Genes

19 pages, 6244 KiB

Open AccessArticle

Expression of Piwi, MMP, TIMP, and Sox during Gut Regeneration in Holothurian Eupentacta fraudatrix (Holothuroidea, Dendrochirotida)

by Igor Yu. Dolmatov, Nadezhda V. Kalacheva, Ekaterina S. Tkacheva, Alena P. Shulga, Eugenia G. Zavalnaya, Ekaterina V. Shamshurina, Alexander S. Girich, Alexey V. Boyko and Marina G. Eliseikina

Genes 2021, 12(8), 1292; https://doi.org/10.3390/genes12081292 - 23 Aug 2021

Cited by 13 | Viewed by 2577

Abstract

Mesodermal cells of holothurian Eupentacta fraudatrix can transdifferentiate into enterocytes during the regeneration of the digestive system. In this study, we investigated the expression of several genes involved in gut regeneration in E. fraudatrix. Moreover, the localization of progenitor cells of coelomocytes, juvenile [...] Read more.

Mesodermal cells of holothurian Eupentacta fraudatrix can transdifferentiate into enterocytes during the regeneration of the digestive system. In this study, we investigated the expression of several genes involved in gut regeneration in E. fraudatrix. Moreover, the localization of progenitor cells of coelomocytes, juvenile cells, and their participation in the formation of the luminal epithelium of the digestive tube were studied. It was shown that Piwi-positive cells were not involved in the formation of the luminal epithelium of the digestive tube. Ef-72 kDa type IV collagenase and Ef-MMP16 had an individual expression profile and possibly different functions. The Ef-tensilin3 gene exhibited the highest expression and indicates its potential role in regeneration. Ef-Sox9/10 and Ef-Sox17 in E. fraudatrix may participate in the mechanism of transdifferentiation of coelomic epithelial cells. Their transcripts mark the cells that plunge into the connective tissue of the gut anlage and give rise to enterocytes. Ef-Sox9/10 probably controls the switching of mesodermal cells to the enterocyte phenotype, while Ef-Sox17 may be involved in the regulation of the initial stages of transdifferentiation. 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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15 pages, 33305 KiB

Open AccessArticle

Regional Specific Differentiation of Integumentary Organs: Regulation of Gene Clusters within the Avian Epidermal Differentiation Complex and Impacts of SATB2 Overexpression

by Gee-Way Lin, Yung-Chih Lai, Ya-Chen Liang, Randall B. Widelitz, Ping Wu and Cheng-Ming Chuong

Genes 2021, 12(8), 1291; https://doi.org/10.3390/genes12081291 - 23 Aug 2021

Cited by 5 | Viewed by 2955

Abstract

The epidermal differentiation complex (EDC) encodes a group of unique proteins expressed in late epidermal differentiation. The EDC gave integuments new physicochemical properties and is critical in evolution. Recently, we showed β-keratins, members of the EDC, undergo gene cluster switching with overexpression of [...] Read more.

The epidermal differentiation complex (EDC) encodes a group of unique proteins expressed in late epidermal differentiation. The EDC gave integuments new physicochemical properties and is critical in evolution. Recently, we showed β-keratins, members of the EDC, undergo gene cluster switching with overexpression of SATB2 (Special AT-rich binding protein-2), considered a chromatin regulator. We wondered whether this unique regulatory mechanism is specific to β-keratins or may be derived from and common to EDC members. Here we explore (1) the systematic expression patterns of non-β-keratin EDC genes and their preferential expression in different skin appendages during development, (2) whether the expression of non-β-keratin EDC sub-clusters are also regulated in clusters by SATB2. We analyzed bulk RNA-seq and ChIP-seq data and also evaluated the disrupted expression patterns caused by overexpressing SATB2. The results show that the expression of whole EDDA and EDQM sub-clusters are possibly mediated by enhancers in E14-feathers. Overexpressing SATB2 down-regulates the enriched EDCRP sub-cluster in feathers and the EDCH sub-cluster in beaks. These results reveal the potential of complex epigenetic regulation activities within the avian EDC, implying transcriptional regulation of EDC members acting at the gene and/or gene cluster level in a temporal and skin regional-specific fashion, which may contribute to the evolution of diverse avian integuments. Full article

(This article belongs to the Special Issue Genomics and Evolution of Sauropsid Traits in the Genomics Era)

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15 pages, 2584 KiB

Open AccessArticle

siRNA Mediate RNA Interference Concordant with Early On-Target Transient Transcriptional Interference

by Zhiming Fang, Zhongming Zhao, Valsamma Eapen and Raymond A. Clarke

Genes 2021, 12(8), 1290; https://doi.org/10.3390/genes12081290 - 23 Aug 2021

Cited by 1 | Viewed by 2506

Abstract

Exogenous siRNAs are commonly used to regulate endogenous gene expression levels for gene function analysis, genotype–phenotype association studies and for gene therapy. Exogenous siRNAs can target mRNAs within the cytosol as well as nascent RNA transcripts within the nucleus, thus complicating siRNA targeting [...] Read more.

Exogenous siRNAs are commonly used to regulate endogenous gene expression levels for gene function analysis, genotype–phenotype association studies and for gene therapy. Exogenous siRNAs can target mRNAs within the cytosol as well as nascent RNA transcripts within the nucleus, thus complicating siRNA targeting specificity. To highlight challenges in achieving siRNA target specificity, we targeted an overlapping gene set that we found associated with a familial form of multiple synostosis syndrome type 4 (SYSN4). In the affected family, we found that a previously unknown non-coding gene TOSPEAK/C8orf37AS1 was disrupted and the adjacent gene GDF6 was downregulated. Moreover, a conserved long-range enhancer for GDF6 was found located within TOSPEAK which in turn overlapped another gene which we named SMALLTALK/C8orf37. In fibroblast cell lines, SMALLTALK is transcribed at much higher levels in the opposite (convergent) direction to TOSPEAK. siRNA targeting of SMALLTALK resulted in post transcriptional gene silencing (PTGS/RNAi) of SMALLTALK that peaked at 72 h together with a rapid early increase in the level of both TOSPEAK and GDF6 that peaked and waned after 24 h. These findings indicated the following sequence of events: Firstly, the siRNA designed to target SMALLTALK mRNA for RNAi in the cytosol had also caused an early and transient transcriptional interference of SMALLTALK in the nucleus; Secondly, the resulting interference of SMALLTALK transcription increased the transcription of TOSPEAK; Thirdly, the increased transcription of TOSPEAK increased the transcription of GDF6. These findings have implications for the design and application of RNA and DNA targeting technologies including siRNA and CRISPR. For example, we used siRNA targeting of SMALLTALK to successfully restore GDF6 levels in the gene therapy of SYNS4 family fibroblasts in culture. To confidently apply gene targeting technologies, it is important to first determine the transcriptional interference effects of the targeting reagent and the targeted gene. Full article

(This article belongs to the Collection Genotype-Phenotype Study in Disease)

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13 pages, 571 KiB

Open AccessReview

MiRNAs and Cancer: Key Link in Diagnosis and Therapy

by Yu Shi, Zihao Liu, Qun Lin, Qing Luo, Yinghuan Cen, Juanmei Li, Xiaolin Fang and Chang Gong

Genes 2021, 12(8), 1289; https://doi.org/10.3390/genes12081289 - 23 Aug 2021

Cited by 62 | Viewed by 5244

Abstract

Since the discovery of the first microRNA (miRNA), the exploration of miRNA biology has come to a new era in recent decades. Monumental studies have proven that miRNAs can be dysregulated in different types of cancers and the roles of miRNAs turn out [...] Read more.

Since the discovery of the first microRNA (miRNA), the exploration of miRNA biology has come to a new era in recent decades. Monumental studies have proven that miRNAs can be dysregulated in different types of cancers and the roles of miRNAs turn out to function to either tumor promoters or tumor suppressors. The interplay between miRNAs and the development of cancers has grabbed attention of miRNAs as novel tools and targets for therapeutic attempts. Moreover, the development of miRNA delivery system accelerates miRNA preclinical implications. In this review, we depict recent advances of miRNAs in cancer and discuss the potential diagnostic or therapeutic approaches of miRNAs. Full article

(This article belongs to the Special Issue The Role of MicroRNA in Cancer)

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24 pages, 59957 KiB

Open AccessReview

Dermoscopic Criteria, Histopathological Correlates and Genetic Findings of Thin Melanoma on Non-Volar Skin

by Cesare Massone, Rainer Hofman-Wellenhof, Stefano Chiodi and Simona Sola

Genes 2021, 12(8), 1288; https://doi.org/10.3390/genes12081288 - 23 Aug 2021

Cited by 7 | Viewed by 4008

Abstract

Dermoscopy is a non-invasive, in vivo technique that allows the visualization of subsurface skin structures in the epidermis, at the dermoepidermal junction, and in the upper dermis. Dermoscopy brought a new dimension in evaluating melanocytic skin neoplasms (MSN) also representing a link between [...] Read more.

Dermoscopy is a non-invasive, in vivo technique that allows the visualization of subsurface skin structures in the epidermis, at the dermoepidermal junction, and in the upper dermis. Dermoscopy brought a new dimension in evaluating melanocytic skin neoplasms (MSN) also representing a link between clinical and pathologic examination of any MSN. However, histopathology remains the gold standard in diagnosing MSN. Dermoscopic–pathologic correlation enhances the level of quality of MSN diagnosis and increases the level of confidence of pathologists. Melanoma is one of the most genetically predisposed among all cancers in humans. The genetic landscape of melanoma has been described in the last years but is still a field in continuous evolution. Melanoma genetic markers play a role not only in melanoma susceptibility, initiation, and progression but also in prognosis and therapeutic decisions. Several studies described the dermoscopic specific criteria and predictors for melanoma and their histopathologic correlates, but only a few studies investigated the correlation among dermoscopy, pathology, and genetic of MSN. The aim of this work is to review the published data about dermoscopic features of melanoma, their histopathological correlates with regards also to genetic alterations. Particularly, this review will focus on low-CSD (cumulative sun damage) melanoma or superficial spreading melanoma, high-CSD melanoma, and nevus-associated melanoma. Full article

(This article belongs to the Special Issue Skin Cancer: Genetics, Diagnosis and Prevention)

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15 pages, 2393 KiB

Open AccessArticle

Evolution and Functional Characteristics of the Novel elovl8 That Play Pivotal Roles in Fatty Acid Biosynthesis

by Shouxiang Sun, Yumei Wang, Pei-Tian Goh, Mónica Lopes-Marques, L. Filipe C. Castro, Óscar Monroig, Meng-Kiat Kuah, Xiaojuan Cao, Alexander Chong Shu-Chien and Jian Gao

Genes 2021, 12(8), 1287; https://doi.org/10.3390/genes12081287 - 23 Aug 2021

Cited by 20 | Viewed by 4061

Abstract

Elongation of very long-chain fatty acid (Elovl) proteins are key enzymes that catalyze the rate-limiting step in the fatty acid elongation pathway. The most recently discovered member of the Elovl family, Elovl8, has been proposed to be a fish-specific elongase with two gene [...] Read more.

Elongation of very long-chain fatty acid (Elovl) proteins are key enzymes that catalyze the rate-limiting step in the fatty acid elongation pathway. The most recently discovered member of the Elovl family, Elovl8, has been proposed to be a fish-specific elongase with two gene paralogs described in teleosts. However, the biological functions of Elovl8 are still to be elucidated. In this study, we showed that in contrast to previous findings, elovl8 is not unique to teleosts, but displays a rather unique and ample phylogenetic distribution. For functional determination, we generated elovl8a (elovl8a⁻^/−) and elovl8b (elovl8b⁻^/−) zebrafish using CRISPR/Cas9 technology. Fatty acid composition in vivo and zebrafish liver cell experiments suggest that the substrate preference of Elovl8 overlapped with other existing Elovl enzymes. Zebrafish Elovl8a could elongate the polyunsaturated fatty acids (PUFAs) C18:2n-6 and C18:3n-3 to C20:2n-6 and C20:3n-3, respectively. Along with PUFA, zebrafish Elovl8b also showed the capacity to elongate C18:0 and C20:1. Gene expression quantification suggests that Elovl8a and Elovl8b may play a potentially important role in fatty acid biosynthesis. Overall, our results provide novel insights into the function of Elovl8a and Elovl8b, representing additional fatty acid elongases not previously described in chordates. Full article

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

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20 pages, 300 KiB

Open AccessReview

Genetic Determinants of Inherited Endocrine Tumors: Do They Have a Direct Role in Bone Metabolism Regulation and Osteoporosis?

by Francesca Marini, Francesca Giusti, Teresa Iantomasi and Maria Luisa Brandi

Genes 2021, 12(8), 1286; https://doi.org/10.3390/genes12081286 - 23 Aug 2021

Cited by 1 | Viewed by 2245

Abstract

Endocrine tumors are neoplasms originating from specialized hormone-secreting cells. They can develop as sporadic tumors, caused by somatic mutations, or in the context of familial Mendelian inherited diseases. Congenital forms, manifesting as syndromic or non-syndromic diseases, are caused by germinal heterozygote autosomal dominant [...] Read more.

Endocrine tumors are neoplasms originating from specialized hormone-secreting cells. They can develop as sporadic tumors, caused by somatic mutations, or in the context of familial Mendelian inherited diseases. Congenital forms, manifesting as syndromic or non-syndromic diseases, are caused by germinal heterozygote autosomal dominant mutations in oncogenes or tumor suppressor genes. The genetic defect leads to a loss of cell growth control in target endocrine tissues and to tumor development. In addition to the classical cancer manifestations, some affected patients can manifest alterations of bone and mineral metabolism, presenting both as pathognomonic and/or non-specific skeletal clinical features, which can be either secondary complications of endocrine functioning primary tumors and/or a direct consequence of the gene mutation. Here, we specifically review the current knowledge on possible direct roles of the genes that cause inherited endocrine tumors in the regulation of bone modeling and remodeling by exploring functional in vitro and in vivo studies highlighting how some of these genes participate in the regulation of molecular pathways involved in bone and mineral metabolism homeostasis, and by describing the potential direct effects of gene mutations on the development of skeletal and mineral metabolism clinical features in patients. Full article

(This article belongs to the Special Issue Key Genetic Determinants of Osteoporosis: From Bench to Bedside)

21 pages, 1438 KiB

Open AccessArticle

Genetic Background and Antibiotic Resistance Profiles of K. pneumoniae NDM-1 Strains Isolated from UTI, ABU, and the GI Tract, from One Hospital in Poland, in Relation to Strains Nationally and Worldwide

by Magdalena Wysocka, Roxana Zamudio, Marco R. Oggioni, Justyna Gołębiewska, Marek Bronk and Beata Krawczyk

Genes 2021, 12(8), 1285; https://doi.org/10.3390/genes12081285 - 22 Aug 2021

Cited by 7 | Viewed by 2943

Abstract

In recent years, there has been an observed increase in infections caused by carbapenem-resistant Klebsiella pneumonia (Kp) strains. The aim of this study was the phenotypic and genotypic analysis of eight K. pneumoniae NDM (Kp NDM) isolates, recovered in Poland during the years [...] Read more.

In recent years, there has been an observed increase in infections caused by carbapenem-resistant Klebsiella pneumonia (Kp) strains. The aim of this study was the phenotypic and genotypic analysis of eight K. pneumoniae NDM (Kp NDM) isolates, recovered in Poland during the years 2016 and 2018 from seven patients with urinary tract infections (UTIs), asymptomatic bacteriuria (ABU), or colonization of the gut. PCR melting profile genotyping indicated a close relationship between the strains derived from 2018, which were not related to the strain isolated in 2016. WGS results were analyzed in relation to international Kp isolates. Clonal and phylogenetic analyses were performed based on multilocus sequence typing (MLST) and single nucleotide polymorphisms (SNPs) of the core genome. The metallo-β-lactamase was assigned to the NDM-1 type and the sequence was identified as ST11. Eleven antimicrobial resistance genes were detected, mostly from plasmid contigs. Unprecedented profiles of plasmid replicons were described with the IncFII/pKPX-1 dominant replicon. In terms of the KL24 and O2v1 capsular antigen profiles, these isolates corresponded to Greek strains. Strains isolated from UTI, ABU, and colonization GI tract patients were not carrying environment-specific virulence genes. Based on the assessment of strain relationships at the genome level and their direction of evolution, the international character of the sublines was demonstrated, with a documented epidemic potential in Poland and Greece. In conclusion, some groups of patients, e.g., renal transplant recipients or those with complicated UTIs, who are frequently hospitalized and undergoing antibiotic therapy, should be monitored not only for the risk of UTI, but also for colonization by Kp NDM strains. Full article

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

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19 pages, 2561 KiB

Open AccessArticle

Development and Evaluation of the Ancestry Informative Marker Panel of the VISAGE Basic Tool

by María de la Puente, Jorge Ruiz-Ramírez, Adrián Ambroa-Conde, Catarina Xavier, Jacobo Pardo-Seco, Jose Álvarez-Dios, Ana Freire-Aradas, Ana Mosquera-Miguel, Theresa E. Gross, Elaine Y. Y. Cheung, Wojciech Branicki, Michael Nothnagel, Walther Parson, Peter M. Schneider, Manfred Kayser, Ángel Carracedo, Maria Victoria Lareu, Christopher Phillips and on behalf of the VISAGE Consortium

Genes 2021, 12(8), 1284; https://doi.org/10.3390/genes12081284 - 22 Aug 2021

Cited by 21 | Viewed by 5388

Abstract

We detail the development of the ancestry informative single nucleotide polymorphisms (SNPs) panel forming part of the VISAGE Basic Tool (BT), which combines 41 appearance predictive SNPs and 112 ancestry predictive SNPs (three SNPs shared between sets) in one massively parallel sequencing (MPS) [...] Read more.

We detail the development of the ancestry informative single nucleotide polymorphisms (SNPs) panel forming part of the VISAGE Basic Tool (BT), which combines 41 appearance predictive SNPs and 112 ancestry predictive SNPs (three SNPs shared between sets) in one massively parallel sequencing (MPS) multiplex, whereas blood-based age analysis using methylation markers is run in a parallel MPS analysis pipeline. The selection of SNPs for the BT ancestry panel focused on established forensic markers that already have a proven track record of good sequencing performance in MPS, and the overall SNP multiplex scale closely matched that of existing forensic MPS assays. SNPs were chosen to differentiate individuals from the five main continental population groups of Africa, Europe, East Asia, America, and Oceania, extended to include differentiation of individuals from South Asia. From analysis of 1000 Genomes and HGDP-CEPH samples from these six population groups, the BT ancestry panel was shown to have no classification error using the Bayes likelihood calculators of the Snipper online analysis portal. The differentiation power of the component ancestry SNPs of BT was balanced as far as possible to avoid bias in the estimation of co-ancestry proportions in individuals with admixed backgrounds. The balancing process led to very similar cumulative population-specific divergence values for Africa, Europe, America, and Oceania, with East Asia being slightly below average, and South Asia an outlier from the other groups. Comparisons were made of the African, European, and Native American estimated co-ancestry proportions in the six admixed 1000 Genomes populations, using the BT ancestry panel SNPs and 572,000 Affymetrix Human Origins array SNPs. Very similar co-ancestry proportions were observed down to a minimum value of 10%, below which, low-level co-ancestry was not always reliably detected by BT SNPs. The Snipper analysis portal provides a comprehensive population dataset for the BT ancestry panel SNPs, comprising a 520-sample standardised reference dataset; 3445 additional samples from 1000 Genomes, HGDP-CEPH, Simons Foundation and Estonian Biocentre genome diversity projects; and 167 samples of six populations from in-house genotyping of individuals from Middle East, North and East African regions complementing those of the sampling regimes of the other diversity projects. Full article

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

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14 pages, 1825 KiB

Open AccessArticle

When Two plus Two Is More than Four: Evidence for a Synergistic Effect of Fatty Acids on Peroxisome Proliferator—Activated Receptor Activity in a Bovine Hepatic Model

by Sebastiano Busato and Massimo Bionaz

Genes 2021, 12(8), 1283; https://doi.org/10.3390/genes12081283 - 21 Aug 2021

Cited by 8 | Viewed by 2774

Abstract

The inclusion of fat in livestock diets represents a valuable and cost-effective way to increase the animal’s caloric intake. Beyond their caloric value, fatty acids can be understood in terms of their bioactivity, via the modulation of the ligand-dependent nuclear peroxisome proliferator-activated receptors [...] Read more.

The inclusion of fat in livestock diets represents a valuable and cost-effective way to increase the animal’s caloric intake. Beyond their caloric value, fatty acids can be understood in terms of their bioactivity, via the modulation of the ligand-dependent nuclear peroxisome proliferator-activated receptors (PPAR). Isotypes of PPAR regulate important metabolic processes in both monogastric and ruminant animals, including the metabolism of fatty acids (FA), the production of milk fat, and the immune response; however, information on the modulation of bovine PPAR by fatty acids is limited. The objective of this study was to expand our understanding on modulation of bovine PPAR by FA, both when used individually and in combination, in an immortalized cell culture model of bovine liver. Of the 10 FA included in the study, the greatest activation of the PPAR reporter was detected with saturated FA C12:0, C16:0, and C18:0, as well as phytanic acid, and the unsaturated FA C16:1 and C18:1. When supplemented in mixtures of 2 FA, the most effective combination was C12:0 + C16:0, while in mixtures of 3 FA, the greatest activation was caused by combinations of C12:0 with C16:0 and either C18:0, C16:1, or C18:1. Some mixtures display a synergistic effect that leads to PPAR activation greater than the sum of their parts, which may be explained by structural dynamics within the PPAR ligand-binding pocket. Our results provide fundamental information for the development of tailored dietary plans that focus on the use of FA mixtures for nutrigenomic purposes. Full article

(This article belongs to the Special Issue Nutrigenomics in Dairy Animals)

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15 pages, 1725 KiB

Open AccessArticle

A Novel Missense Mutation in TNNI3K Causes Recessively Inherited Cardiac Conduction Disease in a Consanguineous Pakistani Family

by Shafaq Ramzan, Stephanie Tennstedt, Muhammad Tariq, Sheraz Khan, Hafiza Noor Ul Ayan, Aamir Ali, Matthias Munz, Holger Thiele, Asad Aslam Korejo, Abdul Razzaq Mughal, Syed Zahid Jamal, Peter Nürnberg, Shahid Mahmood Baig, Jeanette Erdmann and Ilyas Ahmad

Genes 2021, 12(8), 1282; https://doi.org/10.3390/genes12081282 - 21 Aug 2021

Cited by 9 | Viewed by 4484

Abstract

Cardiac conduction disease (CCD), which causes altered electrical impulse propagation in the heart, is a life-threatening condition with high morbidity and mortality. It exhibits genetic and clinical heterogeneity with diverse pathomechanisms, but in most cases, it disrupts the synchronous activity of impulse-generating nodes [...] Read more.

Cardiac conduction disease (CCD), which causes altered electrical impulse propagation in the heart, is a life-threatening condition with high morbidity and mortality. It exhibits genetic and clinical heterogeneity with diverse pathomechanisms, but in most cases, it disrupts the synchronous activity of impulse-generating nodes and impulse-conduction underlying the normal heartbeat. In this study, we investigated a consanguineous Pakistani family comprised of four patients with CCD. We applied whole exome sequencing (WES) and co-segregation analysis, which identified a novel homozygous missense mutation (c.1531T>C;(p.Ser511Pro)) in the highly conserved kinase domain of the cardiac troponin I-interacting kinase (TNNI3K) encoding gene. The behaviors of mutant and native TNNI3K were compared by performing all-atom long-term molecular dynamics simulations, which revealed changes at the protein surface and in the hydrogen bond network. Furthermore, intra and intermolecular interaction analyses revealed that p.Ser511Pro causes structural variation in the ATP-binding pocket and the homodimer interface. These findings suggest p.Ser511Pro to be a pathogenic variant. Our study provides insights into how the variant perturbs the TNNI3K structure-function relationship, leading to a disease state. This is the first report of a recessive mutation in TNNI3K and the first mutation in this gene identified in the Pakistani population. Full article

(This article belongs to the Special Issue Recent Advance in Cardiovascular Genetics)

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18 pages, 1062 KiB

Open AccessReview

Current Epigenetic Insights in Kidney Development

by Katrina Chan and Xiaogang Li

Genes 2021, 12(8), 1281; https://doi.org/10.3390/genes12081281 - 21 Aug 2021

Cited by 7 | Viewed by 6745

Abstract

The kidney is among the best characterized developing tissues, with the genes and signaling pathways that regulate embryonic and adult kidney patterning and development having been extensively identified. It is now widely understood that DNA methylation and histone modification patterns are imprinted during [...] Read more.

The kidney is among the best characterized developing tissues, with the genes and signaling pathways that regulate embryonic and adult kidney patterning and development having been extensively identified. It is now widely understood that DNA methylation and histone modification patterns are imprinted during embryonic development and must be maintained in adult cells for appropriate gene transcription and phenotypic stability. A compelling question then is how these epigenetic mechanisms play a role in kidney development. In this review, we describe the major genes and pathways that have been linked to epigenetic mechanisms in kidney development. We also discuss recent applications of single-cell RNA sequencing (scRNA-seq) techniques in the study of kidney development. Additionally, we summarize the techniques of single-cell epigenomics, which can potentially be used to characterize epigenomes at single-cell resolution in embryonic and adult kidneys. The combination of scRNA-seq and single-cell epigenomics will help facilitate the further understanding of early cell lineage specification at the level of epigenetic modifications in embryonic and adult kidney development, which may also be used to investigate epigenetic mechanisms in kidney diseases. Full article

(This article belongs to the Special Issue Current Genetic Insights in Organ Development)

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13 pages, 5521 KiB

Open AccessArticle

PlantMirP2: An Accurate, Fast and Easy-To-Use Program for Plant Pre-miRNA and miRNA Prediction

by Dashuai Fan, Yuangen Yao and Ming Yi

Genes 2021, 12(8), 1280; https://doi.org/10.3390/genes12081280 - 21 Aug 2021

Cited by 6 | Viewed by 2840

Abstract

MicroRNAs (miRNAs) are a kind of short non-coding ribonucleic acid molecules that can regulate gene expression. The computational identification of plant miRNAs is of great significance to understanding biological functions. In our previous studies, we have put firstly forward and further developed a [...] Read more.

MicroRNAs (miRNAs) are a kind of short non-coding ribonucleic acid molecules that can regulate gene expression. The computational identification of plant miRNAs is of great significance to understanding biological functions. In our previous studies, we have put firstly forward and further developed a set of knowledge-based energy features to construct two plant pre-miRNA prediction tools (plantMirP and riceMirP). However, these two tools cannot be used for miRNA prediction from NGS (Next-Generation Sequencing) data. In addition, for further improving the prediction performance and accessibility, plantMirP2 has been developed. Based on the latest dataset, plantMirP2 achieves a promising performance: 0.9968 (Area Under Curve, AUC), 0.9754 (accuracy), 0.9675 (sensitivity) and 0.9876 (specificity). Additionally, the comparisons with other plant pre-miRNA tools show that plantMirP2 performs better. Finally, the webserver and stand-alone version of plantMirP2 are available. Full article

(This article belongs to the Section Bioinformatics)

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21 pages, 1736 KiB

Open AccessArticle

Population Genomics Reveals Gene Flow and Adaptive Signature in Invasive Weed Mikania micrantha

by Xiaoxian Ruan, Zhen Wang, Yingjuan Su and Ting Wang

Genes 2021, 12(8), 1279; https://doi.org/10.3390/genes12081279 - 20 Aug 2021

Cited by 2 | Viewed by 3100

Abstract

A long-standing and unresolved issue in invasion biology concerns the rapid adaptation of invaders to nonindigenous environments. Mikania micrantha is a notorious invasive weed that causes substantial economic losses and negative ecological consequences in southern China. However, the contributions of gene flow, environmental [...] Read more.

A long-standing and unresolved issue in invasion biology concerns the rapid adaptation of invaders to nonindigenous environments. Mikania micrantha is a notorious invasive weed that causes substantial economic losses and negative ecological consequences in southern China. However, the contributions of gene flow, environmental variables, and functional genes, all generally recognized as important factors driving invasive success, to its successful invasion of southern China are not fully understood. Here, we utilized a genotyping-by-sequencing approach to sequence 306 M. micrantha individuals from 21 invasive populations. Based on the obtained genome-wide single nucleotide polymorphism (SNP) data, we observed that all the populations possessed similar high levels of genetic diversity that were not constrained by longitude and latitude. Mikania micrantha was introduced multiple times and subsequently experienced rapid-range expansion with recurrent high gene flow. Using F_ST outliers, a latent factor mixed model, and the Bayesian method, we identified 38 outlier SNPs associated with environmental variables. The analysis of these outlier SNPs revealed that soil composition, temperature, precipitation, and ecological variables were important determinants affecting the invasive adaptation of M. micrantha. Candidate genes with outlier signatures were related to abiotic stress response. Gene family clustering analysis revealed 683 gene families unique to M. micrantha which may have significant implications for the growth, metabolism, and defense responses of M. micrantha. Forty-one genes showing significant positive selection signatures were identified. These genes mainly function in binding, DNA replication and repair, signature transduction, transcription, and cellular components. Collectively, these findings highlight the contribution of gene flow to the invasion and spread of M. micrantha and indicate the roles of adaptive loci and functional genes in invasive adaptation. Full article

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

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13 pages, 677 KiB

Open AccessArticle

Prediction of Parkinson’s Disease Risk Based on Genetic Profile and Established Risk Factors

by Paraskevi P. Chairta, Andreas Hadjisavvas, Andrea N. Georgiou, Maria A. Loizidou, Kristia Yiangou, Christiana A. Demetriou, Yiolanda P. Christou, Marios Pantziaris, Kyriaki Michailidou and Eleni Zamba-Papanicolaou

Genes 2021, 12(8), 1278; https://doi.org/10.3390/genes12081278 - 20 Aug 2021

Cited by 7 | Viewed by 3182

Abstract

Background: Parkinson’s disease (PD) is a neurodegenerative disorder, and literature suggests that genetics and lifestyle/environmental factors may play a key role in the triggering of the disease. This study aimed to evaluate the predictive performance of a 12-Single Nucleotide Polymorphisms (SNPs) polygenic risk [...] Read more.

Background: Parkinson’s disease (PD) is a neurodegenerative disorder, and literature suggests that genetics and lifestyle/environmental factors may play a key role in the triggering of the disease. This study aimed to evaluate the predictive performance of a 12-Single Nucleotide Polymorphisms (SNPs) polygenic risk score (PRS) in combination with already established PD-environmental/lifestyle factors. Methods: Genotypic and lifestyle/environmental data on 235 PD-patients and 464 controls were obtained from a previous study carried out in the Cypriot population. A PRS was calculated for each individual. Univariate logistic-regression analysis was used to assess the association of PRS and each risk factor with PD-status. Stepwise-regression analysis was used to select the best predictive model for PD combining genetic and lifestyle/environmental factors. Results: The 12-SNPs PRS was significantly increased in PD-cases compared to controls. Furthermore, univariate analyses showed that age, head injury, family history, depression, and Body Mass Index (BMI) were significantly associated with PD-status. Stepwise-regression suggested that a model which includes PRS and seven other independent lifestyle/environmental factors is the most predictive of PD in our population. Conclusions: These results suggest an association between both genetic and environmental factors and PD, and highlight the potential for the use of PRS in combination with the classical risk factors for risk prediction of PD. Full article

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

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19 pages, 1306 KiB

Open AccessArticle

Benefits of Exome Sequencing in Children with Suspected Isolated Hearing Loss

by Roxane Van Heurck, Maria Teresa Carminho-Rodrigues, Emmanuelle Ranza, Caterina Stafuzza, Lina Quteineh, Corinne Gehrig, Eva Hammar, Michel Guipponi, Marc Abramowicz, Pascal Senn, Nils Guinand, Helene Cao-Van and Ariane Paoloni-Giacobino

Genes 2021, 12(8), 1277; https://doi.org/10.3390/genes12081277 - 20 Aug 2021

Cited by 11 | Viewed by 3547

Abstract

Purpose: Hearing loss is characterized by an extensive genetic heterogeneity and remains a common disorder in children. Molecular diagnosis is of particular benefit in children, and permits the early identification of clinically-unrecognized hearing loss syndromes, which permits effective clinical management and follow-up, including [...] Read more.

Purpose: Hearing loss is characterized by an extensive genetic heterogeneity and remains a common disorder in children. Molecular diagnosis is of particular benefit in children, and permits the early identification of clinically-unrecognized hearing loss syndromes, which permits effective clinical management and follow-up, including genetic counselling. Methods: We performed whole-exome sequencing with the analysis of a panel of 189 genes associated with hearing loss in a prospective cohort of 61 children and 9 adults presenting mainly with isolated hearing loss. Results: The overall diagnostic rate using exome sequencing was 47.2% (52.5% in children; 22% in adults). In children with confirmed molecular results, 17/32 (53.2%) showed autosomal recessive inheritance patterns, 14/32 (43.75%) showed an autosomal dominant condition, and one case had X-linked hearing loss. In adults, the two patients showed an autosomal dominant inheritance pattern. Among the 32 children, 17 (53.1%) had nonsyndromic hearing loss and 15 (46.7%) had syndromic hearing loss. One adult was diagnosed with syndromic hearing loss and one with nonsyndromic hearing loss. The most common causative genes were STRC (5 cases), GJB2 (3 cases), COL11A1 (3 cases), and ACTG1 (3 cases). Conclusions: Exome sequencing has a high diagnostic yield in children with hearing loss and can reveal a syndromic hearing loss form before other organs/systems become involved, allowing the surveillance of unrecognized present and/or future complications associated with these syndromes. Full article

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

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12 pages, 1814 KiB

Open AccessArticle

Hypomethylation of AHRR (cg05575921) Is Related to Smoking Status in the Mexican Mestizo Population

by Omar Andrés Bravo-Gutiérrez, Ramcés Falfán-Valencia, Alejandra Ramírez-Venegas, Raúl H. Sansores, Rafael de Jesús Hernández-Zenteno, Andrea Hernández-Pérez, Leonor García-Gómez, Jennifer Osio-Echánove, Edgar Abarca-Rojano and Gloria Pérez-Rubio

Genes 2021, 12(8), 1276; https://doi.org/10.3390/genes12081276 - 20 Aug 2021

Cited by 3 | Viewed by 3579

Abstract

Tobacco smoking results in a multifactorial disease involving environmental and genetic factors; epigenome-wide association studies (EWAS) show changes in DNA methylation levels due to cigarette consumption, partially reversible upon tobacco smoking cessation. Therefore, methylation levels could predict smoking status. This study aimed to [...] Read more.

Tobacco smoking results in a multifactorial disease involving environmental and genetic factors; epigenome-wide association studies (EWAS) show changes in DNA methylation levels due to cigarette consumption, partially reversible upon tobacco smoking cessation. Therefore, methylation levels could predict smoking status. This study aimed to evaluate the DNA methylation level of cg05575921 (AHRR) and cg23771366 (PRSS23) and their correlation with lung function variables, cigarette consumption, and nicotine addiction in the Mexican smoking population. We included 114 non-smokers (NS) and 102 current tobacco smokers (TS); we then further subclassified them as heavy smokers (HS) (n = 53) and light smokers (LS) (n = 49). We used restriction enzymes (MspI/HpaII) and qPCR to determine the DNA methylation level. We observed significant hypomethylation of cg05575921 in smokers compared to NS (p = 0.003); further analysis found a difference between HS and NS (p = 0.02). We did not observe differences between other groups or a positive correlation between methylation levels and age, BMI, cigarette consumption, nicotine addiction, or lung function. In conclusion, the cg05575921 site of AHRR is significantly hypomethylated in Mexican smokers, especially in HS (≥20 cigarettes per day). Full article

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

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14 pages, 602 KiB

Open AccessArticle

A Case Series of Familial ARID1B Variants Illustrating Variable Expression and Suggestions to Update the ACMG Criteria

by Pleuntje J. van der Sluijs, Mariëlle Alders, Alexander J. M. Dingemans, Kareesma Parbhoo, Bregje W. van Bon, Jennifer C. Dempsey, Dan Doherty, Johan T. den Dunnen, Erica H. Gerkes, Ilana M. Milller, Stephanie Moortgat, Debra S. Regier, Claudia A. L. Ruivenkamp, Betsy Schmalz, Thomas Smol, Kyra E. Stuurman, Catherine Vincent-Delorme, Bert B. A. de Vries, Bekim Sadikovic, Scott E. Hickey, Jill A. Rosenfeld, Isabelle Maystadt and Gijs W. E. Santen Show full author list Hide full author list

Genes 2021, 12(8), 1275; https://doi.org/10.3390/genes12081275 - 20 Aug 2021

Cited by 8 | Viewed by 4962

Abstract

ARID1B is one of the most frequently mutated genes in intellectual disability (~1%). Most variants are readily classified, since they are de novo and are predicted to lead to loss of function, and therefore classified as pathogenic according to the American College of [...] Read more.

ARID1B is one of the most frequently mutated genes in intellectual disability (~1%). Most variants are readily classified, since they are de novo and are predicted to lead to loss of function, and therefore classified as pathogenic according to the American College of Medical Genetics and Genomics (ACMG) guidelines for the interpretation of sequence variants. However, familial loss-of-function variants can also occur and can be challenging to interpret. Such variants may be pathogenic with variable expression, causing only a mild phenotype in a parent. Alternatively, since some regions of the ARID1B gene seem to be lacking pathogenic variants, loss-of-function variants in those regions may not lead to ARID1B haploinsufficiency and may therefore be benign. We describe 12 families with potential loss-of-function variants, which were either familial or with unknown inheritance and were in regions where pathogenic variants have not been described or are otherwise challenging to interpret. We performed detailed clinical and DNA methylation studies, which allowed us to confidently classify most variants. In five families we observed transmission of pathogenic variants, confirming their highly variable expression. Our findings provide further evidence for an alternative translational start site and we suggest updates for the ACMG guidelines for the interpretation of sequence variants to incorporate DNA methylation studies and facial analyses. Full article

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

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20 pages, 5499 KiB

Open AccessArticle

Disparity of Hepatocellular Carcinoma in Tumor Microenvironment-Related Genes and Infiltrating Immune Cells between Asian and Non-Asian Populations

by Lien-Hung Huang, Ting-Min Hsieh, Chun-Ying Huang, Yueh-Wei Liu, Shao-Chun Wu, Peng-Chen Chien and Ching-Hua Hsieh

Genes 2021, 12(8), 1274; https://doi.org/10.3390/genes12081274 - 20 Aug 2021

Cited by 4 | Viewed by 2229

Abstract

Hepatocellular carcinoma (HCC) is the most common cause of primary liver cancer deaths worldwide. The major risk factors for liver cancer development are cirrhosis, hepatitis B virus (HBV), hepatitis C virus (HCV) infection, and chronic alcohol abuse. HCC displays heterogeneity in terms of [...] Read more.

Hepatocellular carcinoma (HCC) is the most common cause of primary liver cancer deaths worldwide. The major risk factors for liver cancer development are cirrhosis, hepatitis B virus (HBV), hepatitis C virus (HCV) infection, and chronic alcohol abuse. HCC displays heterogeneity in terms of biology, etiology, and epidemiology. In Southeast Asia and Africa, chronic HBV infection is a major risk factor for HCC, whereas chronic HCV infection is a risk factor for HCC in western countries and Japan. Environmental and genetic conditions also play a role in the regional and temporal variations in the incidence of HCC. In this study, we used the ESTIMATE (ESTIMATE, Estimation of stromal and immune cells in malignant tumor tissues using expression data) algorithm and the CIBERSOFT tool to analyze gene expression profiles and infiltrating immune cells in HCC between Asian and non-Asian patients. The results showed that stromal and immune scores were dependent on overall survival (OS) in non-Asian patients but not in Asian patients. Kaplan–Meier survival analysis revealed four differentially expressed genes (DEGs) that were significantly associated with OS in non-Asian patients only. CIBERSORT (CIBERSORT, Cell type identification by estimating relative subsets of known RNA transcripts) analysis indicated that the composition of infiltrating immune cells was significantly different between Asian and non-Asian patients. By parsing the subclasses of HCC, the ability to predict prognosis and guide therapeutic targets for potentially actionable HCC may be improved. Full article

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

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15 pages, 2401 KiB

Open AccessArticle

Uniparental Lineages from the Oldest Indigenous Population of Ecuador: The Tsachilas

by Tullia Di Corcia, Giuseppina Scano, Cristina Martínez-Labarga, Stefania Sarno, Sara De Fanti, Donata Luiselli and Olga Rickards

Genes 2021, 12(8), 1273; https://doi.org/10.3390/genes12081273 - 20 Aug 2021

Cited by 2 | Viewed by 3241

Abstract

Together with Cayapas, the Tsachilas constitute the oldest population in the country of Ecuador and, according to some historians, they are the last descendants of the ancient Yumbos. Several anthropological issues underlie the interest towards this peculiar population: the uncertainty of their origin, [...] Read more.

Together with Cayapas, the Tsachilas constitute the oldest population in the country of Ecuador and, according to some historians, they are the last descendants of the ancient Yumbos. Several anthropological issues underlie the interest towards this peculiar population: the uncertainty of their origin, their belonging to the Barbacoan linguistic family, which is still at the center of an intense linguistic debate, and the relations of their Yumbo ancestors with the Inca invaders who occupied their ancient territory. Our contribution to the knowledge of their complex past was the reconstruction of their genetic maternal and paternal inheritance through the sequencing of 70 entire mitochondrial genomes and the characterization of the non-recombinant region of the Y chromosome in 26 males. For both markers, we built comprehensive datasets of various populations from the surrounding geographical area, northwestern South America, NW, with a known linguistic affiliation, and we could then compare our sample against the overall variability to infer relationships with other Barbacoan people and with other NW natives. We found contrasting patterns of genetic diversity for the two markers, but generally, our results indicated a possible common origin between the Tsachilas, the Chachi, and other Ecuadorian and Colombian Barbacoans and are suggestive of an interesting ancient linkage to the Inca invaders in Yumbo country. Full article

(This article belongs to the Special Issue The Peopling of the Americas: A Genetic Perspective)

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10 pages, 1276 KiB

Open AccessReview

Alternative Splicing and Hypoxia Puzzle in Alzheimer’s and Parkinson’s Diseases

by Eglė Jakubauskienė and Arvydas Kanopka

Genes 2021, 12(8), 1272; https://doi.org/10.3390/genes12081272 - 20 Aug 2021

Cited by 9 | Viewed by 3959

Abstract

Alternative pre-mRNA splicing plays a very important role in expanding protein diversity as it generates numerous transcripts from a single protein-coding gene. Therefore, alterations lead this process to neurological human disorders, including Alzheimer’s and Parkinson’s diseases. Moreover, accumulating evidence indicates that the splicing [...] Read more.

Alternative pre-mRNA splicing plays a very important role in expanding protein diversity as it generates numerous transcripts from a single protein-coding gene. Therefore, alterations lead this process to neurological human disorders, including Alzheimer’s and Parkinson’s diseases. Moreover, accumulating evidence indicates that the splicing machinery highly contributes to the cells’ ability to adapt to different altered cellular microenvironments, such as hypoxia. Hypoxia is known to have an effect on the expression of proteins involved in a multiple of biological processes, such as erythropoiesis, angiogenesis, and neurogenesis, and is one of the important risk factors in neuropathogenesis. In this review, we discuss the current knowledge of alternatively spliced genes, which, as it is reported, are associated with Alzheimer’s and Parkinson’s diseases. Additionally, we highlight the possible influence of cellular hypoxic microenvironment for the formation of mRNA isoforms contributing to the development of these neurodegenerative diseases. Full article

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

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11 pages, 325 KiB

Open AccessArticle

Clinical Relevance of VEGFA (rs3025039) +936 C>T Polymorphism in Primary Myelofibrosis: Susceptibility, Clinical Co-Variates, and Outcomes

by Laura Villani, Adriana Carolei, Vittorio Rosti, Margherita Massa, Rita Campanelli, Paolo Catarsi, Carlotta Abbà, Robert Peter Gale and Giovanni Barosi

Genes 2021, 12(8), 1271; https://doi.org/10.3390/genes12081271 - 20 Aug 2021

Cited by 5 | Viewed by 2327

Abstract

We evaluated the association of VEGFA rs3025039 polymorphism with clinical co-variates and outcomes in 849 subjects with primary myelofibrosis (PMF) and 250 healthy controls. Minor T-allele frequency was higher in subjects with JAK2^V617F compared with those without JAK2^V617F (18% vs. 13%; [...] Read more.

We evaluated the association of VEGFA rs3025039 polymorphism with clinical co-variates and outcomes in 849 subjects with primary myelofibrosis (PMF) and 250 healthy controls. Minor T-allele frequency was higher in subjects with JAK2^V617F compared with those without JAK2^V617F (18% vs. 13%; p = 0.014). In subjects with JAK2^V617F, the TT genotype was associated at diagnosis with lower platelet concentrations (p = 0.033), higher plasma LDH concentration (p = 0.005), higher blood CD34-positive cells (p = 0.027), lower plasma cholesterol concentration (p = 0.046), and higher concentration of high-sensitivity C-reactive protein (p = 0.018). These associations were not found in subjects with PMF without JAK2^V617F. In subjects with the TT genotype, risk of death was higher compared with subjects with CC/CT genotypes (HR = 2.12 [1.03, 4.35], p = 0.041). Finally, the TT genotype was associated with higher frequency of deep vein thrombosis in typical sites (12.5% vs. 2.5%; OR = 5.46 [1.51, 19.7], p = 0.009). In conclusion, in subjects with PMF, the VEGFA rs3025039 CT or TT genotypes are more common in those with JAK2^V617F than in those without JAK2^V67F mutation and are associated with disease severity, poor prognosis, and risk of deep vein thrombosis. Full article

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

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21 pages, 1397 KiB

Open AccessReview

Complex Interactions in Regulation of Haematopoiesis—An Unexplored Iron Mine

by Ranita De, Kulkarni Uday Prakash and Eunice S. Edison

Genes 2021, 12(8), 1270; https://doi.org/10.3390/genes12081270 - 20 Aug 2021

Cited by 5 | Viewed by 2584

Abstract

Iron is one of the most abundant metals on earth and is vital for the growth and survival of life forms. It is crucial for the functioning of plants and animals as it is an integral component of the photosynthetic apparatus and innumerable [...] Read more.

Iron is one of the most abundant metals on earth and is vital for the growth and survival of life forms. It is crucial for the functioning of plants and animals as it is an integral component of the photosynthetic apparatus and innumerable proteins and enzymes. It plays a pivotal role in haematopoiesis and affects the development and differentiation of different haematopoietic lineages, apart from its obvious necessity in erythropoiesis. A large amount of iron stores in humans is diverted towards the latter process, as iron is an indispensable component of haemoglobin. This review summarises the important players of iron metabolism and homeostasis that have been discovered in recent years and highlights the overall significance of iron in haematopoiesis. Its role in maintenance of haematopoietic stem cells, influence on differentiation of varied haematopoietic lineages and consequences of iron deficiency/overloading on development and maturation of different groups of haematopoietic cells have been discussed. Full article

(This article belongs to the Special Issue Genetic Regulation in Iron Homeostasis)

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16 pages, 1259 KiB

Open AccessArticle

High-Throughput Sequencing to Identify Mutations Associated with Retinal Dystrophies

by Fei Song, Marta Owczarek-Lipska, Tim Ahmels, Marius Book, Sabine Aisenbrey, Moreno Menghini, Daniel Barthelmes, Stefan Schrader, Georg Spital and John Neidhardt

Genes 2021, 12(8), 1269; https://doi.org/10.3390/genes12081269 - 20 Aug 2021

Cited by 3 | Viewed by 2776

Abstract

Retinal dystrophies (RD) are clinically and genetically heterogenous disorders showing mutations in over 270 disease-associated genes. Several millions of people worldwide are affected with different types of RD. Studying the relevance of disease-associated sequence alterations will assist in understanding disorders and may lead [...] Read more.

Retinal dystrophies (RD) are clinically and genetically heterogenous disorders showing mutations in over 270 disease-associated genes. Several millions of people worldwide are affected with different types of RD. Studying the relevance of disease-associated sequence alterations will assist in understanding disorders and may lead to the development of therapeutic approaches. Here, we established a whole exome sequencing (WES) pipeline to rapidly identify disease-associated mutations in patients. Sanger sequencing was applied to identify deep-intronic variants and to verify the co-segregation of WES results within families. We analyzed 26 unrelated patients with different syndromic and non-syndromic clinical manifestations of RD. All patients underwent ophthalmic examinations. We identified nine novel disease-associated sequence variants among 37 variants identified in total. The sequence variants located to 17 different genes. Interestingly, two cases presenting with Stargardt disease carried deep-intronic variants in ABCA4. We have classified 21 variants as pathogenic variants, 4 as benign/likely benign variants, and 12 as variants of uncertain significance. This study highlights the importance of WES-based mutation analyses in RD patients supporting clinical decisions, broadly based genetic diagnosis and support genetic counselling. It is essential for any genetic therapy to expand the mutation spectrum, understand the genes’ function, and correlate phenotypes with genotypes. Full article

(This article belongs to the Special Issue Genetics in Inherited Retinal Diseases)

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6 pages, 454 KiB

Open AccessArticle

Variants Affecting the C-Terminal Tail of UNC93B1 Are Not a Common Risk Factor for Systemic Lupus Erythematosus

by Sarah Kiener, Camillo Ribi, Irene Keller, Carlo Chizzolini, Marten Trendelenburg, Uyen Huynh-Do, Johannes von Kempis, on behalf of Swiss SLE Cohort Study (SSCS) and Tosso Leeb

Genes 2021, 12(8), 1268; https://doi.org/10.3390/genes12081268 - 19 Aug 2021

Viewed by 2350

Abstract

Systemic lupus erythematosus (SLE) is a heterogeneous multifactorial disease. Upregulated TLR7 signaling is a known risk factor for SLE. Recently, it was shown that specific genetic variants in UNC93B1 affect the physiological regulation of TLR7 signaling and cause characteristic autoimmune phenotypes with monogenic [...] Read more.

Systemic lupus erythematosus (SLE) is a heterogeneous multifactorial disease. Upregulated TLR7 signaling is a known risk factor for SLE. Recently, it was shown that specific genetic variants in UNC93B1 affect the physiological regulation of TLR7 signaling and cause characteristic autoimmune phenotypes with monogenic autosomal recessive inheritance in mutant mice and dogs. We therefore hypothesized that homologous variants in the human UNC93B1 gene might be responsible for a fraction of human SLE patients. We analyzed 536 patients of the Swiss SLE Cohort Study for the presence of genetic variants affecting the C-terminal tail of UNC93B1. None of the investigated patients carried bi-allelic UNC93B1 variants that were likely to explain their SLE phenotypes. We conclude that genetic variants affecting the C-terminal tail of UNC93B1 are not a common risk factor for SLE. It cannot be excluded that such variants might contribute to other heritable autoimmune diseases. Full article

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

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14 pages, 4191 KiB

Open AccessArticle

Whole-Genome Sequencing Improves the Diagnosis of DFNB1 Monoallelic Patients

by Anaïs Le Nabec, Mégane Collobert, Cédric Le Maréchal, Rémi Marianowski, Claude Férec and Stéphanie Moisan

Genes 2021, 12(8), 1267; https://doi.org/10.3390/genes12081267 - 19 Aug 2021

Cited by 5 | Viewed by 3189

Abstract

Hearing loss is the most common sensory defect, due in most cases to a genetic origin. Variants in the GJB2 gene are responsible for up to 30% of non-syndromic hearing loss. Today, several deafness genotypes remain incomplete, confronting us with a diagnostic deadlock. [...] Read more.

Hearing loss is the most common sensory defect, due in most cases to a genetic origin. Variants in the GJB2 gene are responsible for up to 30% of non-syndromic hearing loss. Today, several deafness genotypes remain incomplete, confronting us with a diagnostic deadlock. In this study, whole-genome sequencing (WGS) was performed on 10 DFNB1 patients with incomplete genotypes. New variations on GJB2 were identified for four patients. Functional assays were realized to explore the function of one of them in the GJB2 promoter and confirm its impact on GJB2 expression. Thus, in this study WGS resolved patient genotypes, thus unlocking diagnosis. WGS afforded progress and bridged some gaps in our research. Full article

(This article belongs to the Collection Genotype-Phenotype Study in Disease)

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21 pages, 28704 KiB

Open AccessReview

Zona Pellucida Genes and Proteins: Essential Players in Mammalian Oogenesis and Fertility

by Paul M. Wassarman and Eveline S. Litscher

Genes 2021, 12(8), 1266; https://doi.org/10.3390/genes12081266 - 19 Aug 2021

Cited by 33 | Viewed by 10140

Abstract

All mammalian oocytes and eggs are surrounded by a relatively thick extracellular matrix (ECM), the zona pellucida (ZP), that plays vital roles during oogenesis, fertilization, and preimplantation development. Unlike ECM surrounding somatic cells, the ZP is composed of only a few glycosylated proteins, [...] Read more.

All mammalian oocytes and eggs are surrounded by a relatively thick extracellular matrix (ECM), the zona pellucida (ZP), that plays vital roles during oogenesis, fertilization, and preimplantation development. Unlike ECM surrounding somatic cells, the ZP is composed of only a few glycosylated proteins, ZP1–4, that are unique to oocytes and eggs. ZP1–4 have a large region of polypeptide, the ZP domain (ZPD), consisting of two subdomains, ZP-N and ZP-C, separated by a short linker region, that plays an essential role in polymerization of nascent ZP proteins into crosslinked fibrils. Both subdomains adopt immunoglobulin (Ig)-like folds for their 3-dimensional structure. Mouse and human ZP genes are encoded by single-copy genes located on different chromosomes and are highly expressed in the ovary by growing oocytes during late stages of oogenesis. Genes encoding ZP proteins are conserved among mammals, and their expression is regulated by cis-acting sequences located close to the transcription start-site and by the same/similar trans-acting factors. Nascent ZP proteins are synthesized, packaged into vesicles, secreted into the extracellular space, and assembled into long, crosslinked fibrils that have a structural repeat, a ZP2-ZP3 dimer, and constitute the ZP matrix. Fibrils are oriented differently with respect to the oolemma in the inner and outer layers of the ZP. Sequence elements in the ZPD and the carboxy-terminal propeptide of ZP1–4 regulate secretion and assembly of nascent ZP proteins. The presence of both ZP2 and ZP3 is required to assemble ZP fibrils and ZP1 and ZP4 are used to crosslink the fibrils. Inactivation of mouse ZP genes by gene targeting has a detrimental effect on ZP formation around growing oocytes and female fertility. Gene sequence variations in human ZP genes due to point, missense, or frameshift mutations also have a detrimental effect on ZP formation and female fertility. The latter mutations provide additional support for the role of ZPD subdomains and other regions of ZP polypeptide in polymerization of human ZP proteins into fibrils and matrix. Full article

(This article belongs to the Special Issue Genetic and Genomic Regulation of Ovarian and Testicular Functions in Animals)

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15 pages, 2130 KiB

Open AccessArticle

Whole Genome Sequencing Reveals Multiple Linked Genetic Variants on Canine Chromosome 12 Associated with Risk for Symmetrical Lupoid Onychodystrophy (SLO) in the Bearded Collie

by Liza C. Gershony, Janelle M. Belanger, Marjo K. Hytönen, Hannes Lohi and Anita M. Oberbauer

Genes 2021, 12(8), 1265; https://doi.org/10.3390/genes12081265 - 19 Aug 2021

Cited by 4 | Viewed by 4827

Abstract

In dogs, symmetrical lupoid onychodystrophy (SLO) results in nail loss and an abnormal regrowth of the claws. In Bearded Collies, an autoimmune nature has been suggested because certain dog leukocyte antigen (DLA) class II haplotypes are associated with the condition. A genome-wide association [...] Read more.

In dogs, symmetrical lupoid onychodystrophy (SLO) results in nail loss and an abnormal regrowth of the claws. In Bearded Collies, an autoimmune nature has been suggested because certain dog leukocyte antigen (DLA) class II haplotypes are associated with the condition. A genome-wide association study of the Bearded Collie revealed two regions of association that conferred risk for disease: one on canine chromosome (CFA) 12 that encompasses the DLA genes, and one on CFA17. Case-control association was employed on whole genome sequencing data to uncover putative causative variants in SLO within the CFA12 and CFA17 associated regions. Genotype imputation was then employed to refine variants of interest. Although no SLO-associated protein-coding variants were identified on CFA17, multiple variants, many with predicted damaging effects, were identified within potential candidate genes on CFA12. Furthermore, many potentially damaging alleles were fully correlated with the presence of DLA class II risk haplotypes for SLO, suggesting that the variants may reflect DLA class II haplotype association with disease or vice versa. Strong linkage disequilibrium in the region precluded the ability to isolate and assess the individual or combined effect of variants on disease development. Nonetheless, all were predictive of risk for SLO and, with judicious assessment, their application in selective breeding may prove useful to reduce the incidence of SLO in the breed. Full article

(This article belongs to the Special Issue Canine Genetics 2)

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16 pages, 5040 KiB

Open AccessArticle

In Utero Fetal Weight in Pigs Is Regulated by microRNAs and Their Target Genes

by Asghar Ali, Eduard Murani, Frieder Hadlich, Xuan Liu, Klaus Wimmers and Siriluck Ponsuksili

Genes 2021, 12(8), 1264; https://doi.org/10.3390/genes12081264 - 19 Aug 2021

Cited by 8 | Viewed by 2578

Abstract

Impaired skeletal muscle growth in utero can result in reduced birth weight and poor carcass quality in pigs. Recently, we showed the role of microRNAs (miRNAs) and their target genes in prenatal skeletal muscle development and pathogenesis of intrauterine growth restriction (IUGR). In [...] Read more.

Impaired skeletal muscle growth in utero can result in reduced birth weight and poor carcass quality in pigs. Recently, we showed the role of microRNAs (miRNAs) and their target genes in prenatal skeletal muscle development and pathogenesis of intrauterine growth restriction (IUGR). In this study, we performed an integrative miRNA-mRNA transcriptomic analysis in longissimus dorsi muscle (LDM) of pig fetuses at 63 days post conception (dpc) to identify miRNAs and genes correlated to fetal weight. We found 13 miRNAs in LDM significantly correlated to fetal weight, including miR-140, miR-186, miR-101, miR-15, miR-24, miR-29, miR-449, miR-27, miR-142, miR-99, miR-181, miR-199, and miR-210. The expression of these miRNAs decreased with an increase in fetal weight. We also identified 1315 genes significantly correlated to fetal weight at 63 dpc, of which 135 genes were negatively correlated as well as identified as potential targets of the above-listed 13 miRNAs. These miRNAs and their target genes enriched pathways and biological processes important for fetal growth, development, and metabolism. These results indicate that the transcriptomic profile of skeletal muscle can be used to predict fetal weight, and miRNAs correlated to fetal weight can serve as potential biomarkers of prenatal fetal health and growth. Full article

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

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27 pages, 1095 KiB

Open AccessReview

Epigenetic Regulation of Circadian Clocks and Its Involvement in Drug Addiction

by Lamis Saad, Jean Zwiller, Andries Kalsbeek and Patrick Anglard

Genes 2021, 12(8), 1263; https://doi.org/10.3390/genes12081263 - 19 Aug 2021

Cited by 11 | Viewed by 5707

Abstract

Based on studies describing an increased prevalence of addictive behaviours in several rare sleep disorders and shift workers, a relationship between circadian rhythms and addiction has been hinted for more than a decade. Although circadian rhythm alterations and molecular mechanisms associated with neuropsychiatric [...] Read more.

Based on studies describing an increased prevalence of addictive behaviours in several rare sleep disorders and shift workers, a relationship between circadian rhythms and addiction has been hinted for more than a decade. Although circadian rhythm alterations and molecular mechanisms associated with neuropsychiatric conditions are an area of active investigation, success is limited so far, and further investigations are required. Thus, even though compelling evidence connects the circadian clock to addictive behaviour and vice-versa, yet the functional mechanism behind this interaction remains largely unknown. At the molecular level, multiple mechanisms have been proposed to link the circadian timing system to addiction. The molecular mechanism of the circadian clock consists of a transcriptional/translational feedback system, with several regulatory loops, that are also intricately regulated at the epigenetic level. Interestingly, the epigenetic landscape shows profound changes in the addictive brain, with significant alterations in histone modification, DNA methylation, and small regulatory RNAs. The combination of these two observations raises the possibility that epigenetic regulation is a common plot linking the circadian clocks with addiction, though very little evidence has been reported to date. This review provides an elaborate overview of the circadian system and its involvement in addiction, and we hypothesise a possible connection at the epigenetic level that could further link them. Therefore, we think this review may further improve our understanding of the etiology or/and pathology of psychiatric disorders related to drug addiction. Full article

(This article belongs to the Special Issue Gene Expression and Chromatin Modification in the Brain)

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