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Genes, Volume 9, Issue 1 (January 2018)

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Cover Story (view full-size image) In the absence of BPS1 gene function, plants overproduce a mobile BPS1 signaling compound in roots, [...] Read more.
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Editorial

Jump to: Research, Review, Other

Open AccessEditorial Transitioning from Forensic Genetics to Forensic Genomics
Genes 2018, 9(1), 3; doi:10.3390/genes9010003
Received: 13 December 2017 / Revised: 15 December 2017 / Accepted: 15 December 2017 / Published: 22 December 2017
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Abstract
Due to its support of law enforcement, forensics is a conservative field; nevertheless, driven by scientific and technological progress, forensic genetics is slowly transitioning into forensic genomics. With this Special Issue of Genes we acknowledge and appreciate this rather recent development by not
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Due to its support of law enforcement, forensics is a conservative field; nevertheless, driven by scientific and technological progress, forensic genetics is slowly transitioning into forensic genomics. With this Special Issue of Genes we acknowledge and appreciate this rather recent development by not only introducing the field of forensics to the wider community of geneticists, but we do so by emphasizing on different topics of forensic relevance where genomic, transcriptomic, and epigenomic principles, methods, and datasets of humans and beyond are beginning to be used to answer forensic questions. Full article
(This article belongs to the Special Issue Forensic Genomics)
Open AccessEditorial Acknowledgement to Reviewers of Genes in 2017
Genes 2018, 9(1), 33; doi:10.3390/genes9010033
Received: 9 January 2018 / Revised: 9 January 2018 / Accepted: 11 January 2018 / Published: 11 January 2018
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Abstract
Peer review is an essential part in the publication process, ensuring that Genes maintains high quality standards for its published papers.[...] Full article
Open AccessEditorial An Introduction to Integrative Genomics and Systems Medicine in Cancer
Genes 2018, 9(1), 37; doi:10.3390/genes9010037
Received: 9 January 2018 / Revised: 10 January 2018 / Accepted: 10 January 2018 / Published: 12 January 2018
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Abstract
In this Special Issue (SI), with a theme of “Integrative Genomics and Systems Medicine in Cancer”, we have collected a total of 12 research and review articles from researchers in the field of genomics and systems medicine[...] Full article
(This article belongs to the Special Issue Integrative Genomics and Systems Medicine in Cancer)

Research

Jump to: Editorial, Review, Other

Open AccessArticle Differential Preference of Burkholderia and Mesorhizobium to pH and Soil Types in the Core Cape Subregion, South Africa
Genes 2018, 9(1), 2; doi:10.3390/genes9010002
Received: 31 October 2017 / Revised: 8 December 2017 / Accepted: 13 December 2017 / Published: 22 December 2017
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Abstract
Over 760 legume species occur in the ecologically-heterogeneous Core Cape Subregion (CCR) of South Africa. This study tested whether the main symbionts of CCR legumes (Burkholderia and Mesorhizobium) are phylogenetically structured by altitude, pH and soil types. Rhizobial strains were isolated
[...] Read more.
Over 760 legume species occur in the ecologically-heterogeneous Core Cape Subregion (CCR) of South Africa. This study tested whether the main symbionts of CCR legumes (Burkholderia and Mesorhizobium) are phylogenetically structured by altitude, pH and soil types. Rhizobial strains were isolated from field nodules of diverse CCR legumes and sequenced for 16S ribosomic RNA (rRNA), recombinase A (recA) and N-acyltransferase (nodA). Phylogenetic analyses were performed using Bayesian and maximum likelihood techniques. Phylogenetic signals were determined using the D statistic for soil types and Pagel’s λ for altitude and pH. Phylogenetic relationships between symbionts of the narrowly-distributed Indigofera superba and those of some widespread CCR legumes were also determined. Results showed that Burkholderia is restricted to acidic soils, while Mesorhizobium occurs in both acidic and alkaline soils. Both genera showed significant phylogenetic clustering for pH and most soil types, but not for altitude. Therefore, pH and soil types influence the distribution of Burkholderia and Mesorhizobium in the CCR. All strains of Indigofera superba were identified as Burkholderia, and they were nested within various clades containing strains from outside its distribution range. It is, therefore, hypothesized that I. superba does not exhibit rhizobial specificity at the intragenic level. Implications for CCR legume distributions are discussed. Full article
(This article belongs to the Special Issue Genetics and Genomics of the Rhizobium-Legume Symbiosis)
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Open AccessArticle Comparative Transcriptome Analysis Reveals Hormone Signaling Genes Involved in the Launch of Culm-Shape Differentiation in Dendrocalamus sinicus
Genes 2018, 9(1), 4; doi:10.3390/genes9010004
Received: 13 November 2017 / Revised: 9 December 2017 / Accepted: 19 December 2017 / Published: 22 December 2017
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Abstract
Dendrocalamus sinicus is a sympodial bamboo species endemic to Yunnan Province, China, and is the strongest bamboo species in the world. However, there is substantial variation in the basal culm shape, i.e., straight culm (SC) and bent culm (BC), among different D. sinicus
[...] Read more.
Dendrocalamus sinicus is a sympodial bamboo species endemic to Yunnan Province, China, and is the strongest bamboo species in the world. However, there is substantial variation in the basal culm shape, i.e., straight culm (SC) and bent culm (BC), among different D. sinicus as a result of genetic and growth factors. This study performed a comparative transcriptomic analysis of bamboo shoots of two variants at the early, mid-, and late shoot-development stages to examine the molecular basis of this variation. In total, 98,479 unigenes were annotated, of which 13,495 were differentially expressed in pairwise comparisons of the six libraries. More differentially expressed genes (DEGs) were involved in SC than in BC culm development. The DEGs between BC and SC were assigned to 108 metabolic pathways. The 1064 DEGs in early development might mainly control the launch of culm-shape differentiation. Sixty genes encoding components of hormone signaling pathways were differentially expressed between BC5 and SC5, indicating complex hormonal regulation of culm differentiation. The AUX/IAA, ARF, PP2C, SnRK2, and ABF genes involved in auxin and abscisic acid signaling played key roles. These results help us to understand the molecular mechanism of culm variation and other aspects of culm development in D. sinicus. Full article
(This article belongs to the Section Plant Genetics and Genomics)
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Open AccessArticle Evolutionary Dynamics of the W Chromosome in Caenophidian Snakes
Genes 2018, 9(1), 5; doi:10.3390/genes9010005
Received: 30 November 2017 / Revised: 15 December 2017 / Accepted: 20 December 2017 / Published: 28 December 2017
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Abstract
The caenophidian (assigned also as “advanced”) snakes are traditionally viewed as a group of reptiles with a limited karyotypic variation and stable ZZ/ZW sex chromosomes. The W chromosomes of the caenophidian snakes are heterochromatic, and pioneering studies demonstrated that they are rich in
[...] Read more.
The caenophidian (assigned also as “advanced”) snakes are traditionally viewed as a group of reptiles with a limited karyotypic variation and stable ZZ/ZW sex chromosomes. The W chromosomes of the caenophidian snakes are heterochromatic, and pioneering studies demonstrated that they are rich in repetitive elements. However, a comparative study of the evolutionary dynamics of the repetitive content of the W chromosome across the whole lineage is missing. Using molecular-cytogenetic techniques, we explored the distribution of four repetitive motifs (microsatellites GATA, GACA, AG and telomeric-like sequences), which are frequently accumulated in differentiated sex chromosomes in vertebrates, in the genomes of 13 species of the caenophidian snakes covering a wide phylogenetic spectrum of the lineage. The results demonstrate a striking variability in the morphology and the repetitive content of the W chromosomes even between closely-related species, which is in contrast to the homology and long-term stability of the gene content of the caenophidian Z chromosome. We uncovered that the tested microsatellite motifs are accumulated on the degenerated, heterochromatic W chromosomes in all tested species of the caenophidian snakes with the exception of the Javan file snake representing a basal clade. On the other hand, the presence of the accumulation of the telomeric-like sequences on the caenophidian W chromosome is evolutionary much less stable. Moreover, we demonstrated that large accumulations of telomeric-like motifs on the W chromosome contribute to sexual differences in the number of copies of the telomeric and telomeric-like repeats estimated by quantitative PCR, which might be confusing and incorrectly interpreted as sexual differences in telomere length. Full article
(This article belongs to the Special Issue Chromosomal Evolution)
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Open AccessArticle ConGEMs: Condensed Gene Co-Expression Module Discovery Through Rule-Based Clustering and Its Application to Carcinogenesis
Genes 2018, 9(1), 7; doi:10.3390/genes9010007
Received: 2 August 2017 / Revised: 12 December 2017 / Accepted: 12 December 2017 / Published: 28 December 2017
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Abstract
For transcriptomic analysis, there are numerous microarray-based genomic data, especially those generated for cancer research. The typical analysis measures the difference between a cancer sample-group and a matched control group for each transcript or gene. Association rule mining is used to discover interesting
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For transcriptomic analysis, there are numerous microarray-based genomic data, especially those generated for cancer research. The typical analysis measures the difference between a cancer sample-group and a matched control group for each transcript or gene. Association rule mining is used to discover interesting item sets through rule-based methodology. Thus, it has advantages to find causal effect relationships between the transcripts. In this work, we introduce two new rule-based similarity measures—weighted rank-based Jaccard and Cosine measures—and then propose a novel computational framework to detect condensed gene co-expression modules ( C o n G E M s) through the association rule-based learning system and the weighted similarity scores. In practice, the list of evolved condensed markers that consists of both singular and complex markers in nature depends on the corresponding condensed gene sets in either antecedent or consequent of the rules of the resultant modules. In our evaluation, these markers could be supported by literature evidence, KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway and Gene Ontology annotations. Specifically, we preliminarily identified differentially expressed genes using an empirical Bayes test. A recently developed algorithm—RANWAR—was then utilized to determine the association rules from these genes. Based on that, we computed the integrated similarity scores of these rule-based similarity measures between each rule-pair, and the resultant scores were used for clustering to identify the co-expressed rule-modules. We applied our method to a gene expression dataset for lung squamous cell carcinoma and a genome methylation dataset for uterine cervical carcinogenesis. Our proposed module discovery method produced better results than the traditional gene-module discovery measures. In summary, our proposed rule-based method is useful for exploring biomarker modules from transcriptomic data. Full article
(This article belongs to the Special Issue Integrative Genomics and Systems Medicine in Cancer)
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Open AccessArticle RAD4 and RAD23/HMR Contribute to Arabidopsis UV Tolerance
Genes 2018, 9(1), 8; doi:10.3390/genes9010008
Received: 12 October 2017 / Revised: 15 December 2017 / Accepted: 19 December 2017 / Published: 28 December 2017
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Abstract
In plants, exposure to solar ultraviolet (UV) light is unavoidable, resulting in DNA damage. Damaged DNA causes mutations, replication arrest, and cell death, thus efficient repair of the damaged DNA is essential. A light-independent DNA repair pathway called nucleotide excision repair (NER) is
[...] Read more.
In plants, exposure to solar ultraviolet (UV) light is unavoidable, resulting in DNA damage. Damaged DNA causes mutations, replication arrest, and cell death, thus efficient repair of the damaged DNA is essential. A light-independent DNA repair pathway called nucleotide excision repair (NER) is conserved throughout evolution. For example, the damaged DNA-binding protein Radiation sensitive 4 (Rad4) in Saccharomyces cerevisiae is homologous to the mammalian NER protein Xeroderma Pigmentosum complementation group C (XPC). In this study, we examined the role of the Arabidopsis thaliana Rad4/XPC homologue (AtRAD4) in plant UV tolerance by generating overexpression lines. AtRAD4 overexpression, both with and without an N-terminal yellow fluorescent protein (YFP) tag, resulted in increased UV tolerance. YFP-RAD4 localized to the nucleus, and UV treatment did not alter this localization. We also used yeast two-hybrid analysis to examine the interaction of AtRAD4 with Arabidopsis RAD23 and found that RAD4 interacted with RAD23B as well as with the structurally similar protein HEMERA (HMR). In addition, we found that hmr and rad23 mutants exhibited increased UV sensitivity. Thus, our analysis suggests a role for RAD4 and RAD23/HMR in plant UV tolerance. Full article
(This article belongs to the Special Issue DNA Damage Responses in Plants)
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Open AccessArticle In BPS1 Downregulated Roots, the BYPASS1 Signal Disrupts the Induction of Cortical Cell Divisions in Bean-Rhizobium Symbiosis
Genes 2018, 9(1), 11; doi:10.3390/genes9010011
Received: 1 November 2017 / Revised: 23 December 2017 / Accepted: 27 December 2017 / Published: 3 January 2018
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Abstract
BYPASS1 (BPS1), which is a well-conserved gene in plants, is required for normal root and shoot development. In the absence of BPS1 gene function, Arabidopsis overproduces a mobile signalling compound (the BPS1 signal) in roots, and this transmissible signal arrests shoot
[...] Read more.
BYPASS1 (BPS1), which is a well-conserved gene in plants, is required for normal root and shoot development. In the absence of BPS1 gene function, Arabidopsis overproduces a mobile signalling compound (the BPS1 signal) in roots, and this transmissible signal arrests shoot growth and causes abnormal root development. In addition to the shoot and root meristem activities, the legumes also possess transient meristematic activity in root cortical cells during Rhizobium symbiosis. We explored the role of Phaseolus vulgaris BPS1 during nodule primordium development using an RNA-interference (RNAi) silencing approach. Our results show that upon Rhizobium infection, the PvBPS1-RNAi transgenic roots failed to induce cortical cell divisions without affecting the rhizobia-induced root hair curling and infection thread formation. The transcript accumulation of early nodulin genes, cell cyclins, and cyclin-dependent kinase genes was affected in RNAi lines. Interestingly, the PvBPS1-RNAi root nodule phenotype was partially rescued by exogenous application of fluridone, a carotenoid biosynthesis inhibitor, which was used because the carotenoids are precursors of BPS1 signalling molecules. Furthermore, we show that the PvBPS1 promoter was active in the nodule primordia. Together, our data show that PvBPS1 plays a vital role in the induction of meristematic activity in root cortical cells and in the establishment of nodule primordia during Phaseolus-Rhizobium symbiosis. Full article
(This article belongs to the Special Issue Genetics and Genomics of the Rhizobium-Legume Symbiosis)
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Open AccessArticle Transcription Factor and lncRNA Regulatory Networks Identify Key Elements in Lung Adenocarcinoma
Genes 2018, 9(1), 12; doi:10.3390/genes9010012
Received: 19 September 2017 / Revised: 15 December 2017 / Accepted: 21 December 2017 / Published: 5 January 2018
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Abstract
Lung cancer is the second most commonly diagnosed carcinoma and is the leading cause of cancer death. Although significant progress has been made towards its understanding and treatment, unraveling the complexities of lung cancer is still hampered by a lack of comprehensive knowledge
[...] Read more.
Lung cancer is the second most commonly diagnosed carcinoma and is the leading cause of cancer death. Although significant progress has been made towards its understanding and treatment, unraveling the complexities of lung cancer is still hampered by a lack of comprehensive knowledge on the mechanisms underlying the disease. High-throughput and multidimensional genomic data have shed new light on cancer biology. In this study, we developed a network-based approach integrating somatic mutations, the transcriptome, DNA methylation, and protein-DNA interactions to reveal the key regulators in lung adenocarcinoma (LUAD). By combining Bayesian network analysis with tissue-specific transcription factor (TF) and targeted gene interactions, we inferred 15 disease-related core regulatory networks in co-expression gene modules associated with LUAD. Through target gene set enrichment analysis, we identified a set of key TFs, including known cancer genes that potentially regulate the disease networks. These TFs were significantly enriched in multiple cancer-related pathways. Specifically, our results suggest that hepatitis viruses may contribute to lung carcinogenesis, highlighting the need for further investigations into the roles that viruses play in treating lung cancer. Additionally, 13 putative regulatory long non-coding RNAs (lncRNAs), including three that are known to be associated with lung cancer, and nine novel lncRNAs were revealed by our study. These lncRNAs and their target genes exhibited high interaction potentials and demonstrated significant expression correlations between normal lung and LUAD tissues. We further extended our study to include 16 solid-tissue tumor types and determined that the majority of these lncRNAs have putative regulatory roles in multiple cancers, with a few showing lung-cancer specific regulations. Our study provides a comprehensive investigation of transcription factor and lncRNA regulation in the context of LUAD regulatory networks and yields new insights into the regulatory mechanisms underlying LUAD. The novel key regulatory elements discovered by our research offer new targets for rational drug design and accompanying therapeutic strategies. Full article
(This article belongs to the Special Issue Protein-DNA Interactions)
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Open AccessArticle Splicing Analysis of Exonic OCRL Mutations Causing Lowe Syndrome or Dent-2 Disease
Genes 2018, 9(1), 15; doi:10.3390/genes9010015
Received: 9 November 2017 / Revised: 11 December 2017 / Accepted: 27 December 2017 / Published: 4 January 2018
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Abstract
Mutations in the OCRL gene are associated with both Lowe syndrome and Dent-2 disease. Patients with Lowe syndrome present congenital cataracts, mental disabilities and a renal proximal tubulopathy, whereas patients with Dent-2 disease exhibit similar proximal tubule dysfunction but only mild, or no
[...] Read more.
Mutations in the OCRL gene are associated with both Lowe syndrome and Dent-2 disease. Patients with Lowe syndrome present congenital cataracts, mental disabilities and a renal proximal tubulopathy, whereas patients with Dent-2 disease exhibit similar proximal tubule dysfunction but only mild, or no additional clinical defects. It is not yet understood why some OCRL mutations cause the phenotype of Lowe syndrome, while others develop the milder phenotype of Dent-2 disease. Our goal was to gain new insights into the consequences of OCRL exonic mutations on pre-mRNA splicing. Using predictive bioinformatics tools, we selected thirteen missense mutations and one synonymous mutation based on their potential effects on splicing regulatory elements or splice sites. These mutations were analyzed in a minigene splicing assay. Results of the RNA analysis showed that three presumed missense mutations caused alterations in pre-mRNA splicing. Mutation c.741G>T; p.(Trp247Cys) generated splicing silencer sequences and disrupted splicing enhancer motifs that resulted in skipping of exon 9, while mutations c.2581G>A; p.(Ala861Thr) and c.2581G>C; p.(Ala861Pro) abolished a 5′ splice site leading to skipping of exon 23. Mutation c.741G>T represents the first OCRL exonic variant outside the conserved splice site dinucleotides that results in alteration of pre-mRNA splicing. Our results highlight the importance of evaluating the effects of OCRL exonic mutations at the mRNA level. Full article
(This article belongs to the Special Issue Aberrant Pre-mRNA Splicing in Disease)
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Open AccessArticle SNCA Is a Functionally Low-Expressed Gene in Lung Adenocarcinoma
Genes 2018, 9(1), 16; doi:10.3390/genes9010016
Received: 6 December 2017 / Revised: 1 January 2018 / Accepted: 2 January 2018 / Published: 4 January 2018
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Abstract
There is increasing evidence for the contribution of synuclein alpha (SNCA) to the etiology of neurological disorders, such as Parkinson’s disease (PD). However, little is known about the detailed role of SNCA in human cancers, especially lung cancers. Here, we evaluated
[...] Read more.
There is increasing evidence for the contribution of synuclein alpha (SNCA) to the etiology of neurological disorders, such as Parkinson’s disease (PD). However, little is known about the detailed role of SNCA in human cancers, especially lung cancers. Here, we evaluated the effects of SNCA on the occurrence and prognosis of lung adenocarcinoma (ADC). Comprehensive bioinformatics analyses of data obtained from the Oncomine platform, the human protein atlas (HPA) project and the cancer cell line encyclopedia (CCLE) demonstrated that SNCA expression was significantly reduced in both ADC tissues and cancer cells. The results of relevant clinical studies indicated that down-regulation of SNCA was statistically correlated with shorter overall survival time and post-progression survival time. Through analysis of datasets obtained from the Gene Expression Omnibus database, significant low levels of SNCA were identified in cisplatin-resistant ADC cells. Moreover, small interfering RNA (siRNA)-mediated knockdown of protein tyrosine kinase 7 (PTK7) elevated the expression of SNCA in the ADC cell lines H1299 and H2009. Our work demonstrates that low levels of SNCA are specifically found in ADC and that this gene may be a potential therapeutic target for this subset of lung cancers. Determination of the role of SNCA in ADC biology would give us some insightful information for further investigations. Full article
(This article belongs to the Special Issue Computational Approaches for Disease Gene Identification)
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Open AccessArticle Linking DNA Damage and Age-Related Promoter DNA Hyper-Methylation in the Intestine
Genes 2018, 9(1), 17; doi:10.3390/genes9010017
Received: 20 November 2017 / Revised: 21 December 2017 / Accepted: 21 December 2017 / Published: 5 January 2018
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Abstract
Aberrant DNA methylation in stem cells is a hallmark of aging and tumor development. Here, we explore whether and how DNA damage repair might impact on these time-dependent changes, in particular in proliferative intestinal stem cells. We introduce a 3D multiscale computer model
[...] Read more.
Aberrant DNA methylation in stem cells is a hallmark of aging and tumor development. Here, we explore whether and how DNA damage repair might impact on these time-dependent changes, in particular in proliferative intestinal stem cells. We introduce a 3D multiscale computer model of intestinal crypts enabling simulation of aberrant DNA and histone methylation of gene promoters during aging. We assume histone state-dependent activity of de novo DNA methyltransferases (DNMTs) and methylation-dependent binding of maintenance DNMTs to CpGs. We simulate aging with and without repeated DNA repair. Motivated by recent findings on the histone demethylase KDM2b, we consider that DNA repair is associated with chromatin opening and improved recruitment of de novo DNMTs. Our results suggest that methylation-dependent binding of maintenance DNMTs to CpGs, establishing bistable DNA methylation states, is a prerequisite to promoter hyper-methylation following DNA repair. With this, the transient increase in de novo DNMT activity during repair can induce switches from low to high methylation states. These states remain stable after repair, leading to an epigenetic drift. The switches are most frequent in genes with H3K27me3 modified promoters. Our model provides a mechanistic explanation on how even successful DNA repair might confer long term changes of the epigenome. Full article
(This article belongs to the Special Issue The Epigenetics of Aging and Longevity)
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Open AccessArticle High Density Single Nucleotide Polymorphism (SNP) Mapping and Quantitative Trait Loci (QTL) Analysis in a Biparental Spring Triticale Population Localized Major and Minor Effect Fusarium Head Blight Resistance and Associated Traits QTL
Genes 2018, 9(1), 19; doi:10.3390/genes9010019
Received: 15 November 2017 / Revised: 19 December 2017 / Accepted: 28 December 2017 / Published: 5 January 2018
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Abstract
Triticale (xTriticosecale Wittmack) is an important feed crop which suffers severe yield, grade and end-use quality losses due to Fusarium head blight (FHB). Development of resistant triticale cultivars is hindered by lack of effective genetic resistance sources. To dissect FHB resistance, a
[...] Read more.
Triticale (xTriticosecale Wittmack) is an important feed crop which suffers severe yield, grade and end-use quality losses due to Fusarium head blight (FHB). Development of resistant triticale cultivars is hindered by lack of effective genetic resistance sources. To dissect FHB resistance, a doubled haploid spring triticale population produced from the cross TMP16315/AC Ultima using a microspore culture method, was phenotyped for FHB incidence, severity, visual rating index (VRI), deoxynivalenol (DON) and some associated traits (ergot, grain protein content, test weight, yield, plant height and lodging) followed by single nucleotide polymorphism (SNP) genotyping. A high-density map consisting of 5274 SNPs, mapped on all 21 chromosomes with a map density of 0.48 cM/SNP, was constructed. Together, 17 major quantitative trait loci were identified for FHB on chromosomes 1A, 2B, 3A, 4A, 4R, 5A, 5R and 6B; two of incidence loci (on 2B and 5R) also co-located with loci for severity and VRI, and two other loci of VRI (on 1A and 4R) with DON accumulation. Major and minor loci were also identified for all other traits in addition to many epistasis loci. This study provides new insight into the genetic basis of FHB resistance and their association with other traits in triticale. Full article
(This article belongs to the Section Plant Genetics and Genomics)
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Open AccessArticle Identification of Inherited Retinal Disease-Associated Genetic Variants in 11 Candidate Genes
Genes 2018, 9(1), 21; doi:10.3390/genes9010021
Received: 20 October 2017 / Revised: 31 December 2017 / Accepted: 3 January 2018 / Published: 10 January 2018
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Abstract
Inherited retinal diseases (IRDs) display an enormous genetic heterogeneity. Whole exome sequencing (WES) recently identified genes that were mutated in a small proportion of IRD cases. Consequently, finding a second case or family carrying pathogenic variants in the same candidate gene often is
[...] Read more.
Inherited retinal diseases (IRDs) display an enormous genetic heterogeneity. Whole exome sequencing (WES) recently identified genes that were mutated in a small proportion of IRD cases. Consequently, finding a second case or family carrying pathogenic variants in the same candidate gene often is challenging. In this study, we searched for novel candidate IRD gene-associated variants in isolated IRD families, assessed their causality, and searched for novel genotype-phenotype correlations. Whole exome sequencing was performed in 11 probands affected with IRDs. Homozygosity mapping data was available for five cases. Variants with minor allele frequencies ≤ 0.5% in public databases were selected as candidate disease-causing variants. These variants were ranked based on their: (a) presence in a gene that was previously implicated in IRD; (b) minor allele frequency in the Exome Aggregation Consortium database (ExAC); (c) in silico pathogenicity assessment using the combined annotation dependent depletion (CADD) score; and (d) interaction of the corresponding protein with known IRD-associated proteins. Twelve unique variants were found in 11 different genes in 11 IRD probands. Novel autosomal recessive and dominant inheritance patterns were found for variants in Small Nuclear Ribonucleoprotein U5 Subunit 200 (SNRNP200) and Zinc Finger Protein 513 (ZNF513), respectively. Using our pathogenicity assessment, a variant in DEAH-Box Helicase 32 (DHX32) was the top ranked novel candidate gene to be associated with IRDs, followed by eight medium and lower ranked candidate genes. The identification of candidate disease-associated sequence variants in 11 single families underscores the notion that the previously identified IRD-associated genes collectively carry > 90% of the defects implicated in IRDs. To identify multiple patients or families with variants in the same gene and thereby provide extra proof for pathogenicity, worldwide data sharing is needed. Full article
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Open AccessArticle Identification of Transposable Elements Contributing to Tissue-Specific Expression of Long Non-Coding RNAs
Genes 2018, 9(1), 23; doi:10.3390/genes9010023
Received: 30 November 2017 / Revised: 24 December 2017 / Accepted: 28 December 2017 / Published: 9 January 2018
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Abstract
It has been recently suggested that transposable elements (TEs) are re-used as functional elements of long non-coding RNAs (lncRNAs). This is supported by some examples such as the human endogenous retrovirus subfamily H (HERVH) elements contained within lncRNAs and expressed specifically in human
[...] Read more.
It has been recently suggested that transposable elements (TEs) are re-used as functional elements of long non-coding RNAs (lncRNAs). This is supported by some examples such as the human endogenous retrovirus subfamily H (HERVH) elements contained within lncRNAs and expressed specifically in human embryonic stem cells (hESCs), as required to maintain hESC identity. There are at least two unanswered questions about all lncRNAs. How many TEs are re-used within lncRNAs? Are there any other TEs that affect tissue specificity of lncRNA expression? To answer these questions, we comprehensively identify TEs that are significantly related to tissue-specific expression levels of lncRNAs. We downloaded lncRNA expression data corresponding to normal human tissue from the Expression Atlas and transformed the data into tissue specificity estimates. Then, Fisher’s exact tests were performed to verify whether the presence or absence of TE-derived sequences influences the tissue specificity of lncRNA expression. Many TE–tissue pairs associated with tissue-specific expression of lncRNAs were detected, indicating that multiple TE families can be re-used as functional domains or regulatory sequences of lncRNAs. In particular, we found that the antisense promoter region of L1PA2, a LINE-1 subfamily, appears to act as a promoter for lncRNAs with placenta-specific expression. Full article
(This article belongs to the Special Issue Non-coding RNAs)
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Open AccessArticle Structural and Evolutionary Relationships in the Giant Sex Chromosomes of Three Microtus Species
Genes 2018, 9(1), 27; doi:10.3390/genes9010027
Received: 16 November 2017 / Revised: 20 December 2017 / Accepted: 3 January 2018 / Published: 10 January 2018
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Abstract
The genus Microtus has high karyotypic diversity. The existence of notable differences in the length of its sex chromosomes contributes to this variation. Variations in size are attributed to the enlargement of their heterochromatin content, which is of such magnitude in some species
[...] Read more.
The genus Microtus has high karyotypic diversity. The existence of notable differences in the length of its sex chromosomes contributes to this variation. Variations in size are attributed to the enlargement of their heterochromatin content, which is of such magnitude in some species that they are referred to as “giant sex chromosomes”. Here, we perform an intra- and interspecific analysis of the molecular composition of the heterochromatic blocks in three species with giant sex chromosomes (Microtus chrotorrhinus, M. cabrerae and M. agrestis). Our results show that the heterochromatic content is very similar in both the X and Y chromosomes of M. chrotorrhinus, and that their molecular composition is more closely related to the heterochromatic blocks of M. agrestis than to the sex heterochromatin of M. cabrerae; however, species-specific differences do clearly exist. Interestingly, the euchromatic regions of the X chromosome of all three of these species share a homologous region composed of heterochromatic-related sequences. Our results therefore reinforce the idea that certain similarities in the original organization of these X chromosomes could have facilitated their later enlargement. Full article
(This article belongs to the Section Animal Genetics and Genomics)
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Open AccessArticle The Landscape of Small Non-Coding RNAs in Triple-Negative Breast Cancer
Genes 2018, 9(1), 29; doi:10.3390/genes9010029
Received: 7 November 2017 / Revised: 21 December 2017 / Accepted: 4 January 2018 / Published: 10 January 2018
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Abstract
Triple-negative breast cancer (TNBC) is an operational term for breast cancers lacking targetable estrogen receptor expression and HER2 amplifications. TNBC is, therefore, inherently heterogeneous, and is associated with worse prognosis, greater rates of metastasis, and earlier onset. TNBC displays mutational and transcriptional diversity,
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Triple-negative breast cancer (TNBC) is an operational term for breast cancers lacking targetable estrogen receptor expression and HER2 amplifications. TNBC is, therefore, inherently heterogeneous, and is associated with worse prognosis, greater rates of metastasis, and earlier onset. TNBC displays mutational and transcriptional diversity, and distinct mRNA transcriptional subtypes exhibiting unique biology. High-throughput sequencing has extended cancer research far beyond protein coding regions that include non-coding small RNAs, such as miRNA, isomiR, tRNA, snoRNAs, snRNA, yRNA, 7SL, and 7SK. In this study, we performed small RNA profiling of 26 TNBC cell lines, and compared the abundance of non-coding RNAs among the transcriptional subtypes of triple negative breast cancer. We also examined their co-expression pattern with corresponding mRNAs. This study provides a detailed description of small RNA expression in triple-negative breast cancer cell lines that can aid in the development of future biomarker and novel targeted therapies. Full article
(This article belongs to the Special Issue Non-coding RNAs)
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Open AccessArticle Characterization of Translationally Controlled Tumour Protein from the Sea Anemone Anemonia viridis and Transcriptome Wide Identification of Cnidarian Homologues
Genes 2018, 9(1), 30; doi:10.3390/genes9010030
Received: 10 November 2017 / Revised: 5 January 2018 / Accepted: 5 January 2018 / Published: 11 January 2018
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Abstract
Gene family encoding translationally controlled tumour protein (TCTP) is defined as highly conserved among organisms; however, there is limited knowledge of non-bilateria. In this study, the first TCTP homologue from anthozoan was characterised in the Mediterranean Sea anemone, Anemonia viridis. The release
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Gene family encoding translationally controlled tumour protein (TCTP) is defined as highly conserved among organisms; however, there is limited knowledge of non-bilateria. In this study, the first TCTP homologue from anthozoan was characterised in the Mediterranean Sea anemone, Anemonia viridis. The release of the genome sequence of Acropora digitifera, Exaiptasia pallida, Nematostella vectensis and Hydra vulgaris enabled a comprehensive study of the molecular evolution of TCTP family among cnidarians. A comparison among TCTP members from Cnidaria and Bilateria showed conserved intron exon organization, evolutionary conserved TCTP signatures and 3D protein structure. The pattern of mRNA expression profile was also defined in A. viridis. These analyses revealed a constitutive mRNA expression especially in tissues with active proliferation. Additionally, the transcriptional profile of A. viridis TCTP (AvTCTP) after challenges with different abiotic/biotic stresses showed induction by extreme temperatures, heavy metals exposure and immune stimulation. These results suggest the involvement of AvTCTP in the sea anemone defensome taking part in environmental stress and immune responses. Full article
(This article belongs to the Section Population and Evolutionary Genetics and Genomics)
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Open AccessArticle Genome-Wide Methylation Patterns in Androgen-Independent Prostate Cancer Cells: A Comprehensive Analysis Combining MeDIP-Bisulfite, RNA, and microRNA Sequencing Data
Genes 2018, 9(1), 32; doi:10.3390/genes9010032
Received: 30 November 2017 / Revised: 21 December 2017 / Accepted: 30 December 2017 / Published: 11 January 2018
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Abstract
This study aimed to investigate the mechanisms underlying the development of the androgen-independent phenotype in prostate cancer. Methylation patterns were detected in androgen-independent and androgen-dependent lymph node carcinoma of the prostate (LNCaP) prostate carcinoma cells based on methylated DNA immunoprecipitation-bisulfite sequencing data and
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This study aimed to investigate the mechanisms underlying the development of the androgen-independent phenotype in prostate cancer. Methylation patterns were detected in androgen-independent and androgen-dependent lymph node carcinoma of the prostate (LNCaP) prostate carcinoma cells based on methylated DNA immunoprecipitation-bisulfite sequencing data and differentially methylated regions (DMRs) were identified. Differentially expressed genes (DEGs) and micro RNAs (miRNAs) with DMRs (named MDEGs and MDEmiRNAs) were identified by combining transcriptome and methylation data, and transcription factor (TF)-DEGs with DMRs in promoter (PMDEGs) and MDEmiRNA-MDEGs networks were constructed. Furthermore, a time-course analysis of gene transcription during androgen deprivation was performed based on microarray data and DMRs, MDEGs, and DEmiRNAs were validated. In total, 18,447 DMRs, 3369 MDEGs, 850 PMDEGs, and 1 MDEmiRNA (miR-429) were identified. A TF-target network (94 PMDEGs and 5 TFs) and a miRNA–target network (172 MDEGs and miR-429) were constructed. Based on the time-course analysis of genes in the networks, NEDD4L and PBX3 were targeted by SOX5, while GNAQ, ANLN, and KIF11 were targeted by miR-429. The expression levels of these genes and miR-429 were confirmed by quantitative real-time polymerase chain reaction. Additionally, 109 DMRs were confirmed using additional public datasets. The regulatory pathways SOX5-NEDD4L/PBX3, miR429-GNAQ/ANLNRHOA, and miR429-ANLNKIF11 may participate in the progression of the androgen-independent phenotype in prostate cancer. Full article
(This article belongs to the Section Technologies and Resources for Genetics)
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Open AccessArticle Dissection of Myogenic Differentiation Signatures in Chickens by RNA-Seq Analysis
Genes 2018, 9(1), 34; doi:10.3390/genes9010034
Received: 9 November 2017 / Revised: 22 December 2017 / Accepted: 3 January 2018 / Published: 11 January 2018
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Abstract
A series of elaborately regulated and orchestrated changes in gene expression profiles leads to muscle growth and development. In this study, RNA sequencing was used to profile embryonic chicken myoblasts and fused myotube transcriptomes, long non-coding RNAs (lncRNAs), and messenger RNAs (mRNAs) at
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A series of elaborately regulated and orchestrated changes in gene expression profiles leads to muscle growth and development. In this study, RNA sequencing was used to profile embryonic chicken myoblasts and fused myotube transcriptomes, long non-coding RNAs (lncRNAs), and messenger RNAs (mRNAs) at four stages of myoblast differentiation. Of a total of 2484 lncRNA transcripts, 2288 were long intergenic non-coding RNAs (lincRNAs) and 198 were antisense lncRNAs. Additionally, 1530 lncRNAs were neighboring 2041 protein-coding genes (<10 kb upstream and downstream) and functionally enriched in several pathways related to skeletal muscle development that have been extensively studied, indicating that these genes may be in cis-regulatory relationships. In addition, Pearson’s correlation coefficients demonstrated that 990 lncRNAs and 7436 mRNAs were possibly in trans-regulatory relationships. These co-expressed mRNAs were enriched in various developmentally-related biological processes, such as myocyte proliferation and differentiation, myoblast differentiation, and myoblast fusion. The number of transcripts (906 lncRNAs and 4422 mRNAs) differentially expressed across various stages declined with the progression of differentiation. Then, 4422 differentially expressed genes were assigned to four clusters according to K-means analysis. Genes in the K1 cluster likely play important roles in myoblast proliferation and those in the K4 cluster were likely associated with the initiation of myoblast differentiation, while genes in the K2 and K3 clusters were likely related to myoblast fusion. This study provides a catalog of chicken lncRNAs and mRNAs for further experimental investigations and facilitates a better understanding of skeletal muscle development. Full article
(This article belongs to the Section Animal Genetics and Genomics)
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Open AccessArticle Comparative Transcriptome Analysis Identifies Putative Genes Involved in Steroid Biosynthesis in Euphorbia tirucalli
Genes 2018, 9(1), 38; doi:10.3390/genes9010038
Received: 17 November 2017 / Revised: 9 January 2018 / Accepted: 11 January 2018 / Published: 15 January 2018
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Abstract
Phytochemical analysis of different Euphorbia tirucalli tissues revealed a contrasting tissue-specificity for the biosynthesis of euphol and β-sitosterol, which represent the two pharmaceutically active steroids in E. tirucalli. To uncover the molecular mechanism underlying this tissue-specificity for phytochemicals, a comprehensive E. tirucalli
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Phytochemical analysis of different Euphorbia tirucalli tissues revealed a contrasting tissue-specificity for the biosynthesis of euphol and β-sitosterol, which represent the two pharmaceutically active steroids in E. tirucalli. To uncover the molecular mechanism underlying this tissue-specificity for phytochemicals, a comprehensive E. tirucalli transcriptome derived from its root, stem, leaf and latex was constructed, and a total of 91,619 unigenes were generated with 51.08% being successfully annotated against the non-redundant (Nr) protein database. A comparison of the transcriptome from different tissues discovered members of unigenes in the upstream steps of sterol backbone biosynthesis leading to this tissue-specific sterol biosynthesis. Among them, the putative oxidosqualene cyclase (OSC) encoding genes involved in euphol synthesis were notably identified, and their expressions were significantly up-regulated in the latex. In addition, genome-wide differentially expressed genes (DEGs) in the different E. tirucalli tissues were identified. The cluster analysis of those DEGs showed a unique expression pattern in the latex compared with other tissues. The DEGs identified in this study would enrich the insights of sterol biosynthesis and the regulation mechanism of this latex-specificity. Full article
(This article belongs to the Section Plant Genetics and Genomics)
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Open AccessArticle Network-Based Methods for Identifying Key Active Proteins in the Extracellular Electron Transfer Process in Shewanella oneidensis MR-1
Genes 2018, 9(1), 41; doi:10.3390/genes9010041
Received: 13 December 2017 / Revised: 7 January 2018 / Accepted: 12 January 2018 / Published: 16 January 2018
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Abstract
Shewanella oneidensis MR-1 can transfer electrons from the intracellular environment to the extracellular space of the cells to reduce the extracellular insoluble electron acceptors (Extracellular Electron Transfer, EET). Benefiting from this EET capability, Shewanella has been widely used in different areas, such as
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Shewanella oneidensis MR-1 can transfer electrons from the intracellular environment to the extracellular space of the cells to reduce the extracellular insoluble electron acceptors (Extracellular Electron Transfer, EET). Benefiting from this EET capability, Shewanella has been widely used in different areas, such as energy production, wastewater treatment, and bioremediation. Genome-wide proteomics data was used to determine the active proteins involved in activating the EET process. We identified 1012 proteins with decreased expression and 811 proteins with increased expression when the EET process changed from inactivation to activation. We then networked these proteins to construct the active protein networks, and identified the top 20 key active proteins by network centralization analysis, including metabolism- and energy-related proteins, signal and transcriptional regulatory proteins, translation-related proteins, and the EET-related proteins. We also constructed the integrated protein interaction and transcriptional regulatory networks for the active proteins, then found three exclusive active network motifs involved in activating the EET process—Bi-feedforward Loop, Regulatory Cascade with a Feedback, and Feedback with a Protein–Protein Interaction (PPI)—and identified the active proteins involved in these motifs. Both enrichment analysis and comparative analysis to the whole-genome data implicated the multiheme c-type cytochromes and multiple signal processing proteins involved in the process. Furthermore, the interactions of these motif-guided active proteins and the involved functional modules were discussed. Collectively, by using network-based methods, this work reported a proteome-wide search for the key active proteins that potentially activate the EET process. Full article
(This article belongs to the Section Microbial Genetics and Genomics)
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Open AccessArticle Copy Number Variation in SOX6 Contributes to Chicken Muscle Development
Genes 2018, 9(1), 42; doi:10.3390/genes9010042
Received: 31 October 2017 / Revised: 11 January 2018 / Accepted: 12 January 2018 / Published: 17 January 2018
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Abstract
Copy number variations (CNVs), which cover many functional genes, are associated with complex diseases, phenotypic diversity and traits that are economically important to raising chickens. The sex-determining region Y-box 6 (Sox6) plays a key role in fast-twitch muscle fiber differentiation of
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Copy number variations (CNVs), which cover many functional genes, are associated with complex diseases, phenotypic diversity and traits that are economically important to raising chickens. The sex-determining region Y-box 6 (Sox6) plays a key role in fast-twitch muscle fiber differentiation of zebrafish and mice, but it is still unknown whether SOX6 plays a role in chicken skeletal muscle development. We identified two copy number polymorphisms (CNPs) which were significantly related to different traits on the genome level in chickens by AccuCopy® and CNVplex® analyses. Notably, five white recessive rock (CN = 1, CN = 3) variant individuals and two Xinghua (CN = 3) variant individuals contain a CNP13 (chromosome5: 10,500,294–10,675,531) which overlaps with SOX6. There is a disordered region in SOX6 proteins 265–579 aa coded by a partial CNV overlapping region. A quantitative real-time polymerase chain reaction showed that the expression level of SOX6 mRNA was positively associated with CNV and highly expressed during the skeletal muscle cell differentiation in chickens. After the knockdown of the SOX6, the expression levels of IGFIR1, MYF6, SOX9, SHOX and CCND1 were significantly down-regulated. All of them directly linked to muscle development. These results suggest that the number of CNVs in the CNP13 is positively associated with the expression level of SOX6, which promotes the proliferation and differentiation of skeletal muscle cells by up-regulating the expression levels of the muscle-growth-related genes in chickens as in other animal species. Full article
(This article belongs to the Special Issue Complex Genetic Loci)
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Open AccessArticle Molecular Network-Based Identification of Competing Endogenous RNAs in Thyroid Carcinoma
Genes 2018, 9(1), 44; doi:10.3390/genes9010044
Received: 12 December 2017 / Revised: 10 January 2018 / Accepted: 11 January 2018 / Published: 19 January 2018
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Abstract
RNAs may act as competing endogenous RNAs (ceRNAs), a critical mechanism in determining gene expression regulations in many cancers. However, the roles of ceRNAs in thyroid carcinoma remains elusive. In this study, we have developed a novel pipeline called Molecular Network-based Identification of
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RNAs may act as competing endogenous RNAs (ceRNAs), a critical mechanism in determining gene expression regulations in many cancers. However, the roles of ceRNAs in thyroid carcinoma remains elusive. In this study, we have developed a novel pipeline called Molecular Network-based Identification of ceRNA (MNIceRNA) to identify ceRNAs in thyroid carcinoma. MNIceRNA first constructs micro RNA (miRNA)–messenger RNA (mRNA)long non-coding RNA (lncRNA) networks from miRcode database and weighted correlation network analysis (WGCNA), based on which to identify key drivers of differentially expressed RNAs between normal and tumor samples. It then infers ceRNAs of the identified key drivers using the long non-coding competing endogenous database (lnCeDB). We applied the pipeline into The Cancer Genome Atlas (TCGA) thyroid carcinoma data. As a result, 598 lncRNAs, 1025 mRNAs, and 90 microRNA (miRNAs) were inferred to be differentially expressed between normal and thyroid cancer samples. We then obtained eight key driver miRNAs, among which hsa-mir-221 and hsa-mir-222 were key driver RNAs identified by both miRNA–mRNA–lncRNA and WGCNA network. In addition, hsa-mir-375 was inferred to be significant for patients’ survival with 34 associated ceRNAs, among which RUNX2, DUSP6 and SEMA3D are known oncogenes regulating cellular proliferation and differentiation in thyroid cancer. These ceRNAs are critical in revealing the secrets behind thyroid cancer progression and may serve as future therapeutic biomarkers. Full article
(This article belongs to the Special Issue Computational Approaches for Disease Gene Identification)
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Open AccessArticle Using Y-Chromosomal Haplogroups in Genetic Association Studies and Suggested Implications
Genes 2018, 9(1), 45; doi:10.3390/genes9010045
Received: 23 October 2017 / Revised: 16 January 2018 / Accepted: 16 January 2018 / Published: 22 January 2018
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Abstract
Y-chromosomal (Y-DNA) haplogroups are more widely used in population genetics than in genetic epidemiology, although associations between Y-DNA haplogroups and several traits, including cardiometabolic traits, have been reported. In apparently homogeneous populations defined by principal component analyses, there is still Y-DNA haplogroup variation
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Y-chromosomal (Y-DNA) haplogroups are more widely used in population genetics than in genetic epidemiology, although associations between Y-DNA haplogroups and several traits, including cardiometabolic traits, have been reported. In apparently homogeneous populations defined by principal component analyses, there is still Y-DNA haplogroup variation which will result from population history. Therefore, hidden stratification and/or differential phenotypic effects by Y-DNA haplogroups could exist. To test this, we hypothesised that stratifying individuals according to their Y-DNA haplogroups before testing for associations between autosomal single nucleotide polymorphisms (SNPs) and phenotypes will yield difference in association. For proof of concept, we derived Y-DNA haplogroups from 6537 males from two epidemiological cohorts, Avon Longitudinal Study of Parents and Children (ALSPAC) (n = 5080; 816 Y-DNA SNPs) and the 1958 Birth Cohort (n = 1457; 1849 Y-DNA SNPs), and studied the robust associations between 32 SNPs and body mass index (BMI), including SNPs in or near Fat Mass and Obesity-associated protein (FTO) which yield the strongest effects. Overall, no association was replicated in both cohorts when Y-DNA haplogroups were considered and this suggests that, for BMI at least, there is little evidence of differences in phenotype or SNP association by Y-DNA structure. Further studies using other traits, phenome-wide association studies (PheWAS), other haplogroups and/or autosomal SNPs are required to test the generalisability and utility of this approach. Full article
(This article belongs to the Special Issue Complex Genetic Loci)
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Open AccessArticle The IFNG rs1861494 Single Nucleotide Polymorphism Is Associated with Protection against Tuberculosis Disease in Argentina
Genes 2018, 9(1), 46; doi:10.3390/genes9010046
Received: 25 October 2017 / Revised: 9 January 2018 / Accepted: 9 January 2018 / Published: 22 January 2018
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Abstract
Interferon gamma (IFNG) plays a key role during Mycobacterium tuberculosis (Mtb) infection, and several polymorphisms located in its gene are associated with risk of tuberculosis in diverse populations. Nevertheless, the genetic resistance/susceptibility to tuberculosis in Argentina is unknown. The IFNG rs1861494
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Interferon gamma (IFNG) plays a key role during Mycobacterium tuberculosis (Mtb) infection, and several polymorphisms located in its gene are associated with risk of tuberculosis in diverse populations. Nevertheless, the genetic resistance/susceptibility to tuberculosis in Argentina is unknown. The IFNG rs1861494 polymorphism (G→A) was reported to alter the binding of transcription factors to this region, influencing IFNG production. Using a case-control study, we found an association between the AA and AG genotypes and tuberculosis resistance (AA vs. GG: odds ratio (OR) = 0.235, p-value = 0.012; AG vs. GG: OR = 0.303, p-value = 0.044; AA vs. AG: OR = 0.776, p-value = 0.427; AA + AG vs. GG: OR = 0.270, p-value = 0.022). Moreover, Mtb-antigen stimulated peripheral blood mononuclear cells (PBMCs) from healthy donors and AA carriers secreted the highest amounts of IFNG in culture supernatants (p-value = 0.034) and presented the greatest percentage of CD4+IFNG+ lymphocytes (p-value = 0.035), in comparison with GG carriers. No association between the polymorphism and clinical parameters of tuberculosis severity was detected. However, our findings indicate that the rs1861494 single nucleotide polymorphism (SNP) could be considered as a biomarker of tuberculosis resistance in the Argentinean population. Full article
(This article belongs to the Special Issue DNA Variations in Evolution and Human Diseases)
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Open AccessArticle Analysis of the Genetic Diversity and Population Structure of Austrian and Belgian Wheat Germplasm within a Regional Context Based on DArT Markers
Genes 2018, 9(1), 47; doi:10.3390/genes9010047
Received: 9 November 2017 / Revised: 14 December 2017 / Accepted: 21 December 2017 / Published: 22 January 2018
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Abstract
Analysis of crop genetic diversity and structure provides valuable information needed to broaden the narrow genetic base as well as to enhance the breeding and conservation strategies of crops. In this study, 95 Austrian and Belgian wheat cultivars maintained at the Centre for
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Analysis of crop genetic diversity and structure provides valuable information needed to broaden the narrow genetic base as well as to enhance the breeding and conservation strategies of crops. In this study, 95 Austrian and Belgian wheat cultivars maintained at the Centre for Genetic Resources (CGN) in the Netherlands were characterised using 1052 diversity array technology (DArT) markers to evaluate their genetic diversity, relationships and population structure. The rarefacted allelic richness recorded in the Austrian and Belgian breeding pools (A25 = 1.396 and 1.341, respectively) indicated that the Austrian germplasm contained a higher genetic diversity than the Belgian pool. The expected heterozygosity (HE) values of the Austrian and Belgian pools were 0.411 and 0.375, respectively. Moreover, the values of the polymorphic information content (PIC) of the Austrian and Belgian pools were 0.337 and 0.298, respectively. Neighbour-joining tree divided each of the Austrian and Belgian germplasm pools into two genetically distinct groups. The structure analyses of the Austrian and Belgian pools were in a complete concordance with their neighbour-joining trees. Furthermore, the 95 cultivars were compared to 618 wheat genotypes from nine European countries based on a total of 141 common DArT markers in order to place the Austrian and Belgian wheat germplasm in a wider European context. The rarefacted allelic richness (A10) varied from 1.224 (Denmark) to 1.397 (Austria). Cluster and principal coordinates (PCoA) analyses divided the wheat genotypes of the nine European countries into two main clusters. The first cluster comprised the Northern and Western European wheat genotypes, whereas the second included the Central European cultivars. The structure analysis of the 618 European wheat genotypes was in a complete concordance with the results of cluster and PCoA analyses. Interestingly, a highly significant difference was recorded between regions (26.53%). In conclusion, this is the first study to reveal the high diversity levels and structure of the uncharacterised Austrian and Belgian wheat germplasm maintained at the CGN as well as place them in a wider European context. The results should help plant breeders to utilise the most promising wheat genotypes of this study in future breeding programmes for enhancing wheat cultivars. Full article
(This article belongs to the Special Issue Plant Genomics and Epigenomics for Trait Improvement)
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Open AccessArticle Applications of Probe Capture Enrichment Next Generation Sequencing for Whole Mitochondrial Genome and 426 Nuclear SNPs for Forensically Challenging Samples
Genes 2018, 9(1), 49; doi:10.3390/genes9010049
Received: 20 December 2017 / Revised: 14 January 2018 / Accepted: 17 January 2018 / Published: 22 January 2018
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Abstract
The application of next generation sequencing (NGS) for the analysis of mitochondrial (mt) DNA, short tandem repeats (STRs), and single nucleotide polymorphism (SNPs) has demonstrated great promise for challenging forensic specimens, such as degraded, limited, and mixed samples. Target enrichment using probe capture
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The application of next generation sequencing (NGS) for the analysis of mitochondrial (mt) DNA, short tandem repeats (STRs), and single nucleotide polymorphism (SNPs) has demonstrated great promise for challenging forensic specimens, such as degraded, limited, and mixed samples. Target enrichment using probe capture rather than PCR amplification offers advantages for analysis of degraded DNA since two intact PCR primer sites in the template DNA molecule are not required. Furthermore, NGS software programs can help remove PCR duplicates to determine initial template copy numbers of a shotgun library. Moreover, the same shotgun library prepared from a limited DNA source can be enriched for mtDNA as well as nuclear markers by hybrid capture with the relevant probe panels. Here, we demonstrate the use of this strategy in the analysis of limited and mock degraded samples using our custom probe capture panels for massively parallel sequencing of the whole mtgenome and 426 SNP markers. We also applied the mtgenome capture panel in a mixed sample and analyzed using both phylogenetic and variant frequency based bioinformatics tools to resolve the minor and major contributors. Finally, the results obtained on individual telogen hairs demonstrate the potential of probe capture NGS analysis for both mtDNA and nuclear SNPs for challenging forensic specimens. Full article
(This article belongs to the Special Issue Forensic Genomics)
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Open AccessArticle MiR-93-5p Promotes Cell Proliferation through Down-Regulating PPARGC1A in Hepatocellular Carcinoma Cells by Bioinformatics Analysis and Experimental Verification
Genes 2018, 9(1), 51; doi:10.3390/genes9010051
Received: 7 December 2017 / Revised: 15 January 2018 / Accepted: 16 January 2018 / Published: 22 January 2018
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Abstract
Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PPARGC1A, formerly known as PGC-1a) is a transcriptional coactivator and metabolic regulator. Previous studies are mainly focused on the association between PPARGC1A and hepatoma. However, the regulatory mechanism remains unknown. A microRNA associated with cancer (oncomiR), miR-93-5p,
[...] Read more.
Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PPARGC1A, formerly known as PGC-1a) is a transcriptional coactivator and metabolic regulator. Previous studies are mainly focused on the association between PPARGC1A and hepatoma. However, the regulatory mechanism remains unknown. A microRNA associated with cancer (oncomiR), miR-93-5p, has recently been found to play an essential role in tumorigenesis and progression of various carcinomas, including liver cancer. Therefore, this paper aims to explore the regulatory mechanism underlying these two proteins in hepatoma cells. Firstly, an integrative analysis was performed with miRNA–mRNA modules on microarray and The Cancer Genome Atlas (TCGA) data and obtained the core regulatory network and miR-93-5p/PPARGC1A pair. Then, a series of experiments were conducted in hepatoma cells with the results including miR-93-5p upregulated and promoted cell proliferation. Thirdly, the inverse correlation between miR-93-5p and PPARGC1A expression was validated. Finally, we inferred that miR-93-5p plays an essential role in inhibiting PPARGC1A expression by directly targeting the 3′-untranslated region (UTR) of its mRNA. In conclusion, these results suggested that miR-93-5p overexpression contributes to hepatoma development by inhibiting PPARGC1A. It is anticipated to be a promising therapeutic strategy for patients with liver cancer in the future. Full article
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Open AccessArticle Differential Gene Expression in Response to Salinity and Temperature in a Haloarcula Strain from Great Salt Lake, Utah
Genes 2018, 9(1), 52; doi:10.3390/genes9010052
Received: 19 December 2017 / Revised: 11 January 2018 / Accepted: 16 January 2018 / Published: 22 January 2018
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Abstract
Haloarchaea that inhabit Great Salt Lake (GSL), a thalassohaline terminal lake, must respond to the fluctuating climate conditions of the elevated desert of Utah. We investigated how shifting environmental factors, specifically salinity and temperature, affected gene expression in the GSL haloarchaea, NA6-27, which
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Haloarchaea that inhabit Great Salt Lake (GSL), a thalassohaline terminal lake, must respond to the fluctuating climate conditions of the elevated desert of Utah. We investigated how shifting environmental factors, specifically salinity and temperature, affected gene expression in the GSL haloarchaea, NA6-27, which we isolated from the hypersaline north arm of the lake. Combined data from cultivation, microscopy, lipid analysis, antibiotic sensitivity, and 16S rRNA gene alignment, suggest that NA6-27 is a member of the Haloarcula genus. Our prior study demonstrated that archaea in the Haloarcula genus were stable in the GSL microbial community over seasons and years. In this study, RNA arbitrarily primed PCR (RAP-PCR) was used to determine the transcriptional responses of NA6-27 grown under suboptimal salinity and temperature conditions. We observed alteration of the expression of genes related to general stress responses, such as transcription, translation, replication, signal transduction, and energy metabolism. Of the ten genes that were expressed differentially under stress, eight of these genes responded in both conditions, highlighting this general response. We also noted gene regulation specific to salinity and temperature conditions, such as osmoregulation and transport. Taken together, these data indicate that the GSL Haloarcula strain, NA6-27, demonstrates both general and specific responses to salinity and/or temperature stress, and suggest a mechanistic model for homeostasis that may explain the stable presence of this genus in the community as environmental conditions shift. Full article
(This article belongs to the Special Issue Genetics and Genomics of Extremophiles)
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Open AccessArticle MHC-Dependent Mate Selection within 872 Spousal Pairs of European Ancestry from the Health and Retirement Study
Genes 2018, 9(1), 53; doi:10.3390/genes9010053
Received: 15 November 2017 / Revised: 9 January 2018 / Accepted: 15 January 2018 / Published: 22 January 2018
Cited by 1 | PDF Full-text (2790 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Disassortative mating refers to the phenomenon in which individuals with dissimilar genotypes and/or phenotypes mate with one another more frequently than would be expected by chance. Although the existence of disassortative mating is well established in plant and animal species, the only documented
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Disassortative mating refers to the phenomenon in which individuals with dissimilar genotypes and/or phenotypes mate with one another more frequently than would be expected by chance. Although the existence of disassortative mating is well established in plant and animal species, the only documented example of negative assortment in humans involves dissimilarity at the major histocompatibility complex (MHC) locus. Previous studies investigating mating patterns at the MHC have been hampered by limited sample size and contradictory findings. Inspired by the sparse and conflicting evidence, we investigated the role that the MHC region played in human mate selection using genome-wide association data from 872 European American spouses from the Health and Retirement Study (HRS). First, we treated the MHC region as a whole, and investigated genomic similarity between spouses using three levels of genomic variation: single-nucleotide polymorphisms (SNPs), classical human leukocyte antigen (HLA) alleles (both four-digit and two-digit classifications), and amino acid polymorphisms. The extent of MHC dissimilarity between spouses was assessed using a permutation approach. Second, we investigated fine scale mating patterns by testing for deviations from random mating at individual SNPs, HLA genes, and amino acids in HLA molecules. Third, we assessed how extreme the spousal relatedness at the MHC region was compared to the rest of the genome, to distinguish the MHC-specific effects from genome-wide effects. We show that neither the MHC region, nor any single SNPs, classic HLA alleles, or amino acid polymorphisms within the MHC region, were significantly dissimilar between spouses relative to non-spouse pairs. However, dissimilarity in the MHC region was extreme relative to the rest of genome for both spousal and non-spouse pairs. Despite the long-standing controversy, our analyses did not support a significant role of MHC dissimilarity in human mate choice. Full article
(This article belongs to the Special Issue Complex Genetic Loci)
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Open AccessArticle Genome-Wide Identification and Characterization of the Potato bHLH Transcription Factor Family
Genes 2018, 9(1), 54; doi:10.3390/genes9010054
Received: 18 December 2017 / Revised: 9 January 2018 / Accepted: 18 January 2018 / Published: 22 January 2018
Cited by 1 | PDF Full-text (5029 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Plant basic/helix–loop–helix (bHLH) transcription factors participate in a number of biological processes, such as growth, development and abiotic stress responses. The bHLH family has been identified in many plants, and several bHLH transcription factors have been functionally characterized in Arabidopsis. However, no
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Plant basic/helix–loop–helix (bHLH) transcription factors participate in a number of biological processes, such as growth, development and abiotic stress responses. The bHLH family has been identified in many plants, and several bHLH transcription factors have been functionally characterized in Arabidopsis. However, no systematic identification of bHLH family members has been reported in potato (Solanum tuberosum). Here, 124 StbHLH genes were identified and named according to their chromosomal locations. The intron numbers varied from zero to seven. Most StbHLH proteins had the highly conserved intron phase 0, which accounted for 86.2% of the introns. According to the Neighbor-joining phylogenetic tree, 259 bHLH proteins acquired from Arabidopsis and potato were divided into 15 groups. All of the StbHLH genes were randomly distributed on 12 chromosomes, and 20 tandem duplicated genes and four pairs of duplicated gene segments were detected in the StbHLH family. The gene ontology (GO) analysis revealed that StbHLH mainly function in protein and DNA binding. Through the RNA-seq and quantitative real time PCR (qRT-PCR) analyses, StbHLH were found to be expressed in various tissues and to respond to abiotic stresses, including salt, drought and heat. StbHLH1, 41 and 60 were highly expressed in flower tissues, and were predicted to be involved in flower development by GO annotation. StbHLH45 was highly expressed in salt, drought and heat stress, which suggested its important role in abiotic stress response. The results provide comprehensive information for further analyses of the molecular functions of the StbHLH gene family. Full article
(This article belongs to the Section Plant Genetics and Genomics)
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Open AccessArticle Metagenomics of Bacterial Diversity in Villa Luz Caves with Sulfur Water Springs
Genes 2018, 9(1), 55; doi:10.3390/genes9010055
Received: 7 November 2017 / Revised: 12 January 2018 / Accepted: 13 January 2018 / Published: 22 January 2018
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Abstract
New biotechnology applications require in-depth preliminary studies of biodiversity. The methods of massive sequencing using metagenomics and bioinformatics tools offer us sufficient and reliable knowledge to understand environmental diversity, to know new microorganisms, and to take advantage of their functional genes. Villa Luz
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New biotechnology applications require in-depth preliminary studies of biodiversity. The methods of massive sequencing using metagenomics and bioinformatics tools offer us sufficient and reliable knowledge to understand environmental diversity, to know new microorganisms, and to take advantage of their functional genes. Villa Luz caves, in the southern Mexican state of Tabasco, are fed by at least 26 groundwater inlets, containing 300–500 mg L−1 H2S and <0.1 mg L−1 O2. We extracted environmental DNA for metagenomic analysis of collected samples in five selected Villa Luz caves sites, with pH values from 2.5 to 7. Foreign organisms found in this underground ecosystem can oxidize H2S to H2SO4. These include: biovermiculites, a bacterial association that can grow on the rock walls; snottites, that are whitish, viscous biofilms hanging from the rock walls, and sacks or bags of phlegm, which live within the aquatic environment of the springs. Through the emergency food assistance program (TEFAP) pyrosequencing, a total of 20,901 readings of amplification products from hypervariable regions V1 and V3 of 16S rRNA bacterial gene in whole and pure metagenomic DNA samples were generated. Seven bacterial phyla were identified. As a result, Proteobacteria was more frequent than Acidobacteria. Finally, acidophilic Proteobacteria was detected in UJAT5 sample. Full article
(This article belongs to the Special Issue Genetics and Genomics of Extremophiles)
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Open AccessArticle Identification of a Common Different Gene Expression Signature in Ischemic Cardiomyopathy
Genes 2018, 9(1), 56; doi:10.3390/genes9010056
Received: 20 December 2017 / Revised: 9 January 2018 / Accepted: 16 January 2018 / Published: 22 January 2018
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Abstract
The molecular mechanisms underlying the development of ischemic cardiomyopathy (ICM) remain poorly understood. Gene expression profiling is helpful to discover the molecular changes taking place in ICM. The aim of this study was to identify the genes that are significantly changed during the
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The molecular mechanisms underlying the development of ischemic cardiomyopathy (ICM) remain poorly understood. Gene expression profiling is helpful to discover the molecular changes taking place in ICM. The aim of this study was to identify the genes that are significantly changed during the development of heart failure caused by ICM. The differentially expressed genes (DEGs) were identified from 162 control samples and 227 ICM patients. PANTHER was used to perform gene ontology (GO), and Reactome for pathway enrichment analysis. A protein–protein interaction network was established using STRING and Cytoscape. A further validation was performed by real-time polymerase chain reaction (RT-PCR). A total of 255 common DEGs was found. Gene ontology, pathway enrichment, and protein–protein interaction analysis showed that nucleic acid-binding proteins, enzymes, and transcription factors accounted for a great part of the DEGs, while immune system signaling and cytokine signaling displayed the most significant changes. Furthermore, seven hub genes and nine transcription factors were identified. Interestingly, the top five upregulated DEGs were located on chromosome Y, and four of the top five downregulated DEGs were involved in immune and inflammation signaling. Further, the top DEGs were validated by RT-PCR in human samples. Our study explored the possible molecular mechanisms of heart failure caused by ischemic heart disease. Full article
(This article belongs to the Section Human Genomics and Genetic Diseases)
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Open AccessReview Transcriptomic Studies of the Effect of nod Gene-Inducing Molecules in Rhizobia: Different Weapons, One Purpose
Genes 2018, 9(1), 1; doi:10.3390/genes9010001
Received: 24 October 2017 / Revised: 7 December 2017 / Accepted: 15 December 2017 / Published: 21 December 2017
Cited by 1 | PDF Full-text (4006 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Simultaneous quantification of transcripts of the whole bacterial genome allows the analysis of the global transcriptional response under changing conditions. RNA-seq and microarrays are the most used techniques to measure these transcriptomic changes, and both complement each other in transcriptome profiling. In this
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Simultaneous quantification of transcripts of the whole bacterial genome allows the analysis of the global transcriptional response under changing conditions. RNA-seq and microarrays are the most used techniques to measure these transcriptomic changes, and both complement each other in transcriptome profiling. In this review, we exhaustively compiled the symbiosis-related transcriptomic reports (microarrays and RNA sequencing) carried out hitherto in rhizobia. This review is specially focused on transcriptomic changes that takes place when five rhizobial species, Bradyrhizobium japonicum (=diazoefficiens) USDA 110, Rhizobium leguminosarum biovar viciae 3841, Rhizobium tropici CIAT 899, Sinorhizobium (=Ensifer) meliloti 1021 and S. fredii HH103, recognize inducing flavonoids, plant-exuded phenolic compounds that activate the biosynthesis and export of Nod factors (NF) in all analysed rhizobia. Interestingly, our global transcriptomic comparison also indicates that each rhizobial species possesses its own arsenal of molecular weapons accompanying the set of NF in order to establish a successful interaction with host legumes. Full article
(This article belongs to the Special Issue Genetics and Genomics of the Rhizobium-Legume Symbiosis)
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Open AccessReview Genome Sequencing and Assembly by Long Reads in Plants
Genes 2018, 9(1), 6; doi:10.3390/genes9010006
Received: 20 November 2017 / Revised: 18 December 2017 / Accepted: 18 December 2017 / Published: 28 December 2017
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Abstract
Plant genomes generated by Sanger and Next Generation Sequencing (NGS) have provided insight into species diversity and evolution. However, Sanger sequencing is limited in its applications due to high cost, labor intensity, and low throughput, while NGS reads are too short to resolve
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Plant genomes generated by Sanger and Next Generation Sequencing (NGS) have provided insight into species diversity and evolution. However, Sanger sequencing is limited in its applications due to high cost, labor intensity, and low throughput, while NGS reads are too short to resolve abundant repeats and polyploidy, leading to incomplete or ambiguous assemblies. The advent and improvement of long-read sequencing by Third Generation Sequencing (TGS) methods such as PacBio and Nanopore have shown promise in producing high-quality assemblies for complex genomes. Here, we review the development of sequencing, introducing the application as well as considerations of experimental design in TGS of plant genomes. We also introduce recent revolutionary scaffolding technologies including BioNano, Hi-C, and 10× Genomics. We expect that the informative guidance for genome sequencing and assembly by long reads will benefit the initiation of scientists’ projects. Full article
(This article belongs to the Special Issue Plant Genomics and Epigenomics for Trait Improvement)
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Open AccessReview Signaling Pathways Driving Aberrant Splicing in Cancer Cells
Genes 2018, 9(1), 9; doi:10.3390/genes9010009
Received: 6 November 2017 / Revised: 7 December 2017 / Accepted: 18 December 2017 / Published: 29 December 2017
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Abstract
Aberrant profiles of pre-mRNA splicing are frequently observed in cancer. At the molecular level, an altered profile results from a complex interplay between chromatin modifications, the transcriptional elongation rate of RNA polymerase, and effective binding of the spliceosome to the generated transcripts. Key
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Aberrant profiles of pre-mRNA splicing are frequently observed in cancer. At the molecular level, an altered profile results from a complex interplay between chromatin modifications, the transcriptional elongation rate of RNA polymerase, and effective binding of the spliceosome to the generated transcripts. Key players in this interplay are regulatory splicing factors (SFs) that bind to gene-specific splice-regulatory sequence elements. Although mutations in genes of some SFs were described, a major driver of aberrant splicing profiles is oncogenic signal transduction pathways. Signaling can affect either the transcriptional expression levels of SFs or the post-translational modification of SF proteins, and both modulate the ratio of nuclear versus cytoplasmic SFs in a given cell. Here, we will review currently known mechanisms by which cancer cell signaling, including the mitogen-activated protein kinases (MAPK), phosphatidylinositol 3 (PI3)-kinase pathway (PI3K) and wingless (Wnt) pathways but also signals from the tumor microenvironment, modulate the activity or subcellular localization of the Ser/Arg rich (SR) proteins and heterogeneous nuclear ribonucleoproteins (hnRNPs) families of SFs. Full article
(This article belongs to the Special Issue Aberrant Pre-mRNA Splicing in Disease)
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Open AccessReview Microbial Regulation of Glucose Metabolism and Insulin Resistance
Genes 2018, 9(1), 10; doi:10.3390/genes9010010
Received: 30 November 2017 / Revised: 21 December 2017 / Accepted: 21 December 2017 / Published: 29 December 2017
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Abstract
Type 2 diabetes is a combined disease, resulting from a hyperglycemia and peripheral and hepatic insulin resistance. Recent data suggest that the gut microbiota is involved in diabetes development, altering metabolic processes including glucose and fatty acid metabolism. Thus, type 2 diabetes patients
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Type 2 diabetes is a combined disease, resulting from a hyperglycemia and peripheral and hepatic insulin resistance. Recent data suggest that the gut microbiota is involved in diabetes development, altering metabolic processes including glucose and fatty acid metabolism. Thus, type 2 diabetes patients show a microbial dysbiosis, with reduced butyrate-producing bacteria and elevated potential pathogens compared to metabolically healthy individuals. Furthermore, probiotics are a known tool to modulate the microbiota, having a therapeutic potential. Current literature will be discussed to elucidate the complex interaction of gut microbiota, intestinal permeability and inflammation leading to peripheral and hepatic insulin resistance. Therefore, this review aims to generate a deeper understanding of the underlying mechanism of potential microbial strains, which can be used as probiotics. Full article
(This article belongs to the Special Issue Diabetes, Obesity and the Gut Microbiome)
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Open AccessReview Surveillance of Foodborne Pathogens: Towards Diagnostic Metagenomics of Fecal Samples
Genes 2018, 9(1), 14; doi:10.3390/genes9010014
Received: 6 November 2017 / Revised: 5 December 2017 / Accepted: 19 December 2017 / Published: 4 January 2018
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Abstract
Diagnostic metagenomics is a rapidly evolving laboratory tool for culture-independent tracing of foodborne pathogens. The method has the potential to become a generic platform for detection of most pathogens and many sample types. Today, however, it is still at an early and experimental
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Diagnostic metagenomics is a rapidly evolving laboratory tool for culture-independent tracing of foodborne pathogens. The method has the potential to become a generic platform for detection of most pathogens and many sample types. Today, however, it is still at an early and experimental stage. Studies show that metagenomic methods, from sample storage and DNA extraction to library preparation and shotgun sequencing, have a great influence on data output. To construct protocols that extract the complete metagenome but with minimal bias is an ongoing challenge. Many different software strategies for data analysis are being developed, and several studies applying diagnostic metagenomics to human clinical samples have been published, detecting, and sometimes, typing bacterial infections. It is possible to obtain a draft genome of the pathogen and to develop methods that can theoretically be applied in real-time. Finally, diagnostic metagenomics can theoretically be better geared than conventional methods to detect co-infections. The present review focuses on the current state of test development, as well as practical implementation of diagnostic metagenomics to trace foodborne bacterial infections in fecal samples from animals and humans. Full article
(This article belongs to the Special Issue Genetics and Genomics of Foodborne Pathogens)
Open AccessReview Muscle-Specific Mis-Splicing and Heart Disease Exemplified by RBM20
Genes 2018, 9(1), 18; doi:10.3390/genes9010018
Received: 20 November 2017 / Revised: 23 December 2017 / Accepted: 27 December 2017 / Published: 5 January 2018
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Abstract
Alternative splicing is an essential post-transcriptional process to generate multiple functional RNAs or proteins from a single transcript. Progress in RNA biology has led to a better understanding of muscle-specific RNA splicing in heart disease. The recent discovery of the muscle-specific splicing factor
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Alternative splicing is an essential post-transcriptional process to generate multiple functional RNAs or proteins from a single transcript. Progress in RNA biology has led to a better understanding of muscle-specific RNA splicing in heart disease. The recent discovery of the muscle-specific splicing factor RNA-binding motif 20 (RBM20) not only provided great insights into the general alternative splicing mechanism but also demonstrated molecular mechanism of how this splicing factor is associated with dilated cardiomyopathy. Here, we review our current knowledge of muscle-specific splicing factors and heart disease, with an emphasis on RBM20 and its targets, RBM20-dependent alternative splicing mechanism, RBM20 disease origin in induced Pluripotent Stem Cells (iPSCs), and RBM20 mutations in dilated cardiomyopathy. In the end, we will discuss the multifunctional role of RBM20 and manipulation of RBM20 as a potential therapeutic target for heart disease. Full article
(This article belongs to the Special Issue Aberrant Pre-mRNA Splicing in Disease)
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Open AccessReview Wnt, RSPO and Hippo Signalling in the Intestine and Intestinal Stem Cells
Genes 2018, 9(1), 20; doi:10.3390/genes9010020
Received: 30 November 2017 / Revised: 22 December 2017 / Accepted: 28 December 2017 / Published: 8 January 2018
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Abstract
In this review, we address aspects of Wnt, R-Spondin (RSPO) and Hippo signalling, in both healthy and transformed intestinal epithelium. In intestinal stem cells (ISCs), the Wnt pathway is essential for intestinal crypt formation and renewal, whereas RSPO-mediated signalling mainly affects ISC numbers.
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In this review, we address aspects of Wnt, R-Spondin (RSPO) and Hippo signalling, in both healthy and transformed intestinal epithelium. In intestinal stem cells (ISCs), the Wnt pathway is essential for intestinal crypt formation and renewal, whereas RSPO-mediated signalling mainly affects ISC numbers. In human colorectal cancer (CRC), aberrant Wnt signalling is the driving mechanism initiating this type of neoplasia. The signalling role of the RSPO-binding transmembrane proteins, the leucine-rich-repeat-containing G-protein-coupled receptors (LGRs), is possibly more pleiotropic and not only limited to the enhancement of Wnt signalling. There is growing evidence for multiple crosstalk between Hippo and Wnt/β-catenin signalling. In the ON state, Hippo signalling results in serine/threonine phosphorylation of Yes-associated protein (YAP1) and tafazzin (TAZ), promoting formation of the β-catenin destruction complex. In contrast, YAP1 or TAZ dephosphorylation (and YAP1 methylation) results in β-catenin destruction complex deactivation and β-catenin nuclear localization. In the Hippo OFF state, YAP1 and TAZ are engaged with the nuclear β-catenin and participate in the β-catenin-dependent transcription program. Interestingly, YAP1/TAZ are dispensable for intestinal homeostasis; however, upon Wnt pathway hyperactivation, the proteins together with TEA domain (TEAD) transcription factors drive the transcriptional program essential for intestinal cell transformation. In addition, in many CRC cells, YAP1 phosphorylation by YES proto-oncogene 1 tyrosine kinase (YES1) leads to the formation of a transcriptional complex that includes YAP1, β-catenin and T-box 5 (TBX5) DNA-binding protein. YAP1/β-catenin/T-box 5-mediated transcription is necessary for CRC cell proliferation and survival. Interestingly, dishevelled (DVL) appears to be an important mediator involved in both Wnt and Hippo (YAP1/TAZ) signalling and some of the DVL functions were assigned to the nuclear DVL pool. Wnt ligands can trigger alternative signalling that directly involves some of the Hippo pathway components such as YAP1, TAZ and TEADs. By upregulating Wnt pathway agonists, the alternative Wnt signalling can inhibit the canonical Wnt pathway activity. Full article
(This article belongs to the Special Issue Wnt Signaling in Stem Cells)
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Open AccessReview The Aging Mitochondria
Genes 2018, 9(1), 22; doi:10.3390/genes9010022
Received: 26 October 2017 / Revised: 15 December 2017 / Accepted: 4 January 2018 / Published: 9 January 2018
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Abstract
Mitochondrial dysfunction is a central event in many pathologies and contributes as well to age-related processes. However, distinguishing between primary mitochondrial dysfunction driving aging and a secondary mitochondrial impairment resulting from other cell alterations remains challenging. Indeed, even though mitochondria undeniably play a
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Mitochondrial dysfunction is a central event in many pathologies and contributes as well to age-related processes. However, distinguishing between primary mitochondrial dysfunction driving aging and a secondary mitochondrial impairment resulting from other cell alterations remains challenging. Indeed, even though mitochondria undeniably play a crucial role in aging pathways at the cellular and organismal level, the original hypothesis in which mitochondrial dysfunction and production of free radicals represent the main driving force of cell degeneration has been strongly challenged. In this review, we will first describe mitochondrial dysfunctions observed in aged tissue, and how these features have been linked to mitochondrial reactive oxygen species (ROS)–mediated cell damage and mitochondrial DNA (mtDNA) mutations. We will also discuss the clues that led to consider mitochondria as the starting point in the aging process, and how recent research has showed that the mitochondria aging axis represents instead a more complex and multifactorial signaling pathway. New working hypothesis will be also presented in which mitochondria are considered at the center of a complex web of cell dysfunctions that eventually leads to cell senescence and death. Full article
(This article belongs to the Special Issue Mitochondria and Aging)
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Open AccessReview NF-kappaB: Two Sides of the Same Coin
Genes 2018, 9(1), 24; doi:10.3390/genes9010024
Received: 6 December 2017 / Revised: 2 January 2018 / Accepted: 5 January 2018 / Published: 9 January 2018
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Abstract
Nuclear Factor-kappa B (NF-κB) is a transcription factor family that regulates a large number of genes that are involved in important physiological processes, including survival, inflammation, and immune responses. More recently, constitutive expression of NF-κB has been associated with several types of cancer.
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Nuclear Factor-kappa B (NF-κB) is a transcription factor family that regulates a large number of genes that are involved in important physiological processes, including survival, inflammation, and immune responses. More recently, constitutive expression of NF-κB has been associated with several types of cancer. In addition, microorganisms, such as viruses and bacteria, cooperate in the activation of NF-κB in tumors, confirming the multifactorial role of this transcription factor as a cancer driver. Recent reports have shown that the NF-κB signaling pathway should receive attention for the development of therapies. In addition to the direct effects of NF-κB in cancer cells, it might also impact immune cells that can both promote or prevent tumor development. Currently, with the rise of cancer immunotherapy, the link among immune cells, inflammation, and cancer is a major focus, and NF-κB could be an important regulator for the success of these therapies. This review discusses the contrasting roles of NF-κB as a regulator of pro- and antitumor processes and its potential as a therapeutic target. Full article
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Open AccessReview Methods for Using Small Non-Coding RNAs to Improve Recombinant Protein Expression in Mammalian Cells
Genes 2018, 9(1), 25; doi:10.3390/genes9010025
Received: 17 November 2017 / Revised: 19 December 2017 / Accepted: 3 January 2018 / Published: 9 January 2018
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Abstract
The ability to produce recombinant proteins by utilizing different “cell factories” revolutionized the biotherapeutic and pharmaceutical industry. Chinese hamster ovary (CHO) cells are the dominant industrial producer, especially for antibodies. Human embryonic kidney cells (HEK), while not being as widely used as CHO
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The ability to produce recombinant proteins by utilizing different “cell factories” revolutionized the biotherapeutic and pharmaceutical industry. Chinese hamster ovary (CHO) cells are the dominant industrial producer, especially for antibodies. Human embryonic kidney cells (HEK), while not being as widely used as CHO cells, are used where CHO cells are unable to meet the needs for expression, such as growth factors. Therefore, improving recombinant protein expression from mammalian cells is a priority, and continuing effort is being devoted to this topic. Non-coding RNAs are RNA segments that are not translated into a protein and often have a regulatory role. Since their discovery, major progress has been made towards understanding their functions. Non-coding RNA has been investigated extensively in relation to disease, especially cancer, and recently they have also been used as a method for engineering cells to improve their protein expression capability. In this review, we provide information about methods used to identify non-coding RNAs with the potential of improving recombinant protein expression in mammalian cell lines. Full article
(This article belongs to the Special Issue Non-coding RNAs)
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Open AccessReview MiRNA Influences in Neuroblast Modulation: An Introspective Analysis
Genes 2018, 9(1), 26; doi:10.3390/genes9010026
Received: 2 November 2017 / Revised: 22 December 2017 / Accepted: 29 December 2017 / Published: 9 January 2018
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Abstract
Neuroblastoma (NB) is the most common occurring solid paediatric cancer in children under the age of five years. Whether of familial or sporadic origin, chromosome abnormalities contribute to the development of NB and cause dysregulation of microRNAs (miRNAs). MiRNAs are small non-coding, single
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Neuroblastoma (NB) is the most common occurring solid paediatric cancer in children under the age of five years. Whether of familial or sporadic origin, chromosome abnormalities contribute to the development of NB and cause dysregulation of microRNAs (miRNAs). MiRNAs are small non-coding, single stranded RNAs that target messenger RNAs at the post-transcriptional levels by repressing translation within all facets of human physiology. Such gene ‘silencing’ activities by miRNAs allows the development of regulatory feedback loops affecting multiple functions within the cell, including the possible differentiation of neural stem cell (NSC) lineage selection. Neurogenesis includes stages of self-renewal and fate specification of NSCs, migration and maturation of young neurones, and functional integration of new neurones into the neural circuitry, all of which are regulated by miRNAs. The role of miRNAs and their interaction in cellular processes are recognised aspects of cancer genetics, and miRNAs are currently employed as biomarkers for prognosis and tumour characterisation in multiple cancer models. Consequently, thorough understanding of the mechanisms of how these miRNAs interplay at the transcriptomic level will definitely lead to the development of novel, bespoke and efficient therapeutic measures, with this review focusing on the influences of miRNAs on neuroblast modulations leading to neuroblastoma. Full article
(This article belongs to the Special Issue Non-coding RNAs)
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Open AccessReview Scaffolding for Repair: Understanding Molecular Functions of the SMC5/6 Complex
Genes 2018, 9(1), 36; doi:10.3390/genes9010036
Received: 15 November 2017 / Revised: 3 January 2018 / Accepted: 4 January 2018 / Published: 12 January 2018
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Abstract
Chromosome organization, dynamics and stability are required for successful passage through cellular generations and transmission of genetic information to offspring. The key components involved are Structural maintenance of chromosomes (SMC) complexes. Cohesin complex ensures proper chromatid alignment, condensin complex chromosome condensation and the
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Chromosome organization, dynamics and stability are required for successful passage through cellular generations and transmission of genetic information to offspring. The key components involved are Structural maintenance of chromosomes (SMC) complexes. Cohesin complex ensures proper chromatid alignment, condensin complex chromosome condensation and the SMC5/6 complex is specialized in the maintenance of genome stability. Here we summarize recent knowledge on the composition and molecular functions of SMC5/6 complex. SMC5/6 complex was originally identified based on the sensitivity of its mutants to genotoxic stress but there is increasing number of studies demonstrating its roles in the control of DNA replication, sister chromatid resolution and genomic location-dependent promotion or suppression of homologous recombination. Some of these functions appear to be due to a very dynamic interaction with cohesin or other repair complexes. Studies in Arabidopsis indicate that, besides its canonical function in repair of damaged DNA, the SMC5/6 complex plays important roles in regulating plant development, abiotic stress responses, suppression of autoimmune responses and sexual reproduction. Full article
(This article belongs to the Special Issue DNA Damage Responses in Plants)
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Open AccessReview Age-Related Epigenetic Derangement upon Reprogramming and Differentiation of Cells from the Elderly
Genes 2018, 9(1), 39; doi:10.3390/genes9010039
Received: 31 October 2017 / Revised: 22 December 2017 / Accepted: 10 January 2018 / Published: 16 January 2018
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Abstract
Aging is a complex multi-layered phenomenon. The study of aging in humans is based on the use of biological material from hard-to-gather tissues and highly specific cohorts. The introduction of cell reprogramming techniques posed promising features for medical practice and basic research. Recently,
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Aging is a complex multi-layered phenomenon. The study of aging in humans is based on the use of biological material from hard-to-gather tissues and highly specific cohorts. The introduction of cell reprogramming techniques posed promising features for medical practice and basic research. Recently, a growing number of studies have been describing the generation of induced pluripotent stem cells (iPSCs) from old or centenarian biologic material. Nonetheless, Reprogramming techniques determine a profound remodelling on cell epigenetic architecture whose extent is still largely debated. Given that cell epigenetic profile changes with age, the study of cell-fate manipulation approaches on cells deriving from old donors or centenarians may provide new insights not only on regenerative features and physiology of these cells, but also on reprogramming-associated and age-related epigenetic derangement. Full article
(This article belongs to the Special Issue The Epigenetics of Aging and Longevity)
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Open AccessReview Transcriptional-Readthrough RNAs Reflect the Phenomenon of “A Gene Contains Gene(s)” or “Gene(s) within a Gene” in the Human Genome, and Thus Are Not Chimeric RNAs
Genes 2018, 9(1), 40; doi:10.3390/genes9010040
Received: 29 November 2017 / Revised: 29 December 2017 / Accepted: 7 January 2018 / Published: 16 January 2018
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Abstract
Tens of thousands of chimeric RNAs, i.e., RNAs with sequences of two genes, have been identified in human cells. Most of them are formed by two neighboring genes on the same chromosome and are considered to be derived via transcriptional readthrough, but a
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Tens of thousands of chimeric RNAs, i.e., RNAs with sequences of two genes, have been identified in human cells. Most of them are formed by two neighboring genes on the same chromosome and are considered to be derived via transcriptional readthrough, but a true readthrough event still awaits more evidence and trans-splicing that joins two transcripts together remains as a possible mechanism. We regard those genomic loci that are transcriptionally read through as unannotated genes, because their transcriptional and posttranscriptional regulations are the same as those of already-annotated genes, including fusion genes formed due to genetic alterations. Therefore, readthrough RNAs and fusion-gene-derived RNAs are not chimeras. Only those two-gene RNAs formed at the RNA level, likely via trans-splicing, without corresponding genes as genomic parents, should be regarded as authentic chimeric RNAs. However, since in human cells, procedural and mechanistic details of trans-splicing have never been disclosed, we doubt the existence of trans-splicing. Therefore, there are probably no authentic chimeras in humans, after readthrough and fusion-gene derived RNAs are all put back into the group of ordinary RNAs. Therefore, it should be further determined whether in human cells all two-neighboring-gene RNAs are derived from transcriptional readthrough and whether trans-splicing truly exists. Full article
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Open AccessReview Isoform Sequencing and State-of-Art Applications for Unravelling Complexity of Plant Transcriptomes
Genes 2018, 9(1), 43; doi:10.3390/genes9010043
Received: 27 November 2017 / Revised: 30 December 2017 / Accepted: 15 January 2018 / Published: 18 January 2018
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Abstract
Single-molecule real-time (SMRT) sequencing developed by PacBio, also called third-generation sequencing (TGS), offers longer reads than the second-generation sequencing (SGS). Given its ability to obtain full-length transcripts without assembly, isoform sequencing (Iso-Seq) of transcriptomes by PacBio is advantageous for genome annotation, identification of
[...] Read more.
Single-molecule real-time (SMRT) sequencing developed by PacBio, also called third-generation sequencing (TGS), offers longer reads than the second-generation sequencing (SGS). Given its ability to obtain full-length transcripts without assembly, isoform sequencing (Iso-Seq) of transcriptomes by PacBio is advantageous for genome annotation, identification of novel genes and isoforms, as well as the discovery of long non-coding RNA (lncRNA). In addition, Iso-Seq gives access to the direct detection of alternative splicing, alternative polyadenylation (APA), gene fusion, and DNA modifications. Such applications of Iso-Seq facilitate the understanding of gene structure, post-transcriptional regulatory networks, and subsequently proteomic diversity. In this review, we summarize its applications in plant transcriptome study, specifically pointing out challenges associated with each step in the experimental design and highlight the development of bioinformatic pipelines. We aim to provide the community with an integrative overview and a comprehensive guidance to Iso-Seq, and thus to promote its applications in plant research. Full article
(This article belongs to the Special Issue Plant Genomics and Epigenomics for Trait Improvement)
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Open AccessReview PGC1α: Friend or Foe in Cancer?
Genes 2018, 9(1), 48; doi:10.3390/genes9010048
Received: 20 November 2017 / Revised: 15 January 2018 / Accepted: 16 January 2018 / Published: 22 January 2018
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Abstract
The PGC1 family (Peroxisome proliferator-activated receptor γ (PPARγ) coactivators) of transcriptional coactivators are considered master regulators of mitochondrial biogenesis and function. The PGC1α isoform is expressed especially in metabolically active tissues, such as the liver, kidneys and brain, and responds to energy-demanding situations.
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The PGC1 family (Peroxisome proliferator-activated receptor γ (PPARγ) coactivators) of transcriptional coactivators are considered master regulators of mitochondrial biogenesis and function. The PGC1α isoform is expressed especially in metabolically active tissues, such as the liver, kidneys and brain, and responds to energy-demanding situations. Given the altered and highly adaptable metabolism of tumor cells, it is of interest to investigate PGC1α in cancer. Both high and low levels of PGC1α expression have been reported to be associated with cancer and worse prognosis, and PGC1α has been attributed with oncogenic as well as tumor suppressive features. Early in carcinogenesis PGC1α may be downregulated due to a protective anticancer role, and low levels likely reflect a glycolytic phenotype. We suggest mechanisms of PGC1α downregulation and how these might be connected to the increased cancer risk that obesity is now known to entail. Later in tumor progression PGC1α is often upregulated and is reported to contribute to increased lipid and fatty acid metabolism and/or a tumor cell phenotype with an overall metabolic plasticity that likely supports drug resistance as well as metastasis. We conclude that in cancer PGC1α is neither friend nor foe, but rather the obedient servant reacting to metabolic and environmental cues to benefit the tumor cell. Full article
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Open AccessReview Single-Cell Genomic Analysis in Plants
Genes 2018, 9(1), 50; doi:10.3390/genes9010050
Received: 13 December 2017 / Revised: 5 January 2018 / Accepted: 10 January 2018 / Published: 22 January 2018
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Abstract
Individual cells in an organism are variable, which strongly impacts cellular processes. Advances in sequencing technologies have enabled single-cell genomic analysis to become widespread, addressing shortcomings of analyses conducted on populations of bulk cells. While the field of single-cell plant genomics is in
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Individual cells in an organism are variable, which strongly impacts cellular processes. Advances in sequencing technologies have enabled single-cell genomic analysis to become widespread, addressing shortcomings of analyses conducted on populations of bulk cells. While the field of single-cell plant genomics is in its infancy, there is great potential to gain insights into cell lineage and functional cell types to help understand complex cellular interactions in plants. In this review, we discuss current approaches for single-cell plant genomic analysis, with a focus on single-cell isolation, DNA amplification, next-generation sequencing, and bioinformatics analysis. We outline the technical challenges of analysing material from a single plant cell, and then examine applications of single-cell genomics and the integration of this approach with genome editing. Finally, we indicate future directions we expect in the rapidly developing field of plant single-cell genomic analysis. Full article
(This article belongs to the Special Issue Plant Genomics and Epigenomics for Trait Improvement)
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Open AccessCorrection Correction: Reinauer et al., The Clinical Course of Patients with Preschool Manifestation of Type 1 Diabetes Is Independent of the HLA DR-DQ Genotype. Genes 2017, 8, 146
Genes 2018, 9(1), 13; doi:10.3390/genes9010013
Received: 13 December 2017 / Revised: 20 December 2017 / Accepted: 20 December 2017 / Published: 3 January 2018
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Abstract
The article entitled “The Clinical Course of Patients with Preschool Manifestation of Type 1 Diabetes is Independent of the HLA DR-DQ Genotype” contained a calculation error in Table 2 and the statistical methods used were not completely described.[...]
Full article
(This article belongs to the Special Issue Genetics and Functional Genomics of Diabetes Mellitus)
Open AccessBrief Report Physiological and Comparative Genomic Analysis of Arthrobacter sp. SRS-W-1-2016 Provides Insights on Niche Adaptation for Survival in Uraniferous Soils
Genes 2018, 9(1), 31; doi:10.3390/genes9010031
Received: 21 November 2017 / Revised: 22 December 2017 / Accepted: 5 January 2018 / Published: 11 January 2018
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Abstract
Arthrobacter sp. strain SRS-W-1-2016 was isolated on high concentrations of uranium (U) from the Savannah River Site (SRS) that remains co-contaminated by radionuclides, heavy metals, and organics. SRS is located on the northeast bank of the Savannah River (South Carolina, USA), which is
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Arthrobacter sp. strain SRS-W-1-2016 was isolated on high concentrations of uranium (U) from the Savannah River Site (SRS) that remains co-contaminated by radionuclides, heavy metals, and organics. SRS is located on the northeast bank of the Savannah River (South Carolina, USA), which is a U.S. Department of Energy (DOE) managed ecosystem left historically contaminated from decades of nuclear weapons production activities. Predominant contaminants within the impacted SRS environment include U and Nickel (Ni), both of which can be transformed microbially into less toxic forms via metal complexation mechanisms. Strain SRS-W-1-2016 was isolated from the uraniferous SRS soils on high concentrations of U (4200 μM) and Ni (8500 μM), but rapid growth was observed at much lower concentrations of 500 μM U and 1000 μM Ni, respectively. Microcosm studies established with strain SRS-W-1-2016 revealed a rapid decline in the concentration of spiked U such that it was almost undetectable in the supernatant by 72 h of incubation. Conversely, Ni concentrations remained unchanged, suggesting that the strain removed U but not Ni under the tested conditions. To obtain a deeper understanding of the metabolic potential, a draft genome sequence of strain SRS-W-1-2016 was obtained at a coverage of 90×, assembling into 93 contigs with an N50 contig length of 92,788 bases. The genomic size of strain SRS-W-1-2016 was found to be 4,564,701 bases with a total number of 4327 putative genes. An in-depth, genome-wide comparison between strain SRS-W-1-2016 and its four closest taxonomic relatives revealed 1159 distinct genes, representing 26.7% of its total genome; many associating with metal resistance proteins (e.g., for cadmium, cobalt, and zinc), transporter proteins, stress proteins, cytochromes, and drug resistance functions. Additionally, several gene homologues coding for resistance to metals were identified in the strain, such as outer membrane efflux pump proteins, peptide/nickel transport substrate and ATP-binding proteins, a high-affinity nickel-transport protein, and the spoT gene, which was recently implicated in bacterial resistance towards U. Detailed genome mining analysis of strain SRS-W-1-2016 also revealed the presence of a plethora of secondary metabolite biosynthetic gene clusters likely facilitating resistance to antibiotics, biocides, and metals. Additionally, several gene homologous for the well-known oxygenase enzyme system were also identified, potentially functioning to generate energy via the breakdown of organic compounds and thus enabling the successful colonization and natural attenuation of contaminants by Arthrobacter sp. SRS-W-1-2016 at the SRS site. Full article
(This article belongs to the Section Microbial Genetics and Genomics)
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