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Genes, Volume 12, Issue 10 (October 2021) – 187 articles

Cover Story (view full-size image): Major Depressive Disorder (MDD) is a neuropsychiatric condition with strong ties to disease and lifestyle factors. Trait associations at the population level can result from a shared genetic or environmental etiology. In a twin pedigree approach with almost 20.000 relatives, we establish to what degree genetic and environmental factors influence the association between MDD and smoking behavior, physical inactivity, and obesity. We show that each of these traits is heritable, and that the associations between MDD and lifestyle factors are mainly driven by shared genetic factors.View this paper
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Article
Association and Gene–Gene Interactions Study of Late-Onset Alzheimer’s Disease in the Russian Population
Genes 2021, 12(10), 1647; https://doi.org/10.3390/genes12101647 - 19 Oct 2021
Viewed by 313
Abstract
Alzheimer’s disease (AD) is a neurodegenerative disorder, and represents the most common cause of dementia. In this study, we performed several different analyses to detect loci involved in development of the late onset AD in the Russian population. DNA samples from 472 unrelated [...] Read more.
Alzheimer’s disease (AD) is a neurodegenerative disorder, and represents the most common cause of dementia. In this study, we performed several different analyses to detect loci involved in development of the late onset AD in the Russian population. DNA samples from 472 unrelated subjects were genotyped for 63 SNPs using iPLEX Assay and real-time PCR. We identified five genetic loci that were significantly associated with LOAD risk for the Russian population (TOMM40 rs2075650, APOE rs429358 and rs769449, NECTIN rs6857, APOE ε4). The results of the analysis based on comparison of the haplotype frequencies showed two risk haplotypes and one protective haplotype. The GMDR analysis demonstrated three significant models as a result: a one-factor, a two-factor and a three-factor model. A protein–protein interaction network with three subnetworks was formed for the 24 proteins. Eight proteins with a large number of interactions are identified: APOE, SORL1, APOC1, CD33, CLU, TOMM40, CNTNAP2 and CACNA1C. The present study confirms the importance of the APOE-TOMM40 locus as the main risk locus of development and progress of LOAD in the Russian population. Association analysis and bioinformatics approaches detected interactions both at the association level of single SNPs and at the level of genes and proteins. Full article
(This article belongs to the Special Issue Genetics and Genomics of Neurodegenerative Diseases)
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Review
Signaling Pathways That Regulate Normal and Aberrant Red Blood Cell Development
Genes 2021, 12(10), 1646; https://doi.org/10.3390/genes12101646 - 19 Oct 2021
Viewed by 217
Abstract
Blood cell development is regulated through intrinsic gene regulation and local factors including the microenvironment and cytokines. The differentiation of hematopoietic stem and progenitor cells (HSPCs) into mature erythrocytes is dependent on these cytokines binding to and stimulating their cognate receptors and the [...] Read more.
Blood cell development is regulated through intrinsic gene regulation and local factors including the microenvironment and cytokines. The differentiation of hematopoietic stem and progenitor cells (HSPCs) into mature erythrocytes is dependent on these cytokines binding to and stimulating their cognate receptors and the signaling cascades they initiate. Many of these pathways include kinases that can diversify signals by phosphorylating multiple substrates and amplify signals by phosphorylating multiple copies of each substrate. Indeed, synthesis of many of these cytokines is regulated by a number of signaling pathways including phosphoinositide 3-kinase (PI3K)-, extracellular signal related kinases (ERK)-, and p38 kinase-dependent pathways. Therefore, kinases act both upstream and downstream of the erythropoiesis-regulating cytokines. While many of the cytokines are well characterized, the nuanced members of the network of kinases responsible for appropriate induction of, and response to, these cytokines remains poorly defined. Here, we will examine the kinase signaling cascades required for erythropoiesis and emphasize the importance, complexity, enormous amount remaining to be characterized, and therapeutic potential that will accompany our comprehensive understanding of the erythroid kinome in both healthy and diseased states. Full article
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Article
FA-nf: A Functional Annotation Pipeline for Proteins from Non-Model Organisms Implemented in Nextflow
Genes 2021, 12(10), 1645; https://doi.org/10.3390/genes12101645 - 19 Oct 2021
Viewed by 344
Abstract
Functional annotation allows adding biologically relevant information to predicted features in genomic sequences, and it is, therefore, an important procedure of any de novo genome sequencing project. It is also useful for proofreading and improving gene structural annotation. Here, we introduce FA-nf, a [...] Read more.
Functional annotation allows adding biologically relevant information to predicted features in genomic sequences, and it is, therefore, an important procedure of any de novo genome sequencing project. It is also useful for proofreading and improving gene structural annotation. Here, we introduce FA-nf, a pipeline implemented in Nextflow, a versatile computational workflow management engine. The pipeline integrates different annotation approaches, such as NCBI BLAST+, DIAMOND, InterProScan, and KEGG. It starts from a protein sequence FASTA file and, optionally, a structural annotation file in GFF format, and produces several files, such as GO assignments, output summaries of the abovementioned programs and final annotation reports. The pipeline can be broken easily into smaller processes for the purpose of parallelization and easily deployed in a Linux computational environment, thanks to software containerization, thus helping to ensure full reproducibility. Full article
(This article belongs to the Special Issue Trends and Future Perspectives in Genome Annotation)
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Communication
Genetically Predicted Type 2 Diabetes Mellitus Liability, Glycated Hemoglobin and Cardiovascular Diseases: A Wide-Angled Mendelian Randomization Study
Genes 2021, 12(10), 1644; https://doi.org/10.3390/genes12101644 - 19 Oct 2021
Viewed by 288
Abstract
(1) Aim: To investigate the causal effects of T2DM liability and glycated haemoglobin (HbA1c) levels on various cardiovascular disease outcomes, both in the general population and in non-diabetic individuals specifically. (2) Methods: We selected 243 variants as genetic instruments for T2DM liability and [...] Read more.
(1) Aim: To investigate the causal effects of T2DM liability and glycated haemoglobin (HbA1c) levels on various cardiovascular disease outcomes, both in the general population and in non-diabetic individuals specifically. (2) Methods: We selected 243 variants as genetic instruments for T2DM liability and 536 variants for HbA1c. Linear Mendelian randomization analyses were performed to estimate the associations of genetically-predicted T2DM liability and HbA1c with 12 cardiovascular disease outcomes in 367,703 unrelated UK Biobank participants of European ancestries. We performed secondary analyses in participants without diabetes (HbA1c < 6.5% with no diagnosed diabetes), and in participants without diabetes or pre-diabetes (HbA1c < 5.7% with no diagnosed diabetes). (3) Results: Genetically-predicted T2DM liability was positively associated (p < 0.004, 0.05/12) with peripheral vascular disease, aortic valve stenosis, coronary artery disease, heart failure, ischaemic stroke, and any stroke. Genetically-predicted HbA1c was positively associated with coronary artery disease and any stroke. Mendelian randomization estimates generally shifted towards the null when excluding diabetic and pre-diabetic participants from analyses. (4) Conclusions: This genetic evidence supports causal effects of T2DM liability and HbA1c on a range of cardiovascular diseases, suggesting that improving glycaemic control could reduce cardiovascular risk in a general population, with greatest benefit in individuals with diabetes. Full article
(This article belongs to the Special Issue Mendelian Randomization Studies in Cardiometabolic Diseases)
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Article
Mitochondrial Strokes: Diagnostic Challenges and Chameleons
Genes 2021, 12(10), 1643; https://doi.org/10.3390/genes12101643 - 19 Oct 2021
Viewed by 186
Abstract
Mitochondrial stroke-like episodes (SLEs) are a hallmark of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). They should be suspected in anyone with an acute/subacute onset of focal neurological symptoms at any age and are usually driven by seizures. Suggestive features of an [...] Read more.
Mitochondrial stroke-like episodes (SLEs) are a hallmark of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). They should be suspected in anyone with an acute/subacute onset of focal neurological symptoms at any age and are usually driven by seizures. Suggestive features of an underlying mitochondrial pathology include evolving MRI lesions, often originating within the posterior brain regions, the presence of multisystemic involvement, including diabetes, deafness, or cardiomyopathy, and a positive family history. The diagnosis of MELAS has important implications for those affected and their relatives, given it enables early initiation of appropriate treatment and genetic counselling. However, the diagnosis is frequently challenging, particularly during the acute phase of an event. We describe four cases of mitochondrial strokes to highlight the considerable overlap that exists with other neurological disorders, including viral and autoimmune encephalitis, ischemic stroke, and central nervous system (CNS) vasculitis, and discuss the clinical, laboratory, and imaging features that can help distinguish MELAS from these differential diagnoses. Full article
(This article belongs to the Special Issue Expanding the Genetic Landscape of Mitochondrial Diseases)
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Article
Association of PIP4K2A Polymorphisms with Alcohol Use Disorder
Genes 2021, 12(10), 1642; https://doi.org/10.3390/genes12101642 - 19 Oct 2021
Viewed by 215
Abstract
Background: Alcohol use disorder (AUD) not only influences individuals and families but also has a lasting social impact on communities at the national level. Dopaminergic neurotransmission is involved in excessive alcohol consumption. Phosphatidylinositol-5-phosphate-4-kinase type 2 α (PIP4K2A) plays an important role in the [...] Read more.
Background: Alcohol use disorder (AUD) not only influences individuals and families but also has a lasting social impact on communities at the national level. Dopaminergic neurotransmission is involved in excessive alcohol consumption. Phosphatidylinositol-5-phosphate-4-kinase type 2 α (PIP4K2A) plays an important role in the regulation of ascending dopamine pathways. In this study; we determined possible associations between nine polymorphisms in PIP4K2A and AUD in Russian men. Methods: 279 Russian men with AUD were investigated. The control group consisted of 222 healthy men from the general Russian population. Genotyping of DNA samples for nine polymorphic variants of PIP4K2A was carried out by the Applied Biosystems™ QuantStudio™ 5 Real-Time PCR System with use of the TaqMan1 Validated SNP Genotyping Assay (Applied Biosystems; CIIIA). Results: Carriage of the PIP4K2A rs2230469*TT/T genotype/allele was a relative risk factor for developing AUD in men (p = 0.026 and p = 0.0084 accordingly). Moreover; men with AUD had a higher frequency of PIP4K2A rs746203*T allele (p = 0.023) compared to healthy men. Conclusions: For the first time; we demonstrated different PIP4K2A polymorphisms to be associated with AUD presumably due to dopamine system modulation resulting from regulation of the lateral habenula. Full article
(This article belongs to the Special Issue Genetics and Genomics of Addiction)
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Article
Evaluation of the Association of COMT Rs4680 Polymorphism with Swimmers’ Competitive Performance
Genes 2021, 12(10), 1641; https://doi.org/10.3390/genes12101641 - 19 Oct 2021
Viewed by 206
Abstract
Swimmers’ competitive performance is a result of complicated interactions between physiological, biochemical, physical and psychological factors, all of which are strongly affected by water. Recently, great attention has been paid to the role of genetic factors such as the catechol-O-methyltransferase gene (COMT [...] Read more.
Swimmers’ competitive performance is a result of complicated interactions between physiological, biochemical, physical and psychological factors, all of which are strongly affected by water. Recently, great attention has been paid to the role of genetic factors such as the catechol-O-methyltransferase gene (COMT) influencing motivation, emotions, stress tolerance, self-control, sleep regulation, pain processing and perception, addictive behaviour and neurodegeneration, which may underlie differences in achieving remarkable results in sports competition. Thus, this study was performed to investigate the association between the COMT Val158Met (rs4680) polymorphism and athletic performance in Caucasian swimmers. A total of 225 swimmers (171 short distance (SDS) and 54 long distance swimmers (LDS)) of national or international competitive standard and 379 unrelated sedentary controls were genotyped using real-time polymerase chain reaction (real-time PCR). We found no significant differences in genotypic or allelic distributions between (1) male and female athletes; (2) SDS and LDS; (3) all athletes and sedentary controls (under codominant, dominant, recessive, and overdominant genetic models). No association was found between the COMT rs4680 polymorphism and elite swimming athlete status of the studied population. However, more replication studies are needed. Full article
(This article belongs to the Special Issue Genetics and Genomics in Sport)
Article
Single-Cell RNA-Seq Revealed the Gene Expression Pattern during the In Vitro Maturation of Donkey Oocytes
Genes 2021, 12(10), 1640; https://doi.org/10.3390/genes12101640 - 19 Oct 2021
Viewed by 229
Abstract
Donkeys are an important domesticated animal, providing labor, meat, milk, and medicinal materials for humans. However, the donkey population is continuously declining and even at risk of extinction. The application of modern animal production technology, such as oocyte in vitro maturation, is a [...] Read more.
Donkeys are an important domesticated animal, providing labor, meat, milk, and medicinal materials for humans. However, the donkey population is continuously declining and even at risk of extinction. The application of modern animal production technology, such as oocyte in vitro maturation, is a promising method to improve the donkey population. In this study, we explore the gene expression patterns of donkey germinal vesicle (GV) and in vitro matured metaphase II (MII) oocytes using single cell RNA-seq of the candidate genes along with the regulatory mechanisms that affect donkey oocyte maturation. We identified a total of 24,164 oocyte genes of which 9073 were significant differentially expressed in the GV and MII oocytes. Further Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis indicated that these genes were associated with the meiotic cell cycle, mitochondrion activity, and N-glycan biosynthesis, which might be the key genes and regulatory mechanisms affecting the maturation of donkey oocytes. Our study provides considerable understanding regarding the maturation of donkey oocytes and serves as a theoretical basis for improving the development of donkey oocytes, which could ultimately benefit the expansion of the donkey population and conservation of biodiversity and genetic resources. Full article
(This article belongs to the Special Issue Early Embryonic Development of Animals)
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Review
Atypical NF1 Microdeletions: Challenges and Opportunities for Genotype/Phenotype Correlations in Patients with Large NF1 Deletions
Genes 2021, 12(10), 1639; https://doi.org/10.3390/genes12101639 - 19 Oct 2021
Viewed by 234
Abstract
Patients with neurofibromatosis type 1 (NF1) and type 1 NF1 deletions often exhibit more severe clinical manifestations than patients with intragenic NF1 gene mutations, including facial dysmorphic features, overgrowth, severe global developmental delay, severe autistic symptoms and considerably reduced cognitive abilities, all of [...] Read more.
Patients with neurofibromatosis type 1 (NF1) and type 1 NF1 deletions often exhibit more severe clinical manifestations than patients with intragenic NF1 gene mutations, including facial dysmorphic features, overgrowth, severe global developmental delay, severe autistic symptoms and considerably reduced cognitive abilities, all of which are detectable from a very young age. Type 1 NF1 deletions encompass 1.4 Mb and are associated with the loss of 14 protein-coding genes, including NF1 and SUZ12. Atypical NF1 deletions, which do not encompass all 14 protein-coding genes located within the type 1 NF1 deletion region, have the potential to contribute to the delineation of the genotype/phenotype relationship in patients with NF1 microdeletions. Here, we review all atypical NF1 deletions reported to date as well as the clinical phenotype observed in the patients concerned. We compare these findings with those of a newly identified atypical NF1 deletion of 698 kb which, in addition to the NF1 gene, includes five genes located centromeric to NF1. The atypical NF1 deletion in this patient does not include the SUZ12 gene but does encompass CRLF3. Comparative analysis of such atypical NF1 deletions suggests that SUZ12 hemizygosity is likely to contribute significantly to the reduced cognitive abilities, severe global developmental delay and facial dysmorphisms observed in patients with type 1 NF1 deletions. Full article
(This article belongs to the Section Human Genomics and Genetic Diseases)
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Article
Transcriptome Profiling of Maize (Zea mays L.) Leaves Reveals Key Cold-Responsive Genes, Transcription Factors, and Metabolic Pathways Regulating Cold Stress Tolerance at the Seedling Stage
Genes 2021, 12(10), 1638; https://doi.org/10.3390/genes12101638 - 18 Oct 2021
Viewed by 314
Abstract
Cold tolerance is a complex trait that requires a critical perspective to understand its underpinning mechanism. To unravel the molecular framework underlying maize (Zea mays L.) cold stress tolerance, we conducted a comparative transcriptome profiling of 24 cold-tolerant and 22 cold-sensitive inbred [...] Read more.
Cold tolerance is a complex trait that requires a critical perspective to understand its underpinning mechanism. To unravel the molecular framework underlying maize (Zea mays L.) cold stress tolerance, we conducted a comparative transcriptome profiling of 24 cold-tolerant and 22 cold-sensitive inbred lines affected by cold stress at the seedling stage. Using the RNA-seq method, we identified 2237 differentially expressed genes (DEGs), namely 1656 and 581 annotated and unannotated DEGs, respectively. Further analysis of the 1656 annotated DEGs mined out two critical sets of cold-responsive DEGs, namely 779 and 877 DEGs, which were significantly enhanced in the tolerant and sensitive lines, respectively. Functional analysis of the 1656 DEGs highlighted the enrichment of signaling, carotenoid, lipid metabolism, transcription factors (TFs), peroxisome, and amino acid metabolism. A total of 147 TFs belonging to 32 families, including MYB, ERF, NAC, WRKY, bHLH, MIKC MADS, and C2H2, were strongly altered by cold stress. Moreover, the tolerant lines’ 779 enhanced DEGs were predominantly associated with carotenoid, ABC transporter, glutathione, lipid metabolism, and amino acid metabolism. In comparison, the cold-sensitive lines’ 877 enhanced DEGs were significantly enriched for MAPK signaling, peroxisome, ribosome, and carbon metabolism pathways. The biggest proportion of the unannotated DEGs was implicated in the roles of long non-coding RNAs (lncRNAs). Taken together, this study provides valuable insights that offer a deeper understanding of the molecular mechanisms underlying maize response to cold stress at the seedling stage, thus opening up possibilities for a breeding program of maize tolerance to cold stress. Full article
(This article belongs to the Special Issue Genetics and Evolution of Abiotic Stress Tolerance in Plants)
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Review
Generalizability of GWA-Identified Genetic Risk Variants for Metabolic Traits to Populations from the Arabian Peninsula
Genes 2021, 12(10), 1637; https://doi.org/10.3390/genes12101637 - 18 Oct 2021
Viewed by 229
Abstract
The Arabian Peninsula, located at the nexus of Africa, Europe, and Asia, was implicated in early human migration. The Arab population is characterized by consanguinity and endogamy leading to inbreeding. Global genome-wide association (GWA) studies on metabolic traits under-represent the Arab population. Replicability [...] Read more.
The Arabian Peninsula, located at the nexus of Africa, Europe, and Asia, was implicated in early human migration. The Arab population is characterized by consanguinity and endogamy leading to inbreeding. Global genome-wide association (GWA) studies on metabolic traits under-represent the Arab population. Replicability of GWA-identified association signals in the Arab population has not been satisfactorily explored. It is important to assess how well GWA-identified findings generalize if their clinical interpretations are to benefit the target population. Our recent study from Kuwait, which performed genome-wide imputation and meta-analysis, observed 304 (from 151 genes) of the 4746 GWA-identified metabolic risk variants replicable in the Arab population. A recent large GWA study from Qatar found replication of 30 GWA-identified lipid risk variants. These complementing studies from the Peninsula increase the confidence in generalizing metabolic risk loci to the Arab population. However, both the studies reported a low extent of transferability. In this review, we examine the observed low transferability in the context of differences in environment, genetic correlations (allele frequencies, linkage disequilibrium, effect sizes, and heritability), and phenotype variance. We emphasize the need for large-scale GWA studies on deeply phenotyped cohorts of at least 20,000 Arab individuals. The review further presents GWA-identified metabolic risk variants generalizable to the Arab population. Full article
(This article belongs to the Section Population and Evolutionary Genetics and Genomics)
Article
The Origin of Plasma-Derived Bacterial Extracellular Vesicles in Healthy Individuals and Patients with Inflammatory Bowel Disease: A Pilot Study
Genes 2021, 12(10), 1636; https://doi.org/10.3390/genes12101636 - 18 Oct 2021
Viewed by 323
Abstract
The gastrointestinal tract harbors the gut microbiota, structural alterations of which (dysbiosis) are linked with an increase in gut permeability (“leaky gut”), enabling luminal antigens and bacterial products such as nanosized bacterial extracellular vesicles (BEVs) to access the circulatory system. Blood-derived BEVs contain [...] Read more.
The gastrointestinal tract harbors the gut microbiota, structural alterations of which (dysbiosis) are linked with an increase in gut permeability (“leaky gut”), enabling luminal antigens and bacterial products such as nanosized bacterial extracellular vesicles (BEVs) to access the circulatory system. Blood-derived BEVs contain various cargoes and may be useful biomarkers for diagnosis and monitoring of disease status and relapse in conditions such as inflammatory bowel disease (IBD). To progress this concept, we developed a rapid, cost-effective protocol to isolate BEV-associated DNA and used 16S rRNA gene sequencing to identify bacterial origins of the blood microbiome of healthy individuals and patients with Crohn’s disease and ulcerative colitis. The 16S rRNA gene sequencing successfully identified the origin of plasma-derived BEV DNA. The analysis showed that the blood microbiota richness, diversity, or composition in IBD, healthy control, and protocol control groups were not significantly distinct, highlighting the issue of ‘kit-ome’ contamination in low-biomass studies. Our pilot study provides the basis for undertaking larger studies to determine the potential use of blood microbiota profiling as a diagnostic aid in IBD. Full article
(This article belongs to the Special Issue Microbial Extracellular Vesicles)
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Review
ABA and Bud Dormancy in Perennials: Current Knowledge and Future Perspective
Genes 2021, 12(10), 1635; https://doi.org/10.3390/genes12101635 - 18 Oct 2021
Viewed by 294
Abstract
Bud dormancy is an evolved trait that confers adaptation to harsh environments, and affects flower differentiation, crop yield and vegetative growth in perennials. ABA is a stress hormone and a major regulator of dormancy. Although the physiology of bud dormancy is complex, several [...] Read more.
Bud dormancy is an evolved trait that confers adaptation to harsh environments, and affects flower differentiation, crop yield and vegetative growth in perennials. ABA is a stress hormone and a major regulator of dormancy. Although the physiology of bud dormancy is complex, several advancements have been achieved in this field recently by using genetics, omics and bioinformatics methods. Here, we review the current knowledge on the role of ABA and environmental signals, as well as the interplay of other hormones and sucrose, in the regulation of this process. We also discuss emerging potential mechanisms in this physiological process, including epigenetic regulation. Full article
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Review
Maternal One-Carbon Metabolism during the Periconceptional Period and Human Foetal Brain Growth: A Systematic Review
Genes 2021, 12(10), 1634; https://doi.org/10.3390/genes12101634 - 17 Oct 2021
Viewed by 419
Abstract
The maternal environment during the periconceptional period influences foetal growth and development, in part, via epigenetic mechanisms moderated by one-carbon metabolic pathways. During embryonic development, one-carbon metabolism is involved in brain development and neural programming. Derangements in one-carbon metabolism increase (i) the short-term [...] Read more.
The maternal environment during the periconceptional period influences foetal growth and development, in part, via epigenetic mechanisms moderated by one-carbon metabolic pathways. During embryonic development, one-carbon metabolism is involved in brain development and neural programming. Derangements in one-carbon metabolism increase (i) the short-term risk of embryonic neural tube-related defects and (ii) long-term childhood behaviour, cognition, and autism spectrum disorders. Here we investigate the association between maternal one-carbon metabolism and foetal and neonatal brain growth and development. Database searching resulted in 26 articles eligible for inclusion. Maternal vitamin B6, vitamin B12, homocysteine, and choline were not associated with foetal and/or neonatal head growth. First-trimester maternal plasma folate within the normal range (>17 nmol/L) associated with increased foetal head size and head growth, and high erythrocyte folate (1538–1813 nmol/L) with increased cerebellar growth, whereas folate deficiency (<7 nmol/L) associated with a reduced foetal brain volume. Preconceptional folic acid supplement use and specific dietary patterns (associated with increased B vitamins and low homocysteine) increased foetal head size. Although early pregnancy maternal folate appears to be the most independent predictor of foetal brain growth, there is insufficient data to confirm the link between maternal folate and offspring risks for neurodevelopmental diseases. Full article
(This article belongs to the Special Issue Epigenetic Safety after Assisted Reproductive Technologies)
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Review
Mechanisms of Genome Instability in the Fragile X-Related Disorders
Genes 2021, 12(10), 1633; https://doi.org/10.3390/genes12101633 - 17 Oct 2021
Viewed by 350
Abstract
The Fragile X-related disorders (FXDs), which include the intellectual disability fragile X syndrome (FXS), are disorders caused by expansion of a CGG-repeat tract in the 5′ UTR of the X-linked FMR1 gene. These disorders are named for FRAXA, the folate-sensitive fragile site that [...] Read more.
The Fragile X-related disorders (FXDs), which include the intellectual disability fragile X syndrome (FXS), are disorders caused by expansion of a CGG-repeat tract in the 5′ UTR of the X-linked FMR1 gene. These disorders are named for FRAXA, the folate-sensitive fragile site that localizes with the CGG-repeat in individuals with FXS. Two pathological FMR1 allele size classes are distinguished. Premutation (PM) alleles have 54–200 repeats and confer the risk of fragile X-associated tremor/ataxia syndrome (FXTAS) and fragile X-associated primary ovarian insufficiency (FXPOI). PM alleles are prone to both somatic and germline expansion, with female PM carriers being at risk of having a child with >200+ repeats. Inheritance of such full mutation (FM) alleles causes FXS. Contractions of PM and FM alleles can also occur. As a result, many carriers are mosaic for different sized alleles, with the clinical presentation depending on the proportions of these alleles in affected tissues. Furthermore, it has become apparent that the chromosomal fragility of FXS individuals reflects an underlying problem that can lead to chromosomal numerical and structural abnormalities. Thus, large numbers of CGG-repeats in the FMR1 gene predisposes individuals to multiple forms of genome instability. This review will discuss our current understanding of these processes. Full article
(This article belongs to the Special Issue Fragile X Syndrome Genetics)
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Article
Telomerase (hTERT) Overexpression Reveals a Promising Prognostic Biomarker and Therapeutical Target in Different Clinical Subtypes of Pediatric Acute Lymphoblastic Leukaemia
Genes 2021, 12(10), 1632; https://doi.org/10.3390/genes12101632 - 17 Oct 2021
Viewed by 231
Abstract
Acute Lymphoblastic Leukemia (ALL) is a neoplasm of the hematopoietic system defined as a clonal expansion of an abnormal lymphoid precursor cell. It mostly affects children under five years of age and is the most common tumor to afflict pediatric patients. The expression [...] Read more.
Acute Lymphoblastic Leukemia (ALL) is a neoplasm of the hematopoietic system defined as a clonal expansion of an abnormal lymphoid precursor cell. It mostly affects children under five years of age and is the most common tumor to afflict pediatric patients. The expression of the human telomerase gene (hTERT) in patients with ALL has been studied as a biomarker and could become a new therapeutic target. We evaluate the role of hTERT gene expression in ALL pediatric patients, through quantitative real-time PCR technique, and the possible correlation between hTERT expression and clinical variables: gender, age, white blood cells (WBC), gene fusions, and immunophenotyping. The analysis between healthy controls and ALL patients (N = 244) was statistically significant (p < 0.001), demonstrating hTERT overexpression in these patients. In comparison with the usual set of clinical variables, the data were not statistically significant (p > 0.05), indicating that hTERT is equally overexpressed among patients regardless of gender, age, gene fusions, and immunophenotyping. Moreover, patients who presented a higher hTERT expression level had a significant (p < 0.0001) lower overall survival rate. In summary, hTERT expression emerges as an important molecular pathway in leukemogenesis regardless patient’s clinical variables, thus, the data here presented pointed it as a valuable biomarker in pediatric acute lymphoblastic leukemia and a promising target for new therapeutic and prognostic measures. Full article
(This article belongs to the Section Human Genomics and Genetic Diseases)
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Article
Identification of Novel Endogenous Controls for qPCR Normalization in SK-BR-3 Breast Cancer Cell Line
Genes 2021, 12(10), 1631; https://doi.org/10.3390/genes12101631 - 17 Oct 2021
Viewed by 277
Abstract
Normalization of gene expression using internal controls or reference genes (RGs) has been the method of choice for standardizing the technical variations in reverse transcription quantitative polymerase chain reactions (RT-qPCR). Conventionally, ACTB and GAPDH have been used as reference genes despite evidence from [...] Read more.
Normalization of gene expression using internal controls or reference genes (RGs) has been the method of choice for standardizing the technical variations in reverse transcription quantitative polymerase chain reactions (RT-qPCR). Conventionally, ACTB and GAPDH have been used as reference genes despite evidence from literature discouraging their use. Hence, in the present study we identified and investigated novel reference genes in SK-BR-3, an HER2-enriched breast cancer cell line. Transcriptomic data of 82 HER2-E breast cancer samples from TCGA database were analyzed to identify twelve novel genes with stable expression. Additionally, thirteen RGs from the literature were analyzed. The expression variations of the candidate genes were studied over five successive passages (p) in two parallel cultures S1 and S2 and in acute and chronic hypoxia using various algorithms. Finally, the most stable RGs were selected and validated for normalization of the expression of three genes of interest (GOIs) in normoxia and hypoxia. Our results indicate that HSP90AB1, DAD1, PFN1 and PUM1 can be used in any combination of three (triplets) for optimizing intra- and inter-assay gene expression differences in the SK-BR-3 cell line. Additionally, we discourage the use of conventional RGs (ACTB, GAPDH, RPL13A, RNA18S and RNA28S) as internal controls for RT-qPCR in SK-BR-3 cell line. Full article
(This article belongs to the Section Human Genomics and Genetic Diseases)
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Article
Marek’s Disease Virus Telomeric Integration Profiles of Neoplastic Host Tissues Reveal Unbiased Chromosomal Selection and Loss of Cellular Diversity during Tumorigenesis
Genes 2021, 12(10), 1630; https://doi.org/10.3390/genes12101630 - 17 Oct 2021
Viewed by 298
Abstract
The avian α-herpesvirus known as Marek’s disease virus (MDV) linearly integrates its genomic DNA into host telomeres during infection. The resulting disease, Marek’s disease (MD), is characterized by virally-induced lymphomas with high mortality. The temporal dynamics of MDV-positive (MDV+) transformed cells [...] Read more.
The avian α-herpesvirus known as Marek’s disease virus (MDV) linearly integrates its genomic DNA into host telomeres during infection. The resulting disease, Marek’s disease (MD), is characterized by virally-induced lymphomas with high mortality. The temporal dynamics of MDV-positive (MDV+) transformed cells and expansion of MD lymphomas remain targets for further understanding. It also remains to be determined whether specific host chromosomal sites of MDV telomere integration confer an advantage to MDV-transformed cells during tumorigenesis. We applied MDV-specific fluorescence in situ hybridization (MDV FISH) to investigate virus-host cytogenomic interactions within and among a total of 37 gonad lymphomas and neoplastic splenic samples in birds infected with virulent MDV. We also determined single-cell, chromosome-specific MDV integration profiles within and among transformed tissue samples, including multiple samples from the same bird. Most mitotically-dividing cells within neoplastic samples had the cytogenomic phenotype of ‘MDV telomere-integrated only’, and tissue-specific, temporal changes in phenotype frequencies were detected. Transformed cell populations composing gonad lymphomas exhibited significantly lower diversity, in terms of heterogeneity of MDV integration profiles, at the latest stages of tumorigenesis (>50 days post-infection (dpi)). We further report high interindividual and lower intraindividual variation in MDV integration profiles of lymphoma cells. There was no evidence of integration hotspots into a specific host chromosome(s). Collectively, our data suggests that very few transformed MDV+ T cell populations present earlier in MDV-induced lymphomas (32–50 dpi), survive, and expand to become the dominant clonal population in more advanced MD lymphomas (51–62 dpi) and establish metastatic lymphomas. Full article
(This article belongs to the Special Issue Genomics of Avian Viral Infections)
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Review
High-Dimensional Single-Cell Transcriptomics in Melanoma and Cancer Immunotherapy
Genes 2021, 12(10), 1629; https://doi.org/10.3390/genes12101629 - 16 Oct 2021
Viewed by 420
Abstract
Recent advances in single-cell transcriptomics have greatly improved knowledge of complex transcriptional programs, rapidly expanding our knowledge of cellular phenotypes and functions within the tumour microenvironment and immune system. Several new single-cell technologies have been developed over recent years that have enabled expanded [...] Read more.
Recent advances in single-cell transcriptomics have greatly improved knowledge of complex transcriptional programs, rapidly expanding our knowledge of cellular phenotypes and functions within the tumour microenvironment and immune system. Several new single-cell technologies have been developed over recent years that have enabled expanded understanding of the mechanistic cells and biological pathways targeted by immunotherapies such as immune checkpoint inhibitors, which are now routinely used in patient management with high-risk early-stage or advanced melanoma. These technologies have method-specific strengths, weaknesses and capabilities which need to be considered when utilising them to answer translational research questions. Here, we provide guidance for the implementation of single-cell transcriptomic analysis platforms by reviewing the currently available experimental and analysis workflows. We then highlight the use of these technologies to dissect the tumour microenvironment in the context of cancer patients treated with immunotherapy. The strategic use of single-cell analytics in clinical settings are discussed and potential future opportunities are explored with a focus on their use to rationalise the design of novel immunotherapeutic drug therapies that will ultimately lead to improved cancer patient outcomes. Full article
(This article belongs to the Special Issue Genetics and Genomics of Melanoma)
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Article
Lineage-Specific Genes and Family Expansions in Dictyostelid Genomes Display Expression Bias and Evolutionary Diversification during Development
Genes 2021, 12(10), 1628; https://doi.org/10.3390/genes12101628 - 16 Oct 2021
Viewed by 263
Abstract
Gene duplications generate new genes that can contribute to expression changes and the evolution of new functions. Genomes often consist of gene families that undergo expansions, some of which occur in specific lineages that reflect recent adaptive diversification. In this study, lineage-specific genes [...] Read more.
Gene duplications generate new genes that can contribute to expression changes and the evolution of new functions. Genomes often consist of gene families that undergo expansions, some of which occur in specific lineages that reflect recent adaptive diversification. In this study, lineage-specific genes and gene family expansions were studied across five dictyostelid species to determine when and how they are expressed during multicellular development. Lineage-specific genes were found to be enriched among genes with biased expression (predominant expression in one developmental stage) in each species and at most developmental time points, suggesting independent functional innovations of new genes throughout the phylogeny. Biased duplicate genes had greater expression divergence than their orthologs and paralogs, consistent with subfunctionalization or neofunctionalization. Lineage-specific expansions in particular had biased genes with both molecular signals of positive selection and high expression, suggesting adaptive genetic and transcriptional diversification following duplication. Our results present insights into the potential contributions of lineage-specific genes and families in generating species-specific phenotypes during multicellular development in dictyostelids. Full article
(This article belongs to the Special Issue How Do New Genes Originate and Evolve?)
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Article
Intermittent Hypoxia Alters the Circadian Expression of Clock Genes in Mouse Brain and Liver
Genes 2021, 12(10), 1627; https://doi.org/10.3390/genes12101627 - 16 Oct 2021
Viewed by 361
Abstract
At least one-third of adults in the United States experience intermittent hypoxia (IH) due to health or living conditions. The majority of these adults suffer with sleep breathing conditions and associated circadian rhythm disorders. The impact of IH on the circadian clock is [...] Read more.
At least one-third of adults in the United States experience intermittent hypoxia (IH) due to health or living conditions. The majority of these adults suffer with sleep breathing conditions and associated circadian rhythm disorders. The impact of IH on the circadian clock is not well characterized. In the current study, we used an IH mouse model to understand the impact of IH on the circadian gene expression of the canonical clock genes in the central (the brain) and peripheral (the liver) tissues. Gene expression was measured using a Quantitative Reverse Transcription Polymerase Chain Reaction (qRT-PCR). CircaCompare was used to evaluate the differential rhythmicity between normoxia and IH. Our observations suggested that the circadian clock in the liver was less sensitive to IH compared to the circadian clock in the brain. Full article
(This article belongs to the Special Issue Genetics of Circadian Clocks in Eukaryotic Organisms)
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Case Report
Prenatal Diagnosis of Combined Maternal 4q Interstitial Deletion and Paternal 15q Microduplication
Genes 2021, 12(10), 1626; https://doi.org/10.3390/genes12101626 - 16 Oct 2021
Viewed by 259
Abstract
The 4q deletion syndrome is a well-known rare genetic condition caused by partial, terminal, or interstitial deletion in the long arm (q) of chromosome 4. The phenotype of this syndrome shows a broad spectrum of clinical manifestations due to the great variability in [...] Read more.
The 4q deletion syndrome is a well-known rare genetic condition caused by partial, terminal, or interstitial deletion in the long arm (q) of chromosome 4. The phenotype of this syndrome shows a broad spectrum of clinical manifestations due to the great variability in the size and location of the deletion. In the literature, the mostly terminal deletions of chromosome 4q and the relative phenotypes are described, while the interstitial deletions of the long arm of chromosome 4 are rarely cited. Here, we report on a female fetus presenting no abnormal ultrasound evidence but with multiple chromosome aberrations. Comparative genomic hybridization (aCGH) revealed an interstitial 10.09 Mb deletion at the chromosome at the region of 4q28, arr[hg19] 4q28.1q28.3 (124068262_134158728)x1 combined with a 386.81 Kb microduplication at chromosome 15q11.1, arr[hg19] 15.11 (20249932_20636742)x3. At birth, and after 11 months, the baby was confirmed healthy and normal. The identification of this case allows for a deeper understanding of 4q syndrome and provides an explanation for the wide genetic/phenotypic spectrum of this pathology. This report can provide a reference for prenatal diagnosis and genetic counseling in patients who have similar cytogenetic abnormalities, and underlines the importance of reporting unusual variant chromosomes for diagnostic genetic purposes. Full article
(This article belongs to the Section Cytogenomics)
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Article
Structural Protein Analysis of Driver Gene Mutations in Conjunctival Melanoma
Genes 2021, 12(10), 1625; https://doi.org/10.3390/genes12101625 - 15 Oct 2021
Viewed by 112
Abstract
In recent years, there has been tremendous enthusiasm with respect to detailing the genetic basis of many neoplasms, including conjunctival melanoma (CM). We aim to analyze five proteins associated with CM, namely BRAF, NRAS, c-KIT, NF1, and PTEN. We evaluated each protein for [...] Read more.
In recent years, there has been tremendous enthusiasm with respect to detailing the genetic basis of many neoplasms, including conjunctival melanoma (CM). We aim to analyze five proteins associated with CM, namely BRAF, NRAS, c-KIT, NF1, and PTEN. We evaluated each protein for its intrinsically disordered protein regions (IDPRs) and its protein-protein interactions (PPI) with the Predictor of Natural Disordered Protein Regions (PONDR®) and the Search Tool for the Retrieval of Interacting Genes (STRING®). Our PONDR® analysis found high levels of IDPRs in all five proteins with mutations linked to CM. The highest levels of IDPRs were in BRAF (45.95%), followed by PTEN (31.76%), NF1 (22.19%), c-KIT (21.82%), and NRAS (14.81%). Our STRING analysis found that each of these five proteins had more predicted interactions then expected (p-value < 1.0 × 10−16). Our analysis demonstrates that the mutations linked to CM likely affected IDPRs and possibly altered their highly complex PPIs. Quantifying IDPRs in BRAF, NRAS, c-KIT, NF1, and PTEN and understanding these protein regions are important processes as IDPRs can be possible drug targets for novel targeted therapies for treating CM. Full article
(This article belongs to the Special Issue Genetics and Genomics of Melanoma)
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Case Report
WDR36-Associated Neurodegeneration: A Case Report Highlights Possible Mechanisms of Normal Tension Glaucoma
Genes 2021, 12(10), 1624; https://doi.org/10.3390/genes12101624 - 15 Oct 2021
Viewed by 95
Abstract
WDR36 is one of a number of genes implicated in the pathogenesis of adult-onset primary open angle glaucoma (POAG). Here we describe in detail the phenotype of a patient with pathogenic variation in WDR36 who presented with a protracted history of central vision [...] Read more.
WDR36 is one of a number of genes implicated in the pathogenesis of adult-onset primary open angle glaucoma (POAG). Here we describe in detail the phenotype of a patient with pathogenic variation in WDR36 who presented with a protracted history of central vision loss. On exam visual acuities were at 20/100 level, had a tritan color defect and showed central arcuate visual field defects on visual field testing. Enlarged cup-to-disk ratios with normal intraocular pressures were associated with severe thinning of the ganglion cell layer (GCL) and retinal nerve fiber layer consistent with a clinical diagnosis of normal tension glaucoma. Full-field electroretinograms revealed a severe inner retinal dysfunction with reduced amplitudes and remarkably delayed timings of the b-wave, but preserved photoreceptor (a-wave) function. The pattern described herein recapitulates some of the findings of an animal model of WDR36-associated POAG and suggests a mechanism of disease that involves a retina-wide inner retinal dysfunction and neurodegeneration beyond the GCL. Further detailed structural and functional characterizations of patients with a pathogenic variant in the WDR36 gene are required to confirm these findings. Full article
(This article belongs to the Special Issue Insights into Glaucoma Heritability)
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Article
Prevalence and Clinical Characteristics of Hearing Loss Caused by MYH14 Variants
Genes 2021, 12(10), 1623; https://doi.org/10.3390/genes12101623 - 15 Oct 2021
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Abstract
Variants in MYH14 are reported to cause autosomal dominant nonsyndromic hereditary hearing loss (ADNSHL), with 34 variants reported to cause hearing loss in various ethnic groups. However, the available information on prevalence, as well as with regard to clinical features, remains fragmentary. In [...] Read more.
Variants in MYH14 are reported to cause autosomal dominant nonsyndromic hereditary hearing loss (ADNSHL), with 34 variants reported to cause hearing loss in various ethnic groups. However, the available information on prevalence, as well as with regard to clinical features, remains fragmentary. In this study, genetic screening for MYH14 variants was carried out using a large series of Japanese hearing-loss patients to reveal more detailed information. Massively parallel DNA sequencing of 68 target candidate genes was applied in 8074 unrelated Japanese hearing-loss patients (including 1336 with ADNSHL) to identify genomic variations responsible for hearing loss. We identified 11 families with 10 variants. The prevalence was found to be 0.14% (11/8074) among all hearing-loss patients and 0.82% (11/1336) among ADNSHL patients. Nine of the eleven variants identified were novel. The patients typically showed late-onset hearing loss arising later than 20 years of age (64.3%, 9/14) along with progressive (92.3%, 12/13), moderate (62.5%, 10/16), and flat-type hearing loss (68.8%, 11/16). We also confirmed progressive hearing loss in serial audiograms. The clinical information revealed by the present study will contribute to further diagnosis and management of MYH14-associated hearing loss. Full article
(This article belongs to the Section Human Genomics and Genetic Diseases)
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Article
Association of CYP26C1 Promoter Hypomethylation with Small Vessel Occlusion in Korean Subjects
Genes 2021, 12(10), 1622; https://doi.org/10.3390/genes12101622 - 14 Oct 2021
Viewed by 189
Abstract
The risk factors for stroke, a fatal disease, include type two diabetes, hypertension, and genetic influences. Small vessel occlusion (SVO) can be affected by epigenetic alterations, but an association between SVO and the methylation of cytochrome P450 family 26 subfamily C member 1 [...] Read more.
The risk factors for stroke, a fatal disease, include type two diabetes, hypertension, and genetic influences. Small vessel occlusion (SVO) can be affected by epigenetic alterations, but an association between SVO and the methylation of cytochrome P450 family 26 subfamily C member 1 (CYP26C1) has not been identified. In this study, we measured the level of DNA methylation in the CYP26C1 promoter and the 5′ untranslated region of 115 normal subjects and 56 patients with SVO in Korea. The DNA methylation level of each subject was measured by bisulfite amplicon sequencing, and statistical analysis was performed using the general linear model or Pearson’s correlation. The average level of DNA methylation was markedly lower in patients with SVO than in normal subjects (20.4% vs. 17.5%). We found that the methylation of CYP26C1 has a significant positive correlation with blood parameters including white blood cells, hematocrit, lactate dehydrogenase, and Na+ in subjects with SVO. We predicted that binding of RXR-α and RAR-β might be affected by CYP26C1 methylation at CpG sites −246–237 and −294–285. These findings suggest that CYP26C1 methylation in the promoter region may be a predictor of SVO. Full article
(This article belongs to the Special Issue Genomics of Stroke)
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Article
Detection of Spinal Muscular Atrophy Patients Using Dried Saliva Spots
Genes 2021, 12(10), 1621; https://doi.org/10.3390/genes12101621 - 14 Oct 2021
Viewed by 218
Abstract
Spinal muscular atrophy (SMA) is a lower motor neuron disease, once considered incurable. The main symptoms are muscle weakness and muscular atrophy. More than 90% of cases of SMA are caused by homozygous deletion of survival motor neuron 1 (SMN1). Emerging [...] Read more.
Spinal muscular atrophy (SMA) is a lower motor neuron disease, once considered incurable. The main symptoms are muscle weakness and muscular atrophy. More than 90% of cases of SMA are caused by homozygous deletion of survival motor neuron 1 (SMN1). Emerging treatments, such as splicing modulation of SMN2 and SMN gene replacement therapy, have improved the prognoses and motor functions of patients. However, confirmed diagnosis by SMN1 testing is often delayed, suggesting the presence of diagnosis-delayed or undiagnosed cases. To enable patients to access the right treatments, a screening system for SMA is essential. Even so, the current newborn screening system using dried blood spots is still invasive and cumbersome. Here, we developed a completely non-invasive screening system using dried saliva spots (DSS) as an alternative DNA source to detect SMN1 deletion. In this study, 60 DSS (40 SMA patients and 20 controls) were tested. The combination of modified competitive oligonucleotide priming-polymerase chain reaction and melting peak analysis clearly distinguished DSS samples with and without SMN1. In conclusion, these results suggest that our system with DSS is applicable to SMA patient detection in the real world. Full article
(This article belongs to the Special Issue Genetics of Motor Neuron Diseases)
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Review
Roles of Glutathione in Mediating Abscisic Acid Signaling and Its Regulation of Seed Dormancy and Drought Tolerance
Genes 2021, 12(10), 1620; https://doi.org/10.3390/genes12101620 - 14 Oct 2021
Viewed by 261
Abstract
Plant growth and development and interactions with the environment are regulated by phytohormones and other signaling molecules. During their evolution, plants have developed strategies for efficient signal perception and for the activation of signal transduction cascades to maintain proper growth and development, in [...] Read more.
Plant growth and development and interactions with the environment are regulated by phytohormones and other signaling molecules. During their evolution, plants have developed strategies for efficient signal perception and for the activation of signal transduction cascades to maintain proper growth and development, in particular under adverse environmental conditions. Abscisic acid (ABA) is one of the phytohormones known to regulate plant developmental events and tolerance to environmental stresses. The role of ABA is mediated by both its accumulated level, which is regulated by its biosynthesis and catabolism, and signaling, all of which are influenced by complex regulatory mechanisms. Under stress conditions, plants employ enzymatic and non-enzymatic antioxidant strategies to scavenge excess reactive oxygen species (ROS) and mitigate the negative effects of oxidative stress. Glutathione (GSH) is one of the main antioxidant molecules playing a critical role in plant survival under stress conditions through the detoxification of excess ROS, maintaining cellular redox homeostasis and regulating protein functions. GSH has recently emerged as an important signaling molecule regulating ABA signal transduction and associated developmental events, and response to stressors. This review highlights the current knowledge on the interplay between ABA and GSH in regulating seed dormancy, germination, stomatal closure and tolerance to drought. Full article
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Article
More Than a Moggy; A Population Genetics Analysis of the United Kingdom’s Non-Pedigree Cats
Genes 2021, 12(10), 1619; https://doi.org/10.3390/genes12101619 - 14 Oct 2021
Viewed by 206
Abstract
The domestic cat is one of the most popular pets in the world. It is estimated that 89–92% of domestic cats in the UK are non-pedigree Domestic shorthair (DSH), Domestic longhair (DLH), or Domestic semi-longhair cats (DSLH). Despite their popularity, little is known [...] Read more.
The domestic cat is one of the most popular pets in the world. It is estimated that 89–92% of domestic cats in the UK are non-pedigree Domestic shorthair (DSH), Domestic longhair (DLH), or Domestic semi-longhair cats (DSLH). Despite their popularity, little is known of the UK non-pedigree cats’ population structure and breeding dynamics. Using a custom designed single nucleotide variant (SNV) array, this study investigated the population genetics of 1344 UK cats. Principal components analysis (PCA) and fastSTRUCTURE analysis verified that the UK’s DSH, DLH, and DSLH cats are random-bred, rather than admixed, mix breed, or crossbred. In contrast to pedigree cats, the linkage disequilibrium of these random-bred cats was least extensive and decayed rapidly. Homozygosity by descent (HBD) analysis showed the majority of non-pedigree cats had proportionally less of their genome in HBD segments compared to pedigree cats, and that these segments were older. Together, these findings suggest that the DSH, DLH, and DSLH cats should be considered as a population of random-bred cats rather than a crossbred or pedigree-admixed cat. Unexpectedly, 19% of random-bred cat genomes displayed a higher proportion of HBD segments associated with more recent inbreeding events. Therefore, while non-pedigree cats as a whole are genetically diverse, they are not impervious to inbreeding and its health risks. Full article
(This article belongs to the Section Animal Genetics and Genomics)
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Case Report
A Two-Year Clinical Description of a Patient with a Rare Type of Low-GGT Cholestasis Caused by a Novel Variant of USP53
Genes 2021, 12(10), 1618; https://doi.org/10.3390/genes12101618 - 14 Oct 2021
Viewed by 182
Abstract
Here, we report a novel truncating mutation in the ubiquitin-specific peptidase gene (USP53) causing low-γ-GT (GGT) cholestasis. Genetic testing was carried out, including clinical exome sequencing for the proband and Sanger sequencing for the proband and his parents. The proband harbored [...] Read more.
Here, we report a novel truncating mutation in the ubiquitin-specific peptidase gene (USP53) causing low-γ-GT (GGT) cholestasis. Genetic testing was carried out, including clinical exome sequencing for the proband and Sanger sequencing for the proband and his parents. The proband harbored a novel c.1017_1057del (p.(Cys339TrpfsTer7)) mutation in the ubiquitin carboxyl-terminal hydrolase (UCH) domain of USP53; we describe the clinical and laboratory features of the patient with a rare type of low-GGT cholestasis caused by this variant. The clinical presentation was found to be similar to that of phenotypes described in previous studies. However, there was an unusual presence of liver hemangiomas observed in our patient. Thus, our report reinforces the link between USP53 mutations and cholestasis. With this report, we confirm USP53 as the gene for low-GGT cholestasis and describe liver hemangiomas as a possible additional symptom of the phenotype spectrum. The inclusion of USP53 in the OMIM database and liver gene panels can further increase the effectiveness of molecular genetic studies. Full article
(This article belongs to the Section Human Genomics and Genetic Diseases)
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