 2753

Abstract

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

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

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

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11 pages, 1689 KiB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 2 | Viewed by 3641

Abstract

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

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

(This article belongs to the Section Neurogenomics)

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17 pages, 13774 KiB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 2 | Viewed by 1952

Abstract

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

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

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

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15 pages, 5397 KiB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 4 | Viewed by 2668

Abstract

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

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

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

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19 pages, 2954 KiB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 2 | Viewed by 2772

Abstract

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

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

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

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15 pages, 1845 KiB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 1 | Viewed by 3416

Abstract

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

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

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

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17 pages, 2991 KiB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 2 | Viewed by 2319

Abstract

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

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

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

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19 pages, 793 KiB

Open AccessEditor’s ChoiceArticle

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

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

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

Viewed by 1944

Abstract

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

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

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

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11 pages, 850 KiB

Open AccessEditor’s ChoiceCommunication

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

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

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

Cited by 2 | Viewed by 2329

Abstract

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

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

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

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12 pages, 1501 KiB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 1 | Viewed by 2200

Abstract

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

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

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

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25 pages, 7695 KiB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 5 | Viewed by 2539

Abstract

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

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

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

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13 pages, 1963 KiB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 1 | Viewed by 1732

Abstract

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

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

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

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13 pages, 4130 KiB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 3 | Viewed by 2412

Abstract

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

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

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

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13 pages, 6805 KiB

Open AccessEditor’s ChoiceArticle

Genome-Wide Identification and Expression Analysis of TPS Gene Family in Liriodendron chinense

by Zijian Cao, Qianxi Ma, Yuhao Weng, Jisen Shi, Jinhui Chen and Zhaodong Hao

Genes 2023, 14(3), 770; https://doi.org/10.3390/genes14030770 - 22 Mar 2023

Cited by 11 | Viewed by 4014

Abstract

Terpenoids play a key role in plant growth and development, supporting resistance regulation and terpene synthase (TPS), which is the last link in the synthesis process of terpenoids. Liriodendron chinense, commonly called the Chinese tulip tree, is a rare and endangered tree species [...] Read more.

Terpenoids play a key role in plant growth and development, supporting resistance regulation and terpene synthase (TPS), which is the last link in the synthesis process of terpenoids. Liriodendron chinense, commonly called the Chinese tulip tree, is a rare and endangered tree species of the family Magnoliaceae. However, the genome-wide identification of the TPS gene family and its transcriptional responses to development and abiotic stress are still unclear. In the present study, we identified a total of 58 TPS genes throughout the L. chinense genome. A phylogenetic tree analysis showed that they were clustered into five subfamilies and unevenly distributed across six chromosomes. A cis-acting element analysis indicated that LcTPSs were assumed to be highly responsive to stress hormones, such as methyl jasmonate (MeJA) and abscisic acid (ABA). Consistent with this, transcriptome data showed that most LcTPS genes responded to abiotic stress, such as cold, drought, and hot stress, at the transcriptional level. Further analysis showed that LcTPS genes were expressed in a tissue-dependent manner, especially in buds, leaves, and bark. Quantitative reverse transcription PCR (qRT-PCR) analysis confirmed that LcTPS expression was significantly higher in mature leaves compared to young leaves. These results provide a reference for understanding the function and role of the TPS family, laying a foundation for further study of the regulation of TPS in terpenoid biosynthesis in L. chinense. Full article

(This article belongs to the Special Issue Abiotic Stress in Land Plants: Molecular Genetics and Genomics)

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12 pages, 1295 KiB

Open AccessEditor’s ChoiceArticle

Improving Hereditary Hemorrhagic Telangiectasia Molecular Diagnosis: A Referral Center Experience

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

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

Cited by 1 | Viewed by 2485

Abstract

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

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

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

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12 pages, 2610 KiB

Open AccessEditor’s ChoiceArticle

The Expression Patterns of Exogenous Plant miRNAs in Chickens

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

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

Cited by 1 | Viewed by 2358

Abstract

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

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

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

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12 pages, 875 KiB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 2 | Viewed by 2263

Abstract

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

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

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

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22 pages, 6636 KiB

Open AccessEditor’s ChoiceArticle

Transcriptome and Metabolome Profiling Provide Insights into Flavonoid Synthesis in Acanthus ilicifolius Linn

by Zhihua Wu, Zhen Wang, Yaojian Xie, Guo Liu, Xiuhua Shang and Ni Zhan

Genes 2023, 14(3), 752; https://doi.org/10.3390/genes14030752 - 20 Mar 2023

Cited by 6 | Viewed by 2813

Abstract

Acanthus ilicifolius is an important medicinal plant in mangrove forests, which is rich in secondary metabolites with various biological activities. In this study, we used transcriptomic analysis to obtain differentially expressed genes in the flavonoid metabolic pathway and metabolomic methods to detect changes [...] Read more.

Acanthus ilicifolius is an important medicinal plant in mangrove forests, which is rich in secondary metabolites with various biological activities. In this study, we used transcriptomic analysis to obtain differentially expressed genes in the flavonoid metabolic pathway and metabolomic methods to detect changes in the types and content in the flavonoid metabolic synthesis pathway. The results showed that DEGs were identified in the mature roots vs. leaves comparison (9001 up-regulated and 8910 down-regulated), mature roots vs. stems comparison (5861 up-regulated and 7374 down-regulated), and mature stems vs. leaves comparison (10,837 up-regulated and 11,903 down-regulated). Furthermore, two AiCHS genes and four AiCHI genes were up-regulated in the mature roots vs. stems of mature A. ilicifolius, and were down-regulated in mature stems vs. leaves, which were highly expressed in the A. ilicifolius stems. A total of 215 differential metabolites were found in the roots vs. leaves of mature A. ilicifolius, 173 differential metabolites in the roots vs. stems, and 228 differential metabolites in the stems vs. leaves. The metabolomic results showed that some flavonoids in A. ilicifolius stems were higher than in the roots. A total of 18 flavonoid differential metabolites were detected in the roots, stems, and leaves of mature A. ilicifolius. In mature leaves, quercetin-3-O-glucoside-7-O-rhamnoside, gossypitrin, isoquercitrin, quercetin 3,7-bis-O-β-D-glucoside, and isorhamnetin 3-O-β-(2″-O-acetyl-β-D-glucuronide) were found in a high content, while in mature roots, di-O-methylquercetin and isorhamnetin were the major compounds. The combined analysis of the metabolome and transcriptome revealed that DEGs and differential metabolites were related to flavonoid biosynthesis. This study provides a theoretical basis for analyzing the molecular mechanism of flavonoid synthesis in A. ilicifolius and provides a reference for further research and exploitation of its medicinal value. Full article

(This article belongs to the Special Issue Phylogenetics, Genetics, and Breeding of Medicinal Plants)

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11 pages, 704 KiB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 5 | Viewed by 3737

Abstract

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

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

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

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12 pages, 4097 KiB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 3 | Viewed by 2749

Abstract

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

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

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

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10 pages, 640 KiB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 5 | Viewed by 2619

Abstract

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

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

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

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20 pages, 14568 KiB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 5 | Viewed by 2636

Abstract

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

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

(This article belongs to the Section Bioinformatics)

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16 pages, 2248 KiB

Open AccessEditor’s ChoiceArticle

An Investigation into Compound Likelihood Ratios for Forensic DNA Mixtures

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

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

Cited by 1 | Viewed by 2908

Abstract

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

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

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

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12 pages, 444 KiB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 2 | Viewed by 1928

Abstract

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

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

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

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15 pages, 4754 KiB

Open AccessEditor’s ChoiceArticle

Molecular Epidemiology and Diversity of SARS-CoV-2 in Ethiopia, 2020–2022

by Abay Sisay, Derek Tshiabuila, Stephanie van Wyk, Abraham Tesfaye, Gerald Mboowa, Samuel O. Oyola, Sofonias Kifle Tesema, Cheryl Baxter, Darren Martin, Richard Lessells, Houriiyah Tegally, Monika Moir, Jennifer Giandhari, Sureshnee Pillay, Lavanya Singh, Yajna Ramphal, Arisha Maharaj, Yusasha Pillay, Akhil Maharaj, Yeshnee Naidoo, Upasana Ramphal, Lucious Chabuka, Eduan Wilkinson, Tulio de Oliveira, Adey Feleke Desta and James E. San Show full author list Hide full author list

Genes 2023, 14(3), 705; https://doi.org/10.3390/genes14030705 - 13 Mar 2023

Cited by 11 | Viewed by 4718

Abstract

Ethiopia is the second most populous country in Africa and the sixth most affected by COVID-19 on the continent. Despite having experienced five infection waves, >499,000 cases, and ~7500 COVID-19-related deaths as of January 2023, there is still no detailed genomic epidemiological report [...] Read more.

Ethiopia is the second most populous country in Africa and the sixth most affected by COVID-19 on the continent. Despite having experienced five infection waves, >499,000 cases, and ~7500 COVID-19-related deaths as of January 2023, there is still no detailed genomic epidemiological report on the introduction and spread of SARS-CoV-2 in Ethiopia. In this study, we reconstructed and elucidated the COVID-19 epidemic dynamics. Specifically, we investigated the introduction, local transmission, ongoing evolution, and spread of SARS-CoV-2 during the first four infection waves using 353 high-quality near-whole genomes sampled in Ethiopia. Our results show that whereas viral introductions seeded the first wave, subsequent waves were seeded by local transmission. The B.1.480 lineage emerged in the first wave and notably remained in circulation even after the emergence of the Alpha variant. The B.1.480 was outcompeted by the Delta variant. Notably, Ethiopia’s lack of local sequencing capacity was further limited by sporadic, uneven, and insufficient sampling that limited the incorporation of genomic epidemiology in the epidemic public health response in Ethiopia. These results highlight Ethiopia’s role in SARS-CoV-2 dissemination and the urgent need for balanced, near-real-time genomic sequencing. Full article

(This article belongs to the Special Issue Emerging and Reemerging Viral Pathogens)

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17 pages, 1257 KiB

Open AccessEditor’s ChoiceArticle

Doxorubicin and Cisplatin Modulate miR-21, miR-106, miR-126, miR-155 and miR-199 Levels in MCF7, MDA-MB-231 and SK-BR-3 Cells That Makes Them Potential Elements of the DNA-Damaging Drug Treatment Response Monitoring in Breast Cancer Cells—A Preliminary Study

by Anna Mizielska, Iga Dziechciowska, Radosław Szczepański, Małgorzata Cisek, Małgorzata Dąbrowska, Jan Ślężak, Izabela Kosmalska, Marta Rymarczyk, Klaudia Wilkowska, Barbara Jacczak, Ewa Totoń, Natalia Lisiak, Przemysław Kopczyński and Błażej Rubiś

Genes 2023, 14(3), 702; https://doi.org/10.3390/genes14030702 - 12 Mar 2023

Cited by 10 | Viewed by 4174

Abstract

One of the most innovative medical trends is personalized therapy, based on simple and reproducible methods that detect unique features of cancer cells. One of the good prognostic and diagnostic markers may be the miRNA family. Our work aimed to evaluate changes in [...] Read more.

One of the most innovative medical trends is personalized therapy, based on simple and reproducible methods that detect unique features of cancer cells. One of the good prognostic and diagnostic markers may be the miRNA family. Our work aimed to evaluate changes in selected miRNA levels in various breast cancer cell lines (MCF7, MDA-MB-231, SK-BR-3) treated with doxorubicin or cisplatin. The selection was based on literature data regarding the most commonly altered miRNAs in breast cancer (21-3p, 21-5p, 106a-5p, 126-3p, 126-5p, 155-3p, 155-5p, 199b-3p, 199b-5p, 335-3p, 335-5p). qPCR assessment revealed significant differences in the basal levels of some miRNAs in respective cell lines, with the most striking difference in miR-106a-5p, miR-335-5p and miR-335-3p—all of them were lowest in MCF7, while miR-153p was not detected in SK-BR-3. Additionally, different alterations of selected miRNAs were observed depending on the cell line and the drug. However, regardless of these variables, 21-3p/-5p, 106a, 126-3p, 155-3p and 199b-3p miRNAs were shown to respond either to doxorubicin or to cisplatin treatment. These miRNAs seem to be good candidates for markers of breast cancer cell response to doxorubicin or cisplatin. Especially since some earlier reports suggested their role in affecting pathways and expression of genes associated with the DNA-damage response. However, it must be emphasized that the preliminary study shows effects that may be highly related to the applied drug itself and its concentration. Thus, further examination, including human samples, is required. Full article

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

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