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Genes, Volume 9, Issue 12 (December 2018)

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Open AccessReview Chromatin as a Platform for Modulating the Replication Stress Response
Genes 2018, 9(12), 622; https://doi.org/10.3390/genes9120622 (registering DOI)
Received: 30 October 2018 / Revised: 3 December 2018 / Accepted: 4 December 2018 / Published: 11 December 2018
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Abstract
Eukaryotic DNA replication occurs in the context of chromatin. Recent years have seen major advances in our understanding of histone supply, histone recycling and nascent histone incorporation during replication. Furthermore, much is now known about the roles of histone remodellers and post-translational modifications
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Eukaryotic DNA replication occurs in the context of chromatin. Recent years have seen major advances in our understanding of histone supply, histone recycling and nascent histone incorporation during replication. Furthermore, much is now known about the roles of histone remodellers and post-translational modifications in replication. It has also become clear that nucleosome dynamics during replication play critical roles in genome maintenance and that chromatin modifiers are important for preventing DNA replication stress. An understanding of how cells deploy specific nucleosome modifiers, chaperones and remodellers directly at sites of replication fork stalling has been building more slowly. Here we will specifically discuss recent advances in understanding how chromatin composition contribute to replication fork stability and restart. Full article
(This article belongs to the Special Issue Chromosome Replication and Genome Integrity)
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Open AccessReview DNA-Based Super-Resolution Microscopy: DNA-PAINT
Genes 2018, 9(12), 621; https://doi.org/10.3390/genes9120621 (registering DOI)
Received: 24 October 2018 / Revised: 2 December 2018 / Accepted: 3 December 2018 / Published: 11 December 2018
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Abstract
Super-resolution microscopies, such as single molecule localization microscopy (SMLM), allow the visualization of biomolecules at the nanoscale. The requirement to observe molecules multiple times during an acquisition has pushed the field to explore methods that allow the binding of a fluorophore to a
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Super-resolution microscopies, such as single molecule localization microscopy (SMLM), allow the visualization of biomolecules at the nanoscale. The requirement to observe molecules multiple times during an acquisition has pushed the field to explore methods that allow the binding of a fluorophore to a target. This binding is then used to build an image via points accumulation for imaging nanoscale topography (PAINT), which relies on the stochastic binding of a fluorescent ligand instead of the stochastic photo-activation of a permanently bound fluorophore. Recently, systems that use DNA to achieve repeated, transient binding for PAINT imaging have become the cutting edge in SMLM. Here, we review the history of PAINT imaging, with a particular focus on the development of DNA-PAINT. We outline the different variations of DNA-PAINT and their applications for imaging of both DNA origamis and cellular proteins via SMLM. Finally, we reflect on the current challenges for DNA-PAINT imaging going forward. Full article
(This article belongs to the Special Issue DNA Origami and Aptamer Assemblies)
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Open AccessReview Structural Basis of DNMT1 and DNMT3A-Mediated DNA Methylation
Genes 2018, 9(12), 620; https://doi.org/10.3390/genes9120620 (registering DOI)
Received: 7 November 2018 / Revised: 30 November 2018 / Accepted: 4 December 2018 / Published: 11 December 2018
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Abstract
DNA methylation, one of the major epigenetic mechanisms, plays critical roles in regulating gene expression, genomic stability and cell lineage commitment. The establishment and maintenance of DNA methylation in mammals is achieved by two groups of DNA methyltransferases (DNMTs): DNMT3A and DNMT3B, which
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DNA methylation, one of the major epigenetic mechanisms, plays critical roles in regulating gene expression, genomic stability and cell lineage commitment. The establishment and maintenance of DNA methylation in mammals is achieved by two groups of DNA methyltransferases (DNMTs): DNMT3A and DNMT3B, which are responsible for installing DNA methylation patterns during gametogenesis and early embryogenesis, and DNMT1, which is essential for propagating DNA methylation patterns during replication. Both groups of DNMTs are multi-domain proteins, containing a large N-terminal regulatory region in addition to the C-terminal methyltransferase domain. Recent structure-function investigations of the individual domains or large fragments of DNMT1 and DNMT3A have revealed the molecular basis for their substrate recognition and specificity, intramolecular domain-domain interactions, as well as their crosstalk with other epigenetic mechanisms. These studies highlight a multifaceted regulation for both DNMT1 and DNMT3A/3B, which is essential for the precise establishment and maintenance of lineage-specific DNA methylation patterns in cells. This review summarizes current understanding of the structure and mechanism of DNMT1 and DNMT3A-mediated DNA methylation, with emphasis on the functional cooperation between the methyltransferase and regulatory domains. Full article
(This article belongs to the Special Issue Role of DNA Methyltransferases in the Epigenome)
Open AccessArticle RNA Modification Level Estimation with pulseR
Genes 2018, 9(12), 619; https://doi.org/10.3390/genes9120619
Received: 9 November 2018 / Revised: 3 December 2018 / Accepted: 5 December 2018 / Published: 10 December 2018
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Abstract
RNA modifications regulate the complex life of transcripts. An experimental approach called LAIC-seq was developed to characterize modification levels on a transcriptome-wide scale. In this method, the modified and unmodified molecules are separated using antibodies specific for a given RNA modification (e.g., m
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RNA modifications regulate the complex life of transcripts. An experimental approach called LAIC-seq was developed to characterize modification levels on a transcriptome-wide scale. In this method, the modified and unmodified molecules are separated using antibodies specific for a given RNA modification (e.g., m6A). In essence, the procedure of biochemical separation yields three fractions: Input, eluate, and supernatent, which are subjected to RNA-seq. In this work, we present a bioinformatics workflow, which starts from RNA-seq data to infer gene-specific modification levels by a statistical model on a transcriptome-wide scale. Our workflow centers around the pulseR package, which was originally developed for the analysis of metabolic labeling experiments. We demonstrate how to analyze data without external normalization (i.e., in the absence of spike-ins), given high efficiency of separation, and how, alternatively, scaling factors can be derived from unmodified spike-ins. Importantly, our workflow provides an estimate of uncertainty of modification levels in terms of confidence intervals for model parameters, such as gene expression and RNA modification levels. We also compare alternative model parametrizations, log-odds, or the proportion of the modified molecules and discuss the pros and cons of each representation. In summary, our workflow is a versatile approach to RNA modification level estimation, which is open to any read-count-based experimental approach. Full article
(This article belongs to the Special Issue RNA Modifications)
Open AccessArticle Rediscovery of Red Wolf Ghost Alleles in a Canid Population Along the American Gulf Coast
Genes 2018, 9(12), 618; https://doi.org/10.3390/genes9120618
Received: 17 October 2018 / Revised: 29 November 2018 / Accepted: 4 December 2018 / Published: 10 December 2018
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Abstract
Rediscovering species once thought to be extinct or on the edge of extinction is rare. Red wolves have been extinct along the American Gulf Coast since 1980, with their last populations found in coastal Louisiana and Texas. We report the rediscovery of red
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Rediscovering species once thought to be extinct or on the edge of extinction is rare. Red wolves have been extinct along the American Gulf Coast since 1980, with their last populations found in coastal Louisiana and Texas. We report the rediscovery of red wolf ghost alleles in a canid population on Galveston Island, Texas. We analyzed over 7000 single nucleotide polymorphisms (SNPs) in 60 canid representatives from all legally recognized North American Canis species and two phenotypically ambiguous canids from Galveston Island. We found notably high Bayesian cluster assignments of the Galveston canids to captive red wolves with extensive sharing of red wolf private alleles. Today, the only known extant wild red wolves persist in a reintroduced population in North Carolina, which is dwindling amongst political and taxonomic controversy. Our rediscovery of red wolf ancestry after almost 40 years introduces both positive opportunities for additional conservation action and difficult policy challenges. Full article
(This article belongs to the Special Issue Conservation Genetics and Genomics)
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Open AccessReview Mechanisms of DNA Methyltransferase Recruitment in Mammals
Genes 2018, 9(12), 617; https://doi.org/10.3390/genes9120617
Received: 16 November 2018 / Revised: 30 November 2018 / Accepted: 5 December 2018 / Published: 10 December 2018
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Abstract
DNA methylation is an essential epigenetic mark in mammals. The proper distribution of this mark depends on accurate deposition and maintenance mechanisms, and underpins its functional role. This, in turn, depends on the precise recruitment and activation of de novo and maintenance DNA
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DNA methylation is an essential epigenetic mark in mammals. The proper distribution of this mark depends on accurate deposition and maintenance mechanisms, and underpins its functional role. This, in turn, depends on the precise recruitment and activation of de novo and maintenance DNA methyltransferases (DNMTs). In this review, we discuss mechanisms of recruitment of DNMTs by transcription factors and chromatin modifiers—and by RNA—and place these mechanisms in the context of biologically meaningful epigenetic events. We present hypotheses and speculations for future research, and underline the fundamental and practical benefits of better understanding the mechanisms that govern the recruitment of DNMTs. Full article
(This article belongs to the Special Issue Role of DNA Methyltransferases in the Epigenome)
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Open AccessReview Beyond Transcription: Fine-Tuning of Circadian Timekeeping by Post-Transcriptional Regulation
Genes 2018, 9(12), 616; https://doi.org/10.3390/genes9120616
Received: 6 November 2018 / Revised: 29 November 2018 / Accepted: 3 December 2018 / Published: 10 December 2018
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Abstract
The circadian clock is an important endogenous timekeeper, helping plants to prepare for the periodic changes of light and darkness in their environment. The clockwork of this molecular timer is made up of clock proteins that regulate transcription of their own genes with
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The circadian clock is an important endogenous timekeeper, helping plants to prepare for the periodic changes of light and darkness in their environment. The clockwork of this molecular timer is made up of clock proteins that regulate transcription of their own genes with a 24 h rhythm. Furthermore, the rhythmically expressed clock proteins regulate time-of-day dependent transcription of downstream genes, causing messenger RNA (mRNA) oscillations of a large part of the transcriptome. On top of the transcriptional regulation by the clock, circadian rhythms in mRNAs rely in large parts on post-transcriptional regulation, including alternative pre-mRNA splicing, mRNA degradation, and translational control. Here, we present recent insights into the contribution of post-transcriptional regulation to core clock function and to regulation of circadian gene expression in Arabidopsis thaliana. Full article
(This article belongs to the Special Issue Genetic Regulation of Circadian Rhythm in Plants)
Open AccessReview Repetitive Fragile Sites: Centromere Satellite DNA As a Source of Genome Instability in Human Diseases
Genes 2018, 9(12), 615; https://doi.org/10.3390/genes9120615
Received: 5 November 2018 / Revised: 3 December 2018 / Accepted: 3 December 2018 / Published: 7 December 2018
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Abstract
Maintenance of an intact genome is essential for cellular and organismal homeostasis. The centromere is a specialized chromosomal locus required for faithful genome inheritance at each round of cell division. Human centromeres are composed of large tandem arrays of repetitive alpha-satellite DNA, which
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Maintenance of an intact genome is essential for cellular and organismal homeostasis. The centromere is a specialized chromosomal locus required for faithful genome inheritance at each round of cell division. Human centromeres are composed of large tandem arrays of repetitive alpha-satellite DNA, which are often sites of aberrant rearrangements that may lead to chromosome fusions and genetic abnormalities. While the centromere has an essential role in chromosome segregation during mitosis, the long and repetitive nature of the highly identical repeats has greatly hindered in-depth genetic studies, and complete annotation of all human centromeres is still lacking. Here, we review our current understanding of human centromere genetics and epigenetics as well as recent investigations into the role of centromere DNA in disease, with a special focus on cancer, aging, and human immunodeficiency–centromeric instability–facial anomalies (ICF) syndrome. We also highlight the causes and consequences of genomic instability at these large repetitive arrays and describe the possible sources of centromere fragility. The novel connection between alpha-satellite DNA instability and human pathological conditions emphasizes the importance of obtaining a truly complete human genome assembly and accelerating our understanding of centromere repeats’ role in physiology and beyond. Full article
(This article belongs to the Special Issue Chromosome Replication and Genome Integrity)
Open AccessReview DNA Damage Tolerance Mechanisms Revealed from the Analysis of Immunoglobulin V Gene Diversification in Avian DT40 Cells
Genes 2018, 9(12), 614; https://doi.org/10.3390/genes9120614
Received: 30 October 2018 / Revised: 26 November 2018 / Accepted: 30 November 2018 / Published: 7 December 2018
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Abstract
DNA replication is an essential biochemical reaction in dividing cells that frequently stalls at damaged sites. Homologous/homeologous recombination (HR)-mediated template switch and translesion DNA synthesis (TLS)-mediated bypass processes release arrested DNA replication forks. These mechanisms are pivotal for replication fork maintenance and play
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DNA replication is an essential biochemical reaction in dividing cells that frequently stalls at damaged sites. Homologous/homeologous recombination (HR)-mediated template switch and translesion DNA synthesis (TLS)-mediated bypass processes release arrested DNA replication forks. These mechanisms are pivotal for replication fork maintenance and play critical roles in DNA damage tolerance (DDT) and gap-filling. The avian DT40 B lymphocyte cell line provides an opportunity to examine HR-mediated template switch and TLS triggered by abasic sites by sequencing the constitutively diversifying immunoglobulin light-chain variable gene (IgV). During IgV diversification, activation-induced deaminase (AID) converts dC to dU, which in turn is excised by uracil DNA glycosylase and yields abasic sites within a defined window of around 500 base pairs. These abasic sites can induce gene conversion with a set of homeologous upstream pseudogenes via the HR-mediated template switch, resulting in templated mutagenesis, or can be bypassed directly by TLS, resulting in non-templated somatic hypermutation at dC/dG base pairs. In this review, we discuss recent works unveiling IgV diversification mechanisms in avian DT40 cells, which shed light on DDT mode usage in vertebrate cells and tolerance of abasic sites. Full article
(This article belongs to the Special Issue Chromosome Replication and Genome Integrity)
Open AccessArticle Generation of A Mucor circinelloides Reporter Strain—A Promising New Tool to Study Antifungal Drug Efficacy and Mucormycosis
Genes 2018, 9(12), 613; https://doi.org/10.3390/genes9120613
Received: 5 November 2018 / Revised: 3 December 2018 / Accepted: 5 December 2018 / Published: 7 December 2018
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Abstract
Invasive fungal infections caused by Mucorales (mucormycosis) have increased worldwide. These life-threatening infections affect mainly, but not exclusively, immunocompromised patients, and are characterized by rapid progression, severe tissue damage and an unacceptably high rate of mortality. Still, little is known about this disease
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Invasive fungal infections caused by Mucorales (mucormycosis) have increased worldwide. These life-threatening infections affect mainly, but not exclusively, immunocompromised patients, and are characterized by rapid progression, severe tissue damage and an unacceptably high rate of mortality. Still, little is known about this disease and its successful therapy. New tools to understand mucormycosis and a screening method for novel antimycotics are required. Bioluminescent imaging is a powerful tool for in vitro and in vivo approaches. Hence, the objective of this work was to generate and functionally analyze bioluminescent reporter strains of Mucor circinelloides, one mucormycosis-causing pathogen. Reporter strains were constructed by targeted integration of the firefly luciferase gene under control of the M. circinelloides promoter Pzrt1. The luciferase gene was sufficiently expressed, and light emission was detected under several conditions. Phenotypic characteristics, virulence potential and antifungal susceptibility were indifferent to the wild-type strains. Light intensity was dependent on growth conditions and biomass, being suitable to determine antifungal efficacy in vitro. This work describes for the first time the generation of reporter strains in a basal fungus that will allow real-time, non-invasive infection monitoring in insect and murine models, and the testing of antifungal efficacy by means other than survival. Full article
(This article belongs to the Special Issue Fungal Pathogenesis in Humans: The Growing Threat)
Open AccessArticle Acceptor Stem Differences Contribute to Species-Specific Use of Yeast and Human tRNASer
Genes 2018, 9(12), 612; https://doi.org/10.3390/genes9120612
Received: 12 October 2018 / Revised: 22 November 2018 / Accepted: 3 December 2018 / Published: 7 December 2018
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Abstract
The molecular mechanisms of translation are highly conserved in all organisms indicative of a single evolutionary origin. This includes the molecular interactions of tRNAs with their cognate aminoacyl-tRNA synthetase, which must be precise to ensure the specificity of the process. For many tRNAs,
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The molecular mechanisms of translation are highly conserved in all organisms indicative of a single evolutionary origin. This includes the molecular interactions of tRNAs with their cognate aminoacyl-tRNA synthetase, which must be precise to ensure the specificity of the process. For many tRNAs, the anticodon is a major component of the specificity. This is not the case for the aminoacylation of alanine and serine to their cognate tRNAs. Rather, aminoacylation relies on other features of the tRNA. For tRNASer, a key specificity feature is the variable arm, which is positioned between the anticodon arm and the T-arm. The variable arm is conserved from yeast to human. This work was initiated to determine if the structure/function of tRNASer has been conserved from Saccharomyces cerevisiae to human. We did this by detecting mistranslation in yeast cells with tRNASer derivatives having the UGA anticodon converted to UGG for proline. Despite being nearly identical in everything except the acceptor stem, human tRNASer is less active than yeast tRNASer. A chimeric tRNA with the human acceptor stem and other sequences from the yeast molecule acts similarly to the human tRNASer. The 3:70 base pair in the acceptor stem (C:G in yeast and A:U in humans) is a prime determinant of the specificity. Consistent with the functional difference of yeast and human tRNASer resulting from subtle changes in the specificity of their respective SerRS enzymes, the functionality of the human and chimeric tRNASerUGG molecules was enhanced when human SerRS was introduced into yeast. Residues in motif 2 of the aminoacylation domain of SerRS likely participated in the species-specific differences. Trp290 in yeast SerRS (Arg313 in humans) found in motif 2 is proximal to base 70 in models of the tRNA-synthetase interaction. Altering this motif 2 sequence of hSerRS to the yeast sequence decreases the activity of the human enzyme with human tRNASer, supporting the coadaptation of motif 2 loop–acceptor stem interactions. Full article
(This article belongs to the Special Issue Synthetic DNA and RNA Programming)
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Open AccessArticle Evolution and Expression Divergence of the CYP78A Subfamily Genes in Soybean
Genes 2018, 9(12), 611; https://doi.org/10.3390/genes9120611 (registering DOI)
Received: 31 October 2018 / Revised: 23 November 2018 / Accepted: 27 November 2018 / Published: 7 December 2018
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Abstract
Gene expression divergence is an important evolutionary driving force for the retention of duplicate genes. In this study, we identified three CYP78A subfamily genes in soybean, GmCYP78A70, GmCYP78A57 and GmCYP78A72, which experienced different duplication events. GmCYP78A70 was mainly expressed in leaf
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Gene expression divergence is an important evolutionary driving force for the retention of duplicate genes. In this study, we identified three CYP78A subfamily genes in soybean, GmCYP78A70, GmCYP78A57 and GmCYP78A72, which experienced different duplication events. GmCYP78A70 was mainly expressed in leaf tissue and the vegetative phase, whereas GmCYP78A57 was mainly expressed in floral tissue and seed, i.e., the reproductive phase. Expression of GmCYP78A72 could be detected in all the tissues and phases mentioned above. The expression levels of GmCYP78A70 and GmCYP78A57 in different soybean cultivars showed positive correlations with leaf size and 100-seed weight, respectively. The population genetics analysis indicated that the three genes had experienced different selective pressures during domestication and improved breeding of soybean. Deciphering the function of this subfamily of genes may well prove useful to breeders for improving soybean’s agronomic traits. Full article
(This article belongs to the Section Plant Genetics and Genomics)
Open AccessArticle Genomic Characterization of a B Chromosome in Lake Malawi Cichlid Fishes
Genes 2018, 9(12), 610; https://doi.org/10.3390/genes9120610
Received: 3 November 2018 / Revised: 28 November 2018 / Accepted: 30 November 2018 / Published: 5 December 2018
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Abstract
B chromosomes (Bs) were discovered a century ago, and since then, most studies have focused on describing their distribution and abundance using traditional cytogenetics. Only recently have attempts been made to understand their structure and evolution at the level of DNA sequence. Many
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B chromosomes (Bs) were discovered a century ago, and since then, most studies have focused on describing their distribution and abundance using traditional cytogenetics. Only recently have attempts been made to understand their structure and evolution at the level of DNA sequence. Many questions regarding the origin, structure, function, and evolution of B chromosomes remain unanswered. Here, we identify B chromosome sequences from several species of cichlid fish from Lake Malawi by examining the ratios of DNA sequence coverage in individuals with or without B chromosomes. We examined the efficiency of this method, and compared results using both Illumina and PacBio sequence data. The B chromosome sequences detected in 13 individuals from 7 species were compared to assess the rates of sequence replacement. B-specific sequence common to at least 12 of the 13 datasets were identified as the “Core” B chromosome. The location of B sequence homologs throughout the genome provides further support for theories of B chromosome evolution. Finally, we identified genes and gene fragments located on the B chromosome, some of which may regulate the segregation and maintenance of the B chromosome. Full article
(This article belongs to the Special Issue Evolution, Composition and Regulation of Supernumerary B Chromosomes)
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Open AccessArticle Towards a Central Role of ISL1 in the Bladder Exstrophy–Epispadias Complex (BEEC): Computational Characterization of Genetic Variants and Structural Modelling
Genes 2018, 9(12), 609; https://doi.org/10.3390/genes9120609
Received: 26 November 2018 / Accepted: 28 November 2018 / Published: 5 December 2018
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Abstract
Genetic factors play a critical role in the development of human diseases. Recently, several molecular genetic studies have provided multiple lines of evidence for a critical role of genetic factors in the expression of human bladder exstrophy-epispadias complex (BEEC). At this point, ISL1
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Genetic factors play a critical role in the development of human diseases. Recently, several molecular genetic studies have provided multiple lines of evidence for a critical role of genetic factors in the expression of human bladder exstrophy-epispadias complex (BEEC). At this point, ISL1 (ISL LIM homeobox 1) has emerged as the major susceptibility gene for classic bladder exstrophy (CBE), in a multifactorial disease model. Here, GWAS (Genome wide association studies) discovery and replication studies, as well as the re-sequencing of ISL1, identified sequence variants (rs9291768, rs6874700, c.137C > G (p.Ala46Gly)) associated with CBE. Here, we aimed to determine the molecular and functional consequences of these sequence variants and estimate the dependence of ISL1 protein on other predicted candidates. We used: (i) computational analysis of conserved sequence motifs to perform an evolutionary conservation analysis, based on a Bayesian algorithm, and (ii) computational 3D structural modeling. Furthermore, we looked into long non-coding RNAs (lncRNAs) residing within the ISL1 region, aiming to predict their targets. Our analysis suggests that the ISL1 protein specific N-terminal LIM domain (which harbors the variant c.137C>G), limits its transcriptional ability, and might interfere with ISL1-estrogen receptor α interactions. In conclusion, our analysis provides further useful insights about the ISL1 gene, which is involved in the formation of the BEEC, and in the development of the urinary bladder. Full article
(This article belongs to the Section Technologies and Resources for Genetics)
Open AccessArticle Gene-Based Nonparametric Testing of Interactions Using Distance Correlation Coefficient in Case-Control Association Studies
Genes 2018, 9(12), 608; https://doi.org/10.3390/genes9120608
Received: 6 November 2018 / Revised: 24 November 2018 / Accepted: 27 November 2018 / Published: 5 December 2018
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Abstract
Among the various statistical methods for identifying gene–gene interactions in qualitative genome-wide association studies (GWAS), gene-based methods have recently grown in popularity because they confer advantages in both statistical power and biological interpretability. However, most of these methods make strong assumptions about the
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Among the various statistical methods for identifying gene–gene interactions in qualitative genome-wide association studies (GWAS), gene-based methods have recently grown in popularity because they confer advantages in both statistical power and biological interpretability. However, most of these methods make strong assumptions about the form of the relationship between traits and single-nucleotide polymorphisms, which result in limited statistical power. In this paper, we propose a gene-based method based on the distance correlation coefficient called gene-based gene-gene interaction via distance correlation coefficient (GBDcor). The distance correlation (dCor) is a measurement of the dependency between two random vectors with arbitrary, and not necessarily equal, dimensions. We used the difference in dCor in case and control datasets as an indicator of gene–gene interaction, which was based on the assumption that the joint distribution of two genes in case subjects and in control subjects should not be significantly different if the two genes do not interact. We designed a permutation-based statistical test to evaluate the difference between dCor in cases and controls for a pair of genes, and we provided the p-value for the statistic to represent the significance of the interaction between the two genes. In experiments with both simulated and real-world data, our method outperformed previous approaches in detecting interactions accurately. Full article
Open AccessReview tRNA-Derived Small RNAs: Biogenesis, Modification, Function and Potential Impact on Human Disease Development
Genes 2018, 9(12), 607; https://doi.org/10.3390/genes9120607
Received: 9 November 2018 / Revised: 27 November 2018 / Accepted: 29 November 2018 / Published: 5 December 2018
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Abstract
Transfer RNAs (tRNAs) are abundant small non-coding RNAs that are crucially important for decoding genetic information. Besides fulfilling canonical roles as adaptor molecules during protein synthesis, tRNAs are also the source of a heterogeneous class of small RNAs, tRNA-derived small RNAs (tsRNAs). Occurrence
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Transfer RNAs (tRNAs) are abundant small non-coding RNAs that are crucially important for decoding genetic information. Besides fulfilling canonical roles as adaptor molecules during protein synthesis, tRNAs are also the source of a heterogeneous class of small RNAs, tRNA-derived small RNAs (tsRNAs). Occurrence and the relatively high abundance of tsRNAs has been noted in many high-throughput sequencing data sets, leading to largely correlative assumptions about their potential as biologically active entities. tRNAs are also the most modified RNAs in any cell type. Mutations in tRNA biogenesis factors including tRNA modification enzymes correlate with a variety of human disease syndromes. However, whether it is the lack of tRNAs or the activity of functionally relevant tsRNAs that are causative for human disease development remains to be elucidated. Here, we review the current knowledge in regard to tsRNAs biogenesis, including the impact of RNA modifications on tRNA stability and discuss the existing experimental evidence in support for the seemingly large functional spectrum being proposed for tsRNAs. We also argue that improved methodology allowing exact quantification and specific manipulation of tsRNAs will be necessary before developing these small RNAs into diagnostic biomarkers and when aiming to harness them for therapeutic purposes. Full article
(This article belongs to the Special Issue The Epitranscriptome in Human Disease)
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Open AccessArticle Population Genomic Analysis of North American Eastern Wolves (Canis lycaon) Supports Their Conservation Priority Status
Genes 2018, 9(12), 606; https://doi.org/10.3390/genes9120606
Received: 15 October 2018 / Revised: 29 November 2018 / Accepted: 30 November 2018 / Published: 4 December 2018
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Abstract
The threatened eastern wolf is found predominantly in protected areas of central Ontario and has an evolutionary history obscured by interbreeding with coyotes and gray wolves, which challenges its conservation status and subsequent management. Here, we used a population genomics approach to uncover
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The threatened eastern wolf is found predominantly in protected areas of central Ontario and has an evolutionary history obscured by interbreeding with coyotes and gray wolves, which challenges its conservation status and subsequent management. Here, we used a population genomics approach to uncover spatial patterns of variation in 281 canids in central Ontario and the Great Lakes region. This represents the first genome-wide single nucleotide polymorphism (SNP) dataset with substantial sample sizes of representative populations. Although they comprise their own genetic cluster, we found evidence of eastern wolf dispersal outside of the boundaries of protected areas, in that the frequency of eastern wolf genetic variation decreases with increasing distance from provincial parks. We detected eastern wolf alleles in admixed coyotes along the northeastern regions of Lake Huron and Lake Ontario. Our analyses confirm the unique genomic composition of eastern wolves, which are mostly restricted to small fragmented patches of protected habitat in central Ontario. We hope this work will encourage an innovative discussion regarding a plan for managed introgression, which could conserve eastern wolf genetic material in any genome regardless of their potential mosaic ancestry composition and the habitats that promote them. Full article
(This article belongs to the Special Issue Conservation Genetics and Genomics)
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Open AccessReview Review of Ocular Manifestations of Joubert Syndrome
Genes 2018, 9(12), 605; https://doi.org/10.3390/genes9120605
Received: 29 September 2018 / Revised: 13 November 2018 / Accepted: 27 November 2018 / Published: 4 December 2018
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Abstract
Joubert syndrome is a group of rare disorders that stem from defects in a sensory organelle, the primary cilia. Affected patients often present with disorders involving multiple organ systems, including the brain, eyes, and kidneys. Common symptoms include breathing abnormalities, mental developmental delays,
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Joubert syndrome is a group of rare disorders that stem from defects in a sensory organelle, the primary cilia. Affected patients often present with disorders involving multiple organ systems, including the brain, eyes, and kidneys. Common symptoms include breathing abnormalities, mental developmental delays, loss of voluntary muscle coordination, and abnormal eye movements, with a diagnostic “molar tooth” sign observed by magnetic resonance imaging (MRI) of the midbrain. We reviewed the ocular phenotypes that can be found in patients with Joubert syndrome. Ocular motor apraxia is the most frequent (80% of patients), followed by strabismus (74%) and nystagmus (72%). A minority of patients also present with ptosis (43%), chorioretinal coloboma (30%), and optic nerve atrophy (22%). Although mutations in 34 genes have been found to be associated with Joubert syndrome, retinal degeneration has been reported in only 38% of patients. Mutations in AHI1 and CEP290, genes critical to primary cilia function, have been linked to retinal degeneration. In conclusion, Joubert syndrome is a rare pleiotropic group of disorders with variable ocular presentations. Full article
(This article belongs to the Section Human Genomics and Genetic Diseases)
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Open AccessArticle Multiple Sequence Alignments Enhance Boundary Definition of RNA Structures
Genes 2018, 9(12), 604; https://doi.org/10.3390/genes9120604
Received: 25 September 2018 / Revised: 28 November 2018 / Accepted: 29 November 2018 / Published: 4 December 2018
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Abstract
Self-contained structured domains of RNA sequences have often distinct molecular functions. Determining the boundaries of structured domains of a non-coding RNA (ncRNA) is needed for many ncRNA gene finder programs that predict RNA secondary structures in aligned genomes because these methods do not
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Self-contained structured domains of RNA sequences have often distinct molecular functions. Determining the boundaries of structured domains of a non-coding RNA (ncRNA) is needed for many ncRNA gene finder programs that predict RNA secondary structures in aligned genomes because these methods do not necessarily provide precise information about the boundaries or the location of the RNA structure inside the predicted ncRNA. Even without having a structure prediction, it is of interest to search for structured domains, such as for finding common RNA motifs in RNA-protein binding assays. The precise definition of the boundaries are essential for downstream analyses such as RNA structure modelling, e.g., through covariance models, and RNA structure clustering for the search of common motifs. Such efforts have so far been focused on single sequences, thus here we present a comparison for boundary definition between single sequence and multiple sequence alignments. We also present a novel approach, named RNAbound, for finding the boundaries that are based on probabilities of evolutionarily conserved base pairings. We tested the performance of two different methods on a limited number of Rfam families using the annotated structured RNA regions in the human genome and their multiple sequence alignments created from 14 species. The results show that multiple sequence alignments improve the boundary prediction for branched structures compared to single sequences independent of the chosen method. The actual performance of the two methods differs on single hairpin structures and branched structures. For the RNA families with branched structures, including transfer RNA (tRNA) and small nucleolar RNAs (snoRNAs), RNAbound improves the boundary predictions using multiple sequence alignments to median differences of −6 and −11.5 nucleotides (nts) for left and right boundary, respectively (window size of 200 nts). Full article
(This article belongs to the Special Issue Computational Analysis of RNA Structure and Function)
Open AccessReview Homologous Recombination: To Fork and Beyond
Genes 2018, 9(12), 603; https://doi.org/10.3390/genes9120603
Received: 9 November 2018 / Revised: 29 November 2018 / Accepted: 29 November 2018 / Published: 4 December 2018
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Abstract
Accurate completion of genome duplication is threatened by multiple factors that hamper the advance and stability of the replication forks. Cells need to tolerate many of these blocking lesions to timely complete DNA replication, postponing their repair for later. This process of lesion
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Accurate completion of genome duplication is threatened by multiple factors that hamper the advance and stability of the replication forks. Cells need to tolerate many of these blocking lesions to timely complete DNA replication, postponing their repair for later. This process of lesion bypass during DNA damage tolerance can lead to the accumulation of single-strand DNA (ssDNA) fragments behind the fork, which have to be filled in before chromosome segregation. Homologous recombination plays essential roles both at and behind the fork, through fork protection/lesion bypass and post-replicative ssDNA filling processes, respectively. I review here our current knowledge about the recombination mechanisms that operate at and behind the fork in eukaryotes, and how these mechanisms are controlled to prevent unscheduled and toxic recombination intermediates. A unifying model to integrate these mechanisms in a dynamic, replication fork-associated process is proposed from yeast results. Full article
(This article belongs to the Special Issue Chromosome Replication and Genome Integrity)
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Open AccessArticle DNA Methylation Diversification at the Integrated Organellar DNA-Like Sequence
Genes 2018, 9(12), 602; https://doi.org/10.3390/genes9120602
Received: 15 October 2018 / Revised: 20 November 2018 / Accepted: 28 November 2018 / Published: 3 December 2018
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Abstract
Plants have a lot of diversity in epigenetic modifications such as DNA methylation in their natural populations or cultivars. Although many studies observing the epigenetic diversity within and among species have been reported, the mechanisms how these variations are generated are still not
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Plants have a lot of diversity in epigenetic modifications such as DNA methylation in their natural populations or cultivars. Although many studies observing the epigenetic diversity within and among species have been reported, the mechanisms how these variations are generated are still not clear. In addition to the de novo spontaneous epi-mutation, the intra- and inter-specific crossing can also cause a change of epigenetic modifications in their progenies. Here we report an example of diversification of DNA methylation by crossing and succeeding selfing. We traced the inheritance pattern of epigenetic modification during the crossing experiment between two natural strains Columbia (Col), and Landsberg electa (Ler) in model plant Arabidopsis thaliana to observe the inheritance of DNA methylation in two organellar DNA-like sequence regions in the nuclear genome. Because organellar DNA integration to the nuclear genome is common in flowering plants and these sequences are occasionally methylated, such DNA could be the novel source of plant genome evolution. The amplicon sequencing, using bisulfite-converted DNA and a next-generation auto-sequencer, was able to efficiently track the heredity of DNA methylation in F1 and F2 populations. One region showed hypomethylation in the F1 population and succeeding elevation of DNA methylation with large variance in the F2 population. The methylation level of Col and Ler alleles in F2 heterozygotes showed a significant positive correlation, implying the trans-chromosomal effect on DNA methylation. The results may suggest the possible mechanism causing the natural epigenetic diversity within plant populations. Full article
(This article belongs to the Special Issue Transgenerational Epigenetics in Plants)
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Open AccessArticle Reoptimized UNRES Potential for Protein Model Quality Assessment
Genes 2018, 9(12), 601; https://doi.org/10.3390/genes9120601 (registering DOI)
Received: 15 October 2018 / Revised: 25 November 2018 / Accepted: 27 November 2018 / Published: 3 December 2018
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Abstract
Ranking protein structure models is an elusive problem in bioinformatics. These models are evaluated on both the degree of similarity to the native structure and the folding pathway. Here, we simulated the use of the coarse-grained UNited RESidue (UNRES) force field as a
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Ranking protein structure models is an elusive problem in bioinformatics. These models are evaluated on both the degree of similarity to the native structure and the folding pathway. Here, we simulated the use of the coarse-grained UNited RESidue (UNRES) force field as a tool to choose the best protein structure models for a given protein sequence among a pool of candidate models, using server data from the CASP11 experiment. Because the original UNRES was optimized for Molecular Dynamics simulations, we reoptimized UNRES using a deep feed-forward neural network, and we show that introducing additional descriptive features can produce better results. Overall, we found that the reoptimized UNRES performs better in selecting the best structures and tracking protein unwinding from its native state. We also found a relatively poor correlation between UNRES values and the model’s Template Modeling Score (TMS). This is remedied by reoptimization. We discuss some cases where our reoptimization procedure is useful. The reoptimized version of UNRES (OUNRES) is available at http://mamiris.com and http://www.unres.pl. Full article
(This article belongs to the Special Issue Novel Approaches in Protein Structure Prediction)
Open AccessReview The Growing Complexity of UHRF1-Mediated Maintenance DNA Methylation
Genes 2018, 9(12), 600; https://doi.org/10.3390/genes9120600
Received: 1 November 2018 / Revised: 27 November 2018 / Accepted: 29 November 2018 / Published: 3 December 2018
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Abstract
Mammalian DNMT1 is mainly responsible for maintenance DNA methylation that is critical in maintaining stem cell pluripotency and controlling lineage specification during early embryonic development. A number of studies have demonstrated that DNMT1 is an auto-inhibited enzyme and its enzymatic activity is allosterically
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Mammalian DNMT1 is mainly responsible for maintenance DNA methylation that is critical in maintaining stem cell pluripotency and controlling lineage specification during early embryonic development. A number of studies have demonstrated that DNMT1 is an auto-inhibited enzyme and its enzymatic activity is allosterically regulated by a number of interacting partners. UHRF1 has previously been reported to regulate DNMT1 in multiple ways, including control of substrate specificity and the proper genome targeting. In this review, we discuss the recent advances in our understanding of the regulation of DNMT1 enzymatic activity by UHRF1 and highlight a number of unresolved questions. Full article
(This article belongs to the Special Issue Role of DNA Methyltransferases in the Epigenome)
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Open AccessArticle What Is the Giant Wall Gecko Having for Dinner? Conservation Genetics for Guiding Reserve Management in Cabo Verde
Genes 2018, 9(12), 599; https://doi.org/10.3390/genes9120599
Received: 28 October 2018 / Accepted: 17 November 2018 / Published: 3 December 2018
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Abstract
Knowledge on diet composition of a species is an important step to unveil its ecology and guide conservation actions. This is especially important for species that inhabit remote areas within biodiversity hotspots, with little information about their ecological roles. The emblematic giant wall
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Knowledge on diet composition of a species is an important step to unveil its ecology and guide conservation actions. This is especially important for species that inhabit remote areas within biodiversity hotspots, with little information about their ecological roles. The emblematic giant wall gecko of Cabo Verde, Tarentola gigas, is restricted to the uninhabited Branco and Raso islets, and presents two subspecies. It is classified as Endangered, and locally Extinct on Santa Luzia Island; however, little information is known about its diet and behaviour. In this study, we identified the main plant, arthropods, and vertebrates consumed by both gecko subspecies using next generation sequencing (NGS) (metabarcoding of faecal pellets), and compared them with the species known to occur on Santa Luzia. Results showed that plants have a significant role as diet items and identified vertebrate and invertebrate taxa with higher taxonomic resolution than traditional methods. With this study, we now have data on the diet of both subspecies for evaluating the reintroduction of this threatened gecko on Santa Luzia as potentially successful, considering the generalist character of both populations. The information revealed by these ecological networks is important for the development of conservation plans by governmental authorities, and reinforces the essential and commonly neglected role of reptiles on island systems. Full article
(This article belongs to the Special Issue Conservation Genetics and Genomics)
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Open AccessArticle The Genome of the North American Brown Bear or Grizzly: Ursus arctos ssp. horribilis
Genes 2018, 9(12), 598; https://doi.org/10.3390/genes9120598
Received: 29 October 2018 / Revised: 23 November 2018 / Accepted: 28 November 2018 / Published: 30 November 2018
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Abstract
The grizzly bear (Ursus arctos ssp. horribilis) represents the largest population of brown bears in North America. Its genome was sequenced using a microfluidic partitioning library construction technique, and these data were supplemented with sequencing from a nanopore-based long read platform.
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The grizzly bear (Ursus arctos ssp. horribilis) represents the largest population of brown bears in North America. Its genome was sequenced using a microfluidic partitioning library construction technique, and these data were supplemented with sequencing from a nanopore-based long read platform. The final assembly was 2.33 Gb with a scaffold N50 of 36.7 Mb, and the genome is of comparable size to that of its close relative the polar bear (2.30 Gb). An analysis using 4104 highly conserved mammalian genes indicated that 96.1% were found to be complete within the assembly. An automated annotation of the genome identified 19,848 protein coding genes. Our study shows that the combination of the two sequencing modalities that we used is sufficient for the construction of highly contiguous reference quality mammalian genomes. The assembled genome sequence and the supporting raw sequence reads are available from the NCBI (National Center for Biotechnology Information) under the bioproject identifier PRJNA493656, and the assembly described in this paper is version QXTK01000000. Full article
(This article belongs to the Section Animal Genetics and Genomics)
Open AccessReview Understanding the Role of the BAI Subfamily of Adhesion G Protein-Coupled Receptors (GPCRs) in Pathological and Physiological Conditions
Genes 2018, 9(12), 597; https://doi.org/10.3390/genes9120597
Received: 22 October 2018 / Revised: 24 November 2018 / Accepted: 28 November 2018 / Published: 30 November 2018
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Abstract
Brain-specific angiogenesis inhibitors (BAIs) 1, 2, and 3 are members of the adhesion G protein-coupled receptors, subfamily B, which share a conserved seven-transmembrane structure and an N-terminal extracellular domain. In cell- and animal-based studies, these receptors have been shown to play diverse roles
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Brain-specific angiogenesis inhibitors (BAIs) 1, 2, and 3 are members of the adhesion G protein-coupled receptors, subfamily B, which share a conserved seven-transmembrane structure and an N-terminal extracellular domain. In cell- and animal-based studies, these receptors have been shown to play diverse roles under physiological and pathological conditions. BAI1 is an engulfment receptor and performs major functions in apoptotic-cell clearance and interacts (as a pattern recognition receptor) with pathogen components. BAI1 and -3 also participate in myoblast fusion. Furthermore, BAI1–3 have been linked to tumor progression and neurological diseases. In this review, we summarize the current understanding of the functions of BAI1–3 in pathological and physiological conditions and discuss future directions in terms of the importance of BAIs as pharmacological targets in diseases. Full article
(This article belongs to the Section Molecular Genetics and Genomics)
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Open AccessReview N6-methyladenosine (m6A): Revisiting the Old with Focus on New, an Arabidopsis thaliana Centered Review
Genes 2018, 9(12), 596; https://doi.org/10.3390/genes9120596
Received: 25 October 2018 / Revised: 26 November 2018 / Accepted: 28 November 2018 / Published: 30 November 2018
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Abstract
N6-methyladenosine (m6A) is known to occur in plant and animal messenger RNAs (mRNAs) since the 1970s. However, the scope and function of this modification remained un-explored till very recently. Since the beginning of this decade, owing to major technological
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N6-methyladenosine (m6A) is known to occur in plant and animal messenger RNAs (mRNAs) since the 1970s. However, the scope and function of this modification remained un-explored till very recently. Since the beginning of this decade, owing to major technological breakthroughs, the interest in m6A has peaked again. Similar to animal mRNAs, plant mRNAs are also m6A methylated, within a specific sequence motif which is conserved across these kingdoms. m6A has been found to be pivotal for plant development and necessary for processes ranging from seed germination to floral development. A wide range of proteins involved in methylation of adenosine have been identified alongside proteins that remove or identify m6A. This review aims to put together the current knowledge regarding m6A in Arabidopsis thaliana. Full article
(This article belongs to the Special Issue RNA Modifications)
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Open AccessArticle Trade in Zambian Edible Orchids—DNA Barcoding Reveals the Use of Unexpected Orchid Taxa for Chikanda
Genes 2018, 9(12), 595; https://doi.org/10.3390/genes9120595
Received: 24 October 2018 / Revised: 17 November 2018 / Accepted: 22 November 2018 / Published: 30 November 2018
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Abstract
In Zambia, wild edible terrestrial orchids are used to produce a local delicacy called chikanda, which has become increasingly popular throughout the country. Commercialization puts orchid populations in Zambia and neighbouring countries at risk of overharvesting. Hitherto, no study has documented which
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In Zambia, wild edible terrestrial orchids are used to produce a local delicacy called chikanda, which has become increasingly popular throughout the country. Commercialization puts orchid populations in Zambia and neighbouring countries at risk of overharvesting. Hitherto, no study has documented which orchid species are traded on local markets, as orchid tubers are difficult to identify morphologically. In this study, the core land-plant DNA barcoding markers rbcL and matK were used in combination with nrITS to determine which species were sold in Zambian markets. Eighty-two interviews were conducted to determine harvesting areas, as well as possible sustainability concerns. By using nrITS DNA barcoding, a total of 16 orchid species in six different genera could be identified. Both rbcL and matK proved suitable to identify the tubers up to the genus or family level. Disa robusta, Platycoryne crocea and Satyrium buchananii were identified most frequently and three previously undocumented species were encountered on the market. Few orchid species are currently listed on the global International Union for the Conservation of Nature (IUCN) Red List. Local orchid populations and endemic species could be at risk of overharvesting due to the intensive and indiscriminate harvesting of chikanda orchids, and we therefore encourage increased conservation assessment of terrestrial African orchids. Full article
(This article belongs to the Special Issue DNA Barcoding and Metabarcoding of Complex Matrices)
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Open AccessArticle Two-State Co-Expression Network Analysis to Identify Genes Related to Salt Tolerance in Thai Rice
Genes 2018, 9(12), 594; https://doi.org/10.3390/genes9120594
Received: 4 October 2018 / Revised: 8 November 2018 / Accepted: 19 November 2018 / Published: 29 November 2018
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Abstract
Khao Dawk Mali 105 (KDML105) rice is one of the most important crops of Thailand. It is a challenging task to identify the genes responding to salinity in KDML105 rice. The analysis of the gene co-expression network has been widely performed to prioritize
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Khao Dawk Mali 105 (KDML105) rice is one of the most important crops of Thailand. It is a challenging task to identify the genes responding to salinity in KDML105 rice. The analysis of the gene co-expression network has been widely performed to prioritize significant genes, in order to select the key genes in a specific condition. In this work, we analyzed the two-state co-expression networks of KDML105 rice under salt-stress and normal grown conditions. The clustering coefficient was applied to both networks and exhibited significantly different structures between the salt-stress state network and the original (normal-grown) network. With higher clustering coefficients, the genes that responded to the salt stress formed a dense cluster. To prioritize and select the genes responding to the salinity, we investigated genes with small partners under normal conditions that were highly expressed and were co-working with many more partners under salt-stress conditions. The results showed that the genes responding to the abiotic stimulus and relating to the generation of the precursor metabolites and energy were the great candidates, as salt tolerant marker genes. In conclusion, in the case of the complexity of the environmental conditions, gaining more information in order to deal with the co-expression network provides better candidates for further analysis. Full article
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Open AccessArticle Improving the Gene Ontology Resource to Facilitate More Informative Analysis and Interpretation of Alzheimer’s Disease Data
Genes 2018, 9(12), 593; https://doi.org/10.3390/genes9120593
Received: 31 October 2018 / Revised: 22 November 2018 / Accepted: 23 November 2018 / Published: 29 November 2018
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Abstract
The analysis and interpretation of high-throughput datasets relies on access to high-quality bioinformatics resources, as well as processing pipelines and analysis tools. Gene Ontology (GO, geneontology.org) is a major resource for gene enrichment analysis. The aim of this project, funded by the Alzheimer’s
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The analysis and interpretation of high-throughput datasets relies on access to high-quality bioinformatics resources, as well as processing pipelines and analysis tools. Gene Ontology (GO, geneontology.org) is a major resource for gene enrichment analysis. The aim of this project, funded by the Alzheimer’s Research United Kingdom (ARUK) foundation and led by the University College London (UCL) biocuration team, was to enhance the GO resource by developing new neurological GO terms, and use GO terms to annotate gene products associated with dementia. Specifically, proteins and protein complexes relevant to processes involving amyloid-beta and tau have been annotated and the resulting annotations are denoted in GO databases as ‘ARUK-UCL’. Biological knowledge presented in the scientific literature was captured through the association of GO terms with dementia-relevant protein records; GO itself was revised, and new GO terms were added. This literature biocuration increased the number of Alzheimer’s-relevant gene products that were being associated with neurological GO terms, such as ‘amyloid-beta clearance’ or ‘learning or memory’, as well as neuronal structures and their compartments. Of the total 2055 annotations that we contributed for the prioritised gene products, 526 have associated proteins and complexes with neurological GO terms. To ensure that these descriptive annotations could be provided for Alzheimer’s-relevant gene products, over 70 new GO terms were created. Here, we describe how the improvements in ontology development and biocuration resulting from this initiative can benefit the scientific community and enhance the interpretation of dementia data. Full article
(This article belongs to the Special Issue Systems Analytics and Integration of Big Omics Data)
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