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13 pages, 1466 KiB

Open AccessArticle

Gene-by-Sex Interactions: Genome-Wide Association Study Reveals Five SNPs Associated with Obesity and Overweight in a Male Population

by Maria-Anna Kyrgiafini, Theologia Sarafidou, Themistoklis Giannoulis, Alexia Chatziparasidou, Nikolaos Christoforidis and Zissis Mamuris

Genes 2023, 14(4), 799; https://doi.org/10.3390/genes14040799 - 26 Mar 2023

Cited by 3 | Viewed by 2436

Abstract

Obesity is a chronic health problem associated with severe complications and with an increasing prevalence in the Western world. Body-fat composition and distribution are closely associated with obesity, but the human body’s composition is a sexually dimorphic trait, as differences between the two [...] Read more.

Obesity is a chronic health problem associated with severe complications and with an increasing prevalence in the Western world. Body-fat composition and distribution are closely associated with obesity, but the human body’s composition is a sexually dimorphic trait, as differences between the two sexes are evident even from fetal life. The effect of sex hormones contributes to this phenomenon. However, studies investigating gene-by-sex interactions for obesity are limited. Therefore, the aim of the present study was to identify single-nucleotide polymorphisms (SNPs) associated with obesity and overweight in a male population. A genome-wide association study (GWAS) that included 104 control, 125 overweight, and 61 obese subjects revealed four SNPs associated with overweight (rs7818910, rs7863750, rs1554116, and rs7500401) and one SNP (rs114252547) associated with obesity in males. An in silico functional annotation was subsequently used to further investigate their role. Most of the SNPs were found in genes regulating energy metabolism and homeostasis, and some of them were expression quantitative trait loci (eQTL). These findings contribute to the understanding of the molecular mechanisms underlying obesity-related traits, especially in males, and pave the road for future research toward the improvement of the diagnosis and therapy of obese individuals. Full article

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

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15 pages, 4567 KiB

Open AccessFeature PaperArticle

Transcriptional Profiling of Rat Prefrontal Cortex after Acute Inescapable Footshock Stress

by Paolo Martini, Jessica Mingardi, Giulia Carini, Stefania Mattevi, Elona Ndoj, Luca La Via, Chiara Magri, Massimo Gennarelli, Isabella Russo, Maurizio Popoli, Laura Musazzi and Alessandro Barbon

Genes 2023, 14(3), 740; https://doi.org/10.3390/genes14030740 - 17 Mar 2023

Cited by 3 | Viewed by 2047

Abstract

Stress is a primary risk factor for psychiatric disorders such as Major Depressive Disorder (MDD) and Post Traumatic Stress Disorder (PTSD). The response to stress involves the regulation of transcriptional programs, which is supposed to play a role in coping with stress. To [...] Read more.

Stress is a primary risk factor for psychiatric disorders such as Major Depressive Disorder (MDD) and Post Traumatic Stress Disorder (PTSD). The response to stress involves the regulation of transcriptional programs, which is supposed to play a role in coping with stress. To evaluate transcriptional processes implemented after exposure to unavoidable traumatic stress, we applied microarray expression analysis to the PFC of rats exposed to acute footshock (FS) stress that were sacrificed immediately after the 40 min session or 2 h or 24 h after. While no substantial changes were observed at the single gene level immediately after the stress session, gene set enrichment analysis showed alterations in neuronal pathways associated with glia development, glia–neuron networking, and synaptic function. Furthermore, we found alterations in the expression of gene sets regulated by specific transcription factors that could represent master regulators of the acute stress response. Of note, these pathways and transcriptional programs are activated during the early stress response (immediately after FS) and are already turned off after 2 h—while at 24 h, the transcriptional profile is largely unaffected. Overall, our analysis provided a transcriptional landscape of the early changes triggered by acute unavoidable FS stress in the PFC of rats, suggesting that the transcriptional wave is fast and mild, but probably enough to activate a cellular response to acute stress. Full article

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

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16 pages, 741 KiB

Open AccessArticle

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

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

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

Cited by 2 | Viewed by 2191

Abstract

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

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

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

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15 pages, 8115 KiB

Open AccessArticle

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

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

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

Cited by 1 | Viewed by 1924

Abstract

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

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

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

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12 pages, 1620 KiB

Open AccessArticle

What Have We Learned from Patients Who Have Arboleda-Tham Syndrome Due to a De Novo KAT6A Pathogenic Variant with Impaired Histone Acetyltransferase Function? A Precise Clinical Description May Be Critical for Genetic Testing Approach and Final Diagnosis

by Nenad Bukvic, Massimiliano Chetta, Rosanna Bagnulo, Valentina Leotta, Antonino Pantaleo, Orazio Palumbo, Pietro Palumbo, Maria Oro, Maria Rivieccio, Nicola Laforgia, Marta De Rinaldis, Alessandra Rosati, Jennifer Kerkhof, Bekim Sadikovic and Nicoletta Resta

Genes 2023, 14(1), 165; https://doi.org/10.3390/genes14010165 - 7 Jan 2023

Cited by 3 | Viewed by 4157

Abstract

Pathogenic variants in genes are involved in histone acetylation and deacetylation resulting in congenital anomalies, with most patients displaying a neurodevelopmental disorder and dysmorphism. Arboleda-Tham syndrome caused by pathogenic variants in KAT6A (Lysine Acetyltransferase 6A; OMIM 601408) has been recently described as a [...] Read more.

Pathogenic variants in genes are involved in histone acetylation and deacetylation resulting in congenital anomalies, with most patients displaying a neurodevelopmental disorder and dysmorphism. Arboleda-Tham syndrome caused by pathogenic variants in KAT6A (Lysine Acetyltransferase 6A; OMIM 601408) has been recently described as a new neurodevelopmental disorder. Herein, we describe a patient characterized by complex phenotype subsequently diagnosed using the clinical exome sequencing (CES) with Arboleda-Tham syndrome (ARTHS; OMIM 616268). The analysis revealed the presence of de novo pathogenic variant in KAT6A gene, a nucleotide c.3385C>T substitution that introduces a premature termination codon (p.Arg1129*). The need for straight multidisciplinary collaboration and accurate clinical description findings (bowel obstruction/megacolon/intestinal malrotation) was emphasized, together with the utility of CES in establishing an etiological basis in clinical and genetical heterogeneous conditions. Therefore, considering the phenotypic characteristics, the condition’s rarity and the reviewed literature, we propose additional diagnostic criteria that could help in the development of future clinical diagnostic guidelines. This was possible thanks to objective examinations performed during the long follow-up period, which permitted scrupulous registration of phenotypic changes over time to further assess this rare disorder. Finally, given that different genetic syndromes are associated with distinct genomic DNA methylation patterns used for diagnostic testing and/or as biomarker of disease, a specific episignature for ARTHS has been identified. Full article

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

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13 pages, 3023 KiB

Open AccessArticle

Transcriptomic Profiling Reveals an Enhancer RNA Signature for Recurrence Prediction in Colorectal Cancer

by Divya Sahu, Chen-Ching Lin and Ajay Goel

Genes 2023, 14(1), 137; https://doi.org/10.3390/genes14010137 - 3 Jan 2023

Viewed by 2108

Abstract

Background: Colorectal cancer (CRC) is one of the most fatal malignancies worldwide, and this is in part due to high rates of tumor recurrence in these patients. Currently, TNM staging remains the gold standard for predicting prognosis and recurrence in CRC patients; however, [...] Read more.

Background: Colorectal cancer (CRC) is one of the most fatal malignancies worldwide, and this is in part due to high rates of tumor recurrence in these patients. Currently, TNM staging remains the gold standard for predicting prognosis and recurrence in CRC patients; however, this approach is inadequate for identifying high-risk patients with the highest likelihood of disease recurrence. Recent evidence has revealed that enhancer RNAs (eRNAs) represent a higher level of cellular regulation, and their expression is frequently dysregulated in several cancers, including CRC. However, the clinical significance of eRNAs as recurrence predictor biomarkers in CRC remains unexplored, which is the primary aim of this study. Results: We performed a systematic analysis of eRNA expression profiles in colon cancer (CC) and rectal cancer (RC) patients from the TCGA dataset. By using rigorous biomarker discovery approaches by splitting the entire dataset into a training and testing cohort, we identified a 22-eRNA panel in CC and a 19-eRNA panel in RC for predicting tumor recurrence. The Kaplan–Meier analysis showed that biomarker panels robustly stratified low and high-risk CC (p = 7.29 × 10⁻⁵) and RC (p = 6.81 × 10⁻³) patients with recurrence. Multivariate and LASSO Cox regression models indicated that both biomarker panels were independent predictors of recurrence and significantly superior to TNM staging in CC (HR = 11.89, p = 9.54 × 10⁻⁴) and RC (HR = 3.91, p = 3.52 × 10⁻²). Notably, the ROC curves demonstrated that both panels exhibited excellent recurrence prediction accuracy in CC (AUC = 0.833; 95% CI: 0.74–0.93) and RC (AUC = 0.834; 95% CI: 0.72–0.92) patients. Subsequently, a combination signature that included the eRNA panels and TNM staging achieved an even greater predictive accuracy in patients with CC (AUC = 0.85). Conclusions: Herein, we report a novel eRNA signature for predicting recurrence in patients with CRC. Further experimental validation in independent clinical cohorts, these biomarkers can potentially improve current risk stratification approaches for guiding precision oncology treatments in patients suffering from this lethal malignancy. Full article

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

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Review

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32 pages, 1104 KiB

Open AccessEditor’s ChoiceReview

Genes and Athletic Performance: The 2023 Update

by Ekaterina A. Semenova, Elliott C. R. Hall and Ildus I. Ahmetov

Genes 2023, 14(6), 1235; https://doi.org/10.3390/genes14061235 - 8 Jun 2023

Cited by 36 | Viewed by 22229

Abstract

Phenotypes of athletic performance and exercise capacity are complex traits influenced by both genetic and environmental factors. This update on the panel of genetic markers (DNA polymorphisms) associated with athlete status summarises recent advances in sports genomics research, including findings from candidate gene [...] Read more.

Phenotypes of athletic performance and exercise capacity are complex traits influenced by both genetic and environmental factors. This update on the panel of genetic markers (DNA polymorphisms) associated with athlete status summarises recent advances in sports genomics research, including findings from candidate gene and genome-wide association (GWAS) studies, meta-analyses, and findings involving larger-scale initiatives such as the UK Biobank. As of the end of May 2023, a total of 251 DNA polymorphisms have been associated with athlete status, of which 128 genetic markers were positively associated with athlete status in at least two studies (41 endurance-related, 45 power-related, and 42 strength-related). The most promising genetic markers include the AMPD1 rs17602729 C, CDKN1A rs236448 A, HFE rs1799945 G, MYBPC3 rs1052373 G, NFIA-AS2 rs1572312 C, PPARA rs4253778 G, and PPARGC1A rs8192678 G alleles for endurance; ACTN3 rs1815739 C, AMPD1 rs17602729 C, CDKN1A rs236448 C, CPNE5 rs3213537 G, GALNTL6 rs558129 T, IGF2 rs680 G, IGSF3 rs699785 A, NOS3 rs2070744 T, and TRHR rs7832552 T alleles for power; and ACTN3 rs1815739 C, AR ≥21 CAG repeats, LRPPRC rs10186876 A, MMS22L rs9320823 T, PHACTR1 rs6905419 C, and PPARG rs1801282 G alleles for strength. It should be appreciated, however, that elite performance still cannot be predicted well using only genetic testing. Full article

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

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17 pages, 1161 KiB

Open AccessReview

Molecular Evolution of SARS-CoV-2 during the COVID-19 Pandemic

by Luis Daniel González-Vázquez and Miguel Arenas

Genes 2023, 14(2), 407; https://doi.org/10.3390/genes14020407 - 4 Feb 2023

Cited by 14 | Viewed by 4302

Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) produced diverse molecular variants during its recent expansion in humans that caused different transmissibility and severity of the associated disease as well as resistance to monoclonal antibodies and polyclonal sera, among other treatments. In order [...] Read more.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) produced diverse molecular variants during its recent expansion in humans that caused different transmissibility and severity of the associated disease as well as resistance to monoclonal antibodies and polyclonal sera, among other treatments. In order to understand the causes and consequences of the observed SARS-CoV-2 molecular diversity, a variety of recent studies investigated the molecular evolution of this virus during its expansion in humans. In general, this virus evolves with a moderate rate of evolution, in the order of 10⁻³–10⁻⁴ substitutions per site and per year, which presents continuous fluctuations over time. Despite its origin being frequently associated with recombination events between related coronaviruses, little evidence of recombination was detected, and it was mostly located in the spike coding region. Molecular adaptation is heterogeneous among SARS-CoV-2 genes. Although most of the genes evolved under purifying selection, several genes showed genetic signatures of diversifying selection, including a number of positively selected sites that affect proteins relevant for the virus replication. Here, we review current knowledge about the molecular evolution of SARS-CoV-2 in humans, including the emergence and establishment of variants of concern. We also clarify relationships between the nomenclatures of SARS-CoV-2 lineages. We conclude that the molecular evolution of this virus should be monitored over time for predicting relevant phenotypic consequences and designing future efficient treatments. Full article

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

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