Genes

17 pages, 5296 KiB

Open AccessArticle

TCGA Pan-Cancer Genomic Analysis of Alternative Lengthening of Telomeres (ALT) Related Genes

by Isaac Armendáriz-Castillo, Andrés López-Cortés, Jennyfer García-Cárdenas, Patricia Guevara-Ramírez, Paola E. Leone, Andy Pérez-Villa, Verónica Yumiceba, Ana K. Zambrano, Santiago Guerrero and César Paz-y-Miño

Genes 2020, 11(7), 834; https://doi.org/10.3390/genes11070834 - 21 Jul 2020

Cited by 9 | Viewed by 4875

Abstract

Telomere maintenance mechanisms (TMM) are used by cancer cells to avoid apoptosis, 85–90% reactivate telomerase, while 10–15% use the alternative lengthening of telomeres (ALT). Due to anti-telomerase-based treatments, some tumors switch from a telomerase-dependent mechanism to ALT; in fact, the co-existence between both [...] Read more.

Telomere maintenance mechanisms (TMM) are used by cancer cells to avoid apoptosis, 85–90% reactivate telomerase, while 10–15% use the alternative lengthening of telomeres (ALT). Due to anti-telomerase-based treatments, some tumors switch from a telomerase-dependent mechanism to ALT; in fact, the co-existence between both mechanisms has been observed in some cancers. Although different elements in the ALT pathway are uncovered, some molecular mechanisms are still poorly understood. Therefore, with the aim to identify potential molecular markers for the study of ALT, we combined in silico approaches in a 411 telomere maintenance gene set. As a consequence, we conducted a genomic analysis of these genes in 31 Pan-Cancer Atlas studies from The Cancer Genome Atlas and found 325,936 genomic alterations; from which, we identified 20 genes highly mutated in the cancer studies. Finally, we made a protein-protein interaction network and enrichment analysis to observe the main pathways of these genes and discuss their role in ALT-related processes, like homologous recombination and homology directed repair. Overall, due to the lack of understanding of the molecular mechanisms of ALT cancers, we proposed a group of genes, which after ex vivo validations, could represent new potential therapeutic markers in the study of ALT. Full article

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

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17 pages, 861 KiB

Open AccessArticle

High Rates of Three Common GJB2 Mutations c.516G>C, c.-23+1G>A, c.235delC in Deaf Patients from Southern Siberia Are Due to the Founder Effect

by Marina V. Zytsar, Marita S. Bady-Khoo, Valeriia Yu. Danilchenko, Ekaterina A. Maslova, Nikolay A. Barashkov, Igor V. Morozov, Alexander A. Bondar and Olga L. Posukh

Genes 2020, 11(7), 833; https://doi.org/10.3390/genes11070833 - 21 Jul 2020

Cited by 12 | Viewed by 4358

Abstract

The mutations in the GJB2 gene (13q12.11, MIM 121011) encoding transmembrane protein connexin 26 (Cx26) account for a significant portion of hereditary hearing loss worldwide. Earlier we found a high prevalence of recessive GJB2 mutations c.516G>C, c.-23+1G>A, c.235delC in indigenous Turkic-speaking Siberian peoples [...] Read more.

The mutations in the GJB2 gene (13q12.11, MIM 121011) encoding transmembrane protein connexin 26 (Cx26) account for a significant portion of hereditary hearing loss worldwide. Earlier we found a high prevalence of recessive GJB2 mutations c.516G>C, c.-23+1G>A, c.235delC in indigenous Turkic-speaking Siberian peoples (Tuvinians and Altaians) from the Tyva Republic and Altai Republic (Southern Siberia, Russia) and proposed the founder effect as a cause for their high rates in these populations. To reconstruct the haplotypes associated with each of these mutations, the genotyping of polymorphic genetic markers both within and flanking the GJB2 gene was performed in 28 unrelated individuals homozygous for c.516G>C (n = 18), c.-23+1G>A (n = 6), or c.235delC (n = 4) as well as in the ethnically matched controls (62 Tuvinians and 55 Altaians) without these mutations. The common haplotypes specific for mutations c.516G>C, c.-23+1G>A, or c.235delC were revealed implying a single origin of each of these mutations. The age of mutations estimated by the DMLE+ v2.3 software and the single marker method is discussed in relation to ethnic history of Tuvinians and Altaians. The data obtained in this study support a crucial role of the founder effect in the high prevalence of GJB2 mutations c.516G>C, c.-23+1G>A, c.235delC in indigenous populations of Southern Siberia. Full article

(This article belongs to the Special Issue Genetics of Hearing Impairment)

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14 pages, 7538 KiB

Open AccessArticle

Deciphering the Impact of a Bacterial Infection on Meiotic Recombination in Arabidopsis with Fluorescence Tagged Lines

by Ariane Gratias and Valérie Geffroy

Genes 2020, 11(7), 832; https://doi.org/10.3390/genes11070832 - 21 Jul 2020

Cited by 1 | Viewed by 3010

Abstract

Plants are under strong evolutionary pressure to maintain surveillance against pathogens. One major disease resistance mechanism is based on NB-LRR (NLR) proteins that specifically recognize pathogen effectors. The cluster organization of the NLR gene family could favor sequence exchange between NLR genes via [...] Read more.

Plants are under strong evolutionary pressure to maintain surveillance against pathogens. One major disease resistance mechanism is based on NB-LRR (NLR) proteins that specifically recognize pathogen effectors. The cluster organization of the NLR gene family could favor sequence exchange between NLR genes via recombination, favoring their evolutionary dynamics. Increasing data, based on progeny analysis, suggest the existence of a link between the perception of biotic stress and the production of genetic diversity in the offspring. This could be driven by an increased rate of meiotic recombination in infected plants, but this has never been strictly demonstrated. In order to test if pathogen infection can increase DNA recombination in pollen meiotic cells, we infected Arabidopsis Fluorescent Tagged Lines (FTL) with the virulent bacteria Pseudomonas syringae. We measured the meiotic recombination rate in two regions of chromosome 5, containing or not an NLR gene cluster. In all tested intervals, no significant difference in genetic recombination frequency between infected and control plants was observed. Although it has been reported that pathogen exposure can sometimes increase the frequency of recombinant progeny in plants, our findings suggest that meiotic recombination rate in Arabidopsis may be resilient to at least some pathogen attack. Alternative mechanisms are discussed. Full article

(This article belongs to the Special Issue NLR Gene Evolution in Plants)

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33 pages, 6934 KiB

Open AccessFeature PaperArticle

Computational Analysis of the Global Effects of Ly6E in the Immune Response to Coronavirus Infection Using Gene Networks

by Fernando M. Delgado-Chaves, Francisco Gómez-Vela, Federico Divina, Miguel García-Torres and Domingo S. Rodriguez-Baena

Genes 2020, 11(7), 831; https://doi.org/10.3390/genes11070831 - 21 Jul 2020

Cited by 11 | Viewed by 4578

Abstract

Gene networks have arisen as a promising tool in the comprehensive modeling and analysis of complex diseases. Particularly in viral infections, the understanding of the host-pathogen mechanisms, and the immune response to these, is considered a major goal for the rational design of [...] Read more.

Gene networks have arisen as a promising tool in the comprehensive modeling and analysis of complex diseases. Particularly in viral infections, the understanding of the host-pathogen mechanisms, and the immune response to these, is considered a major goal for the rational design of appropriate therapies. For this reason, the use of gene networks may well encourage therapy-associated research in the context of the coronavirus pandemic, orchestrating experimental scrutiny and reducing costs. In this work, gene co-expression networks were reconstructed from RNA-Seq expression data with the aim of analyzing the time-resolved effects of gene Ly6E in the immune response against the coronavirus responsible for murine hepatitis (MHV). Through the integration of differential expression analyses and reconstructed networks exploration, significant differences in the immune response to virus were observed in Ly6E

^{Δ H S C}

compared to wild type animals. Results show that Ly6E ablation at hematopoietic stem cells (HSCs) leads to a progressive impaired immune response in both liver and spleen. Specifically, depletion of the normal leukocyte mediated immunity and chemokine signaling is observed in the liver of Ly6E

^{Δ H S C}

mice. On the other hand, the immune response in the spleen, which seemed to be mediated by an intense chromatin activity in the normal situation, is replaced by ECM remodeling in Ly6E

^{Δ H S C}

mice. These findings, which require further experimental characterization, could be extrapolated to other coronaviruses and motivate the efforts towards novel antiviral approaches. Full article

(This article belongs to the Special Issue Computational Methods for the Analysis of Genomic Data and Biological Processes)

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11 pages, 2419 KiB

Open AccessArticle

Identification of High Molecular Variation Loci in Complete Chloroplast Genomes of Mammillaria (Cactaceae, Caryophyllales)

by Delil A. Chincoya, Alejandro Sanchez-Flores, Karel Estrada, Clara E. Díaz-Velásquez, Antonio González-Rodríguez, Felipe Vaca-Paniagua, Patricia Dávila, Salvador Arias and Sofía Solórzano

Genes 2020, 11(7), 830; https://doi.org/10.3390/genes11070830 - 21 Jul 2020

Cited by 9 | Viewed by 3291

Abstract

In plants, partial DNA sequences of chloroplasts have been widely used in evolutionary studies. However, the Cactaceae family (1500–1800 species) lacks molecular markers that allow a phylogenetic resolution between species and genera. In order to identify sequences with high variation levels, we compared [...] Read more.

In plants, partial DNA sequences of chloroplasts have been widely used in evolutionary studies. However, the Cactaceae family (1500–1800 species) lacks molecular markers that allow a phylogenetic resolution between species and genera. In order to identify sequences with high variation levels, we compared previously reported complete chloroplast genomes of seven species of Mammillaria. We identified repeated sequences (RSs) and two types of DNA variation: short sequence repeats (SSRs) and divergent homologous loci. The species with the highest number of RSs was M. solisioides (256), whereas M. pectinifera contained the highest amount of SSRs (84). In contrast, M. zephyranthoides contained the lowest number (35) of both RSs and SSRs. In addition, five of the SSRs were found in the seven species, but only three of them showed variation. A total of 180 homologous loci were identified among the seven species. Out of these, 20 loci showed a molecular variation of 5% to 31%, and 12 had a length within the range of 150 to 1000 bp. We conclude that the high levels of variation at the reported loci represent valuable knowledge that may help to resolve phylogenetic relationships and that may potentially be convenient as molecular markers for population genetics and phylogeographic studies. Full article

(This article belongs to the Special Issue Molecular Evolutionary and Comparative Genomics Analyses in Plants)

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25 pages, 1061 KiB

Open AccessReview

The Effects of Genetic and Epigenetic Alterations of BARD1 on the Development of Non-Breast and Non-Gynecological Cancers

by Andrea K. Watters, Emily S. Seltzer, Danny MacKenzie, Jr., Melody Young, Jonathan Muratori, Rama Hussein, Andrej M. Sodoma, Julie To, Manrose Singh and Dong Zhang

Genes 2020, 11(7), 829; https://doi.org/10.3390/genes11070829 - 21 Jul 2020

Cited by 14 | Viewed by 4549

Abstract

Breast Cancer 1 (BRCA1) gene is a well-characterized tumor suppressor gene, mutations of which are primarily found in women with breast and ovarian cancers. BRCA1-associated RING domain 1 (BARD1) gene has also been identified as an important tumor suppressor [...] Read more.

Breast Cancer 1 (BRCA1) gene is a well-characterized tumor suppressor gene, mutations of which are primarily found in women with breast and ovarian cancers. BRCA1-associated RING domain 1 (BARD1) gene has also been identified as an important tumor suppressor gene in breast, ovarian, and uterine cancers. Underscoring the functional significance of the BRCA1 and BARD1 interactions, prevalent mutations in the BRCA1 gene are found in its RING domain, through which it binds the RING domain of BARD1. BARD1-BRCA1 heterodimer plays a crucial role in a variety of DNA damage response (DDR) pathways, including DNA damage checkpoint and homologous recombination (HR). However, many mutations in both BARD1 and BRCA1 also exist in other domains that significantly affect their biological functions. Intriguingly, recent genome-wide studies have identified various single nucleotide polymorphisms (SNPs), genetic alterations, and epigenetic modifications in or near the BARD1 gene that manifested profound effects on tumorigenesis in a variety of non-breast and non-gynecological cancers. In this review, we will briefly discuss the molecular functions of BARD1, including its BRCA1-dependent as well as BRCA1-independent functions. We will then focus on evaluating the common BARD1 related SNPs as well as genetic and epigenetic changes that occur in the non-BRCA1-dominant cancers, including neuroblastoma, lung, and gastrointestinal cancers. Furthermore, the pro- and anti-tumorigenic functions of different SNPs and BARD1 variants will also be discussed. Full article

(This article belongs to the Special Issue BARD1 in Cancer)

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17 pages, 3043 KiB

Open AccessArticle

Flavonoids as Potential Drugs for VPS13-Dependent Rare Neurodegenerative Diseases

by Piotr Soczewka, Krzysztof Flis, Déborah Tribouillard-Tanvier, Jean-Paul di Rago, Cláudia N. Santos, Regina Menezes, Joanna Kaminska and Teresa Zoladek

Genes 2020, 11(7), 828; https://doi.org/10.3390/genes11070828 - 21 Jul 2020

Cited by 12 | Viewed by 3498

Abstract

Several rare neurodegenerative diseases, including chorea acanthocytosis, are caused by mutations in the VPS13A–D genes. Only symptomatic treatments for these diseases are available. Saccharomyces cerevisiae contains a unique VPS13 gene and the yeast vps13Δ mutant has been proven as a [...] Read more.

Several rare neurodegenerative diseases, including chorea acanthocytosis, are caused by mutations in the VPS13A–D genes. Only symptomatic treatments for these diseases are available. Saccharomyces cerevisiae contains a unique VPS13 gene and the yeast vps13Δ mutant has been proven as a suitable model for drug tests. A library of drugs and an in-house library of natural compounds and their derivatives were screened for molecules preventing the growth defect of vps13Δ cells on medium with sodium dodecyl sulfate (SDS). Seven polyphenols, including the iron-binding flavone luteolin, were identified. The structure–activity relationship and molecular mechanisms underlying the action of luteolin were characterized. The FET4 gene, which encodes an iron transporter, was found to be a multicopy suppressor of vps13Δ, pointing out the importance of iron in response to SDS stress. The growth defect of vps13Δ in SDS-supplemented medium was also alleviated by the addition of iron salts. Suppression did not involve cell antioxidant responses, as chemical antioxidants were not active. Our findings support that luteolin and iron may target the same cellular process, possibly the synthesis of sphingolipids. Unveiling the mechanisms of action of chemical and genetic suppressors of vps13Δ may help to better understand VPS13A–D-dependent pathogenesis and to develop novel therapeutic strategies. Full article

(This article belongs to the Special Issue Genetic Aspects of Yeast: Cell Biology, Ecology and Biotechnology)

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27 pages, 3639 KiB

Open AccessReview

Consequence of Paradigm Shift with Repeat Landscapes in Reptiles: Powerful Facilitators of Chromosomal Rearrangements for Diversity and Evolution

by Syed Farhan Ahmad, Worapong Singchat, Maryam Jehangir, Thitipong Panthum and Kornsorn Srikulnath

Genes 2020, 11(7), 827; https://doi.org/10.3390/genes11070827 - 21 Jul 2020

Cited by 29 | Viewed by 5696

Abstract

Reptiles are notable for the extensive genomic diversity and species richness among amniote classes, but there is nevertheless a need for detailed genome-scale studies. Although the monophyletic amniotes have recently been a focus of attention through an increasing number of genome sequencing projects, [...] Read more.

Reptiles are notable for the extensive genomic diversity and species richness among amniote classes, but there is nevertheless a need for detailed genome-scale studies. Although the monophyletic amniotes have recently been a focus of attention through an increasing number of genome sequencing projects, the abundant repetitive portion of the genome, termed the “repeatome”, remains poorly understood across different lineages. Consisting predominantly of transposable elements or mobile and satellite sequences, these repeat elements are considered crucial in causing chromosomal rearrangements that lead to genomic diversity and evolution. Here, we propose major repeat landscapes in representative reptilian species, highlighting their evolutionary dynamics and role in mediating chromosomal rearrangements. Distinct karyotype variability, which is typically a conspicuous feature of reptile genomes, is discussed, with a particular focus on rearrangements correlated with evolutionary reorganization of micro- and macrochromosomes and sex chromosomes. The exceptional karyotype variation and extreme genomic diversity of reptiles are used to test several hypotheses concerning genomic structure, function, and evolution. Full article

(This article belongs to the Special Issue Causes and Consequences of Chromosomal Aberrations)

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15 pages, 917 KiB

Open AccessArticle

Major QTLs for Trunk Height and Correlated Agronomic Traits Provide Insights into Multiple Trait Integration in Oil Palm Breeding

by Chee-Keng Teh, Ai-Ling Ong, Sean Mayes, Festo Massawe and David Ross Appleton

Genes 2020, 11(7), 826; https://doi.org/10.3390/genes11070826 - 21 Jul 2020

Cited by 13 | Viewed by 4168

Abstract

Superior oil yield is always the top priority of the oil palm industry. Short trunk height (THT) and compactness traits have become increasingly important to improve harvesting efficiency since the industry started to suffer yield losses due to labor shortages. Breeding populations with [...] Read more.

Superior oil yield is always the top priority of the oil palm industry. Short trunk height (THT) and compactness traits have become increasingly important to improve harvesting efficiency since the industry started to suffer yield losses due to labor shortages. Breeding populations with low THT and short frond length (FL) are actually available, such as Dumpy AVROS pisifera (DAV) and Gunung Melayu dura (GM). However, multiple trait stacking still remains a challenge for oil palm breeding, which usually requires 12–20 years to complete a breeding cycle. In this study, yield and height increment in the GM × GM (GM-3341) and the GM × DAV (GM-DAV-3461) crossing programs were evaluated and palms with good yield and smaller height increment were identified. In the GM-3341 family, non-linear THT growth between THT_2008 (seven years old) and THT_2014 (13 years old) was revealed by a moderate correlation, suggesting that inter-palm competition becomes increasingly important. In total, 19 quantitative trait loci (QTLs) for THT_2008 (8), oil per palm (O/P) (7) and FL (4) were localized on the GM-3341 linkage map, with an average mapping interval of 2.01 cM. Three major QTLs for THT_2008, O/P and FL are co-located on chromosome 11 and reflect the correlation of THT_2008 with O/P and FL. Multiple trait selection for high O/P and low THT (based on the cumulative effects of positive alleles per trait) identified one palm from 100 palms, but with a large starting population of 1000–1500 seedling per cross, this low frequency could be easily compensated for during breeding selection. Full article

(This article belongs to the Special Issue Selection Methods in Plant Breeding: From Visual Phenotyping to NGS)

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11 pages, 645 KiB

Open AccessReview

The Role of BMI1 in Late-Onset Sporadic Alzheimer’s Disease

by Ryan Hogan, Anthony Flamier, Eleonora Nardini and Gilbert Bernier

Genes 2020, 11(7), 825; https://doi.org/10.3390/genes11070825 - 21 Jul 2020

Cited by 6 | Viewed by 4163

Abstract

Late-onset sporadic Alzheimer’s disease (LOAD) seems to contain a “hidden” component that cannot be explained by classical Mendelian genetics, with advanced aging being the strongest risk factor. More surprisingly, whole genome sequencing analyses of early-onset sporadic Alzheimer’s disease cohorts also revealed that most [...] Read more.

Late-onset sporadic Alzheimer’s disease (LOAD) seems to contain a “hidden” component that cannot be explained by classical Mendelian genetics, with advanced aging being the strongest risk factor. More surprisingly, whole genome sequencing analyses of early-onset sporadic Alzheimer’s disease cohorts also revealed that most patients do not present classical disease-associated variants or mutations. In this short review, we propose that BMI1 is possibly epigenetically silenced in LOAD. Reduced BMI1 expression is unique to LOAD compared to familial early-onset AD (EOAD) and other related neurodegenerative disorders; moreover, reduced expression of this single gene is sufficient to reproduce most LOAD pathologies in cellular and animal models. We also show the apparent amyloid and Tau-independent nature of this epigenetic alteration of BMI1 expression. Lastly, examples of the mechanisms underlying epigenetic dysregulation of other LOAD-related genes are also illustrated. Full article

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

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8 pages, 1359 KiB

Open AccessBrief Report

P14^ARF: The Absence that Makes the Difference

by Danilo Cilluffo, Viviana Barra and Aldo Di Leonardo

Genes 2020, 11(7), 824; https://doi.org/10.3390/genes11070824 - 20 Jul 2020

Cited by 15 | Viewed by 4900

Abstract

P14^ARF is a tumor suppressor encoded by the CDKN2a locus that is frequently inactivated in human tumors. P14^ARF protein quenches oncogene stimuli by inhibiting cell cycle progression and inducing apoptosis. P14^ARF functions can be played through interactions with several proteins. [...] Read more.

P14^ARF is a tumor suppressor encoded by the CDKN2a locus that is frequently inactivated in human tumors. P14^ARF protein quenches oncogene stimuli by inhibiting cell cycle progression and inducing apoptosis. P14^ARF functions can be played through interactions with several proteins. However, the majority of its activities are notoriously mediated by the p53 protein. Interestingly, recent studies suggest a new role of p14^ARF in the maintenance of chromosome stability. Here, we deepened this new facet of p14^ARF which we believe is relevant to its tumor suppressive role in the cell. To this aim, we generated a monoclonal HCT116 cell line expressing the p14^ARF cDNA cloned in the piggyback vector and then induced aneuploidy by treating HCT116 cells with the CENP-E inhibitor GSK923295. P14^ARF ectopic re-expression restored the near-diploid phenotype of HCT116 cells, confirming that p14^ARF counteracts aneuploid cell generation/proliferation. Full article

(This article belongs to the Special Issue Pleiotropic Roles of Tumor Suppressors)

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14 pages, 2672 KiB

Open AccessArticle

Identifying Candidate Genes for Hypoxia Adaptation of Tibet Chicken Embryos by Selection Signature Analyses and RNA Sequencing

by Xiayi Liu, Xiaochen Wang, Jing Liu, Xiangyu Wang and Haigang Bao

Genes 2020, 11(7), 823; https://doi.org/10.3390/genes11070823 - 20 Jul 2020

Cited by 7 | Viewed by 3304

Abstract

The Tibet chicken (Gallus gallus) lives on the Qinghai–Tibet Plateau and adapts to the hypoxic environment very well. The objectives of this study was to obtain candidate genes associated with hypoxia adaptation in the Tibet chicken embryos. In the present study, [...] Read more.

The Tibet chicken (Gallus gallus) lives on the Qinghai–Tibet Plateau and adapts to the hypoxic environment very well. The objectives of this study was to obtain candidate genes associated with hypoxia adaptation in the Tibet chicken embryos. In the present study, we used the fixation index (Fst) and cross population extended haplotype homozygosity (XPEHH) statistical methods to detect signatures of positive selection of the Tibet chicken, and analyzed the RNA sequencing data from the embryonic liver and heart with HISAT, StringTie and Ballgown for differentially expressed genes between the Tibet chicken and White leghorn (Gallus gallus, a kind of lowland chicken) embryos hatched under hypoxia condition. Genes which were screened out by both selection signature analysis and RNA sequencing analysis could be regarded as candidate genes for hypoxia adaptation of chicken embryos. We screened out 1772 genes by XPEHH and 601 genes by Fst, and obtained 384 and 353 differentially expressed genes in embryonic liver and heart, respectively. Among these genes, 89 genes were considered as candidate genes for hypoxia adaptation in chicken embryos. ARNT, AHR, GSTK1 and FGFR1 could be considered the most important candidate genes. Our findings provide references to elucidate the molecular mechanism of hypoxia adaptation in Tibet chicken embryos. Full article

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

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11 pages, 671 KiB

Open AccessArticle

CYP4F2 and VKORC1 Polymorphisms Amplify the Risk of Carotid Plaque Formation

by Stefan Cristian Vesa, Sonia Irina Vlaicu, Vitalie Vacaras, Sorin Crisan, Octavia Sabin, Sergiu Pasca, Adrian Pavel Trifa, Tamas Rusz-Fogarasi, Madalina Sava and Anca Dana Buzoianu

Genes 2020, 11(7), 822; https://doi.org/10.3390/genes11070822 - 20 Jul 2020

Cited by 6 | Viewed by 3032

Abstract

Introduction: Atherosclerosis represents the process by which fibrous plaques are formed in the arterial wall, increasing its rigidity with a subsequent decrease in blood flow which can lead to several cardiovascular events. Seeing as vitamin K antagonists are involved in the pathogenesis of [...] Read more.

Introduction: Atherosclerosis represents the process by which fibrous plaques are formed in the arterial wall, increasing its rigidity with a subsequent decrease in blood flow which can lead to several cardiovascular events. Seeing as vitamin K antagonists are involved in the pathogenesis of atherosclerosis, we decided to investigate whether polymorphisms in genes that influence vitamin K metabolism might have an impact in modulating the risk of plaque formation. Patients and Methods: In the current study we included adult patients admitted in the Clinical Municipal Hospital of Cluj-Napoca without any carotid or femoral plaques clinically visible at the initial investigation, and a five year follow-up was subsequently performed. We recorded the following patient characteristics: age at inclusion, gender, area of living, smoking, presence of carotid and/or femoral plaques at five years, ischemic heart disease, arterial hypertension, atrial fibrillation, heart failure, diabetes mellitus, obesity, dyslipidemia, drug (oral anticoagulants, antihypertensives, hypolipidemic, anti-diabetic) use and status for the following gene polymorphisms: VKORC1 1639 G>A, CYP4F2 1347 G>T and GGCX 12970 C>G. Results: We observed that the major predictor of both carotid and femoral plaque formation is represented by ischemic cardiac disease. VKORC1 and CYP4F2 polymorphisms did not predict plaque formation, except for VKORC1 homozygous mutants. Nonetheless, both VKORC1 and CYP4F2 interacted with ischemic cardiac disease, increasing the risk of developing a carotid plaque, while only CYP4F2, but not VKORC1, interacted with ischemic cardiac disease to increase the risk of femoral plaque formation. Conclusions: We documented that CYP4F2 and VKORC1 polymorphisms boost the proinflammatory plaque environment (observed indirectly through the presence of ischemic heart disease), increasing the risk of plaque development. Full article

(This article belongs to the Special Issue Cardiovascular Genetics)

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6 pages, 669 KiB

Open AccessBrief Report

A Family Case of Congenital Myasthenic Syndrome-22 Induced by Different Combinations of Molecular Causes in Siblings

by Olga Shchagina, Ludmila Bessonova, Igor Bychkov, Tatiana Beskorovainaya and Aleksander Poliakov

Genes 2020, 11(7), 821; https://doi.org/10.3390/genes11070821 - 19 Jul 2020

Cited by 4 | Viewed by 2979

Abstract

Congenital myasthenic syndrome-22 (CMS22, OMIM 616224) is a very rare recessive hereditary disorder. At the moment, ten CMS22 patients are described, with the disorder caused by nine different Loss-of-Function mutations and 14 gross deletions in the PREPL gene. The materials for [...] Read more.

Congenital myasthenic syndrome-22 (CMS22, OMIM 616224) is a very rare recessive hereditary disorder. At the moment, ten CMS22 patients are described, with the disorder caused by nine different Loss-of-Function mutations and 14 gross deletions in the PREPL gene. The materials for our study were DNA samples of five family members: two patients with myasthenia, their healthy sibling and parents. Clinical exome analysis was carried out for one patient, then the whole family was checked for target variants with Sanger sequencing, quantitative multiplex ligation-dependent probe amplification, and chromosome 2 microsatellite markers study. To determine the functional significance of the splicing variant, we applied the minigene assay. The cause of the proband’s disorder is a compound heterozygous state of two previously non-described pathogenic PREPL variants: a c.1528C>T (p.(Arg510Ter)) nonsense mutation and a c.2094G>T pseudo-missense variant, which, simultaneously with a p.(Lys698Asn) amino acid substitution, affects splicing, leading to exon 14 skipping in mRNA. The second patient’s disorder was caused by a homozygous nonsense c.1528C>T (p.(Arg510Ter)) mutation due to maternal uniparental disomy (UPD) of chromosome 2. In this study, we describe a unique case, in which two siblings with a rare disorder have different pathologic genotypes. Full article

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

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14 pages, 2579 KiB

Open AccessArticle

RNA-Seq Analysis Reveals Localization-Associated Alternative Splicing across 13 Cell Lines

by Chao Zeng and Michiaki Hamada

Genes 2020, 11(7), 820; https://doi.org/10.3390/genes11070820 - 18 Jul 2020

Cited by 9 | Viewed by 4718

Abstract

Alternative splicing, a ubiquitous phenomenon in eukaryotes, is a regulatory mechanism for the biological diversity of individual genes. Most studies have focused on the effects of alternative splicing for protein synthesis. However, the transcriptome-wide influence of alternative splicing on RNA subcellular localization has [...] Read more.

Alternative splicing, a ubiquitous phenomenon in eukaryotes, is a regulatory mechanism for the biological diversity of individual genes. Most studies have focused on the effects of alternative splicing for protein synthesis. However, the transcriptome-wide influence of alternative splicing on RNA subcellular localization has rarely been studied. By analyzing RNA-seq data obtained from subcellular fractions across 13 human cell lines, we identified 8720 switching genes between the cytoplasm and the nucleus. Consistent with previous reports, intron retention was observed to be enriched in the nuclear transcript variants. Interestingly, we found that short and structurally stable introns were positively correlated with nuclear localization. Motif analysis reveals that fourteen RNA-binding protein (RBPs) are prone to be preferentially bound with such introns. To our knowledge, this is the first transcriptome-wide study to analyze and evaluate the effect of alternative splicing on RNA subcellular localization. Our findings reveal that alternative splicing plays a promising role in regulating RNA subcellular localization. Full article

(This article belongs to the Special Issue Splicing: The New Frontier in Therapeutics)

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28 pages, 1158 KiB

Open AccessArticle

Classification of Microarray Gene Expression Data Using an Infiltration Tactics Optimization (ITO) Algorithm

by Javed Zahoor and Kashif Zafar

Genes 2020, 11(7), 819; https://doi.org/10.3390/genes11070819 - 18 Jul 2020

Cited by 21 | Viewed by 4315

Abstract

A number of different feature selection and classification techniques have been proposed in literature including parameter-free and parameter-based algorithms. The former are quick but may result in local maxima while the latter use dataset-specific parameter-tuning for higher accuracy. However, higher accuracy may not [...] Read more.

A number of different feature selection and classification techniques have been proposed in literature including parameter-free and parameter-based algorithms. The former are quick but may result in local maxima while the latter use dataset-specific parameter-tuning for higher accuracy. However, higher accuracy may not necessarily mean higher reliability of the model. Thus, generalized optimization is still a challenge open for further research. This paper presents a warzone inspired “infiltration tactics” based optimization algorithm (ITO)—not to be confused with the ITO algorithm based on the Itõ Process in the field of Stochastic calculus. The proposed ITO algorithm combines parameter-free and parameter-based classifiers to produce a high-accuracy-high-reliability (HAHR) binary classifier. The algorithm produces results in two phases: (i) Lightweight Infantry Group (LIG) converges quickly to find non-local maxima and produces comparable results (i.e., 70 to 88% accuracy) (ii) Followup Team (FT) uses advanced tuning to enhance the baseline performance (i.e., 75 to 99%). Every soldier of the ITO army is a base model with its own independently chosen Subset selection method, pre-processing, and validation methods and classifier. The successful soldiers are combined through heterogeneous ensembles for optimal results. The proposed approach addresses a data scarcity problem, is flexible to the choice of heterogeneous base classifiers, and is able to produce HAHR models comparable to the established MAQC-II results. Full article

(This article belongs to the Special Issue Computational Methods for the Analysis of Genomic Data and Biological Processes)

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11 pages, 5905 KiB

Open AccessArticle

Evidence of Interspecific Chromosomal Diversification in Rainbowfishes (Melanotaeniidae, Teleostei)

by Zuzana Majtánová, Peter J. Unmack, Tulyawat Prasongmaneerut, Foyez Shams, Kornsorn Srikulnath, Petr Ráb and Tariq Ezaz

Genes 2020, 11(7), 818; https://doi.org/10.3390/genes11070818 - 18 Jul 2020

Cited by 4 | Viewed by 5405

Abstract

Rainbowfishes (Melanotaeniidae) are the largest monophyletic group of freshwater fishes occurring in Australia and New Guinea, with 112 species currently recognised. Despite their high taxonomic diversity, rainbowfishes remain poorly studied from a cytogenetic perspective. Using conventional (Giemsa staining, C banding, chromomycin A₃ [...] Read more.

Rainbowfishes (Melanotaeniidae) are the largest monophyletic group of freshwater fishes occurring in Australia and New Guinea, with 112 species currently recognised. Despite their high taxonomic diversity, rainbowfishes remain poorly studied from a cytogenetic perspective. Using conventional (Giemsa staining, C banding, chromomycin A₃ staining) and molecular (fluorescence in situ hybridisation with ribosomal DNA (rDNA) and telomeric probes) cytogenetic protocols, karyotypes and associated chromosomal characteristics of five species were examined. We covered all major lineages of this group, namely, Running River rainbowfish Melanotaenia sp., red rainbowfish Glossolepis incisus, threadfin rainbowfish Iriatherina werneri, ornate rainbowfish Rhadinocentrus ornatus, and Cairns rainbowfish Cairnsichthys rhombosomoides. All species had conserved diploid chromosome numbers 2n = 48, but karyotypes differed among species; while Melanotaenia sp., G. incisus, and I. werneri possessed karyotypes composed of exclusively subtelo/acrocentric chromosomes, the karyotype of R. ornatus displayed six pairs of submetacentric and 18 pairs of subtelo/acrocentric chromosomes, while C. rhombosomoides possessed a karyotype composed of four pairs of submetacentric and 20 pairs of subtelo/acrocentric chromosomes. No heteromorphic sex chromosomes were detected using conventional cytogenetic techniques. Our data indicate a conserved 2n in Melanotaeniidae, but morphologically variable karyotypes, rDNA sites, and heterochromatin distributions. Differences were observed especially in taxonomically divergent species, suggesting interspecies chromosome rearrangements. Full article

(This article belongs to the Special Issue Vertebrate Karyotype Evolution: How Far Have We Come, and Where Are We Going?)

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22 pages, 4221 KiB

Open AccessArticle

SOMmelier—Intuitive Visualization of the Topology of Grapevine Genome Landscapes Using Artificial Neural Networks

by Maria Nikoghosyan, Maria Schmidt, Kristina Margaryan, Henry Loeffler-Wirth, Arsen Arakelyan and Hans Binder

Genes 2020, 11(7), 817; https://doi.org/10.3390/genes11070817 - 17 Jul 2020

Cited by 8 | Viewed by 4320

Abstract

Background: Whole-genome studies of vine cultivars have brought novel knowledge about the diversity, geographical relatedness, historical origin and dissemination, phenotype associations and genetic markers. Method: We applied SOM (self-organizing maps) portrayal, a neural network-based machine learning method, to re-analyze the genome-wide Single Nucleotide [...] Read more.

Background: Whole-genome studies of vine cultivars have brought novel knowledge about the diversity, geographical relatedness, historical origin and dissemination, phenotype associations and genetic markers. Method: We applied SOM (self-organizing maps) portrayal, a neural network-based machine learning method, to re-analyze the genome-wide Single Nucleotide Polymorphism (SNP) data of nearly eight hundred grapevine cultivars. The method generates genome-specific data landscapes. Their topology reflects the geographical distribution of cultivars, indicates paths of cultivar dissemination in history and genome-phenotype associations about grape utilization. Results: The landscape of vine genomes resembles the geographic map of the Mediterranean world, reflecting two major dissemination paths from South Caucasus along a northern route via Balkan towards Western Europe and along a southern route via Palestine and Maghreb towards Iberian Peninsula. The Mediterranean and Black Sea, as well as the Pyrenees, constitute barriers for genetic exchange. On the coarsest level of stratification, cultivars divide into three major groups: Western Europe and Italian grapes, Iberian grapes and vine cultivars from Near East and Maghreb regions. Genetic landmarks were associated with agronomic traits, referring to their utilization as table and wine grapes. Pseudotime analysis describes the dissemination of grapevines in an East to West direction in different waves of cultivation. Conclusion: In analogy to the tasks of the wine waiter in gastronomy, the sommelier, our ‘SOMmelier’-approach supports understanding the diversity of grapevine genomes in the context of their geographic and historical background, using SOM portrayal. It offers an option to supplement vine cultivar passports by genome fingerprint portraits. Full article

(This article belongs to the Special Issue Disentangling Mechanisms of Genomic Regulation of Cell Functions at the Gene Level)

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13 pages, 3559 KiB

Open AccessArticle

BCL2L15 Depletion Inhibits Endometrial Receptivity via the STAT1 Signaling Pathway

by Diqi Yang, Ai Liu, Yanqin Wu, Bin Li, Sha Nan, Ruiling Yin, Hongmei Zhu, Jianguo Chen, Yi Ding and Mingxing Ding

Genes 2020, 11(7), 816; https://doi.org/10.3390/genes11070816 - 17 Jul 2020

Cited by 10 | Viewed by 3384

Abstract

In domestic ruminants, endometrial receptivity is critical for a successful pregnancy and economic efficiency. Although the endometrium undergoes major cellular changes during peri-implantation, the precise mechanisms regulating goat endometrial receptivity remain unknown. In this study, we investigated the functional roles and signal transduction [...] Read more.

In domestic ruminants, endometrial receptivity is critical for a successful pregnancy and economic efficiency. Although the endometrium undergoes major cellular changes during peri-implantation, the precise mechanisms regulating goat endometrial receptivity remain unknown. In this study, we investigated the functional roles and signal transduction of the B-cell lymphoma 2 (Bcl-2)-like protein 15 (BCL2L15) in the regulation of endometrial receptivity in vitro. Our results showed that BCL2L15 was up-regulated in goat endometrial epithelial cells (EECs) under progesterone (P₄), estradiol (E₂), and interferon-tau (IFN-τ) treatments. Our knockdown of BCL2L15 by specific shRNA that significantly hampered endometrial receptivity. In the absence of BCL2L15, the signal transducer and activator of transcription (STAT)1 and STAT3 pathway were activated. Additionally, pretreatment with the STAT1 inhibitor, fludarabine, restored the effect of silencing BCL2L15 on the endometrial receptivity, but not the STAT3 inhibitor Stattic. Overall, these results suggested that BCL2L15 is the key regulator of endometrial receptivity in goats, regulating the endometrial receptivity through the STAT1 pathway. Understanding the function of BCL2L15-STAT1 in endometrial receptivity is important to the exploration of new targets for the diagnosis and treatment of early pregnancy failure, and improving the success rates for artificial reproduction. Full article

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

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27 pages, 8282 KiB

Open AccessArticle

Cortical Granule Distribution and Expression Pattern of Genes Regulating Cellular Component Size, Morphogenesis, and Potential to Differentiation are Related to Oocyte Developmental Competence and Maturational Capacity In Vivo and In Vitro

by Magdalena Kulus, Wiesława Kranc, Michal Jeseta, Patrycja Sujka-Kordowska, Aneta Konwerska, Sylwia Ciesiółka, Piotr Celichowski, Lisa Moncrieff, Ievgeniia Kocherova, Małgorzata Józkowiak, Jakub Kulus, Maria Wieczorkiewicz, Hanna Piotrowska-Kempisty, Mariusz T. Skowroński, Dorota Bukowska, Marie Machatkova, Sarka Hanulakova, Paul Mozdziak, Jędrzej M. Jaśkowski, Bartosz Kempisty and Paweł Antosik Show full author list Hide full author list

Genes 2020, 11(7), 815; https://doi.org/10.3390/genes11070815 - 17 Jul 2020

Cited by 11 | Viewed by 4633

Abstract

Polyspermia is an adverse phenomenon during mammalian fertilization when more than one sperm fuses with a single oocyte. The egg cell is prepared to prevent polyspermia by, among other ways, producing cortical granules (CGs), which are specialized intracellular structures containing enzymes that aim [...] Read more.

Polyspermia is an adverse phenomenon during mammalian fertilization when more than one sperm fuses with a single oocyte. The egg cell is prepared to prevent polyspermia by, among other ways, producing cortical granules (CGs), which are specialized intracellular structures containing enzymes that aim to harden the zona pellucida and block the fusion of subsequent sperm. This work focused on exploring the expression profile of genes that may be associated with cortical reactions, and evaluated the distribution of CGs in immature oocytes and the peripheral density of CGs in mature oocytes. Oocytes were isolated and then processed for in vitro maturation (IVM). Transcriptomic analysis of genes belonging to five ontological groups has been conducted. Six genes showed increased expression after IVM (ARHGEF2, MAP1B, CXCL12, FN1, DAB2, and SOX9), while the majority of genes decreased expression after IVM. Using CG distribution analysis in immature oocytes, movement towards the cortical zone of the oocyte during meiotic competence acquisition was observed. CGs peripheral density decreased with the rise in meiotic competence during the IVM process. The current results reveal important new insights into the in vitro maturation of oocytes. Our results may serve as a basis for further studies to investigate the cortical reaction of oocytes. Full article

(This article belongs to the Special Issue Genomic Studies in the Mammalian Reproductive Tract)

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18 pages, 2232 KiB

Open AccessArticle

TLR4 Receptor D299G/T399I Haplotype Polymorphism Is Associated with Insulin Resistance in Obese Female Subjects

by Elham Sharif, Mariam Al-Wakeel, Afnan Mohamed, Abdelhamid kerkadi and Nasser Rizk

Genes 2020, 11(7), 814; https://doi.org/10.3390/genes11070814 - 17 Jul 2020

Cited by 4 | Viewed by 2983

Abstract

Background: Activation of Toll-like-receptor 4 (TLR4) causes chronic inflammation that can result in obesity and metabolic syndrome (MeS). Aim: This study aimed to investigate the role of TLR4 polymorphisms of TLR4D299G/T399I, and its impact on protein expression of TLR4 in [...] Read more.

Background: Activation of Toll-like-receptor 4 (TLR4) causes chronic inflammation that can result in obesity and metabolic syndrome (MeS). Aim: This study aimed to investigate the role of TLR4 polymorphisms of TLR4D299G/T399I, and its impact on protein expression of TLR4 in obese female subjects. Methodology: A prospective cross-sectional association study was performed on Arab female subjects from Qatar University. The subjects were categorized according to BMI classifications into two groups: “obese; n = 69” and “non-obese; n = 136”. Anthropometric measurements, weight (kg), height (m) and waist circumference (WC) were evaluated, and the body mass index (BMI) was calculated. Fasting blood samples were collected, and assessment of glucose, lipid profile, C-reactive protein (CRP), leptin, IL-6 and insulin was performed. Insulin resistance was computed using HOMA-IR. Genotyping of the TLR4 polymorphisms of TLR4D299G (rs4986790) and TLR4T399I (rs4986791) was performed by the 5′ nuclease assay by TaqMan MGB probe. Flow cytometry was used to evaluate the monocyte cell surface expression of TLR4. Results: The frequency distribution of the genotype revealed that homozygous AA is the most frequent among obese subjects (86.4%) for (TLR4D299G, A > G) and the homozygous CC genotype is the most frequent (92.4%) for (TLR4T399I, C > T). Haplotype analysis of TLR4 D299G/T399I showed that GT carriers had a significant association with increased probability of insulin resistance (odds ratio = 4.73; 95% CI 1.19–18.90; p-value = 0.016). The monocyte cell surface of TLR4 was significantly higher by 1.3 folds in obese compared to non-obese subjects. Conclusions: TLR4 D299G/T399I haplotype polymorphism is associated with an increased risk of insulin resistance with the upregulation of TLR4 protein expression in obese subjects. Full article

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

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7 pages, 453 KiB

Open AccessCommunication

Preferentially Paternal Origin of De Novo 11p13 Chromosome Deletions Revealed in Patients with Congenital Aniridia and WAGR Syndrome

by Tatyana A. Vasilyeva, Andrey V. Marakhonov, Natella V. Sukhanova, Sergey I. Kutsev and Rena A. Zinchenko

Genes 2020, 11(7), 812; https://doi.org/10.3390/genes11070812 - 17 Jul 2020

Cited by 4 | Viewed by 2917

Abstract

The frequency of pathogenic large chromosome rearrangements detected in patients with different Mendelian diseases is truly diverse and can be remarkably high. Chromosome breaks could arise through different known mechanisms. Congenital PAX6-associated aniridia is a hereditary eye disorder caused by mutations or [...] Read more.

The frequency of pathogenic large chromosome rearrangements detected in patients with different Mendelian diseases is truly diverse and can be remarkably high. Chromosome breaks could arise through different known mechanisms. Congenital PAX6-associated aniridia is a hereditary eye disorder caused by mutations or chromosome rearrangements involving the PAX6 gene. In our recent study, we identified 11p13 chromosome deletions in 30 out of 91 probands with congenital aniridia or WAGR syndrome (characterized by Wilms’ tumor, Aniridia, and Genitourinary abnormalities as well as mental Retardation). The loss of heterozygosity analysis (LOH) was performed in 10 families with de novo chromosome deletion in proband. In 7 out of 8 informative families, the analysis revealed that deletions occurred at the paternal allele. If paternal origin is not random, chromosome breaks could arise either (i) during spermiogenesis, which is possible due to specific male chromatin epigenetic program and its vulnerability to the breakage-causing factors, or (ii) in early zygotes at a time when chromosomes transmitted from different parents still carry epigenetic marks of the origin, which is also possible due to diverse and asymmetric epigenetic reprogramming occurring in male and female pronuclei. Some new data is needed to make a well-considered conclusion on the reasons for preferential paternal origin of 11p13 deletions. Full article

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

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21 pages, 2466 KiB

Open AccessReview

Sensing, Signaling, and Secretion: A Review and Analysis of Systems for Regulating Host Interaction in Wolbachia

by Amelia R. I. Lindsey

Genes 2020, 11(7), 813; https://doi.org/10.3390/genes11070813 - 16 Jul 2020

Cited by 17 | Viewed by 4812

Abstract

Wolbachia (Anaplasmataceae) is an endosymbiont of arthropods and nematodes that resides within host cells and is well known for manipulating host biology to facilitate transmission via the female germline. The effects Wolbachia has on host physiology, combined with reproductive manipulations, make this bacterium [...] Read more.

Wolbachia (Anaplasmataceae) is an endosymbiont of arthropods and nematodes that resides within host cells and is well known for manipulating host biology to facilitate transmission via the female germline. The effects Wolbachia has on host physiology, combined with reproductive manipulations, make this bacterium a promising candidate for use in biological- and vector-control. While it is becoming increasingly clear that Wolbachia’s effects on host biology are numerous and vary according to the host and the environment, we know very little about the molecular mechanisms behind Wolbachia’s interactions with its host. Here, I analyze 29 Wolbachia genomes for the presence of systems that are likely central to the ability of Wolbachia to respond to and interface with its host, including proteins for sensing, signaling, gene regulation, and secretion. Second, I review conditions under which Wolbachia alters gene expression in response to changes in its environment and discuss other instances where we might hypothesize Wolbachia to regulate gene expression. Findings will direct mechanistic investigations into gene regulation and host-interaction that will deepen our understanding of intracellular infections and enhance applied management efforts that leverage Wolbachia. Full article

(This article belongs to the Special Issue Evolutionary Genetics of Microbial Symbiosis)

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21 pages, 1719 KiB

Open AccessReview

DNA Methylation Dysfunction in Chronic Kidney Disease

by Diego Ingrosso and Alessandra F. Perna

Genes 2020, 11(7), 811; https://doi.org/10.3390/genes11070811 - 16 Jul 2020

Cited by 18 | Viewed by 4526

Abstract

Renal disease is the common denominator of a number of underlying disease conditions, whose prevalence has been dramatically increasing over the last two decades. Two aspects are particularly relevant to the subject of this review: (I) most cases are gathered under the umbrella [...] Read more.

Renal disease is the common denominator of a number of underlying disease conditions, whose prevalence has been dramatically increasing over the last two decades. Two aspects are particularly relevant to the subject of this review: (I) most cases are gathered under the umbrella of chronic kidney disease since they require—predictably for several lustrums—continuous clinical monitoring and treatment to slow down disease progression and prevent complications; (II) cardiovascular disease is a terrible burden in this population of patients, in that it claims many lives yearly, while only a scant minority reach the renal disease end stage. Why indeed a review on DNA methylation and renal disease? As we hope to convince you, the present evidence supports the role of the existence of various derangements of the epigenetic control of gene expression in renal disease, which hold the potential to improve our ability, in the future, to more effectively act toward disease progression, predict outcomes and offer novel therapeutic approaches. Full article

(This article belongs to the Special Issue DNA Methylation in Health and Diseases)

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24 pages, 2754 KiB

Open AccessReview

Guarding the Genome: CENP-A-Chromatin in Health and Cancer

by Megan A. Mahlke and Yael Nechemia-Arbely

Genes 2020, 11(7), 810; https://doi.org/10.3390/genes11070810 - 16 Jul 2020

Cited by 40 | Viewed by 7860

Abstract

Faithful chromosome segregation is essential for the maintenance of genomic integrity and requires functional centromeres. Centromeres are epigenetically defined by the histone H3 variant, centromere protein A (CENP-A). Here we highlight current knowledge regarding CENP-A-containing chromatin structure, specification of centromere identity, regulation of [...] Read more.

Faithful chromosome segregation is essential for the maintenance of genomic integrity and requires functional centromeres. Centromeres are epigenetically defined by the histone H3 variant, centromere protein A (CENP-A). Here we highlight current knowledge regarding CENP-A-containing chromatin structure, specification of centromere identity, regulation of CENP-A deposition and possible contribution to cancer formation and/or progression. CENP-A overexpression is common among many cancers and predicts poor prognosis. Overexpression of CENP-A increases rates of CENP-A deposition ectopically at sites of high histone turnover, occluding CCCTC-binding factor (CTCF) binding. Ectopic CENP-A deposition leads to mitotic defects, centromere dysfunction and chromosomal instability (CIN), a hallmark of cancer. CENP-A overexpression is often accompanied by overexpression of its chaperone Holliday Junction Recognition Protein (HJURP), leading to epigenetic addiction in which increased levels of HJURP and CENP-A become necessary to support rapidly dividing p53 deficient cancer cells. Alterations in CENP-A posttranslational modifications are also linked to chromosome segregation errors and CIN. Collectively, CENP-A is pivotal to genomic stability through centromere maintenance, perturbation of which can lead to tumorigenesis. Full article

(This article belongs to the Special Issue The Role of Centromeres in Genome Stability)

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19 pages, 2592 KiB

Open AccessReview

Epigenetics as an Evolutionary Tool for Centromere Flexibility

by Laura Leo, Marcella Marchetti, Simona Giunta and Laura Fanti

Genes 2020, 11(7), 809; https://doi.org/10.3390/genes11070809 - 16 Jul 2020

Cited by 8 | Viewed by 4350

Abstract

Centromeres are the complex structures responsible for the proper segregation of chromosomes during cell division. Structural or functional alterations of the centromere cause aneuploidies and other chromosomal aberrations that can induce cell death with consequences on health and survival of the organism as [...] Read more.

Centromeres are the complex structures responsible for the proper segregation of chromosomes during cell division. Structural or functional alterations of the centromere cause aneuploidies and other chromosomal aberrations that can induce cell death with consequences on health and survival of the organism as a whole. Because of their essential function in the cell, centromeres have evolved high flexibility and mechanisms of tolerance to preserve their function following stress, whether it is originating from within or outside the cell. Here, we review the main epigenetic mechanisms of centromeres’ adaptability to preserve their functional stability, with particular reference to neocentromeres and holocentromeres. The centromere position can shift in response to altered chromosome structures, but how and why neocentromeres appear in a given chromosome region are still open questions. Models of neocentromere formation developed during the last few years will be hereby discussed. Moreover, we will discuss the evolutionary significance of diffuse centromeres (holocentromeres) in organisms such as nematodes. Despite the differences in DNA sequences, protein composition and centromere size, all of these diverse centromere structures promote efficient chromosome segregation, balancing genome stability and adaptability, and ensuring faithful genome inheritance at each cellular generation. Full article

(This article belongs to the Special Issue The Role of Centromeres in Genome Stability)

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6 pages, 592 KiB

Open AccessCommentary

Intestinal Microbiota Influences DNA Methylome and Susceptibility to Colorectal Cancer

by Aïcha Zouggar, Joshua R. Haebe and Yannick D. Benoit

Genes 2020, 11(7), 808; https://doi.org/10.3390/genes11070808 - 16 Jul 2020

Cited by 13 | Viewed by 3607

Abstract

In a recent publication, Ansari et al. identified gut microbiota as a critical mediator of the intestinal inflammatory response through epigenetic programming of host intestinal epithelium. Exposure to the microbiota induces Ten-Eleven-Translocation (TET)-dependent hypomethylation of genomic elements regulating genes associated with inflammatory response [...] Read more.

In a recent publication, Ansari et al. identified gut microbiota as a critical mediator of the intestinal inflammatory response through epigenetic programming of host intestinal epithelium. Exposure to the microbiota induces Ten-Eleven-Translocation (TET)-dependent hypomethylation of genomic elements regulating genes associated with inflammatory response and colorectal cancer. Here, we discuss the impact of such a discovery on the understanding of how the intestinal microbiota may contribute to epigenetic reprogramming and influence the onset of colorectal tumorigenesis. Finally, we examine the prospect of TET inhibition strategies as a therapeutic and/or preventive approach for colorectal cancer in patients afflicted by inflammatory bowel disease. Full article

(This article belongs to the Special Issue Colorectal Cancer Genetics, Epigenetics, and Emerging Therapies)

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30 pages, 9439 KiB

Open AccessArticle

Target-Genes Reveal Species and Genotypic Specificity of Anthocyanin Pigmentation in Citrus and Related Genera

by Chiara Catalano, Angelo Ciacciulli, Fabrizio Salonia, Maria Patrizia Russo, Paola Caruso, Marco Caruso, Giuseppe Russo, Gaetano Distefano and Concetta Licciardello

Genes 2020, 11(7), 807; https://doi.org/10.3390/genes11070807 - 16 Jul 2020

Cited by 8 | Viewed by 3482

Abstract

Background: Anthocyanin pigmentation characterizes a number of tissues of Citrus and its relatives. The gain and loss of pigmentation is intriguing and is inherited variously among species. Methods: Citrus germplasm was used to investigate the anthocyanin pigmentation of tissues never before considered, including [...] Read more.

Background: Anthocyanin pigmentation characterizes a number of tissues of Citrus and its relatives. The gain and loss of pigmentation is intriguing and is inherited variously among species. Methods: Citrus germplasm was used to investigate the anthocyanin pigmentation of tissues never before considered, including stamen, style and stigma, and of young leaves, petals, rind and flesh of 28 genotypes belonging to 14 species. Citrus genotypes encompassed citron, lemon, sweet orange, lime, and Citrus relatives included Microcitrus, Murraya, and Severinia. A relative qRT-PCR analysis was carried out on the structural and regulatory genes: phenylalanine ammonia-lyase (PAL), chalcone synthase (CHS), chalcone isomerase (CHI), flavanone 3′-hydroxylase (F3H), dihydroflavonol 4-reductase (DFR), anthocyanidin synthase (ANS), uridine diphosphate glucose flavonoid glucosyl-transferase (UFGT), glutathione S-transferase (GST), Ruby and Noemi. Image analysis and a genomic approach were employed to evaluate how the red pigmentation is inherited among tissues and species. Results: Pigmentation of young leaves and petals is specific to citron and its hybrids. Ruby controls the pigmentation of petals, but not of leaves. The red color of the rind and flesh is a trait that particularly characterizes a diversity of sweet oranges, citron hybrids and Citrus relatives. Color expression depends on external factors and also on developmental stage. The coloration of stamen and style is citron-specific, while a red stigma is exclusive to Moro orange and its hybrids. Conclusion: It is hypothesized that there is a relationship among Citrus species and genes controlling anthocyanin pigmentation. Full article

(This article belongs to the Special Issue Genetic Basis of Fruit Quality Traits)

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15 pages, 1258 KiB

Open AccessArticle

Genetic Diversity of C₄ Photosynthesis Pathway Genes in Sorghum bicolor (L.)

by Yongfu Tao, Barbara George-Jaeggli, Marie Bouteillé-Pallas, Shuaishuai Tai, Alan Cruickshank, David Jordan and Emma Mace

Genes 2020, 11(7), 806; https://doi.org/10.3390/genes11070806 - 16 Jul 2020

Cited by 4 | Viewed by 7204

Abstract

C₄ photosynthesis has evolved in over 60 different plant taxa and is an excellent example of convergent evolution. Plants using the C₄ photosynthetic pathway have an efficiency advantage, particularly in hot and dry environments. They account for 23% of global primary [...] Read more.

C₄ photosynthesis has evolved in over 60 different plant taxa and is an excellent example of convergent evolution. Plants using the C₄ photosynthetic pathway have an efficiency advantage, particularly in hot and dry environments. They account for 23% of global primary production and include some of our most productive cereals. While previous genetic studies comparing phylogenetically related C₃ and C₄ species have elucidated the genetic diversity underpinning the C₄ photosynthetic pathway, no previous studies have described the genetic diversity of the genes involved in this pathway within a C₄ crop species. Enhanced understanding of the allelic diversity and selection signatures of genes in this pathway may present opportunities to improve photosynthetic efficiency, and ultimately yield, by exploiting natural variation. Here, we present the first genetic diversity survey of 8 known C₄ gene families in an important C₄ crop, Sorghum bicolor (L.) Moench, using sequence data of 48 genotypes covering wild and domesticated sorghum accessions. Average nucleotide diversity of C₄ gene families varied more than 20-fold from the NADP-malate dehydrogenase (MDH) gene family (θπ = 0.2 × 10⁻³) to the pyruvate orthophosphate dikinase (PPDK) gene family (θπ = 5.21 × 10⁻³). Genetic diversity of C₄ genes was reduced by 22.43% in cultivated sorghum compared to wild and weedy sorghum, indicating that the group of wild and weedy sorghum may constitute an untapped reservoir for alleles related to the C₄ photosynthetic pathway. A SNP-level analysis identified purifying selection signals on C₄ PPDK and carbonic anhydrase (CA) genes, and balancing selection signals on C₄ PPDK-regulatory protein (RP) and phosphoenolpyruvate carboxylase (PEPC) genes. Allelic distribution of these C₄ genes was consistent with selection signals detected. A better understanding of the genetic diversity of C4 pathway in sorghum paves the way for mining the natural allelic variation for the improvement of photosynthesis. Full article

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

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20 pages, 2453 KiB

Open AccessArticle

Shedding the Light on Litopenaeus vannamei Differential Muscle and Hepatopancreas Immune Responses in White Spot Syndrome Virus (WSSV) Exposure

by Camilla A. Santos, Sónia C. S. Andrade, Jorge M. O. Fernandes and Patrícia D. Freitas

Genes 2020, 11(7), 805; https://doi.org/10.3390/genes11070805 - 16 Jul 2020

Cited by 15 | Viewed by 3884

Abstract

White Spot Syndrome Virus (WSSV) is one of the main threats to farming Litopenaeus vannamei, the most important crustacean commercialized in aquaculture worldwide. Here, we performed RNA-seq analyses in hepatopancreas and muscle from WSSV-negative (healthy) and WSSV-positive (unhealthy) L. vannamei, previously exposed [...] Read more.

White Spot Syndrome Virus (WSSV) is one of the main threats to farming Litopenaeus vannamei, the most important crustacean commercialized in aquaculture worldwide. Here, we performed RNA-seq analyses in hepatopancreas and muscle from WSSV-negative (healthy) and WSSV-positive (unhealthy) L. vannamei, previously exposed to the virus, to obtain new insights about the molecular basis of resistance to WSSV. We detected 71% of our reads mapped against the recently described L. vannamei genome. This is the first report mapping RNA-seq transcripts from shrimps exposed to WSSV against the species reference genome. Differentially expressed gene (DEG) analyses were performed for four independent comparisons, and 13,338 DEGs were identified. When the redundancies and isoforms were disregarded, we observed 8351 and 6514 DEGs, respectively. Interestingly, after crossing the data, we detected a common set of DEGs for hepatopancreas and healthy shrimps, as well as another one for muscle and unhealthy shrimps. Our findings indicate that genes related to apoptosis, melanization, and the Imd pathway are likely to be involved in response to WSSV, offering knowledge about WSSV defense in shrimps exposed to the virus but not infected. These data present potential to be applied in further genetic studies in penaeids and other farmed shrimp species. Full article

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

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