Genes

23 pages, 638 KiB

Open AccessEditor’s ChoiceReview

The Genetics of Parkinson’s Disease and Implications for Clinical Practice

by Jacob Oliver Day and Stephen Mullin

Genes 2021, 12(7), 1006; https://doi.org/10.3390/genes12071006 - 30 Jun 2021

Cited by 76 | Viewed by 20124

The genetic landscape of Parkinson’s disease (PD) is characterised by rare high penetrance pathogenic variants causing familial disease, genetic risk factor variants driving PD risk in a significant minority in PD cases and high frequency, low penetrance variants, which contribute a small increase [...] Read more.

The genetic landscape of Parkinson’s disease (PD) is characterised by rare high penetrance pathogenic variants causing familial disease, genetic risk factor variants driving PD risk in a significant minority in PD cases and high frequency, low penetrance variants, which contribute a small increase of the risk of developing sporadic PD. This knowledge has the potential to have a major impact in the clinical care of people with PD. We summarise these genetic influences and discuss the implications for therapeutics and clinical trial design. Full article

(This article belongs to the Special Issue Preclinical and Clinical Genetics in Parkinson’s Disease)

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16 pages, 3812 KiB

Open AccessEditor’s ChoiceArticle

Altered Expression of DAAM1 and PREP Induced by Cadmium Toxicity Is Counteracted by Melatonin in the Rat Testis

by Massimo Venditti, Mariem Ben Rhouma, Maria Zelinda Romano, Imed Messaoudi, Russel J. Reiter and Sergio Minucci

Genes 2021, 12(7), 1016; https://doi.org/10.3390/genes12071016 - 30 Jun 2021

Cited by 26 | Viewed by 3162

Abstract

Cadmium (Cd) is one of the most toxic pollutants for health due to its accumulation in several tissues, including testis. This report confirms that Cd increased oxidative stress and apoptosis of germ and somatic cells and provoked testicular injury, as documented by biomolecular [...] Read more.

Cadmium (Cd) is one of the most toxic pollutants for health due to its accumulation in several tissues, including testis. This report confirms that Cd increased oxidative stress and apoptosis of germ and somatic cells and provoked testicular injury, as documented by biomolecular and histological alterations, i.e., CAT and SOD activity, the protein level of steroidogenic enzymes (StAR and 3β-HSD), and morphometric parameters. Additionally, it further documents the melatonin (MLT) coadministration produces affects in mitigating Cd-induced toxicity on adult rat testis, as demonstrated by the reduction of oxidative stress and apoptosis, with reversal of the observed histological changes; moreover, a role of MLT in partially restoring steroidogenic enzymes expression was evidenced. Importantly, the cytoarchitecture of testicular cells was perturbed by Cd exposure, as highlighted by impairment of the expression and localization of two cytoskeleton-associated proteins DAAM1 and PREP, which are involved in the germ cells’ differentiation into spermatozoa, altering the normal spermatogenesis. Here, for the first time, we found that the co-treatment with MLT attenuated the Cd-induced toxicity on the testicular DAAM1 and PREP expression. The combined findings provide additional clues about a protective effect of MLT against Cd-induced testicular toxicity by acting on DAAM1 and PREP expression, encouraging further studies to prove its effectiveness in human health. Full article

(This article belongs to the Special Issue Male Reproduction: Regulation, Differentiation and Epigenetics)

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15 pages, 5061 KiB

Open AccessEditor’s ChoiceArticle

A Genome-Wide Analysis of Pathogenesis-Related Protein-1 (PR-1) Genes from Piper nigrum Reveals Its Critical Role during Phytophthora capsici Infection

by Divya Kattupalli, Asha Srinivasan and Eppurath Vasudevan Soniya

Genes 2021, 12(7), 1007; https://doi.org/10.3390/genes12071007 - 30 Jun 2021

Cited by 22 | Viewed by 3569

Abstract

Black pepper (Piper nigrum L.) is a prominent spice that is an indispensable ingredient in cuisine and traditional medicine. Phytophthora capsici, the causative agent of footrot disease, causes a drastic constraint in P. nigrum cultivation and productivity. To counterattack various biotic [...] Read more.

Black pepper (Piper nigrum L.) is a prominent spice that is an indispensable ingredient in cuisine and traditional medicine. Phytophthora capsici, the causative agent of footrot disease, causes a drastic constraint in P. nigrum cultivation and productivity. To counterattack various biotic and abiotic stresses, plants employ a broad array of mechanisms that includes the accumulation of pathogenesis-related (PR) proteins. Through a genome-wide survey, eleven PR-1 genes that belong to a CAP superfamily protein with a caveolin-binding motif (CBM) and a CAP-derived peptide (CAPE) were identified from P. nigrum. Despite the critical functional domains, PnPR-1 homologs differ in their signal peptide motifs and core amino acid composition in the functional protein domains. The conserved motifs of PnPR-1 proteins were identified using MEME. Most of the PnPR-1 proteins were basic in nature. Secondary and 3D structure analyses of the PnPR-1 proteins were also predicted, which may be linked to a functional role in P. nigrum. The GO and KEGG functional annotations predicted their function in the defense responses of plant-pathogen interactions. Furthermore, a transcriptome-assisted FPKM analysis revealed PnPR-1 genes mapped to the P. nigrum-P. capsici interaction pathway. An altered expression pattern was detected for PnPR-1 transcripts among which a significant upregulation was noted for basic PnPR-1 genes such as CL10113.C1 and Unigene17664. The drastic variation in the transcript levels of CL10113.C1 was further validated through qRT-PCR and it showed a significant upregulation in infected leaf samples compared with the control. A subsequent analysis revealed the structural details, phylogenetic relationships, conserved sequence motifs and critical cis-regulatory elements of PnPR-1 genes. This is the first genome-wide study that identified the role of PR-1 genes during P. nigrum-P. capsici interactions. The detailed in silico experimental analysis revealed the vital role of PnPR-1 genes in regulating the first layer of defense towards a P. capsici infection in Panniyur-1 plants. Full article

(This article belongs to the Special Issue Proteins: Proteomics and Beyond)

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9 pages, 1097 KiB

Open AccessEditor’s ChoiceReview

Extracellular Vesicles and Host–Pathogen Interactions: A Review of Inter-Kingdom Signaling by Small Noncoding RNA

by Bruce A. Stanton

Genes 2021, 12(7), 1010; https://doi.org/10.3390/genes12071010 - 30 Jun 2021

Cited by 29 | Viewed by 4215

Abstract

The focus of this brief review is to describe the role of noncoding regulatory RNAs, including short RNAs (sRNA), transfer RNA (tRNA) fragments and microRNAs (miRNA) secreted in extracellular vesicles (EVs), in inter-kingdom communication between bacteria and mammalian (human) host cells. Bacteria secrete [...] Read more.

The focus of this brief review is to describe the role of noncoding regulatory RNAs, including short RNAs (sRNA), transfer RNA (tRNA) fragments and microRNAs (miRNA) secreted in extracellular vesicles (EVs), in inter-kingdom communication between bacteria and mammalian (human) host cells. Bacteria secrete vesicles that contain noncoding regulatory RNAs, and recent studies have shown that the bacterial vesicles fuse with and deliver regulatory RNAs to host cells, and similar to eukaryotic miRNAs, regulatory RNAs modulate the host immune response to infection. Recent studies have also demonstrated that mammalian cells secrete EVs containing miRNAs that regulate the gut microbiome, biofilm formation and the bacterial response to antibiotics. Thus, as evidence accumulates it is becoming clear that the secretion of noncoding regulatory RNAs and miRNAs in extracellular vesicles is an important mechanism of bidirectional communication between bacteria and mammalian (human) host cells. However, additional research is necessary to elucidate how noncoding regulatory RNAs and miRNA secreted in extracellular vesicles mediate inter-kingdom communication. Full article

(This article belongs to the Special Issue Microbial Extracellular Vesicles)

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12 pages, 1385 KiB

Open AccessEditor’s ChoiceReview

Molecular Genetics and Complex Inheritance of Congenital Heart Disease

by Nicholas S. Diab, Syndi Barish, Weilai Dong, Shujuan Zhao, Garrett Allington, Xiaobing Yu, Kristopher T. Kahle, Martina Brueckner and Sheng Chih Jin

Genes 2021, 12(7), 1020; https://doi.org/10.3390/genes12071020 - 30 Jun 2021

Cited by 44 | Viewed by 7709

Abstract

Congenital heart disease (CHD) is the most common congenital malformation and the leading cause of mortality therein. Genetic etiologies contribute to an estimated 90% of CHD cases, but so far, a molecular diagnosis remains unsolved in up to 55% of patients. Copy number [...] Read more.

Congenital heart disease (CHD) is the most common congenital malformation and the leading cause of mortality therein. Genetic etiologies contribute to an estimated 90% of CHD cases, but so far, a molecular diagnosis remains unsolved in up to 55% of patients. Copy number variations and aneuploidy account for ~23% of cases overall, and high-throughput genomic technologies have revealed additional types of genetic variation in CHD. The first CHD risk genotypes identified through high-throughput sequencing were de novo mutations, many of which occur in chromatin modifying genes. Murine models of cardiogenesis further support the damaging nature of chromatin modifying CHD mutations. Transmitted mutations have also been identified through sequencing of population scale CHD cohorts, and many transmitted mutations are enriched in cilia genes and Notch or VEGF pathway genes. While we have come a long way in identifying the causes of CHD, more work is required to end the diagnostic odyssey for all CHD families. Complex genetic explanations of CHD are emerging but will require increasingly sophisticated analysis strategies applied to very large CHD cohorts before they can come to fruition in providing molecular diagnoses to genetically unsolved patients. In this review, we discuss the genetic architecture of CHD and biological pathways involved in its pathogenesis. Full article

(This article belongs to the Special Issue Genetics and Epigenetics of Human Congenital Heart Disease)

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10 pages, 529 KiB

Open AccessEditor’s ChoiceArticle

Sensory Reactivity Phenotype in Phelan–McDermid Syndrome Is Distinct from Idiopathic ASD

by Teresa Tavassoli, Christina Layton, Tess Levy, Mikaela Rowe, Julia George-Jones, Jessica Zweifach, Stacey Lurie, Joseph D. Buxbaum, Alexander Kolevzon and Paige M. Siper

Genes 2021, 12(7), 977; https://doi.org/10.3390/genes12070977 - 26 Jun 2021

Cited by 14 | Viewed by 2703

Abstract

Phelan–McDermid syndrome (PMS) is one of the most common genetic forms of autism spectrum disorder (ASD). While sensory reactivity symptoms are widely reported in idiopathic ASD (iASD), few studies have examined sensory symptoms in PMS. The current study delineates the sensory reactivity phenotype [...] Read more.

Phelan–McDermid syndrome (PMS) is one of the most common genetic forms of autism spectrum disorder (ASD). While sensory reactivity symptoms are widely reported in idiopathic ASD (iASD), few studies have examined sensory symptoms in PMS. The current study delineates the sensory reactivity phenotype and examines genotype–phenotype interactions in a large sample of children with PMS. Sensory reactivity was measured in a group of 52 children with PMS, 132 children with iASD, and 54 typically developing (TD) children using the Sensory Assessment for Neurodevelopmental Disorders (SAND). The SAND is a clinician-administered observation and corresponding caregiver interview that captures sensory symptoms based on the DSM-5 criteria for ASD. Children with PMS demonstrated significantly greater hyporeactivity symptoms and fewer hyperreactivity and seeking symptoms compared to children with iASD and TD controls. There were no differences between those with Class I deletions or sequence variants and those with larger Class II deletions, suggesting that haploinsufficiency of SHANK3 is the main driver of the sensory phenotype seen in PMS. The syndrome-specific sensory phenotype identified in this study is distinct from other monogenic forms of ASD and offers insight into the potential role of SHANK3 deficiency in sensory reactivity. Understanding sensory reactivity abnormalities in PMS, in the context of known glutamatergic dysregulation, may inform future clinical trials in the syndrome. Full article

(This article belongs to the Special Issue Genomics of Neuropsychiatric Disorders)

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22 pages, 2398 KiB

Open AccessEditor’s ChoiceReview

Rubinstein-Taybi Syndrome: A Model of Epigenetic Disorder

by Julien Van Gils, Frederique Magdinier, Patricia Fergelot and Didier Lacombe

Genes 2021, 12(7), 968; https://doi.org/10.3390/genes12070968 - 24 Jun 2021

Cited by 37 | Viewed by 10597

Abstract

The Rubinstein-Taybi syndrome (RSTS) is a rare congenital developmental disorder characterized by a typical facial dysmorphism, distal limb abnormalities, intellectual disability, and many additional phenotypical features. It occurs at between 1/100,000 and 1/125,000 births. Two genes are currently known to cause RSTS, CREBBP [...] Read more.

The Rubinstein-Taybi syndrome (RSTS) is a rare congenital developmental disorder characterized by a typical facial dysmorphism, distal limb abnormalities, intellectual disability, and many additional phenotypical features. It occurs at between 1/100,000 and 1/125,000 births. Two genes are currently known to cause RSTS, CREBBP and EP300, mutated in around 55% and 8% of clinically diagnosed cases, respectively. To date, 500 pathogenic variants have been reported for the CREBBP gene and 118 for EP300. These two genes encode paralogs acting as lysine acetyltransferase involved in transcriptional regulation and chromatin remodeling with a key role in neuronal plasticity and cognition. Because of the clinical heterogeneity of this syndrome ranging from the typical clinical diagnosis to features overlapping with other Mendelian disorders of the epigenetic machinery, phenotype/genotype correlations remain difficult to establish. In this context, the deciphering of the patho-physiological process underlying these diseases and the definition of a specific episignature will likely improve the diagnostic efficiency but also open novel therapeutic perspectives. This review summarizes the current clinical and molecular knowledge and highlights the epigenetic regulation of RSTS as a model of chromatinopathy. Full article

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

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15 pages, 846 KiB

Open AccessEditor’s ChoiceArticle

Complex Modes of Inheritance in Hereditary Red Blood Cell Disorders: A Case Series Study of 155 Patients

by Immacolata Andolfo, Stefania Martone, Barbara Eleni Rosato, Roberta Marra, Antonella Gambale, Gian Luca Forni, Valeria Pinto, Magnus Göransson, Vasiliki Papadopoulou, Mathilde Gavillet, Mohsen Elalfy, Antonella Panarelli, Giovanna Tomaiuolo, Achille Iolascon and Roberta Russo

Genes 2021, 12(7), 958; https://doi.org/10.3390/genes12070958 - 23 Jun 2021

Cited by 24 | Viewed by 3303

Abstract

Hereditary erythrocytes disorders include a large group of conditions with heterogeneous molecular bases and phenotypes. We analyzed here a case series of 155 consecutive patients with clinical suspicion of hereditary erythrocyte defects referred to the Medical Genetics Unit from 2018 to 2020. All [...] Read more.

Hereditary erythrocytes disorders include a large group of conditions with heterogeneous molecular bases and phenotypes. We analyzed here a case series of 155 consecutive patients with clinical suspicion of hereditary erythrocyte defects referred to the Medical Genetics Unit from 2018 to 2020. All of the cases followed a diagnostic workflow based on a targeted next-generation sequencing panel of 86 genes causative of hereditary red blood cell defects. We obtained an overall diagnostic yield of 84% of the tested patients. Monogenic inheritance was seen for 69% (107/155), and multi-locus inheritance for 15% (23/155). PIEZO1 and SPTA1 were the most mutated loci. Accordingly, 16/23 patients with multi-locus inheritance showed dual molecular diagnosis of dehydrated hereditary stomatocytosis/xerocytosis and hereditary spherocytosis. These dual inheritance cases were fully characterized and were clinically indistinguishable from patients with hereditary spherocytosis. Additionally, their ektacytometry curves highlighted alterations of dual inheritance patients compared to both dehydrated hereditary stomatocytosis and hereditary spherocytosis. Our findings expand the genotypic spectrum of red blood cell disorders and indicate that multi-locus inheritance should be considered for analysis and counseling of these patients. Of note, the genetic testing was crucial for diagnosis of patients with a complex mode of inheritance. Full article

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

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26 pages, 4558 KiB

Open AccessEditor’s ChoiceReview

Ocular Involvement in Hereditary Amyloidosis

by Angelo Maria Minnella, Roberta Rissotto, Elena Antoniazzi, Marco Di Girolamo, Marco Luigetti, Martina Maceroni, Daniela Bacherini, Benedetto Falsini, Stanislao Rizzo and Laura Obici

Genes 2021, 12(7), 955; https://doi.org/10.3390/genes12070955 - 22 Jun 2021

Cited by 35 | Viewed by 4389

Abstract

The term amyloidosis describes a group of rare diseases caused by protein conformation abnormalities resulting in extracellular deposition and accumulation of insoluble fibrillar aggregates. So far, 36 amyloid precursor proteins have been identified, and each one is responsible for a specific disease entity. [...] Read more.

The term amyloidosis describes a group of rare diseases caused by protein conformation abnormalities resulting in extracellular deposition and accumulation of insoluble fibrillar aggregates. So far, 36 amyloid precursor proteins have been identified, and each one is responsible for a specific disease entity. Transthyretin amyloidosis (ATTRv) is one of the most common forms of systemic and ocular amyloidosis, due to the deposition of transthyretin (TTR), which is a transport protein mainly synthesized in the liver but also in the retinal pigment epithelial cells. ATTRv amyloidosis may be misdiagnosed with several other conditions, resulting in a significant diagnostic delay. Gelsolin and keratoepithelin are other proteins that, when mutated, are responsible for a systemic amyloid disease with significant ocular manifestations that not infrequently appear before systemic involvement. The main signs of ocular amyloid deposition are in the cornea, irido-corneal angle and vitreous, causing complications related to vasculopathy and neuropathy at the local level. This review aims at describing the main biochemical, histopathological and clinical features of systemic amyloidosis associated with eye involvement, with particular emphasis on the inherited forms. We discuss currently available treatments, focusing on ocular involvement and specific ophthalmologic management and highlighting the importance of a prompt treatment for the potential sight-threatening complications derived from amyloid deposition in ocular tissues. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Neuromuscular Disorders)

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9 pages, 986 KiB

Open AccessEditor’s ChoiceArticle

Genotype-Phenotype Correlations in 208 Individuals with Coffin-Siris Syndrome

by Ashley Vasko, Theodore G. Drivas and Samantha A. Schrier Vergano

Genes 2021, 12(6), 937; https://doi.org/10.3390/genes12060937 - 19 Jun 2021

Cited by 31 | Viewed by 6207

Abstract

Coffin-Siris syndrome (CSS, MIM 135900) is a multi-system intellectual disability syndrome characterized by classic dysmorphic features, developmental delays, and organ system anomalies. Genes in the BRG1(BRM)-associated factors (BAF, Brahma associated factor) complex have been shown to be causative, including ARID1A, ARID1B, [...] Read more.

Coffin-Siris syndrome (CSS, MIM 135900) is a multi-system intellectual disability syndrome characterized by classic dysmorphic features, developmental delays, and organ system anomalies. Genes in the BRG1(BRM)-associated factors (BAF, Brahma associated factor) complex have been shown to be causative, including ARID1A, ARID1B, ARID2, DPF2, SMARCA4, SMARCB1, SMARCC2, SMARCE1, SOX11, and SOX4. In order to describe more robust genotype-phenotype correlations, we collected data from 208 individuals from the CSS/BAF complex registry with pathogenic variants in seven of these genes. Data were organized into cohorts by affected gene, comparing genotype groups across a number of binary and quantitative phenotypes. We determined that, while numerous phenotypes are seen in individuals with variants in the BAF complex, hypotonia, hypertrichosis, sparse scalp hair, and hypoplasia of the distal phalanx are still some of the most common features. It has been previously proposed that individuals with ARID-related variants are thought to have more learning and developmental struggles, and individuals with SMARC-related variants, while they also have developmental delay, tend to have more severe organ-related complications. SOX-related variants also have developmental differences and organ-related complications but are most associated with neurodevelopmental differences. While these generalizations still overall hold true, we have found that all individuals with BAF-related conditions are at risk of many aspects of the phenotype, and management and surveillance should be broad. Full article

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

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21 pages, 1736 KiB

Open AccessEditor’s ChoiceReview

How Depressing Is Inbreeding? A Meta-Analysis of 30 Years of Research on the Effects of Inbreeding in Livestock

by Harmen P. Doekes, Piter Bijma and Jack J. Windig

Genes 2021, 12(6), 926; https://doi.org/10.3390/genes12060926 - 18 Jun 2021

Cited by 49 | Viewed by 5906

Abstract

Inbreeding depression has been widely documented for livestock and other animal and plant populations. Inbreeding is generally expected to have a stronger unfavorable effect on fitness traits than on other traits. Traditionally, the degree of inbreeding depression in livestock has been estimated as [...] Read more.

Inbreeding depression has been widely documented for livestock and other animal and plant populations. Inbreeding is generally expected to have a stronger unfavorable effect on fitness traits than on other traits. Traditionally, the degree of inbreeding depression in livestock has been estimated as the slope of the linear regression of phenotypic values on pedigree-based inbreeding coefficients. With the increasing availability of SNP-data, pedigree inbreeding can now be replaced by SNP-based measures. We performed a meta-analysis of 154 studies, published from 1990 to 2020 on seven livestock species, and compared the degree of inbreeding depression (1) across different trait groups, and (2) across different pedigree-based and SNP-based measures of inbreeding. Across all studies and traits, a 1% increase in pedigree inbreeding was associated with a median decrease in phenotypic value of 0.13% of a trait’s mean, or 0.59% of a trait’s standard deviation. Inbreeding had an unfavorable effect on all sorts of traits and there was no evidence for a stronger effect on primary fitness traits (e.g., reproduction/survival traits) than on other traits (e.g., production traits or morphological traits). p-values of inbreeding depression estimates were smaller for SNP-based inbreeding measures than for pedigree inbreeding, suggesting more power for SNP-based measures. There were no consistent differences in p-values for percentage of homozygous SNPs, inbreeding based on runs of homozygosity (ROH) or inbreeding based on a genomic relationship matrix. The number of studies that directly compares these different measures, however, is limited and comparisons are furthermore complicated by differences in scale and arbitrary definitions of particularly ROH-based inbreeding. To facilitate comparisons across studies in future, we provide the dataset with inbreeding depression estimates of 154 studies and stress the importance of always reporting detailed information (on traits, inbreeding coefficients, and models used) along with inbreeding depression estimates. Full article

(This article belongs to the Special Issue Inbreeding)

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32 pages, 1239 KiB

Open AccessEditor’s ChoiceReview

Cytogenetics of Pediatric Acute Myeloid Leukemia: A Review of the Current Knowledge

by Julie Quessada, Wendy Cuccuini, Paul Saultier, Marie Loosveld, Christine J. Harrison and Marina Lafage-Pochitaloff

Genes 2021, 12(6), 924; https://doi.org/10.3390/genes12060924 - 17 Jun 2021

Cited by 41 | Viewed by 11089

Abstract

Pediatric acute myeloid leukemia is a rare and heterogeneous disease in relation to morphology, immunophenotyping, germline and somatic cytogenetic and genetic abnormalities. Over recent decades, outcomes have greatly improved, although survival rates remain around 70% and the relapse rate is high, at around [...] Read more.

Pediatric acute myeloid leukemia is a rare and heterogeneous disease in relation to morphology, immunophenotyping, germline and somatic cytogenetic and genetic abnormalities. Over recent decades, outcomes have greatly improved, although survival rates remain around 70% and the relapse rate is high, at around 30%. Cytogenetics is an important factor for diagnosis and indication of prognosis. The main cytogenetic abnormalities are referenced in the current WHO classification of acute myeloid leukemia, where there is an indication for risk-adapted therapy. The aim of this article is to provide an updated review of cytogenetics in pediatric AML, describing well-known WHO entities, as well as new subgroups and germline mutations with therapeutic implications. We describe the main chromosomal abnormalities, their frequency according to age and AML subtypes, and their prognostic relevance within current therapeutic protocols. We focus on de novo AML and on cytogenetic diagnosis, including the practical difficulties encountered, based on the most recent hematological and cytogenetic recommendations. Full article

(This article belongs to the Special Issue Genetics and Epigenetics of Pediatric Leukemia)

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21 pages, 3808 KiB

Open AccessEditor’s ChoiceArticle

New RAD51 Inhibitors to Target Homologous Recombination in Human Cells

by Irina S. Shkundina, Alexander A. Gall, Alexej Dick, Simon Cocklin and Alexander V. Mazin

Genes 2021, 12(6), 920; https://doi.org/10.3390/genes12060920 - 16 Jun 2021

Cited by 20 | Viewed by 4362

Abstract

Targeting DNA repair proteins with small-molecule inhibitors became a proven anti-cancer strategy. Previously, we identified an inhibitor of a major protein of homologous recombination (HR) RAD51, named B02. B02 inhibited HR in human cells and sensitized them to chemotherapeutic drugs in vitro and [...] Read more.

Targeting DNA repair proteins with small-molecule inhibitors became a proven anti-cancer strategy. Previously, we identified an inhibitor of a major protein of homologous recombination (HR) RAD51, named B02. B02 inhibited HR in human cells and sensitized them to chemotherapeutic drugs in vitro and in vivo. Here, using a medicinal chemistry approach, we aimed to improve the potency of B02. We identified the B02 analog, B02-isomer, which inhibits HR in human cells with significantly higher efficiency. We also show that B02-iso sensitizes triple-negative breast cancer MDA-MB-231 cells to the PARP inhibitor (PARPi) olaparib. Full article

(This article belongs to the Special Issue The Key of DNA Recombination and Replication—Recombination Mediator Proteins)

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27 pages, 2496 KiB

Open AccessEditor’s ChoiceReview

The Structural, Functional and Evolutionary Impact of Transposable Elements in Eukaryotes

by Dareen Almojil, Yann Bourgeois, Marcin Falis, Imtiyaz Hariyani, Justin Wilcox and Stéphane Boissinot

Genes 2021, 12(6), 918; https://doi.org/10.3390/genes12060918 - 15 Jun 2021

Cited by 27 | Viewed by 6602

Abstract

Transposable elements (TEs) are nearly ubiquitous in eukaryotes. The increase in genomic data, as well as progress in genome annotation and molecular biology techniques, have revealed the vast number of ways mobile elements have impacted the evolution of eukaryotes. In addition to being [...] Read more.

Transposable elements (TEs) are nearly ubiquitous in eukaryotes. The increase in genomic data, as well as progress in genome annotation and molecular biology techniques, have revealed the vast number of ways mobile elements have impacted the evolution of eukaryotes. In addition to being the main cause of difference in haploid genome size, TEs have affected the overall organization of genomes by accumulating preferentially in some genomic regions, by causing structural rearrangements or by modifying the recombination rate. Although the vast majority of insertions is neutral or deleterious, TEs have been an important source of evolutionary novelties and have played a determinant role in the evolution of fundamental biological processes. TEs have been recruited in the regulation of host genes and are implicated in the evolution of regulatory networks. They have also served as a source of protein-coding sequences or even entire genes. The impact of TEs on eukaryotic evolution is only now being fully appreciated and the role they may play in a number of biological processes, such as speciation and adaptation, remains to be deciphered. Full article

(This article belongs to the Special Issue Nucleotide Sequences and Genome Organization)

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11 pages, 569 KiB

Open AccessEditor’s ChoiceReview

The Development of Herbicide Resistance Crop Plants Using CRISPR/Cas9-Mediated Gene Editing

by Huirong Dong, Yong Huang and Kejian Wang

Genes 2021, 12(6), 912; https://doi.org/10.3390/genes12060912 - 12 Jun 2021

Cited by 38 | Viewed by 13371

Abstract

The rapid increase in herbicide-resistant weeds creates a huge challenge to global food security because it can reduce crop production, causing considerable losses. Combined with a lack of novel herbicides, cultivating herbicide-resistant crops becomes an effective strategy to control weeds because of reduced [...] Read more.

The rapid increase in herbicide-resistant weeds creates a huge challenge to global food security because it can reduce crop production, causing considerable losses. Combined with a lack of novel herbicides, cultivating herbicide-resistant crops becomes an effective strategy to control weeds because of reduced crop phytotoxicity, and it expands the herbicidal spectrum. Recently developed clustered regularly interspaced short palindromic repeat/CRISPR-associated protein (CRISPR/Cas)-mediated genome editing techniques enable efficiently targeted modification and hold great potential in creating desired plants with herbicide resistance. In the present review, we briefly summarize the mechanism responsible for herbicide resistance in plants and then discuss the applications of traditional mutagenesis and transgenic breeding in cultivating herbicide-resistant crops. We mainly emphasize the development and use of CRISPR/Cas technology in herbicide-resistant crop improvement. Finally, we discuss the future applications of the CRISPR/Cas system for developing herbicide-resistant crops. Full article

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

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20 pages, 617 KiB

Open AccessEditor’s ChoiceReview

Drugging the Undruggable: Advances on RAS Targeting in Cancer

by Miriam Molina-Arcas, Amit Samani and Julian Downward

Genes 2021, 12(6), 899; https://doi.org/10.3390/genes12060899 - 10 Jun 2021

Cited by 36 | Viewed by 6690

Abstract

Around 20% of all malignancies harbour activating mutations in RAS isoforms. Despite this, there is a deficiency of RAS-targeting agents licensed for therapeutic use. The picomolar affinity of RAS for GTP, and the lack of suitable pockets for high-affinity small-molecule binding, precluded effective [...] Read more.

Around 20% of all malignancies harbour activating mutations in RAS isoforms. Despite this, there is a deficiency of RAS-targeting agents licensed for therapeutic use. The picomolar affinity of RAS for GTP, and the lack of suitable pockets for high-affinity small-molecule binding, precluded effective therapies despite decades of research. Recently, characterisation of the biochemical properties of KRAS-G12C along with discovery of its ‘switch-II pocket’ have allowed development of effective mutant-specific inhibitors. Currently seven KRAS-G12C inhibitors are in clinical trials and sotorasib has become the first one to be granted FDA approval. Here, we discuss historical efforts to target RAS directly and approaches to target RAS effector signalling, including combinations that overcome limitations of single-agent targeting. We also review pre-clinical and clinical evidence for the efficacy of KRAS-G12C inhibitor monotherapy followed by an illustration of combination therapies designed to overcome primary resistance and extend durability of response. Finally, we briefly discuss novel approaches to targeting non-G12C mutant isoforms. Full article

(This article belongs to the Special Issue RAS Signaling in Health and Disease)

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15 pages, 4462 KiB

Open AccessEditor’s ChoiceArticle

Arabidopsis NPF4.6 and NPF5.1 Control Leaf Stomatal Aperture by Regulating Abscisic Acid Transport

by Takafumi Shimizu, Yuri Kanno, Hiromi Suzuki, Shunsuke Watanabe and Mitsunori Seo

Genes 2021, 12(6), 885; https://doi.org/10.3390/genes12060885 - 08 Jun 2021

Cited by 24 | Viewed by 4746

Abstract

The plant hormone abscisic acid (ABA) is actively synthesized in vascular tissues and transported to guard cells to promote stomatal closure. Although several transmembrane ABA transporters have been identified, how the movement of ABA within plants is regulated is not fully understood. In [...] Read more.

The plant hormone abscisic acid (ABA) is actively synthesized in vascular tissues and transported to guard cells to promote stomatal closure. Although several transmembrane ABA transporters have been identified, how the movement of ABA within plants is regulated is not fully understood. In this study, we determined that Arabidopsis NPF4.6, previously identified as an ABA transporter expressed in vascular tissues, is also present in guard cells and positively regulates stomatal closure in leaves. We also found that mutants defective in NPF5.1 had a higher leaf surface temperature compared to the wild type. Additionally, NPF5.1 mediated cellular ABA uptake when expressed in a heterologous yeast system. Promoter activities of NPF5.1 were detected in several leaf cell types. Taken together, these observations indicate that NPF5.1 negatively regulates stomatal closure by regulating the amount of ABA that can be transported from vascular tissues to guard cells. Full article

(This article belongs to the Special Issue New Advances in Research on the Role of Abscisic Acid in Plant Development)

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19 pages, 1695 KiB

Open AccessEditor’s ChoiceArticle

TOMM40 RNA Transcription in Alzheimer’s Disease Brain and Its Implication in Mitochondrial Dysfunction

by Eun-Gyung Lee, Sunny Chen, Lesley Leong, Jessica Tulloch and Chang-En Yu

Genes 2021, 12(6), 871; https://doi.org/10.3390/genes12060871 - 06 Jun 2021

Cited by 18 | Viewed by 4281

Abstract

Increasing evidence suggests that the Translocase of Outer Mitochondria Membrane 40 (TOMM40) gene may contribute to the risk of Alzheimer’s disease (AD). Currently, there is no consensus as to whether TOMM40 expression is up- or down-regulated in AD brains, hindering a [...] Read more.

Increasing evidence suggests that the Translocase of Outer Mitochondria Membrane 40 (TOMM40) gene may contribute to the risk of Alzheimer’s disease (AD). Currently, there is no consensus as to whether TOMM40 expression is up- or down-regulated in AD brains, hindering a clear interpretation of TOMM40’s role in this disease. The aim of this study was to determine if TOMM40 RNA levels differ between AD and control brains. We applied RT-qPCR to study TOMM40 transcription in human postmortem brain (PMB) and assessed associations of these RNA levels with genetic variants in APOE and TOMM40. We also compared TOMM40 RNA levels with mitochondrial functions in human cell lines. Initially, we found that the human genome carries multiple TOMM40 pseudogenes capable of producing highly homologous RNAs that can obscure precise TOMM40 RNA measurements. To circumvent this obstacle, we developed a novel RNA expression assay targeting the primary transcript of TOMM40. Using this assay, we showed that TOMM40 RNA was upregulated in AD PMB. Additionally, elevated TOMM40 RNA levels were associated with decreases in mitochondrial DNA copy number and mitochondrial membrane potential in oxidative stress-challenged cells. Overall, differential transcription of TOMM40 RNA in the brain is associated with AD and could be an indicator of mitochondrial dysfunction. Full article

(This article belongs to the Special Issue Genetics of Alzheimer’s Disease)

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16 pages, 2350 KiB

Open AccessEditor’s ChoiceReview

Subcellular Localization of miRNAs and Implications in Cellular Homeostasis

by Minwen Jie, Tong Feng, Wei Huang, Moran Zhang, Yuliang Feng, Hao Jiang and Zhili Wen

Genes 2021, 12(6), 856; https://doi.org/10.3390/genes12060856 - 02 Jun 2021

Cited by 22 | Viewed by 3426

Abstract

MicroRNAs (miRNAs) are thought to act as post-transcriptional regulators in the cytoplasm by either dampening translation or stimulating degradation of target mRNAs. With the increasing resolution and scope of RNA mapping, recent studies have revealed novel insights into the subcellular localization of miRNAs. [...] Read more.

MicroRNAs (miRNAs) are thought to act as post-transcriptional regulators in the cytoplasm by either dampening translation or stimulating degradation of target mRNAs. With the increasing resolution and scope of RNA mapping, recent studies have revealed novel insights into the subcellular localization of miRNAs. Based on miRNA subcellular localization, unconventional functions and mechanisms at the transcriptional and post-transcriptional levels have been identified. This minireview provides an overview of the subcellular localization of miRNAs and the mechanisms by which they regulate transcription and cellular homeostasis in mammals, with a particular focus on the roles of phase-separated biomolecular condensates. Full article

(This article belongs to the Special Issue MicroRNAs Applications in Cancer, Therapeutics and Related Toxicities)

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11 pages, 1092 KiB

Open AccessEditor’s ChoiceReview

ATM: Main Features, Signaling Pathways, and Its Diverse Roles in DNA Damage Response, Tumor Suppression, and Cancer Development

by Liem Minh Phan and Abdol-Hossein Rezaeian

Genes 2021, 12(6), 845; https://doi.org/10.3390/genes12060845 - 30 May 2021

Cited by 25 | Viewed by 7450

Abstract

ATM is among of the most critical initiators and coordinators of the DNA-damage response. ATM canonical and non-canonical signaling pathways involve hundreds of downstream targets that control many important cellular processes such as DNA damage repair, apoptosis, cell cycle arrest, metabolism, proliferation, oxidative [...] Read more.

ATM is among of the most critical initiators and coordinators of the DNA-damage response. ATM canonical and non-canonical signaling pathways involve hundreds of downstream targets that control many important cellular processes such as DNA damage repair, apoptosis, cell cycle arrest, metabolism, proliferation, oxidative sensing, among others. Of note, ATM is often considered a major tumor suppressor because of its ability to induce apoptosis and cell cycle arrest. However, in some advanced stage tumor cells, ATM signaling is increased and confers remarkable advantages for cancer cell survival, resistance to radiation and chemotherapy, biosynthesis, proliferation, and metastasis. This review focuses on addressing major characteristics, signaling pathways and especially the diverse roles of ATM in cellular homeostasis and cancer development. Full article

(This article belongs to the Special Issue Role of ATM and MRE11 in Genomic Stability and Oxidative Stress Responses)

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30 pages, 2036 KiB

Open AccessEditor’s ChoiceReview

The Crossroads between RAS and RHO Signaling Pathways in Cellular Transformation, Motility and Contraction

by Olga Soriano, Marta Alcón-Pérez, Miguel Vicente-Manzanares and Esther Castellano

Genes 2021, 12(6), 819; https://doi.org/10.3390/genes12060819 - 27 May 2021

Cited by 32 | Viewed by 8897

Abstract

Ras and Rho proteins are GTP-regulated molecular switches that control multiple signaling pathways in eukaryotic cells. Ras was among the first identified oncogenes, and it appears mutated in many forms of human cancer. It mainly promotes proliferation and survival through the MAPK pathway [...] Read more.

Ras and Rho proteins are GTP-regulated molecular switches that control multiple signaling pathways in eukaryotic cells. Ras was among the first identified oncogenes, and it appears mutated in many forms of human cancer. It mainly promotes proliferation and survival through the MAPK pathway and the PI3K/AKT pathways, respectively. However, the myriad proteins close to the plasma membrane that activate or inhibit Ras make it a major regulator of many apparently unrelated pathways. On the other hand, Rho is weakly oncogenic by itself, but it critically regulates microfilament dynamics; that is, actin polymerization, disassembly and contraction. Polymerization is driven mainly by the Arp2/3 complex and formins, whereas contraction depends on myosin mini-filament assembly and activity. These two pathways intersect at numerous points: from Ras-dependent triggering of Rho activators, some of which act through PI3K, to mechanical feedback driven by actomyosin action. Here, we describe the main points of connection between the Ras and Rho pathways as they coordinately drive oncogenic transformation. We emphasize the biochemical crosstalk that drives actomyosin contraction driven by Ras in a Rho-dependent manner. We also describe possible routes of mechanical feedback through which myosin II activation may control Ras/Rho activation. Full article

(This article belongs to the Special Issue RAS Signaling in Health and Disease)

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21 pages, 988 KiB

Open AccessEditor’s ChoiceReview

Harnessing Crop Wild Diversity for Climate Change Adaptation

by Andrés J. Cortés and Felipe López-Hernández

Genes 2021, 12(5), 783; https://doi.org/10.3390/genes12050783 - 20 May 2021

Cited by 66 | Viewed by 7754

Abstract

Warming and drought are reducing global crop production with a potential to substantially worsen global malnutrition. As with the green revolution in the last century, plant genetics may offer concrete opportunities to increase yield and crop adaptability. However, the rate at which the [...] Read more.

Warming and drought are reducing global crop production with a potential to substantially worsen global malnutrition. As with the green revolution in the last century, plant genetics may offer concrete opportunities to increase yield and crop adaptability. However, the rate at which the threat is happening requires powering new strategies in order to meet the global food demand. In this review, we highlight major recent ‘big data’ developments from both empirical and theoretical genomics that may speed up the identification, conservation, and breeding of exotic and elite crop varieties with the potential to feed humans. We first emphasize the major bottlenecks to capture and utilize novel sources of variation in abiotic stress (i.e., heat and drought) tolerance. We argue that adaptation of crop wild relatives to dry environments could be informative on how plant phenotypes may react to a drier climate because natural selection has already tested more options than humans ever will. Because isolated pockets of cryptic diversity may still persist in remote semi-arid regions, we encourage new habitat-based population-guided collections for genebanks. We continue discussing how to systematically study abiotic stress tolerance in these crop collections of wild and landraces using geo-referencing and extensive environmental data. By uncovering the genes that underlie the tolerance adaptive trait, natural variation has the potential to be introgressed into elite cultivars. However, unlocking adaptive genetic variation hidden in related wild species and early landraces remains a major challenge for complex traits that, as abiotic stress tolerance, are polygenic (i.e., regulated by many low-effect genes). Therefore, we finish prospecting modern analytical approaches that will serve to overcome this issue. Concretely, genomic prediction, machine learning, and multi-trait gene editing, all offer innovative alternatives to speed up more accurate pre- and breeding efforts toward the increase in crop adaptability and yield, while matching future global food demands in the face of increased heat and drought. In order for these ‘big data’ approaches to succeed, we advocate for a trans-disciplinary approach with open-source data and long-term funding. The recent developments and perspectives discussed throughout this review ultimately aim to contribute to increased crop adaptability and yield in the face of heat waves and drought events. Full article

(This article belongs to the Special Issue Evolutionary Genetics of Plant Crop-Wild Complexes: From Fundamental to Applied Research)

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21 pages, 8548 KiB

Open AccessEditor’s ChoiceArticle

Genome-Wide Analysis of Potassium Channel Genes in Rice: Expression of the OsAKT and OsKAT Genes under Salt Stress

by Zahra Musavizadeh, Hamid Najafi-Zarrini, Seyed Kamal Kazemitabar, Seyed Hamidreza Hashemi, Sahar Faraji, Gianni Barcaccia and Parviz Heidari

Genes 2021, 12(5), 784; https://doi.org/10.3390/genes12050784 - 20 May 2021

Cited by 50 | Viewed by 5735

Abstract

Potassium (K+), as a vital element, is involved in regulating important cellular processes such as enzyme activity, cell turgor, and nutrient movement in plant cells, which affects plant growth and production. Potassium channels are involved in the transport and release of potassium in [...] Read more.

Potassium (K+), as a vital element, is involved in regulating important cellular processes such as enzyme activity, cell turgor, and nutrient movement in plant cells, which affects plant growth and production. Potassium channels are involved in the transport and release of potassium in plant cells. In the current study, three OsKAT genes and two OsAKT genes, along with 11 nonredundant putative potassium channel genes in the rice genome, were characterized based on their physiochemical properties, protein structure, evolution, duplication, in silico gene expression, and protein–protein interactions. In addition, the expression patterns of OsAKTs and OsKATs were studied in root and shoot tissues under salt stress using real-time PCR in three rice cultivars. K+ channel genes were found to have diverse functions and structures, and OsKATs showed high genetic divergence from other K+ channel genes. Furthermore, the Ka/Ks ratios of duplicated gene pairs from the K+ channel gene family in rice suggested that these genes underwent purifying selection. Among the studied K+ channel proteins, OsKAT1 and OsAKT1 were identified as proteins with high potential N-glycosylation and phosphorylation sites, and LEU, VAL, SER, PRO, HIS, GLY, LYS, TYR, CYC, and ARG amino acids were predicted as the binding residues in the ligand-binding sites of K+ channel proteins. Regarding the coexpression network and KEGG ontology results, several metabolic pathways, including sugar metabolism, purine metabolism, carbon metabolism, glycerophospholipid metabolism, monoterpenoid biosynthesis, and folate biosynthesis, were recognized in the coexpression network of K+ channel proteins. Based on the available RNA-seq data, the K+ channel genes showed differential expression levels in rice tissues in response to biotic and abiotic stresses. In addition, the real-time PCR results revealed that OsAKTs and OsKATs are induced by salt stress in root and shoot tissues of rice cultivars, and OsKAT1 was identified as a key gene involved in the rice response to salt stress. In the present study, we found that the repression of OsAKTs, OsKAT2, and OsKAT2 in roots was related to salinity tolerance in rice. Our findings provide valuable insights for further structural and functional assays of K+ channel genes in rice. Full article

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

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7 pages, 2206 KiB

Open AccessEditor’s ChoiceArticle

Changes in Lactate Production, Lactate Dehydrogenase Genes Expression and DNA Methylation in Response to Tamoxifen Resistance Development in MCF-7 Cell Line

by Lama Hamadneh, Lara Al-Lakkis, Ala A. Alhusban, Shahd Tarawneh, Bashaer Abu-Irmaileh, Sokiyna Albustanji and Abdel Qader Al-Bawab

Genes 2021, 12(5), 777; https://doi.org/10.3390/genes12050777 - 19 May 2021

Cited by 16 | Viewed by 2864

Abstract

Lactate dehydrogenase (LDH) is a key enzyme in the last step of glycolysis, playing a role in the pyruvate-to-lactate reaction. It is associated with the prognosis and metastasis of many cancers, including breast cancer. In this study, we investigated the changes in LDH [...] Read more.

Lactate dehydrogenase (LDH) is a key enzyme in the last step of glycolysis, playing a role in the pyruvate-to-lactate reaction. It is associated with the prognosis and metastasis of many cancers, including breast cancer. In this study, we investigated the changes in LDH gene expression and lactate concentrations in the culture media during tamoxifen resistance development in the MCF-7 cell line, and examined LDHB promoter methylation levels. An upregulation of 2.9 times of LDHB gene expression was observed around the IC50 concentration of tamoxifen in treated cells, while fluctuation in LDHA gene expression levels was found. Furthermore, morphological changes in the cell shape accompanied the changes in gene expression. Bisulfate treatment followed by sequencing of the LDHB promoter was performed to track any change in methylation levels; hypomethylation of CpG areas was found, suggesting that gene expression upregulation could be due to methylation level changes. Changes in LDHA and LDHB gene expression were correlated with the increase in lactate concentration in the culture media of treated MCF-7 cells. Full article

(This article belongs to the Special Issue Deciphering Epigenetic Signature in Human Health and Disease)

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8 pages, 1834 KiB

Open AccessEditor’s ChoiceArticle

Tumor-Associated Macrophage Promotes the Survival of Cancer Cells upon Docetaxel Chemotherapy via the CSF1/CSF1R–CXCL12/CXCR4 Axis in Castration-Resistant Prostate Cancer

by Wei Guan, Fan Li, Zhenyu Zhao, Zongbiao Zhang, Junhui Hu and Yan Zhang

Genes 2021, 12(5), 773; https://doi.org/10.3390/genes12050773 - 19 May 2021

Cited by 30 | Viewed by 3005

Abstract

Castration-resistant prostate cancer (CRPC) is an advanced stage of prostate cancer that can progress rapidly even in patients treated with castration. Previously, we found that tumor-associated macrophages (TAM) can be recruited by CSF-1 secreted by docetaxel-treated prostate cancer cells and promote the survival [...] Read more.

Castration-resistant prostate cancer (CRPC) is an advanced stage of prostate cancer that can progress rapidly even in patients treated with castration. Previously, we found that tumor-associated macrophages (TAM) can be recruited by CSF-1 secreted by docetaxel-treated prostate cancer cells and promote the survival of cancer cells in response to chemotherapy. The inhibition of CSF-1R can impede this effect and significantly prolong survival in xenograft mice. However, the actual mechanism of how TAM improves cancer cell survival still remains elusive and controversial. Here, for the first time, we found that the enhanced survival of cancer cells achieved by TAM was mainly mediated by CXCR4 activation from the increased secretion of CXCL12 from CSF-1 activated TAM. This finding helps to clarify the mechanism of chemoresistance for second-line chemotherapy using docetaxel, facilitating the development of novel drugs to overcome immune tolerance in castration-resistant prostate cancer. Full article

(This article belongs to the Special Issue Pharmacogenomics: Precision Medicine and Drug Response)

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25 pages, 3538 KiB

Open AccessEditor’s ChoiceArticle

Genome Expression Dynamics Reveal the Parasitism Regulatory Landscape of the Root-Knot Nematode Meloidogyne incognita and a Promoter Motif Associated with Effector Genes

by Martine Da Rocha, Caroline Bournaud, Julie Dazenière, Peter Thorpe, Marc Bailly-Bechet, Clément Pellegrin, Arthur Péré, Priscila Grynberg, Laetitia Perfus-Barbeoch, Sebastian Eves-van den Akker and Etienne G. J. Danchin

Genes 2021, 12(5), 771; https://doi.org/10.3390/genes12050771 - 18 May 2021

Cited by 21 | Viewed by 4751

Abstract

Root-knot nematodes (genus Meloidogyne) are the major contributor to crop losses caused by nematodes. These nematodes secrete effector proteins into the plant, derived from two sets of pharyngeal gland cells, to manipulate host physiology and immunity. Successful completion of the life cycle, [...] Read more.

Root-knot nematodes (genus Meloidogyne) are the major contributor to crop losses caused by nematodes. These nematodes secrete effector proteins into the plant, derived from two sets of pharyngeal gland cells, to manipulate host physiology and immunity. Successful completion of the life cycle, involving successive molts from egg to adult, covers morphologically and functionally distinct stages and will require precise control of gene expression, including effector genes. The details of how root-knot nematodes regulate transcription remain sparse. Here, we report a life stage-specific transcriptome of Meloidogyne incognita. Combined with an available annotated genome, we explore the spatio-temporal regulation of gene expression. We reveal gene expression clusters and predicted functions that accompany the major developmental transitions. Focusing on effectors, we identify a putative cis-regulatory motif associated with expression in the dorsal glands, providing an insight into effector regulation. We combine the presence of this motif with several other criteria to predict a novel set of putative dorsal gland effectors. Finally, we show this motif, and thereby its utility, is broadly conserved across the Meloidogyne genus, and we name it Mel-DOG. Taken together, we provide the first genome-wide analysis of spatio-temporal gene expression in a root-knot nematode and identify a new set of candidate effector genes that will guide future functional analyses. Full article

(This article belongs to the Special Issue Genomics of Plant-Nematode Interactions)

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27 pages, 2910 KiB

Open AccessEditor’s ChoiceArticle

Meta-Analysis of Heifer Traits Identified Reproductive Pathways in Bos indicus Cattle

by Muhammad S. Tahir, Laercio R. Porto-Neto, Cedric Gondro, Olasege B. Shittu, Kimberley Wockner, Andre W. L. Tan, Hugo R. Smith, Gabriela C. Gouveia, Jagish Kour and Marina R. S. Fortes

Genes 2021, 12(5), 768; https://doi.org/10.3390/genes12050768 - 18 May 2021

Cited by 28 | Viewed by 5394

Abstract

Fertility traits measured early in life define the reproductive potential of heifers. Knowledge of genetics and biology can help devise genomic selection methods to improve heifer fertility. In this study, we used ~2400 Brahman cattle to perform GWAS and multi-trait meta-analysis to determine [...] Read more.

Fertility traits measured early in life define the reproductive potential of heifers. Knowledge of genetics and biology can help devise genomic selection methods to improve heifer fertility. In this study, we used ~2400 Brahman cattle to perform GWAS and multi-trait meta-analysis to determine genomic regions associated with heifer fertility. Heifer traits measured were pregnancy at first mating opportunity (PREG1, a binary trait), first conception score (FCS, score 1 to 3) and rebreeding score (REB, score 1 to 3.5). The heritability estimates were 0.17 (0.03) for PREG1, 0.11 (0.05) for FCS and 0.28 (0.05) for REB. The three traits were highly genetically correlated (0.75–0.83) as expected. Meta-analysis was performed using SNP effects estimated for each of the three traits, adjusted for standard error. We identified 1359 significant SNPs (p-value < 9.9 × 10⁻⁶ at FDR < 0.0001) in the multi-trait meta-analysis. Genomic regions of 0.5 Mb around each significant SNP from the meta-analysis were annotated to create a list of 2560 positional candidate genes. The most significant SNP was in the vicinity of a genomic region on chromosome 8, encompassing the genes SLC44A1, FSD1L, FKTN, TAL2 and TMEM38B. The genomic region in humans that contains homologs of these genes is associated with age at puberty in girls. Top significant SNPs pointed to additional fertility-related genes, again within a 0.5 Mb region, including ESR2, ITPR1, GNG2, RGS9BP, ANKRD27, TDRD12, GRM1, MTHFD1, PTGDR and NTNG1. Functional pathway enrichment analysis resulted in many positional candidate genes relating to known fertility pathways, including GnRH signaling, estrogen signaling, progesterone mediated oocyte maturation, cAMP signaling, calcium signaling, glutamatergic signaling, focal adhesion, PI3K-AKT signaling and ovarian steroidogenesis pathway. The comparison of results from this study with previous transcriptomics and proteomics studies on puberty of the same cattle breed (Brahman) but in a different population identified 392 genes in common from which some genes—BRAF, GABRA2, GABR1B, GAD1, FSHR, CNGA3, PDE10A, SNAP25, ESR2, GRIA2, ORAI1, EGFR, CHRNA5, VDAC2, ACVR2B, ORAI3, CYP11A1, GRIN2A, ATP2B3, CAMK2A, PLA2G, CAMK2D and MAPK3—are also part of the above-mentioned pathways. The biological functions of the positional candidate genes and their annotation to known pathways allowed integrating the results into a bigger picture of molecular mechanisms related to puberty in the hypothalamus–pituitary–ovarian axis. A reasonable number of genes, common between previous puberty studies and this study on early reproductive traits, corroborates the proposed molecular mechanisms. This study identified the polymorphism associated with early reproductive traits, and candidate genes that provided a visualization of the proposed mechanisms, coordinating the hypothalamic, pituitary, and ovarian functions for reproductive performance in Brahman cattle. Full article

(This article belongs to the Special Issue Genome-Wide Association Analysis of Cattle)

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18 pages, 7053 KiB

Open AccessEditor’s ChoiceReview

Regeneration Potential of Jellyfish: Cellular Mechanisms and Molecular Insights

by Sosuke Fujita, Erina Kuranaga and Yu-ichiro Nakajima

Genes 2021, 12(5), 758; https://doi.org/10.3390/genes12050758 - 17 May 2021

Cited by 17 | Viewed by 9231

Abstract

Medusozoans, the Cnidarian subphylum, have multiple life stages including sessile polyps and free-swimming medusae or jellyfish, which are typically bell-shaped gelatinous zooplanktons that exhibit diverse morphologies. Despite having a relatively complex body structure with well-developed muscles and nervous systems, the adult medusa stage [...] Read more.

Medusozoans, the Cnidarian subphylum, have multiple life stages including sessile polyps and free-swimming medusae or jellyfish, which are typically bell-shaped gelatinous zooplanktons that exhibit diverse morphologies. Despite having a relatively complex body structure with well-developed muscles and nervous systems, the adult medusa stage maintains a high regenerative ability that enables organ regeneration as well as whole body reconstitution from the part of the body. This remarkable regeneration potential of jellyfish has long been acknowledged in different species; however, recent studies have begun dissecting the exact processes underpinning regeneration events. In this article, we introduce the current understanding of regeneration mechanisms in medusae, particularly focusing on cellular behaviors during regeneration such as wound healing, blastema formation by stem/progenitor cells or cell fate plasticity, and the organism-level patterning that restores radial symmetry. We also discuss putative molecular mechanisms involved in regeneration processes and introduce a variety of novel model jellyfish species in the effort to understand common principles and diverse mechanisms underlying the regeneration of complex organs and the entire body. Full article

(This article belongs to the Special Issue The Molecular Genetics and Major Concepts Underlying Whole Body Regeneration in the Animal World)

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12 pages, 1526 KiB

Open AccessEditor’s ChoiceArticle

Identification and Validation of Reference Genes for Gene Expression Analysis in Schima superba

by Zhongyi Yang, Rui Zhang and Zhichun Zhou

Genes 2021, 12(5), 732; https://doi.org/10.3390/genes12050732 - 13 May 2021

Cited by 32 | Viewed by 2427

Abstract

Real-time quantitative PCR (RT-qPCR) is a reliable and high-throughput technique for gene expression studies, but its accuracy depends on the expression stability of reference genes. Schima superba is a fast-growing timber species with strong resistance. However, thus far, reliable reference gene identifications have [...] Read more.

Real-time quantitative PCR (RT-qPCR) is a reliable and high-throughput technique for gene expression studies, but its accuracy depends on the expression stability of reference genes. Schima superba is a fast-growing timber species with strong resistance. However, thus far, reliable reference gene identifications have not been reported in S. superba. In this study, 19 candidate reference genes were selected and evaluated for their expression stability in different tissues of S. superba. Three software programs (geNorm, NormFinder, and BestKeeper) were used to evaluate the reference gene transcript stabilities, and comprehensive stability ranking was generated by the geometric mean method. Our results show that SsuACT was the most stable reference gene and that SsuACT + SsuRIB was the best reference gene combination for different tissues. Finally, the stable and less stable reference genes were verified using SsuSND1 expression in different tissues. To our knowledge, this is the first report to verify appropriate reference genes for normalizing gene expression in S. superba for different tissues, which will facilitate the future elucidation of gene regulations in this species and useful references for relative species. Full article

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

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14 pages, 4451 KiB

Open AccessEditor’s ChoiceArticle

Sp1-Mediated circRNA circHipk2 Regulates Myogenesis by Targeting Ribosomal Protein Rpl7

by Junyu Yan, Yalan Yang, Xinhao Fan, Yijie Tang and Zhonglin Tang

Genes 2021, 12(5), 696; https://doi.org/10.3390/genes12050696 - 08 May 2021

Cited by 17 | Viewed by 3027

Abstract

Circular RNAs (circRNAs) represent a class of covalently closed single-stranded RNA molecules that are emerging as essential regulators of various biological processes. The circRNA circHipk2 originates from exon 2 of the Hipk2 gene in mice and was reported to be involved in acute [...] Read more.

Circular RNAs (circRNAs) represent a class of covalently closed single-stranded RNA molecules that are emerging as essential regulators of various biological processes. The circRNA circHipk2 originates from exon 2 of the Hipk2 gene in mice and was reported to be involved in acute promyelocytic leukemia and myocardial injury. However, the functions and mechanisms of circHipk2 in myogenesis are largely unknown. Here, to deepen our knowledge about the role of circHipk2, we studied the expression and function of circHipk2 during skeletal myogenesis. We found that circHipk2 was mostly distributed in the cytoplasm, and dynamically and differentially expressed in various myogenesis systems in vitro and in vivo. Functionally, overexpression of circHipk2 inhibited myoblast proliferation and promoted myotube formation in C2C12 cells, whereas the opposite effects were observed after circHipk2 knockdown. Mechanistically, circHipk2 could directly bind to ribosomal protein Rpl7, an essential 60S preribosomal assembly factor, to inhibit ribosome translation. In addition, we verified that transcription factor Sp1 directly bound to the promoter of circHipk2 and affected the expression of Hipk2 and circHipk2 in C2C12 myoblasts. Collectively, these findings identify circHipk2 as a candidate circRNA regulating ribosome biogenesis and myogenesis proliferation and differentiation. Full article

(This article belongs to the Special Issue Alternative Splicing in Human Physiology and Disease)

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24 pages, 1545 KiB

Open AccessEditor’s ChoiceReview

Regulation of Vitamin C Accumulation for Improved Tomato Fruit Quality and Alleviation of Abiotic Stress

by Ifigeneia Mellidou, Athanasios Koukounaras, Stefanos Kostas, Efstathia Patelou and Angelos K. Kanellis

Genes 2021, 12(5), 694; https://doi.org/10.3390/genes12050694 - 06 May 2021

Cited by 42 | Viewed by 5506

Abstract

Ascorbic acid (AsA) is an essential multifaceted phytonutrient for both the human diet and plant growth. Optimum levels of AsA accumulation combined with balanced redox homeostasis are required for normal plant development and defense response to adverse environmental stimuli. Notwithstanding its moderate AsA [...] Read more.

Ascorbic acid (AsA) is an essential multifaceted phytonutrient for both the human diet and plant growth. Optimum levels of AsA accumulation combined with balanced redox homeostasis are required for normal plant development and defense response to adverse environmental stimuli. Notwithstanding its moderate AsA levels, tomatoes constitute a good source of vitamin C in the human diet. Therefore, the enhancement of AsA levels in tomato fruit attracts considerable attention, not only to improve its nutritional value but also to stimulate stress tolerance. Genetic regulation of AsA concentrations in plants can be achieved through the fine-tuning of biosynthetic, recycling, and transport mechanisms; it is also linked to changes in the whole fruit metabolism. Emerging evidence suggests that tomato synthesizes AsA mainly through the l-galactose pathway, but alternative pathways through d-galacturonate or myo-inositol, or seemingly unrelated transcription and regulatory factors, can be also relevant in certain developmental stages or in response to abiotic factors. Considering the recent advances in our understanding of AsA regulation in model and other non-model species, this review attempts to link the current consensus with novel technologies to provide a comprehensive strategy for AsA enhancement in tomatoes, without any detrimental effect on plant growth or fruit development. Full article

(This article belongs to the Special Issue Genomics of Tomato and Molecular Biology for Phytonutrients in Tomato Fruit)

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23 pages, 1060 KiB

Open AccessEditor’s ChoiceReview

40 Years of RAS—A Historic Overview

by Alberto Fernández-Medarde, Javier De Las Rivas and Eugenio Santos

Genes 2021, 12(5), 681; https://doi.org/10.3390/genes12050681 - 01 May 2021

Cited by 20 | Viewed by 6588

Abstract

It has been over forty years since the isolation of the first human oncogene (HRAS), a crucial milestone in cancer research made possible through the combined efforts of a few selected research groups at the beginning of the 1980s. Those initial discoveries led [...] Read more.

It has been over forty years since the isolation of the first human oncogene (HRAS), a crucial milestone in cancer research made possible through the combined efforts of a few selected research groups at the beginning of the 1980s. Those initial discoveries led to a quantitative leap in our understanding of cancer biology and set up the onset of the field of molecular oncology. The following four decades of RAS research have produced a huge pool of new knowledge about the RAS family of small GTPases, including how they regulate signaling pathways controlling many cellular physiological processes, or how oncogenic mutations trigger pathological conditions, including developmental syndromes or many cancer types. However, despite the extensive body of available basic knowledge, specific effective treatments for RAS-driven cancers are still lacking. Hopefully, recent advances involving the discovery of novel pockets on the RAS surface as well as highly specific small-molecule inhibitors able to block its interaction with effectors and/or activators may lead to the development of new, effective treatments for cancer. This review intends to provide a quick, summarized historical overview of the main milestones in RAS research spanning from the initial discovery of the viral RAS oncogenes in rodent tumors to the latest attempts at targeting RAS oncogenes in various human cancers. Full article

(This article belongs to the Special Issue RAS Signaling in Health and Disease)

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11 pages, 1093 KiB

Open AccessEditor’s ChoiceArticle

Sensitivity to Immune Checkpoint Blockade in Advanced Non-Small Cell Lung Cancer Patients with EGFR Exon 20 Insertion Mutations

by Giulio Metro, Sara Baglivo, Guido Bellezza, Martina Mandarano, Alessio Gili, Giovanni Marchetti, Marco Toraldo, Carmen Molica, Maria Sole Reda, Francesca Romana Tofanetti, Annamaria Siggillino, Enrico Prosperi, Antonella Giglietti, Bruna Di Girolamo, Miriam Garaffa, Francesca Marasciulo, Vincenzo Minotti, Marco Gunnellini, Annalisa Guida, Monica Sassi, Angelo Sidoni, Fausto Roila and Vienna Ludovini Show full author list Hide full author list

Genes 2021, 12(5), 679; https://doi.org/10.3390/genes12050679 - 30 Apr 2021

Cited by 29 | Viewed by 3582

Abstract

Besides platinum-based chemotherapy, no established treatment option exists for advanced non-small-cell lung cancer (NSCLC) patients with EGFR exon 20 (Ex20ins) insertion mutations. We sought to determine the clinical outcome of patients with this EGFR mutation subtype in the immunotherapy era. Thirty NSCLCs with [...] Read more.

Besides platinum-based chemotherapy, no established treatment option exists for advanced non-small-cell lung cancer (NSCLC) patients with EGFR exon 20 (Ex20ins) insertion mutations. We sought to determine the clinical outcome of patients with this EGFR mutation subtype in the immunotherapy era. Thirty NSCLCs with EGFR Ex20ins mutations were identified, of whom 15 had received immune checkpoint blockade (ICB) treatment as monotherapy (N = 12), in combination with chemotherapy (N = 2) or with another immunotherapeutic agent (N = 1). The response rate was observed in 1 out of 15 patients (6.7%), median progression-free survival (PFS) was 2.0 months and median overall survival (OS) was 5.3 months. A trend towards an inferior outcome in terms of PFS and OS was observed for patients receiving ICB treatment in the first versus second line setting (PFS: 1.6 months versus 2.7 months, respectively, p = 0.16—OS: 2.0 months versus 8.1 months, respectively, p = 0.09). Median OS from the time of diagnosis of advanced disease was shorter for patients treated with ICB versus those who did not receive immunotherapy (12.9 months versus 25.2 months, respectively, p = 0.08), which difference remained associated with a worse survival outcome at multivariate analysis (p = 0.04). Treatment with ICB is poorly effective in NSCLCs with EGFR Ex20ins mutations, especially when given in the first-line setting. This information is crucial in order to select the optimal treatment strategy for patients with this subtype of EGFR mutation. Full article

(This article belongs to the Special Issue Genetics and Genomics of Lung Cancer May Contribute to the Development of Precision Medicine)

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12 pages, 2888 KiB

Open AccessEditor’s ChoiceArticle

Microbiological Evaluation and Sperm DNA Fragmentation in Semen Samples of Patients Undergoing Fertility Investigation

by Chiara Pagliuca, Federica Cariati, Francesca Bagnulo, Elena Scaglione, Consolata Carotenuto, Fabrizio Farina, Valeria D’Argenio, Francesca Carraturo, Paola D’Aprile, Mariateresa Vitiello, Ida Strina, Carlo Alviggi, Roberta Colicchio, Rossella Tomaiuolo and Paola Salvatore

Genes 2021, 12(5), 654; https://doi.org/10.3390/genes12050654 - 27 Apr 2021

Cited by 22 | Viewed by 2639

Abstract

Fifteen percent of male infertility is associated with urogenital infections; several pathogens are able to alter the testicular and accessory glands’ microenvironment, resulting in the impairment of biofunctional sperm parameters. The purpose of this study was to assess the influence of urogenital infections [...] Read more.

Fifteen percent of male infertility is associated with urogenital infections; several pathogens are able to alter the testicular and accessory glands’ microenvironment, resulting in the impairment of biofunctional sperm parameters. The purpose of this study was to assess the influence of urogenital infections on the quality of 53 human semen samples through standard analysis, microbiological evaluation, and molecular characterization of sperm DNA damage. The results showed a significant correlation between infected status and semen volume, sperm concentration, and motility. Moreover, a high risk of fragmented sperm DNA was demonstrated in the altered semen samples. Urogenital infections are often asymptomatic and thus an in-depth evaluation of the seminal sample can allow for both the diagnosis and therapy of infections while providing more indicators for male infertility management. Full article

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

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19 pages, 2576 KiB

Open AccessEditor’s ChoiceArticle

Species-Specific Quality Control, Assembly and Contamination Detection in Microbial Isolate Sequences with AQUAMIS

by Carlus Deneke, Holger Brendebach, Laura Uelze, Maria Borowiak, Burkhard Malorny and Simon H. Tausch

Genes 2021, 12(5), 644; https://doi.org/10.3390/genes12050644 - 26 Apr 2021

Cited by 40 | Viewed by 3904

Abstract

Sequencing of whole microbial genomes has become a standard procedure for cluster detection, source tracking, outbreak investigation and surveillance of many microorganisms. An increasing number of laboratories are currently in a transition phase from classical methods towards next generation sequencing, generating unprecedented amounts [...] Read more.

Sequencing of whole microbial genomes has become a standard procedure for cluster detection, source tracking, outbreak investigation and surveillance of many microorganisms. An increasing number of laboratories are currently in a transition phase from classical methods towards next generation sequencing, generating unprecedented amounts of data. Since the precision of downstream analyses depends significantly on the quality of raw data generated on the sequencing instrument, a comprehensive, meaningful primary quality control is indispensable. Here, we present AQUAMIS, a Snakemake workflow for an extensive quality control and assembly of raw Illumina sequencing data, allowing laboratories to automatize the initial analysis of their microbial whole-genome sequencing data. AQUAMIS performs all steps of primary sequence analysis, consisting of read trimming, read quality control (QC), taxonomic classification, de-novo assembly, reference identification, assembly QC and contamination detection, both on the read and assembly level. The results are visualized in an interactive HTML report including species-specific QC thresholds, allowing non-bioinformaticians to assess the quality of sequencing experiments at a glance. All results are also available as a standard-compliant JSON file, facilitating easy downstream analyses and data exchange. We have applied AQUAMIS to analyze ~13,000 microbial isolates as well as ~1000 in-silico contaminated datasets, proving the workflow’s ability to perform in high throughput routine sequencing environments and reliably predict contaminations. We found that intergenus and intragenus contaminations can be detected most accurately using a combination of different QC metrics available within AQUAMIS. Full article

(This article belongs to the Special Issue Applied Genomics: Bridging the Gap between R&D and Practical Implementations within Clinical and Public Health Settings)

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30 pages, 2881 KiB

Open AccessEditor’s ChoiceReview

The Role of Lipid Sensing Nuclear Receptors (PPARs and LXR) and Metabolic Lipases in Obesity, Diabetes and NAFLD

by Emmanuel D. Dixon, Alexander D. Nardo, Thierry Claudel and Michael Trauner

Genes 2021, 12(5), 645; https://doi.org/10.3390/genes12050645 - 26 Apr 2021

Cited by 42 | Viewed by 6183

Abstract

Obesity and type 2 diabetes mellitus (T2DM) are metabolic disorders characterized by metabolic inflexibility with multiple pathological organ manifestations, including non-alcoholic fatty liver disease (NAFLD). Nuclear receptors are ligand-dependent transcription factors with a multifaceted role in controlling many metabolic activities, such as regulation [...] Read more.

Obesity and type 2 diabetes mellitus (T2DM) are metabolic disorders characterized by metabolic inflexibility with multiple pathological organ manifestations, including non-alcoholic fatty liver disease (NAFLD). Nuclear receptors are ligand-dependent transcription factors with a multifaceted role in controlling many metabolic activities, such as regulation of genes involved in lipid and glucose metabolism and modulation of inflammatory genes. The activity of nuclear receptors is key in maintaining metabolic flexibility. Their activity depends on the availability of endogenous ligands, like fatty acids or oxysterols, and their derivatives produced by the catabolic action of metabolic lipases, most of which are under the control of nuclear receptors. For example, adipose triglyceride lipase (ATGL) is activated by peroxisome proliferator-activated receptor γ (PPARγ) and conversely releases fatty acids as ligands for PPARα, therefore, demonstrating the interdependency of nuclear receptors and lipases. The diverse biological functions and importance of nuclear receptors in metabolic syndrome and NAFLD has led to substantial effort to target them therapeutically. This review summarizes recent findings on the roles of lipases and selected nuclear receptors, PPARs, and liver X receptor (LXR) in obesity, diabetes, and NAFLD. Full article

(This article belongs to the Special Issue Lipid Metabolism, Adipogenesis and Fat Tissue Metabolism: Gene Regulation)

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21 pages, 3045 KiB

Open AccessEditor’s ChoiceArticle

Down-Regulation of SlGRAS10 in Tomato Confers Abiotic Stress Tolerance

by Sidra Habib, Yee Yee Lwin and Ning Li

Genes 2021, 12(5), 623; https://doi.org/10.3390/genes12050623 - 22 Apr 2021

Cited by 24 | Viewed by 2407

Abstract

Adverse environmental factors like salt stress, drought, and extreme temperatures, cause damage to plant growth, development, and crop yield. GRAS transcription factors (TFs) have numerous functions in biological processes. Some studies have reported that the GRAS protein family plays significant functions in plant [...] Read more.

Adverse environmental factors like salt stress, drought, and extreme temperatures, cause damage to plant growth, development, and crop yield. GRAS transcription factors (TFs) have numerous functions in biological processes. Some studies have reported that the GRAS protein family plays significant functions in plant growth and development under abiotic stresses. In this study, we demonstrated the functional characterization of a tomato SlGRAS10 gene under abiotic stresses such as salt stress and drought. Down-regulation of SlGRAS10 by RNA interference (RNAi) produced dwarf plants with smaller leaves, internode lengths, and enhanced flavonoid accumulation. We studied the effects of abiotic stresses on RNAi and wild-type (WT) plants. Moreover, SlGRAS10-RNAi plants were more tolerant to abiotic stresses (salt, drought, and Abscisic acid) than the WT plants. Down-regulation of SlGRAS10 significantly enhanced the expressions of catalase (CAT), peroxidase (POD), and superoxide dismutase (SOD) to reduce the effects of reactive oxygen species (ROS) such as O²⁻ and H₂O₂. Malondialdehyde (MDA) and proline contents were remarkably high in SlGRAS10-RNAi plants. Furthermore, the expression levels of chlorophyll biosynthesis, flavonoid biosynthesis, and stress-related genes were also enhanced under abiotic stress conditions. Collectively, our conclusions emphasized the significant function of SlGRAS10 as a stress tolerate transcription factor in a certain variety of abiotic stress tolerance by enhancing osmotic potential, flavonoid biosynthesis, and ROS scavenging system in the tomato plant. Full article

(This article belongs to the Special Issue Genetics and Physiology of Multiple-Stress Tolerance in Crops)

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21 pages, 1115 KiB

Open AccessEditor’s ChoiceReview

Achromobacter xylosoxidans and Stenotrophomonas maltophilia: Emerging Pathogens Well-Armed for Life in the Cystic Fibrosis Patients’ Lung

by Quentin Menetrey, Pauline Sorlin, Estelle Jumas-Bilak, Raphaël Chiron, Chloé Dupont and Hélène Marchandin

Genes 2021, 12(5), 610; https://doi.org/10.3390/genes12050610 - 21 Apr 2021

Cited by 40 | Viewed by 4791

Abstract

In patients with cystic fibrosis (CF), the lung is a remarkable ecological niche in which the microbiome is subjected to important selective pressures. An inexorable colonization by bacteria of both endogenous and environmental origin is observed in most patients, leading to a vicious [...] Read more.

In patients with cystic fibrosis (CF), the lung is a remarkable ecological niche in which the microbiome is subjected to important selective pressures. An inexorable colonization by bacteria of both endogenous and environmental origin is observed in most patients, leading to a vicious cycle of infection–inflammation. In this context, long-term colonization together with competitive interactions among bacteria can lead to over-inflammation. While Pseudomonas aeruginosa and Staphylococcus aureus, the two pathogens most frequently identified in CF, have been largely studied for adaptation to the CF lung, in the last few years, there has been a growing interest in emerging pathogens of environmental origin, namely Achromobacter xylosoxidans and Stenotrophomonas maltophilia. The aim of this review is to gather all the current knowledge on the major pathophysiological traits, their supporting mechanisms, regulation and evolutionary modifications involved in colonization, virulence, and competitive interactions with other members of the lung microbiota for these emerging pathogens, with all these mechanisms being major drivers of persistence in the CF lung. Currently available research on A. xylosoxidans complex and S. maltophilia shows that these emerging pathogens share important pathophysiological features with well-known CF pathogens, making them important members of the complex bacterial community living in the CF lung. Full article

(This article belongs to the Special Issue Phenotypic Variability of Cystic Fibrosis: New Challenges)

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15 pages, 1149 KiB

Open AccessEditor’s ChoiceCommunication

Protective Role of a TMPRSS2 Variant on Severe COVID-19 Outcome in Young Males and Elderly Women

by Maria Monticelli, Bruno Hay Mele, Elisa Benetti, Chiara Fallerini, Margherita Baldassarri, Simone Furini, Elisa Frullanti, Francesca Mari, GEN-COVID Multicenter Study, Giuseppina Andreotti, Maria Vittoria Cubellis and Alessandra Renieri

Genes 2021, 12(4), 596; https://doi.org/10.3390/genes12040596 - 19 Apr 2021

Cited by 40 | Viewed by 5540

Abstract

The protease encoded by the TMPRSS2 gene facilitates viral infections and has been implicated in the pathogenesis of SARS-CoV-2. We analyzed the TMPRSS2 sequence and correlated the protein variants with the clinical features of a cohort of 1177 patients affected by COVID-19 in [...] Read more.

The protease encoded by the TMPRSS2 gene facilitates viral infections and has been implicated in the pathogenesis of SARS-CoV-2. We analyzed the TMPRSS2 sequence and correlated the protein variants with the clinical features of a cohort of 1177 patients affected by COVID-19 in Italy. Nine relatively common variants (allele frequency > 0.01) and six missense variants which may affect the protease activity according to PolyPhen-2 in HumVar-trained mode were identified. Among them, p.V197M (p.Val197Met) (rs12329760) emerges as a common variant that has a deleterious effect on the protease and a protective effect on the patients. Its role appears particularly relevant in two subgroups of patients—young males and elderly women—and among those affected by co-morbidities, where the variant frequency is higher among individuals who were mildly affected by the disease and did not need hospitalization or oxygen therapy than among those more severely affected, who required oxygen therapy, ventilation or intubation. This study provides useful information for the identification of patients at risk of developing a severe form of COVID-19, and encourages the usage of drugs affecting the expression of TMPRSS2 or inhibiting protein activity. Full article

(This article belongs to the Special Issue COVID-19 and Molecular Genetics)

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21 pages, 1852 KiB

Open AccessEditor’s ChoiceReview

Inosine in Biology and Disease

by Sundaramoorthy Srinivasan, Adrian Gabriel Torres and Lluís Ribas de Pouplana

Genes 2021, 12(4), 600; https://doi.org/10.3390/genes12040600 - 19 Apr 2021

Cited by 48 | Viewed by 9789

Abstract

The nucleoside inosine plays an important role in purine biosynthesis, gene translation, and modulation of the fate of RNAs. The editing of adenosine to inosine is a widespread post-transcriptional modification in transfer RNAs (tRNAs) and messenger RNAs (mRNAs). At the wobble position of [...] Read more.

The nucleoside inosine plays an important role in purine biosynthesis, gene translation, and modulation of the fate of RNAs. The editing of adenosine to inosine is a widespread post-transcriptional modification in transfer RNAs (tRNAs) and messenger RNAs (mRNAs). At the wobble position of tRNA anticodons, inosine profoundly modifies codon recognition, while in mRNA, inosines can modify the sequence of the translated polypeptide or modulate the stability, localization, and splicing of transcripts. Inosine is also found in non-coding and exogenous RNAs, where it plays key structural and functional roles. In addition, molecular inosine is an important secondary metabolite in purine metabolism that also acts as a molecular messenger in cell signaling pathways. Here, we review the functional roles of inosine in biology and their connections to human health. Full article

(This article belongs to the Special Issue tRNAs in Biology)

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16 pages, 9573 KiB

Open AccessEditor’s ChoiceReview

Growth Restriction and Genomic Imprinting-Overlapping Phenotypes Support the Concept of an Imprinting Network

by Thomas Eggermann, Justin H. Davies, Maithé Tauber, Erica van den Akker, Anita Hokken-Koelega, Gudmundur Johansson and Irène Netchine

Genes 2021, 12(4), 585; https://doi.org/10.3390/genes12040585 - 17 Apr 2021

Cited by 19 | Viewed by 4877

Abstract

Intrauterine and postnatal growth disturbances are major clinical features of imprinting disorders, a molecularly defined group of congenital syndromes caused by molecular alterations affecting parentally imprinted genes. These genes are expressed monoallelically and in a parent-of-origin manner, and they have an impact on [...] Read more.

Intrauterine and postnatal growth disturbances are major clinical features of imprinting disorders, a molecularly defined group of congenital syndromes caused by molecular alterations affecting parentally imprinted genes. These genes are expressed monoallelically and in a parent-of-origin manner, and they have an impact on human growth and development. In fact, several genes with an exclusive expression from the paternal allele have been shown to promote foetal growth, whereas maternally expressed genes suppress it. The evolution of this correlation might be explained by the different interests of the maternal and paternal genomes, aiming for the conservation of maternal resources for multiple offspring versus extracting maximal maternal resources. Since not all imprinted genes in higher mammals show the same imprinting pattern in different species, the findings from animal models are not always transferable to human. Therefore, human imprinting disorders might serve as models to understand the complex regulation and interaction of imprinted loci. This knowledge is a prerequisite for the development of precise diagnostic tools and therapeutic strategies for patients affected by imprinting disorders. In this review we will specifically overview the current knowledge on imprinting disorders associated with growth retardation, and its increasing relevance in a personalised medicine direction and the need for a multidisciplinary therapeutic approach. Full article

(This article belongs to the Special Issue Genomic Imprinting and the Regulation of Growth and Metabolism)

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15 pages, 3226 KiB

Open AccessEditor’s ChoiceArticle

Deciphering the Monilinia fructicola Genome to Discover Effector Genes Possibly Involved in Virulence

by Laura Vilanova, Claudio A. Valero-Jiménez and Jan A.L. van Kan

Genes 2021, 12(4), 568; https://doi.org/10.3390/genes12040568 - 14 Apr 2021

Cited by 22 | Viewed by 2589

Abstract

Brown rot is the most economically important fungal disease of stone fruits and is primarily caused by Monilinia laxa and Monlinia fructicola. Both species co-occur in European orchards although M. fructicola is considered to cause the most severe yield losses in stone [...] Read more.

Brown rot is the most economically important fungal disease of stone fruits and is primarily caused by Monilinia laxa and Monlinia fructicola. Both species co-occur in European orchards although M. fructicola is considered to cause the most severe yield losses in stone fruit. This study aimed to generate a high-quality genome of M. fructicola and to exploit it to identify genes that may contribute to pathogen virulence. PacBio sequencing technology was used to assemble the genome of M. fructicola. Manual structural curation of gene models, supported by RNA-Seq, and functional annotation of the proteome yielded 10,086 trustworthy gene models. The genome was examined for the presence of genes that encode secreted proteins and more specifically effector proteins. A set of 134 putative effectors was defined. Several effector genes were cloned into Agrobacterium tumefaciens for transient expression in Nicotiana benthamiana plants, and some of them triggered necrotic lesions. Studying effectors and their biological properties will help to better understand the interaction between M. fructicola and its stone fruit host plants. Full article

(This article belongs to the Special Issue Omics Research of Pathogenic Microorganisms)

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14 pages, 312 KiB

Open AccessEditor’s ChoiceArticle

Deepening of In Silico Evaluation of SARS-CoV-2 Detection RT-qPCR Assays in the Context of New Variants

by Mathieu Gand, Kevin Vanneste, Isabelle Thomas, Steven Van Gucht, Arnaud Capron, Philippe Herman, Nancy H. C. Roosens and Sigrid C. J. De Keersmaecker

Genes 2021, 12(4), 565; https://doi.org/10.3390/genes12040565 - 13 Apr 2021

Cited by 23 | Viewed by 3507

Abstract

For 1 year now, the world is undergoing a coronavirus disease-2019 (COVID-19) pandemic due to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The most widely used method for COVID-19 diagnosis is the detection of viral RNA by RT-qPCR with a specific set [...] Read more.

For 1 year now, the world is undergoing a coronavirus disease-2019 (COVID-19) pandemic due to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The most widely used method for COVID-19 diagnosis is the detection of viral RNA by RT-qPCR with a specific set of primers and probe. It is important to frequently evaluate the performance of these tests and this can be done first by an in silico approach. Previously, we reported some mismatches between the oligonucleotides of publicly available RT-qPCR assays and SARS-CoV-2 genomes collected from GISAID and NCBI, potentially impacting proper detection of the virus. In the present study, 11 primers and probe sets investigated during the first study were evaluated again with 84,305 new SARS-CoV-2 unique genomes collected between June 2020 and January 2021. The lower inclusivity of the China CDC assay targeting the gene N has continued to decrease with new mismatches detected, whereas the other evaluated assays kept their inclusivity above 99%. Additionally, some mutations specific to new SARS-CoV-2 variants of concern were found to be located in oligonucleotide annealing sites. This might impact the strategy to be considered for future SARS-CoV-2 testing. Given the potential threat of the new variants, it is crucial to assess if they can still be correctly targeted by the primers and probes of the RT-qPCR assays. Our study highlights that considering the evolution of the virus and the emergence of new variants, an in silico (re-)evaluation should be performed on a regular basis. Ideally, this should be done for all the RT-qPCR assays employed for SARS-CoV-2 detection, including also commercial tests, although the primer and probe sequences used in these kits are rarely disclosed, which impedes independent performance evaluation. Full article

(This article belongs to the Special Issue COVID-19 and Molecular Genetics)

15 pages, 682 KiB

Open AccessEditor’s ChoiceReview

Cystic Fibrosis Lung Disease Modifiers and Their Relevance in the New Era of Precision Medicine

by Afsoon Sepahzad, Deborah J. Morris-Rosendahl and Jane C. Davies

Genes 2021, 12(4), 562; https://doi.org/10.3390/genes12040562 - 13 Apr 2021

Cited by 19 | Viewed by 4252

Abstract

Our understanding of cystic fibrosis (CF) has grown exponentially since the discovery of the cystic fibrosis transmembrane conductance regulator (CFTR) gene in 1989. With evolving genetic and genomic tools, we have come to better understand the role of CFTR genotypes in [...] Read more.

Our understanding of cystic fibrosis (CF) has grown exponentially since the discovery of the cystic fibrosis transmembrane conductance regulator (CFTR) gene in 1989. With evolving genetic and genomic tools, we have come to better understand the role of CFTR genotypes in the pathophysiology of the disease. This, in turn, has paved the way for the development of modulator therapies targeted at mutations in the CFTR, which are arguably one of the greatest advances in the treatment of CF. These modulator therapies, however, do not target all the mutations in CFTR that are seen in patients with CF and, furthermore, a variation in response is seen in patients with the same genotype who are taking modulator therapies. There is growing evidence to support the role of non-CFTR modifiers, both genetic and environmental, in determining the variation seen in CF morbidity and mortality and also in the response to existing therapies. This review focusses on key findings from studies using candidate gene and genome-wide approaches to identify CF modifier genes of lung disease in cystic fibrosis and considers the interaction between modifiers and the response to modulator therapies. As the use of modulator therapies expands and we gain data around outcomes, it will be of great interest to investigate this interaction further. Going forward, it will also be crucial to better understand the relative influence of genomic versus environmental factors. With this understanding, we can truly begin to deliver personalised care by better profiling the likely disease phenotype for each patient and their response to treatment. Full article

(This article belongs to the Special Issue Phenotypic Variability of Cystic Fibrosis: New Challenges)

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21 pages, 6386 KiB

Open AccessEditor’s ChoiceArticle

OTUs and ASVs Produce Comparable Taxonomic and Diversity from Shrimp Microbiota 16S Profiles Using Tailored Abundance Filters

by Rodrigo García-López, Fernanda Cornejo-Granados, Alonso A. Lopez-Zavala, Andrés Cota-Huízar, Rogerio R. Sotelo-Mundo, Bruno Gómez-Gil and Adrian Ochoa-Leyva

Genes 2021, 12(4), 564; https://doi.org/10.3390/genes12040564 - 13 Apr 2021

Cited by 23 | Viewed by 6495

Abstract

The interplay between shrimp immune system, its environment, and microbiota contributes to the organism’s homeostasis and optimal production. The metagenomic composition is typically studied using 16S rDNA profiling by clustering amplicon sequences into operational taxonomic units (OTUs) and, more recently, amplicon sequence variants [...] Read more.

The interplay between shrimp immune system, its environment, and microbiota contributes to the organism’s homeostasis and optimal production. The metagenomic composition is typically studied using 16S rDNA profiling by clustering amplicon sequences into operational taxonomic units (OTUs) and, more recently, amplicon sequence variants (ASVs). Establish the compatibility of the taxonomy, α, and β diversity described by both methods is necessary to compare past and future shrimp microbiota studies. Here, we used identical sequences to survey the V3 16S hypervariable-region using 97% and 99% OTUs and ASVs to assess the hepatopancreas and intestine microbiota of L. vannamei from two ponds under standardized rearing conditions. We found that applying filters to retain clusters >0.1% of the total abundance per sample enabled a consistent taxonomy comparison while preserving >94% of the total reads. The three sets turned comparable at the family level, whereas the 97% identity OTU set produced divergent genus and species profiles. Interestingly, the detection of organ and pond variations was robust to the clustering method’s choice, producing comparable α and β-diversity profiles. For comparisons on shrimp microbiota between past and future studies, we strongly recommend that ASVs be compared at the family level to 97% identity OTUs or use 99% identity OTUs, both using tailored frequency filters. Full article

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

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17 pages, 3284 KiB

Open AccessEditor’s ChoiceArticle

Allelic Diversity at Abiotic Stress Responsive Genes in Relationship to Ecological Drought Indices for Cultivated Tepary Bean, Phaseolus acutifolius A. Gray, and Its Wild Relatives

by María A. Buitrago-Bitar, Andrés J. Cortés, Felipe López-Hernández, Jorge M. Londoño-Caicedo, Jaime E. Muñoz-Florez, L. Carmenza Muñoz and Matthew Wohlgemuth Blair

Genes 2021, 12(4), 556; https://doi.org/10.3390/genes12040556 - 12 Apr 2021

Cited by 35 | Viewed by 4350

Abstract

Some of the major impacts of climate change are expected in regions where drought stress is already an issue. Grain legumes are generally drought susceptible. However, tepary bean and its wild relatives within Phaseolus acutifolius or P. parvifolius are from arid areas between [...] Read more.

Some of the major impacts of climate change are expected in regions where drought stress is already an issue. Grain legumes are generally drought susceptible. However, tepary bean and its wild relatives within Phaseolus acutifolius or P. parvifolius are from arid areas between Mexico and the United States. Therefore, we hypothesize that these bean accessions have diversity signals indicative of adaptation to drought at key candidate genes such as: Asr2, Dreb2B, and ERECTA. By sequencing alleles of these genes and comparing to estimates of drought tolerance indices from climate data for the collection site of geo-referenced, tepary bean accessions, we determined the genotype x environmental association (GEA) of each gene. Diversity analysis found that cultivated and wild P. acutifolius were intermingled with var. tenuifolius and P. parvifolius, signifying that allele diversity was ample in the wild and cultivated clade over a broad sense (sensu lato) evaluation. Genes Dreb2B and ERECTA harbored signatures of directional selection, represented by six SNPs correlated with the environmental drought indices. This suggests that wild tepary bean is a reservoir of novel alleles at genes for drought tolerance, as expected for a species that originated in arid environments. Our study corroborated that candidate gene approach was effective for marker validation across a broad genetic base of wild tepary accessions. Full article

(This article belongs to the Special Issue Evolutionary Genetics of Plant Crop-Wild Complexes: From Fundamental to Applied Research)

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16 pages, 312 KiB

Open AccessEditor’s ChoiceArticle

Towards a Change in the Diagnostic Algorithm of Autism Spectrum Disorders: Evidence Supporting Whole Exome Sequencing as a First-Tier Test

by Ana Arteche-López, Maria José Gómez Rodríguez, Maria Teresa Sánchez Calvin, Juan Francisco Quesada-Espinosa, Jose Miguel Lezana Rosales, Carmen Palma Milla, Irene Gómez-Manjón, Irene Hidalgo Mayoral, Rubén Pérez de la Fuente, Arancha Díaz de Bustamante, María Teresa Darnaude, Belén Gil-Fournier, Soraya Ramiro León, Patricia Ramos Gómez, Olalla Sierra Tomillo, Alexandra Juárez Rufián, Maria Isabel Arranz Cano, Rebeca Villares Alonso, Pablo Morales-Pérez, Alejandro Segura-Tudela, Ana Camacho, Noemí Nuñez, Rogelio Simón, Marta Moreno-García and Maria Isabel Alvarez-Mora Show full author list Hide full author list

Genes 2021, 12(4), 560; https://doi.org/10.3390/genes12040560 - 12 Apr 2021

Cited by 18 | Viewed by 4208

Abstract

Autism spectrum disorder (ASD) is a prevalent and extremely heterogeneous neurodevelopmental disorder (NDD) with a strong genetic component. In recent years, the clinical relevance of de novo mutations to the aetiology of ASD has been demonstrated. Current guidelines recommend chromosomal microarray (CMA) and [...] Read more.

Autism spectrum disorder (ASD) is a prevalent and extremely heterogeneous neurodevelopmental disorder (NDD) with a strong genetic component. In recent years, the clinical relevance of de novo mutations to the aetiology of ASD has been demonstrated. Current guidelines recommend chromosomal microarray (CMA) and a FMR1 testing as first-tier tests, but there is increasing evidence that support the use of NGS for the diagnosis of NDDs. Specifically in ASD, it has not been extensively evaluated and, thus, we performed and compared the clinical utility of CMA, FMR1 testing, and/or whole exome sequencing (WES) in a cohort of 343 ASD patients. We achieved a global diagnostic rate of 12.8% (44/343), the majority of them being characterised by WES (33/44; 75%) compared to CMA (9/44; 20.4%) or FMR1 testing (2/44; 4.5%). Taking into account the age at which genetic testing was carried out, we identified a causal genetic alteration in 22.5% (37/164) of patients over 5 years old, but only in 3.9% (7/179) of patients under this age. Our data evidence the higher diagnostic power of WES compared to CMA in the study of ASD and support the implementation of WES as a first-tier test for the genetic diagnosis of this disorder, when there is no suspicion of fragile X syndrome. Full article

(This article belongs to the Special Issue Genetics of Psychiatric Disease and the Basics of Neurobiology)

16 pages, 10042 KiB

Open AccessEditor’s ChoiceArticle

Kinetics and Topology of DNA Associated with Circulating Extracellular Vesicles Released during Exercise

by Elmo W. I. Neuberger, Barlo Hillen, Katharina Mayr, Perikles Simon, Eva-Maria Krämer-Albers and Alexandra Brahmer

Genes 2021, 12(4), 522; https://doi.org/10.3390/genes12040522 - 02 Apr 2021

Cited by 21 | Viewed by 3134

Abstract

Although it is widely accepted that cancer-derived extracellular vesicles (EVs) carry DNA cargo, the association of cell-free circulating DNA (cfDNA) and EVs in plasma of healthy humans remains elusive. Using a physiological exercise model, where EVs and cfDNA are synchronously released, we aimed [...] Read more.

Although it is widely accepted that cancer-derived extracellular vesicles (EVs) carry DNA cargo, the association of cell-free circulating DNA (cfDNA) and EVs in plasma of healthy humans remains elusive. Using a physiological exercise model, where EVs and cfDNA are synchronously released, we aimed to characterize the kinetics and localization of DNA associated with EVs. EVs were separated from human plasma using size exclusion chromatography or immuno-affinity capture for CD9⁺, CD63⁺, and CD81⁺ EVs. DNA was quantified with an ultra-sensitive qPCR assay targeting repetitive LINE elements, with or without DNase digestion. This model shows that a minute part of circulating cell-free DNA is associated with EVs. During rest and following exercise, only 0.12% of the total cfDNA occurs in association with CD9⁺/CD63⁺/CD81⁺EVs. DNase digestion experiments indicate that the largest part of EV associated DNA is sensitive to DNase digestion and only ~20% are protected within the lumen of the separated EVs. A single bout of running or cycling exercise increases the levels of EVs, cfDNA, and EV-associated DNA. While EV surface DNA is increasing, DNAse-resistant DNA remains at resting levels, indicating that EVs released during exercise (ExerVs) do not contain DNA. Consequently, DNA is largely associated with the outer surface of circulating EVs. ExerVs recruit cfDNA to their corona, but do not carry DNA in their lumen. Full article

(This article belongs to the Special Issue Nucleic Acids within Extracellular Vesicles: Functional Role in Health and Disease)

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8 pages, 1033 KiB

Open AccessEditor’s ChoiceCase Report

MCAT Mutations Cause Nuclear LHON-like Optic Neuropathy

by Sylvie Gerber, Christophe Orssaud, Josseline Kaplan, Catrine Johansson and Jean-Michel Rozet

Genes 2021, 12(4), 521; https://doi.org/10.3390/genes12040521 - 02 Apr 2021

Cited by 21 | Viewed by 2449

Abstract

Pathological variants in the nuclear malonyl-CoA-acyl carrier protein transacylase (MCAT) gene, which encodes a mitochondrial protein involved in fatty-acid biogenesis, have been reported in two siblings from China affected by insidious optic nerve degeneration in childhood, leading to blindness in the [...] Read more.

Pathological variants in the nuclear malonyl-CoA-acyl carrier protein transacylase (MCAT) gene, which encodes a mitochondrial protein involved in fatty-acid biogenesis, have been reported in two siblings from China affected by insidious optic nerve degeneration in childhood, leading to blindness in the first decade of life. After analysing 51 families with negative molecular diagnostic tests, from a cohort of 200 families with hereditary optic neuropathy (HON), we identified two novel MCAT mutations in a female patient who presented with acute, sudden, bilateral, yet asymmetric, central visual loss at the age of 20. This presentation is consistent with a Leber hereditary optic neuropathy (LHON)-like phenotype, whose existence and association with NDUFS2 and DNAJC30 has only recently been described. Our findings reveal a wider phenotypic presentation of MCAT mutations, and a greater genetic heterogeneity of nuclear LHON-like phenotypes. Although MCAT pathological variants are very uncommon, this gene should be investigated in HON patients, irrespective of disease presentation. Full article

(This article belongs to the Special Issue Genetics in Ophthalmology)

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14 pages, 312 KiB

Open AccessEditor’s ChoiceReview

Chances and Challenges of New Genetic Screening Technologies (NIPT) in Prenatal Medicine from a Clinical Perspective: A Narrative Review

by Ivonne Bedei, Aline Wolter, Axel Weber, Fabrizio Signore and Roland Axt-Fliedner

Genes 2021, 12(4), 501; https://doi.org/10.3390/genes12040501 - 29 Mar 2021

Cited by 33 | Viewed by 7919

Abstract

In 1959, 63 years after the death of John Langdon Down, Jérôme Lejeune discovered trisomy 21 as the genetic reason for Down syndrome. Screening for Down syndrome has been applied since the 1960s by using maternal age as the risk parameter. Since then, [...] Read more.

In 1959, 63 years after the death of John Langdon Down, Jérôme Lejeune discovered trisomy 21 as the genetic reason for Down syndrome. Screening for Down syndrome has been applied since the 1960s by using maternal age as the risk parameter. Since then, several advances have been made. First trimester screening, combining maternal age, maternal serum parameters and ultrasound findings, emerged in the 1990s with a detection rate (DR) of around 90–95% and a false positive rate (FPR) of around 5%, also looking for trisomy 13 and 18. With the development of high-resolution ultrasound, around 50% of fetal anomalies are now detected in the first trimester. Non-invasive prenatal testing (NIPT) for trisomy 21, 13 and 18 is a highly efficient screening method and has been applied as a first-line or a contingent screening approach all over the world since 2012, in some countries without a systematic screening program. Concomitant with the rise in technology, the possibility of screening for other genetic conditions by analysis of cfDNA, such as sex chromosome anomalies (SCAs), rare autosomal anomalies (RATs) and microdeletions and duplications, is offered by different providers to an often not preselected population of pregnant women. Most of the research in the field is done by commercial providers, and some of the tests are on the market without validated data on test performance. This raises difficulties in the counseling process and makes it nearly impossible to obtain informed consent. In parallel with the advent of new screening technologies, an expansion of diagnostic methods has begun to be applied after invasive procedures. The karyotype has been the gold standard for decades. Chromosomal microarrays (CMAs) able to detect deletions and duplications on a submicroscopic level have replaced the conventional karyotyping in many countries. Sequencing methods such as whole exome sequencing (WES) and whole genome sequencing (WGS) tremendously amplify the diagnostic yield in fetuses with ultrasound anomalies. Full article

(This article belongs to the Special Issue Genetic Research in Fetal Medicine)

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