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Volume 9
Issue 7
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Genes, Volume 9, Issue 7 (July 2018) – 57 articles

Cover Story (view full-size image): Domestic geese specimens from 15 archaeological sites in Russia subjected to an ancient DNA analysis, demonstrated that a mitochondrial haplogroup diagnostic for current domestic geese was already present in High Medieval domestic geese (11–13th centuries) and persisted through Late Medieval and Post Medieval times. Different mitochondrial DNA haplogroups characterize the wild progenitor of domestic geese, the greylag. This is the most detailed ancient DNA study on domestic geese to date. View this paper.
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30 pages, 1915 KiB  
Review
Bioengineering Strategies for Protein-Based Nanoparticles
by Dennis Diaz, Andrew Care and Anwar Sunna
Genes 2018, 9(7), 370; https://doi.org/10.3390/genes9070370 - 23 Jul 2018
Cited by 83 | Viewed by 11725
Abstract
In recent years, the practical application of protein-based nanoparticles (PNPs) has expanded rapidly into areas like drug delivery, vaccine development, and biocatalysis. PNPs possess unique features that make them attractive as potential platforms for a variety of nanobiotechnological applications. They self-assemble from multiple [...] Read more.
In recent years, the practical application of protein-based nanoparticles (PNPs) has expanded rapidly into areas like drug delivery, vaccine development, and biocatalysis. PNPs possess unique features that make them attractive as potential platforms for a variety of nanobiotechnological applications. They self-assemble from multiple protein subunits into hollow monodisperse structures; they are highly stable, biocompatible, and biodegradable; and their external components and encapsulation properties can be readily manipulated by chemical or genetic strategies. Moreover, their complex and perfect symmetry have motivated researchers to mimic their properties in order to create de novo protein assemblies. This review focuses on recent advances in the bioengineering and bioconjugation of PNPs and the implementation of synthetic biology concepts to exploit and enhance PNP’s intrinsic properties and to impart them with novel functionalities. Full article
(This article belongs to the Special Issue Emerging Applications in Synthetic Biology)
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27 pages, 21488 KiB  
Article
Mutation in the pssZ Gene Negatively Impacts Exopolysaccharide Synthesis, Surface Properties, and Symbiosis of Rhizobium leguminosarum bv. trifolii with Clover
by Paulina Lipa, José-María Vinardell, Joanna Kopcińska, Agnieszka Zdybicka-Barabas and Monika Janczarek
Genes 2018, 9(7), 369; https://doi.org/10.3390/genes9070369 - 23 Jul 2018
Cited by 12 | Viewed by 4803
Abstract
Rhizobium leguminosarum bv. trifolii is a soil bacterium capable of establishing a nitrogen-fixing symbiosis with clover plants (Trifolium spp.). This bacterium secretes large amounts of acidic exopolysaccharide (EPS), which plays an essential role in the symbiotic interaction with the host plant. This [...] Read more.
Rhizobium leguminosarum bv. trifolii is a soil bacterium capable of establishing a nitrogen-fixing symbiosis with clover plants (Trifolium spp.). This bacterium secretes large amounts of acidic exopolysaccharide (EPS), which plays an essential role in the symbiotic interaction with the host plant. This polymer is biosynthesized by a multi-enzymatic complex located in the bacterial inner membrane, whose components are encoded by a large chromosomal gene cluster, called Pss-I. In this study, we characterize R. leguminosarum bv. trifolii strain Rt297 that harbors a Tn5 transposon insertion located in the pssZ gene from the Pss-I region. This gene codes for a protein that shares high identity with bacterial serine/threonine protein phosphatases. We demonstrated that the pssZ mutation causes pleiotropic effects in rhizobial cells. Strain Rt297 exhibited several physiological and symbiotic defects, such as lack of EPS production, reduced growth kinetics and motility, altered cell-surface properties, and failure to infect the host plant. These data indicate that the protein encoded by the pssZ gene is indispensable for EPS synthesis, but also required for proper functioning of R. leguminosarum bv. trifolii cells. Full article
(This article belongs to the Section Microbial Genetics and Genomics)
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16 pages, 1610 KiB  
Review
Adaptation and Therapeutic Exploitation of the Plasma Membrane of African Trypanosomes
by Juan F. Quintana, Ricardo Canavate Del Pino, Kayo Yamada, Ning Zhang and Mark C. Field
Genes 2018, 9(7), 368; https://doi.org/10.3390/genes9070368 - 20 Jul 2018
Cited by 9 | Viewed by 5986
Abstract
African trypanosomes are highly divergent from their metazoan hosts, and as part of adaptation to a parasitic life style have developed a unique endomembrane system. The key virulence mechanism of many pathogens is successful immune evasion, to enable survival within a host, a [...] Read more.
African trypanosomes are highly divergent from their metazoan hosts, and as part of adaptation to a parasitic life style have developed a unique endomembrane system. The key virulence mechanism of many pathogens is successful immune evasion, to enable survival within a host, a feature that requires both genetic events and membrane transport mechanisms in African trypanosomes. Intracellular trafficking not only plays a role in immune evasion, but also in homeostasis of intracellular and extracellular compartments and interactions with the environment. Significantly, historical and recent work has unraveled some of the connections between these processes and highlighted how immune evasion mechanisms that are associated with adaptations to membrane trafficking may have, paradoxically, provided specific sensitivity to drugs. Here, we explore these advances in understanding the membrane composition of the trypanosome plasma membrane and organelles and provide a perspective for how transport could be exploited for therapeutic purposes. Full article
(This article belongs to the Special Issue Membrane Proteins in Parasitic Protozoa)
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18 pages, 2207 KiB  
Article
Over a Thousand Years of Evolutionary History of Domestic Geese from Russian Archaeological Sites, Analysed Using Ancient DNA
by Johanna Honka, Matti T. Heino, Laura Kvist, Igor V. Askeyev, Dilyara N. Shaymuratova, Oleg V. Askeyev, Arthur O. Askeyev, Marja E. Heikkinen, Jeremy B. Searle and Jouni Aspi
Genes 2018, 9(7), 367; https://doi.org/10.3390/genes9070367 - 20 Jul 2018
Cited by 18 | Viewed by 6925
Abstract
The European domestic goose is a widely farmed species known to have descended from the wild greylag goose (Anser anser). However, the evolutionary history of this domesticate is still poorly known. Ancient DNA studies have been useful for many species, but [...] Read more.
The European domestic goose is a widely farmed species known to have descended from the wild greylag goose (Anser anser). However, the evolutionary history of this domesticate is still poorly known. Ancient DNA studies have been useful for many species, but there has been little such work on geese. We have studied temporal genetic variation among domestic goose specimens excavated from Russian archaeological sites (4th–18th centuries) using a 204 base pair fragment of the mitochondrial control region. Specimens fell into three different genetic clades: the domestic D-haplogroup, the F-haplogroup that includes both wild and domestic geese, and a clade comprising another species, the taiga bean goose. Most of the subfossil geese carried typical domestic D-haplotypes. The domestication status of the geese carrying F-haplotypes is less certain, as the haplotypes identified were not present among modern domestic geese and could represent wild geese (misclassified as domestics), introgression from wild geese, or local domestication events. The bones of taiga bean goose were most probably misidentified as domestic goose but the domestication of bean goose or hybridization with domestic goose is also possible. Samples from the 4th to 10th century were clearly differentiated from the later time periods due to a haplotype that was found only in this early period, but otherwise no temporal or geographical variation in haplotype frequencies was apparent. Full article
(This article belongs to the Section Population and Evolutionary Genetics and Genomics)
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14 pages, 2344 KiB  
Article
Integrase-Controlled Excision of Metal-Resistance Genomic Islands in Acinetobacter baumannii
by Zaaima AL-Jabri, Roxana Zamudio, Eva Horvath-Papp, Joseph D. Ralph, Zakariya AL-Muharrami, Kumar Rajakumar and Marco R. Oggioni
Genes 2018, 9(7), 366; https://doi.org/10.3390/genes9070366 - 20 Jul 2018
Cited by 10 | Viewed by 5510
Abstract
Genomic islands (GIs) are discrete gene clusters encoding for a variety of functions including antibiotic and heavy metal resistance, some of which are tightly associated to lineages of the core genome phylogenetic tree. We have investigated the functions of two distinct integrase genes [...] Read more.
Genomic islands (GIs) are discrete gene clusters encoding for a variety of functions including antibiotic and heavy metal resistance, some of which are tightly associated to lineages of the core genome phylogenetic tree. We have investigated the functions of two distinct integrase genes in the mobilization of two metal resistant GIs, G08 and G62, of Acinetobacter baumannii. Real-time PCR demonstrated integrase-dependent GI excision, utilizing isopropyl β-d-1-thiogalactopyranoside IPTG-inducible integrase genes in plasmid-based mini-GIs in Escherichia coli. In A. baumannii, integrase-dependent excision of the original chromosomal GIs could be observed after mitomycin C induction. In both E. coli plasmids and A. baumannii chromosome, the rate of excision and circularization was found to be dependent on the expression level of the integrases. Susceptibility testing in A. baumannii strain ATCC 17978, A424, and their respective ΔG62 and ΔG08 mutants confirmed the contribution of the GI-encoded efflux transporters to heavy metal decreased susceptibility. In summary, the data evidenced the functionality of two integrases in the excision and circularization of the two Acinetobacter heavy-metal resistance GIs, G08 and G62, in E. coli, as well as when chromosomally located in their natural host. These recombination events occur at different frequencies resulting in genome plasticity and may participate in the spread of resistance determinants in A. baumannii. Full article
(This article belongs to the Special Issue Genomics of Bacterial Metal Resistance)
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18 pages, 1811 KiB  
Review
Cellular Genomic Sites of Hepatitis B Virus DNA Integration
by Magdalena A. Budzinska, Nicholas A. Shackel, Stephan Urban and Thomas Tu
Genes 2018, 9(7), 365; https://doi.org/10.3390/genes9070365 - 20 Jul 2018
Cited by 56 | Viewed by 9556
Abstract
Infection with the Hepatitis B Virus (HBV) is one of the strongest risk-factors for liver cancer (hepatocellular carcinoma, HCC). One of the reported drivers of HCC is the integration of HBV DNA into the host cell genome, which may induce pro-carcinogenic pathways. These [...] Read more.
Infection with the Hepatitis B Virus (HBV) is one of the strongest risk-factors for liver cancer (hepatocellular carcinoma, HCC). One of the reported drivers of HCC is the integration of HBV DNA into the host cell genome, which may induce pro-carcinogenic pathways. These reported pathways include: induction of chromosomal instability; generation of insertional mutagenesis in key cancer-associated genes; transcription of downstream cancer-associated cellular genes; and/or formation of a persistent source of viral protein expression (particularly HBV surface and X proteins). The contribution of each of these specific mechanisms towards carcinogenesis is currently unclear. Here, we review the current knowledge of specific sites of HBV DNA integration into the host genome, which sheds light on these mechanisms. We give an overview of previously-used methods to detect HBV DNA integration and the enrichment of integration events in specific functional and structural cellular genomic sites. Finally, we posit a theoretical model of HBV DNA integration during disease progression and highlight open questions in the field. Full article
(This article belongs to the Special Issue Hepatitis B Virus Infection: An Update on Epidemiology, Diagnosis, Treatment and Prevention)
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17 pages, 2939 KiB  
Article
Genome-Scale Metabolic Model of Actinosynnema pretiosum ATCC 31280 and Its Application for Ansamitocin P-3 Production Improvement
by Jian Li, Renliang Sun, Xinjuan Ning, Xinran Wang and Zhuo Wang
Genes 2018, 9(7), 364; https://doi.org/10.3390/genes9070364 - 20 Jul 2018
Cited by 12 | Viewed by 4109
Abstract
Actinosynnema pretiosum ATCC 31280 is the producer of antitumor agent ansamitocin P-3 (AP-3). Understanding of the AP-3 biosynthetic pathway and the whole metabolic network in A. pretiosum is important for the improvement of AP-3 titer. In this study, we reconstructed the first complete [...] Read more.
Actinosynnema pretiosum ATCC 31280 is the producer of antitumor agent ansamitocin P-3 (AP-3). Understanding of the AP-3 biosynthetic pathway and the whole metabolic network in A. pretiosum is important for the improvement of AP-3 titer. In this study, we reconstructed the first complete Genome-Scale Metabolic Model (GSMM) Aspm1282 for A. pretiosum ATCC 31280 based on the newly sequenced genome, with 87% reactions having definite functional annotation. The model has been validated by effectively predicting growth and the key genes for AP-3 biosynthesis. Then we built condition-specific models for an AP-3 high-yield mutant NXJ-24 by integrating Aspm1282 model with time-course transcriptome data. The changes of flux distribution reflect the metabolic shift from growth-related pathway to secondary metabolism pathway since the second day of cultivation. The AP-3 and methionine metabolisms were both enriched in active flux for the last two days, which uncovered the relationships among cell growth, activation of methionine metabolism, and the biosynthesis of AP-3. Furthermore, we identified four combinatorial gene modifications for overproducing AP-3 by in silico strain design, which improved the theoretical flux of AP-3 biosynthesis from 0.201 to 0.372 mmol/gDW/h. Upregulation of methionine metabolic pathway is a potential strategy to improve the production of AP-3. Full article
(This article belongs to the Special Issue Selected Papers from the Bioinformatics and Intelligent Information Processing Conference (BIIP2018))
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19 pages, 2803 KiB  
Article
Genome-Wide Comparative Analysis of Aspergillus fumigatus Strains: The Reference Genome as a Matter of Concern
by Rocio Garcia-Rubio, Sara Monzon, Laura Alcazar-Fuoli, Isabel Cuesta and Emilia Mellado
Genes 2018, 9(7), 363; https://doi.org/10.3390/genes9070363 - 19 Jul 2018
Cited by 40 | Viewed by 5980
Abstract
Aspergillus fumigatus is a ubiquitous saprophytic mold and a major pathogen in immunocompromised patients. The effectiveness of triazole compounds, the A. fumigatus first line treatment, is being threatened by a rapid and global emergence of azole resistance. Whole genome sequencing (WGS) has emerged [...] Read more.
Aspergillus fumigatus is a ubiquitous saprophytic mold and a major pathogen in immunocompromised patients. The effectiveness of triazole compounds, the A. fumigatus first line treatment, is being threatened by a rapid and global emergence of azole resistance. Whole genome sequencing (WGS) has emerged as an invaluable tool for the analysis of genetic differences between A. fumigatus strains, their genetic background, and antifungal resistance development. Although WGS analyses can provide a valuable amount of novel information, there are some limitations that should be considered. These analyses, based on genome-wide comparative data and single nucleotide variant (SNV) calling, are dependent on the quality of sequencing, assembling, the variant calling criteria, as well as on the suitable selection of the reference genome, which must be genetically close to the genomes included in the analysis. In this study, 28 A. fumigatus genomes sequenced in-house and 73 available in public data bases have been analyzed. All genomes were distributed in four clusters and showed a variable number of SNVs depending on the genome used as reference (Af293 or A1163). Each reference genome belonged to a different cluster. The results highlighted the importance of choosing the most suitable A. fumigatus reference genome to avoid misleading conclusions. Full article
(This article belongs to the Special Issue Fungal Pathogenesis in Humans: The Growing Threat)
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18 pages, 2315 KiB  
Article
Dual RNA-Seq Analysis of Trichophyton rubrum and HaCat Keratinocyte Co-Culture Highlights Important Genes for Fungal-Host Interaction
by Monise Fazolin Petrucelli, Kamila Peronni, Pablo Rodrigo Sanches, Tatiana Takahasi Komoto, Josie Budag Matsuda, Wilson Araújo da Silva, Jr., Rene Oliveira Beleboni, Nilce Maria Martinez-Rossi, Mozart Marins and Ana Lúcia Fachin
Genes 2018, 9(7), 362; https://doi.org/10.3390/genes9070362 - 19 Jul 2018
Cited by 29 | Viewed by 6347
Abstract
The dermatophyte Trichophyton rubrum is the major fungal pathogen of skin, hair, and nails that uses keratinized substrates as the primary nutrients during infection. Few strategies are available that permit a better understanding of the molecular mechanisms involved in the interaction of T. [...] Read more.
The dermatophyte Trichophyton rubrum is the major fungal pathogen of skin, hair, and nails that uses keratinized substrates as the primary nutrients during infection. Few strategies are available that permit a better understanding of the molecular mechanisms involved in the interaction of T. rubrum with the host because of the limitations of models mimicking this interaction. Dual RNA-seq is a powerful tool to unravel this complex interaction since it enables simultaneous evaluation of the transcriptome of two organisms. Using this technology in an in vitro model of co-culture, this study evaluated the transcriptional profile of genes involved in fungus-host interactions in 24 h. Our data demonstrated the induction of glyoxylate cycle genes, ERG6 and TERG_00916, which encodes a carboxylic acid transporter that may improve the assimilation of nutrients and fungal survival in the host. Furthermore, genes encoding keratinolytic proteases were also induced. In human keratinocytes (HaCat) cells, the SLC11A1, RNASE7, and CSF2 genes were induced and the products of these genes are known to have antimicrobial activity. In addition, the FLG and KRT1 genes involved in the epithelial barrier integrity were inhibited. This analysis showed the modulation of important genes involved in T. rubrum–host interaction, which could represent potential antifungal targets for the treatment of dermatophytoses. Full article
(This article belongs to the Special Issue Fungal Pathogenesis in Humans: The Growing Threat)
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12 pages, 2118 KiB  
Article
GADD45B as a Prognostic and Predictive Biomarker in Stage II Colorectal Cancer
by Zhixun Zhao, Yibo Gao, Xu Guan, Zheng Liu, Zheng Jiang, Xiuyun Liu, Huixin Lin, Ming Yang, Chunxiang Li, Runkun Yang, Shuangmei Zou and Xishan Wang
Genes 2018, 9(7), 361; https://doi.org/10.3390/genes9070361 - 19 Jul 2018
Cited by 26 | Viewed by 6420
Abstract
GADD45B acts as a member of the growth arrest DNA damage-inducible gene family, which has demonstrated to play critical roles in DNA damage repair, cell growth, and apoptosis. This study aimed to explore the potential relationship between GADD45B expression and tumor progression and [...] Read more.
GADD45B acts as a member of the growth arrest DNA damage-inducible gene family, which has demonstrated to play critical roles in DNA damage repair, cell growth, and apoptosis. This study aimed to explore the potential relationship between GADD45B expression and tumor progression and evaluate the clinical value of GADD45B in stage II colorectal cancer (CRC). The expression patterns and prognostic value of GADD45B in CRC were analyzed based on The Cancer Genomic Atlas (TCGA). GADD45B expression features of 306 patients with stage II CRC and 201 patients with liver metastasis of CRC were investigated using immunochemical staining on tissue microarrays. Afterward, survival analysis and stratification analysis were performed in stage II to explore the prognostic and predictive significance of GADD45B. Overexpressed GADD45B is associated with poorer prognosis for CRC patients both in overall survival (OS) (p < 0.001) and disease-free survival (DFS) (p = 0.001) based on the TCGA database. Analysis results according to the stage II CRC cohort and the liver metastatic CRC cohort revealed that GADD45B was gradually upregulated in normal mucosa including primary colorectal cancer (PCC). Colorectal liver metastases (CLM) tissues were arranged in order (normal tissue vs. PCC p = 0.005 and PCC vs. CLM p = 0.001). The low GADD45B group had a significantly longer five-year OS (p = 0.001) and progression-free survival (PFS) (p < 0.001) than the high GADD45B group for the stage II patients. The multivariate Cox regression analysis results proved that the expression level of GADD45B was an independent prognostic factor for stage II after radical surgery (OS: Hazard Ratio (HR) 0.479, [95% confidence interval (CI) 0.305–0.753] and PFS:HR 0.490, [95% CI 0.336–0.714]). In high GADD45B expression subgroup of stage II cohort, the patients who underwent adjuvant chemotherapy had longer PFS than those who did not (p = 0.008). High expression levels of GADD45B is an independent prognostic factor of decreased OS and PFS in stage II CRC patients. The stage II CRC patients with high GADD45B expression might benefit from adjuvant chemotherapy. Full article
(This article belongs to the Special Issue Computational Approaches for Disease Gene Identification)
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11 pages, 255 KiB  
Article
Application of Whole Exome and Targeted Panel Sequencing in the Clinical Molecular Diagnosis of 319 Chinese Families with Inherited Retinal Dystrophy and Comparison Study
by Likun Wang, Jinlu Zhang, Ningning Chen, Lei Wang, Fengsheng Zhang, Zhizhong Ma, Genlin Li and Liping Yang
Genes 2018, 9(7), 360; https://doi.org/10.3390/genes9070360 - 19 Jul 2018
Cited by 50 | Viewed by 6167
Abstract
Inherited retinal dystrophies (IRDs) are a group of clinically and genetically heterogeneous diseases involving more than 280 genes and no less than 20 different clinical phenotypes. In this study, our aims were to identify the disease-causing gene variants of 319 Chinese patients with [...] Read more.
Inherited retinal dystrophies (IRDs) are a group of clinically and genetically heterogeneous diseases involving more than 280 genes and no less than 20 different clinical phenotypes. In this study, our aims were to identify the disease-causing gene variants of 319 Chinese patients with IRD, and compare the pros and cons of targeted panel sequencing and whole exome sequencing (WES). Patients were assigned for analysis with a hereditary eye disease enrichment panel (HEDEP) or WES examination based on time of recruitment. This HEDEP was able to capture 441 hereditary eye disease genes, which included 291 genes related to IRD. As RPGR ORF15 was difficult to capture, all samples were subjected to Sanger sequencing for this region. Among the 163 disease-causing variants identified in this study, 73 had been previously reported, and the other 90 were novel. Genes most commonly implicated in different inheritances of IRDs in this cohort were presented. HEDEP and WES achieved diagnostic yield with 41.2% and 33.0%, respectively. In addition, nine patients were found to carry pathogenic mutations in the RPGR ORF15 region with Sanger sequencing. Our study demonstrates that HEDEP can be used as a first-tier test for patients with IRDs. Full article
(This article belongs to the Special Issue Selected Papers from the Bioinformatics and Intelligent Information Processing Conference (BIIP2018))
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14 pages, 1427 KiB  
Concept Paper
Strengthening the One Health Agenda: The Role of Molecular Epidemiology in Aspergillus Threat Management
by Eta E. Ashu and Jianping Xu
Genes 2018, 9(7), 359; https://doi.org/10.3390/genes9070359 - 19 Jul 2018
Cited by 6 | Viewed by 3791
Abstract
The United Nations’ One Health initiative advocates the collaboration of multiple sectors within the global and local health authorities toward the goal of better public health management outcomes. The emerging global health threat posed by Aspergillus species is an example of a management [...] Read more.
The United Nations’ One Health initiative advocates the collaboration of multiple sectors within the global and local health authorities toward the goal of better public health management outcomes. The emerging global health threat posed by Aspergillus species is an example of a management challenge that would benefit from the One Health approach. In this paper, we explore the potential role of molecular epidemiology in Aspergillus threat management and strengthening of the One Health initiative. Effective management of Aspergillus at a public health level requires the development of rapid and accurate diagnostic tools to not only identify the infecting pathogen to species level, but also to the level of individual genotype, including drug susceptibility patterns. While a variety of molecular methods have been developed for Aspergillus diagnosis, their use at below-species level in clinical settings has been very limited, especially in resource-poor countries and regions. Here we provide a framework for Aspergillus threat management and describe how molecular epidemiology and experimental evolution methods could be used for predicting resistance through drug exposure. Our analyses highlight the need for standardization of loci and methods used for molecular diagnostics, and surveillance across Aspergillus species and geographic regions. Such standardization will enable comparisons at national and global levels and through the One Health approach, strengthen Aspergillus threat management efforts. Full article
(This article belongs to the Special Issue Fungal Pathogenesis in Humans: The Growing Threat)
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12 pages, 982 KiB  
Review
Evolutionary and Medical Consequences of Archaic Introgression into Modern Human Genomes
by Olga Dolgova and Oscar Lao
Genes 2018, 9(7), 358; https://doi.org/10.3390/genes9070358 - 18 Jul 2018
Cited by 23 | Viewed by 11132
Abstract
The demographic history of anatomically modern humans (AMH) involves multiple migration events, population extinctions and genetic adaptations. As genome-wide data from complete genome sequencing becomes increasingly abundant and available even from extinct hominins, new insights of the evolutionary history of our species are [...] Read more.
The demographic history of anatomically modern humans (AMH) involves multiple migration events, population extinctions and genetic adaptations. As genome-wide data from complete genome sequencing becomes increasingly abundant and available even from extinct hominins, new insights of the evolutionary history of our species are discovered. It is currently known that AMH interbred with archaic hominins once they left the African continent. Modern non-African human genomes carry fragments of archaic origin. This review focuses on the fitness consequences of archaic interbreeding in current human populations. We discuss new insights and challenges that researchers face when interpreting the potential impact of introgression on fitness and testing hypotheses about the role of selection within the context of health and disease. Full article
(This article belongs to the Special Issue Evolutionary Medicine)
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11 pages, 3079 KiB  
Article
Genetic Targeting of GRP78 in the VMH Improves Obesity Independently of Food Intake
by Laura Liñares-Pose, Eva Rial-Pensado, Ánxela Estévez-Salguero, Edward Milbank, Ismael González-García, Claudia Rodríguez, Patricia Seoane-Collazo, Noelia Martinez-Sánchez, Rubén Nogueiras, Dolores Prieto, Carlos Diéguez, Cristina Contreras and Miguel López
Genes 2018, 9(7), 357; https://doi.org/10.3390/genes9070357 - 17 Jul 2018
Cited by 15 | Viewed by 4925
Abstract
Recent data have demonstrated that the hypothalamic GRP78/BiP (glucose regulated protein 78 kDa/binding immunoglobulin protein) modulates brown adipose tissue (BAT) thermogenesis by acting downstream on AMP-activated protein kinase (AMPK). Herein, we aimed to investigate whether genetic over-expression of GRP78 in the ventromedial nucleus [...] Read more.
Recent data have demonstrated that the hypothalamic GRP78/BiP (glucose regulated protein 78 kDa/binding immunoglobulin protein) modulates brown adipose tissue (BAT) thermogenesis by acting downstream on AMP-activated protein kinase (AMPK). Herein, we aimed to investigate whether genetic over-expression of GRP78 in the ventromedial nucleus of the hypothalamus (VMH: a key site regulating thermogenesis) could ameliorate very high fat diet (vHFD)-induced obesity. Our data showed that stereotaxic treatment with adenoviruses harboring GRP78 in the VMH reduced hypothalamic endoplasmic reticulum ER stress and reversed vHFD-induced obesity. Herein, we also demonstrated that this body weight decrease was more likely associated with an increased BAT thermogenesis and browning of white adipose tissue (WAT) than to anorexia. Overall, these results indicate that the modulation of GRP78 in the VMH may be a target against obesity. Full article
(This article belongs to the Special Issue Advances in Genetics of Regeneration in Metabesity)
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13 pages, 472 KiB  
Article
An Evolutionary Mechanism for the Generation of Competing RNA Structures Associated with Mutually Exclusive Exons
by Timofei M. Ivanov and Dmitri D. Pervouchine
Genes 2018, 9(7), 356; https://doi.org/10.3390/genes9070356 - 17 Jul 2018
Cited by 12 | Viewed by 3659
Abstract
Alternative splicing is a commonly-used mechanism of diversifying gene products. Mutually exclusive exons (MXE) represent a particular type of alternative splicing, in which one and only one exon from an array is included in the mature RNA. A number of genes with MXE [...] Read more.
Alternative splicing is a commonly-used mechanism of diversifying gene products. Mutually exclusive exons (MXE) represent a particular type of alternative splicing, in which one and only one exon from an array is included in the mature RNA. A number of genes with MXE do so by using a mechanism that depends on RNA structure. Transcripts of these genes contain multiple sites called selector sequences that are all complementary to a regulatory element called the docking site; only one of the competing base pairings can form at a time, which exposes one exon from the cluster to the spliceosome. MXE tend to have similar lengths and sequence content and are believed to originate through tandem genomic duplications. Here, we report that pre-mRNAs of this class of exons have an increased capacity to fold into competing secondary structures. We propose an evolutionary mechanism for the generation of such structures via duplications that affect not only exons, but also their adjacent introns with stem-loop structures. If one of the two arms of a stem-loop is duplicated, it will generate two selector sequences that compete for the same docking site, a pattern that is associated with MXE splicing. A similar partial duplication of two independent stem-loops produces a pattern that is consistent with the so-called bidirectional pairing model. These models explain why tandem exon duplications frequently result in mutually exclusive splicing. Full article
(This article belongs to the Special Issue Computational Analysis of RNA Structure and Function)
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21 pages, 4846 KiB  
Article
Mitochondrial HTRA2 Plays a Positive, Protective Role in Dictyostelium discoideum but Is Cytotoxic When Overexpressed
by Suwei Chen, Oana Sanislav, Sarah J. Annesley and Paul R. Fisher
Genes 2018, 9(7), 355; https://doi.org/10.3390/genes9070355 - 16 Jul 2018
Cited by 9 | Viewed by 3936
Abstract
HTRA2 is a mitochondrial protein, mutations in which are associated with autosomal dominant late-onset Parkinson’s disease (PD). The mechanisms by which HTRA2 mutations result in PD are poorly understood. HTRA2 is proposed to play a proteolytic role in protein quality control and homeostasis [...] Read more.
HTRA2 is a mitochondrial protein, mutations in which are associated with autosomal dominant late-onset Parkinson’s disease (PD). The mechanisms by which HTRA2 mutations result in PD are poorly understood. HTRA2 is proposed to play a proteolytic role in protein quality control and homeostasis in the mitochondrial intermembrane space. Its loss has been reported to result in accumulation of unfolded and misfolded proteins. However, in at least one case, PD-associated HTRA2 mutation can cause its hyperphosphorylation, possibly resulting in protease hyperactivity. The consequences of overactive mitochondrial HTRA2 are not clear. Dictyostelium discoideum provides a well-established model for studying mitochondrial dysfunction, such as has been implicated in the pathology of PD. We identified a single homologue of human HTRA2 encoded in the Dictyostelium discoideum genome and showed that it is localized to the mitochondria where it plays a cytoprotective role. Knockdown of HTRA2 expression caused defective morphogenesis in the multicellular phases of the Dictyostelium life cycle. In vegetative cells, it did not impair mitochondrial respiration but nonetheless caused slow growth (particularly when the cells were utilizing a bacterial food source), unaccompanied by significant defects in the requisite endocytic pathways. Despite its protective roles, we could not ectopically overexpress wild type HTRA2, suggesting that mitochondrial HTRA2 hyperactivity is lethal. This toxicity was abolished by replacing the essential catalytic serine S300 with alanine to ablate serine protease activity. Overexpression of protease-dead HTRA2 phenocopied the effects of knockdown, suggesting that the mutant protein competitively inhibits interactions between wild type HTRA2 and its binding partners. Our results show that cytopathological dysfunction can be caused either by too little or too much HTRA2 activity in the mitochondria and suggest that either could be a cause of PD. Full article
(This article belongs to the Special Issue Mitochondria and Aging)
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19 pages, 1555 KiB  
Article
Genome Mining of Non-Conventional Yeasts: Search and Analysis of MAL Clusters and Proteins
by Katrin Viigand, Kristina Põšnograjeva, Triinu Visnapuu and Tiina Alamäe
Genes 2018, 9(7), 354; https://doi.org/10.3390/genes9070354 - 16 Jul 2018
Cited by 11 | Viewed by 4337
Abstract
Genomic clustering of functionally related genes is rare in yeasts and other eukaryotes with only few examples available. Here, we summarize our data on a nontelomeric MAL cluster of a non-conventional methylotrophic yeast Ogataea (Hansenula) polymorpha containing genes for α-glucosidase MAL1, [...] Read more.
Genomic clustering of functionally related genes is rare in yeasts and other eukaryotes with only few examples available. Here, we summarize our data on a nontelomeric MAL cluster of a non-conventional methylotrophic yeast Ogataea (Hansenula) polymorpha containing genes for α-glucosidase MAL1, α-glucoside permease MAL2 and two hypothetical transcriptional activators. Using genome mining, we detected MAL clusters of varied number, position and composition in many other maltose-assimilating non-conventional yeasts from different phylogenetic groups. The highest number of MAL clusters was detected in Lipomyces starkeyi while no MAL clusters were found in Schizosaccharomyces pombe and Blastobotrys adeninivorans. Phylograms of α-glucosidases and α-glucoside transporters of yeasts agreed with phylogenesis of the respective yeast species. Substrate specificity of unstudied α-glucosidases was predicted from protein sequence analysis. Specific activities of Scheffersomycesstipitis α-glucosidases MAL7, MAL8, and MAL9 heterologously expressed in Escherichia coli confirmed the correctness of the prediction—these proteins were verified promiscuous maltase-isomaltases. α-Glucosidases of earlier diverged yeasts L. starkeyi, B. adeninivorans and S. pombe showed sequence relatedness with α-glucosidases of filamentous fungi and bacilli. Full article
(This article belongs to the Section Population and Evolutionary Genetics and Genomics)
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13 pages, 1321 KiB  
Article
Morphological Stasis and Proteome Innovation in Cephalochordates
by László Bányai, Krisztina Kerekes, Mária Trexler and László Patthy
Genes 2018, 9(7), 353; https://doi.org/10.3390/genes9070353 - 16 Jul 2018
Cited by 2 | Viewed by 3560
Abstract
Lancelets, extant representatives of basal chordates, are prototypic examples of evolutionary stasis; they preserved a morphology and body-plan most similar to the fossil chordates from the early Cambrian. Such a low level of morphological evolution is in harmony with a low rate of [...] Read more.
Lancelets, extant representatives of basal chordates, are prototypic examples of evolutionary stasis; they preserved a morphology and body-plan most similar to the fossil chordates from the early Cambrian. Such a low level of morphological evolution is in harmony with a low rate of amino acid substitution; cephalochordate proteins were shown to evolve slower than those of the slowest evolving vertebrate, the elephant shark. Surprisingly, a study comparing the predicted proteomes of Chinese amphioxus, Branchiostoma belcheri and the Florida amphioxus, Branchiostoma floridae has led to the conclusion that the rate of creation of novel domain combinations is orders of magnitude greater in lancelets than in any other Metazoa, a finding that contradicts the notion that high rates of protein innovation are usually associated with major evolutionary innovations. Our earlier studies on a representative sample of proteins have provided evidence suggesting that the differences in the domain architectures of predicted proteins of these two lancelet species reflect annotation errors, rather than true innovations. In the present work, we have extended these studies to include a larger sample of genes and two additional lancelet species, Asymmetron lucayanum and Branchiostoma lanceolatum. These analyses have confirmed that the domain architecture differences of orthologous proteins of the four lancelet species are because of errors of gene prediction, the error rate in the given species being inversely related to the quality of the transcriptome dataset that was used to aid gene prediction. Full article
(This article belongs to the Special Issue Evolution and Structure of Proteins and Proteomes)
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21 pages, 7001 KiB  
Review
Evolutionary Divergent Suppressor Mutations in Conformational Diseases
by Noel Mesa-Torres, Isabel Betancor-Fernández, Elisa Oppici, Barbara Cellini, Eduardo Salido and Angel L. Pey
Genes 2018, 9(7), 352; https://doi.org/10.3390/genes9070352 - 13 Jul 2018
Cited by 13 | Viewed by 3788
Abstract
Neutral and adaptive mutations are key players in the evolutionary dynamics of proteins at molecular, cellular and organismal levels. Conversely, largely destabilizing mutations are rarely tolerated by evolution, although their occurrence in diverse human populations has important roles in the pathogenesis of conformational [...] Read more.
Neutral and adaptive mutations are key players in the evolutionary dynamics of proteins at molecular, cellular and organismal levels. Conversely, largely destabilizing mutations are rarely tolerated by evolution, although their occurrence in diverse human populations has important roles in the pathogenesis of conformational diseases. We have recently proposed that divergence at certain sites from the consensus (amino acid) state during mammalian evolution may have rendered some human proteins more vulnerable towards disease-associated mutations, primarily by decreasing their conformational stability. We herein extend and refine this hypothesis discussing results from phylogenetic and structural analyses, structure-based energy calculations and structure-function studies at molecular and cellular levels. As proof-of-principle, we focus on different mammalian orthologues of the NQO1 (NAD(P)H:quinone oxidoreductase 1) and AGT (alanine:glyoxylate aminotransferase) proteins. We discuss the different loss-of-function pathogenic mechanisms associated with diseases involving the two enzymes, including enzyme inactivation, accelerated degradation, intracellular mistargeting, and aggregation. Last, we take into account the potentially higher robustness of mammalian orthologues containing certain consensus amino acids as suppressors of human disease, and their relation with different intracellular post-translational modifications and protein quality control capacities, to be discussed as sources of phenotypic variability between human and mammalian models of disease and as tools for improving current therapeutic approaches. Full article
(This article belongs to the Special Issue Evolution and Structure of Proteins and Proteomes)
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12 pages, 1002 KiB  
Review
Targeted Approaches for In Situ Gut Microbiome Manipulation
by Hui Ling Lee, Haosheng Shen, In Young Hwang, Hua Ling, Wen Shan Yew, Yung Seng Lee and Matthew Wook Chang
Genes 2018, 9(7), 351; https://doi.org/10.3390/genes9070351 - 12 Jul 2018
Cited by 37 | Viewed by 9040
Abstract
Microbial communities and their collective genomes form the gut microbiome, of which bacteria are the major contributor. Through their secreted metabolites, bacteria interact with the host, influencing human health and physiology. Perturbation of the microbiota and metabolome has been associated with various diseases [...] Read more.
Microbial communities and their collective genomes form the gut microbiome, of which bacteria are the major contributor. Through their secreted metabolites, bacteria interact with the host, influencing human health and physiology. Perturbation of the microbiota and metabolome has been associated with various diseases and metabolic conditions. As knowledge on fundamental host-microbiome interactions and genetic engineering tools becomes readily available, targeted manipulation of the gut microbiome for therapeutic applications gains favourable attention. Manipulation of the gut microbiome can be achieved by altering the microbiota population and composition, or by modifying the functional metabolic activity of the microbiome to promote health and restore the microbiome balance. In this article, we review current works that demonstrate various strategies employed to manipulate the gut microbiome in situ to various degrees of precision. Full article
(This article belongs to the Special Issue Emerging Applications in Synthetic Biology)
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11 pages, 1342 KiB  
Article
Ensemble Consensus-Guided Unsupervised Feature Selection to Identify Huntington’s Disease-Associated Genes
by Xia Guo, Xue Jiang, Jing Xu, Xiongwen Quan, Min Wu and Han Zhang
Genes 2018, 9(7), 350; https://doi.org/10.3390/genes9070350 - 12 Jul 2018
Cited by 7 | Viewed by 3746
Abstract
Due to the complexity of the pathological mechanisms of neurodegenerative diseases, traditional differentially-expressed gene selection methods cannot detect disease-associated genes accurately. Recent studies have shown that consensus-guided unsupervised feature selection (CGUFS) performs well in feature selection for identifying disease-associated genes. Since the random [...] Read more.
Due to the complexity of the pathological mechanisms of neurodegenerative diseases, traditional differentially-expressed gene selection methods cannot detect disease-associated genes accurately. Recent studies have shown that consensus-guided unsupervised feature selection (CGUFS) performs well in feature selection for identifying disease-associated genes. Since the random initialization of the feature selection matrix in CGUFS results in instability of the final disease-associated gene set, for the purposes of this study we proposed an ensemble method based on CGUFS—namely, ensemble consensus-guided unsupervised feature selection (ECGUFS) in order to further improve the accuracy of disease-associated genes and the stability of feature gene sets. We also proposed a bagging integration strategy to integrate the results of CGUFS. Lastly, we conducted experiments with Huntington’s disease RNA sequencing (RNA-Seq) data and obtained the final feature gene set, where we detected 287 disease-associated genes. Enrichment analysis on these genes has shown that postsynaptic density and the postsynaptic membrane, synapse, and cell junction are all affected during the disease’s progression. However, ECGUFS greatly improved the accuracy of disease-associated gene prediction and the stability of the disease-associated gene set. We conducted a classification of samples with labels based on the linear support vector machine with 10-fold cross-validation. The average accuracy is 0.9, which suggests the effectiveness of the feature gene set. Full article
(This article belongs to the Special Issue Selected Papers from the Bioinformatics and Intelligent Information Processing Conference (BIIP2018))
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10 pages, 1452 KiB  
Article
Description of Genetic Variants in BRCA Genes in Mexican Patients with Ovarian Cancer: A First Step towards Implementing Personalized Medicine
by Jesus Rolando Delgado-Balderas, Maria Lourdes Garza-Rodriguez, Gabriela Sofia Gomez-Macias, Alvaro Barboza-Quintana, Oralia Barboza-Quintana, Ricardo M. Cerda-Flores, Ivett Miranda-Maldonado, Hugo Mauricio Vazquez-Garcia, Lezmes Dionicio Valdez-Chapa, Mauro Antonio-Macedo, Michael Dean and Hugo A. Barrera-Saldaña
Genes 2018, 9(7), 349; https://doi.org/10.3390/genes9070349 - 11 Jul 2018
Cited by 4 | Viewed by 4938
Abstract
Gynecologic cancers are among the leading causes of death worldwide, ovarian cancer being the one with the highest mortality rate. Olaparib is a targeted therapy used in patients presenting mutations in BRCA1 and BRCA2 genes. The aim of this study was to describe [...] Read more.
Gynecologic cancers are among the leading causes of death worldwide, ovarian cancer being the one with the highest mortality rate. Olaparib is a targeted therapy used in patients presenting mutations in BRCA1 and BRCA2 genes. The aim of this study was to describe BRCA1 and BRCA2 gene variants in Mexican patients with ovarian cancer. Sequencing of BRCA1 and BRCA2 genes from tumors of 50 Mexican patients with ovarian cancer was made in a retrospective, non-randomized, and exploratory study. We found genetic variants in 48 of 50 cases. A total of 76 polymorphic variants were found in BRCA1, of which 50 (66%) had not been previously reported. Furthermore, 104 polymorphic variants were found in BRCA2, of which 63 (60%) had not been reported previously. Of these polymorphisms, 5/76 (6.6%) and 4/104 (3.8%) were classified as pathogenic in BRCA1 and BRCA2, respectively. We have described the genetic variants in BRCA1 and BRCA2 of tumors from Northeast Mexican patients with sporadic ovarian cancers. Our results showed that the use of genetic testing helps recognize patients that carry pathogenic variants which could be beneficial for personalized medicine treatments. Full article
(This article belongs to the Special Issue Genetic Epidemiology of Complex Diseases in Latin America)
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16 pages, 1410 KiB  
Perspective
The Multiplanetary Future of Plant Synthetic Biology
by Briardo Llorente, Thomas C. Williams and Hugh D. Goold
Genes 2018, 9(7), 348; https://doi.org/10.3390/genes9070348 - 10 Jul 2018
Cited by 33 | Viewed by 22980
Abstract
The interest in human space journeys to distant planets and moons has been re-ignited in recent times and there are ongoing plans for sending the first manned missions to Mars in the near future. In addition to generating oxygen, fixing carbon, and recycling [...] Read more.
The interest in human space journeys to distant planets and moons has been re-ignited in recent times and there are ongoing plans for sending the first manned missions to Mars in the near future. In addition to generating oxygen, fixing carbon, and recycling waste and water, plants could play a critical role in producing food and biomass feedstock for the microbial manufacture of materials, chemicals, and medicines in long-term interplanetary outposts. However, because life on Earth evolved under the conditions of the terrestrial biosphere, plants will not perform optimally in different planetary habitats. The construction or transportation of plant growth facilities and the availability of resources, such as sunlight and liquid water, may also be limiting factors, and would thus impose additional challenges to efficient farming in an extraterrestrial destination. Using the framework of the forthcoming human missions to Mars, here we discuss a series of bioengineering endeavors that will enable us to take full advantage of plants in the context of a Martian greenhouse. We also propose a roadmap for research on adapting life to Mars and outline our opinion that synthetic biology efforts towards this goal will contribute to solving some of the main agricultural and industrial challenges here on Earth. Full article
(This article belongs to the Special Issue Emerging Applications in Synthetic Biology)
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15 pages, 2318 KiB  
Article
Possible Role of Envelope Components in the Extreme Copper Resistance of the Biomining Acidithiobacillus ferrooxidans
by Nia Oetiker, Rodrigo Norambuena, Cristóbal Martínez-Bussenius, Claudio A. Navarro, Fernando Amaya, Sergio A. Álvarez, Alberto Paradela and Carlos A. Jerez
Genes 2018, 9(7), 347; https://doi.org/10.3390/genes9070347 - 10 Jul 2018
Cited by 17 | Viewed by 5155
Abstract
Acidithiobacillus ferrooxidans resists extremely high concentrations of copper. Strain ATCC 53993 is much more resistant to the metal compared with strain ATCC 23270, possibly due to the presence of a genomic island in the former one. The global response of strain ATCC 53993 [...] Read more.
Acidithiobacillus ferrooxidans resists extremely high concentrations of copper. Strain ATCC 53993 is much more resistant to the metal compared with strain ATCC 23270, possibly due to the presence of a genomic island in the former one. The global response of strain ATCC 53993 to copper was analyzed using iTRAQ (isobaric tag for relative and absolute quantitation) quantitative proteomics. Sixty-seven proteins changed their levels of synthesis in the presence of the metal. On addition of CusCBA efflux system proteins, increased levels of other envelope proteins, such as a putative periplasmic glucan biosynthesis protein (MdoG) involved in the osmoregulated synthesis of glucans and a putative antigen O polymerase (Wzy), were seen in the presence of copper. The expression of A. ferrooxidansmdoG or wzy genes in a copper sensitive Escherichia coli conferred it a higher metal resistance, suggesting the possible role of these components in copper resistance of A. ferrooxidans. Transcriptional levels of genes wzy, rfaE and wzz also increased in strain ATCC 23270 grown in the presence of copper, but not in strain ATCC 53993. Additionally, in the absence of this metal, lipopolysaccharide (LPS) amounts were 3-fold higher in A. ferrooxidans ATCC 53993 compared with strain 23270. Nevertheless, both strains grown in the presence of copper contained similar LPS quantities, suggesting that strain 23270 synthesizes higher amounts of LPS to resist the metal. On the other hand, several porins diminished their levels in the presence of copper. The data presented here point to an essential role for several envelope components in the extreme copper resistance by this industrially important acidophilic bacterium. Full article
(This article belongs to the Special Issue Genomics of Bacterial Metal Resistance)
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21 pages, 1850 KiB  
Article
The Genetics of a Behavioral Speciation Phenotype in an Island System
by Thomas Blankers, Kevin P. Oh and Kerry L. Shaw
Genes 2018, 9(7), 346; https://doi.org/10.3390/genes9070346 - 10 Jul 2018
Cited by 12 | Viewed by 5594
Abstract
Mating behavior divergence can make significant contributions to reproductive isolation and speciation in various biogeographic contexts. However, whether the genetic architecture underlying mating behavior divergence is related to the biogeographic history and the tempo and mode of speciation remains poorly understood. Here, we [...] Read more.
Mating behavior divergence can make significant contributions to reproductive isolation and speciation in various biogeographic contexts. However, whether the genetic architecture underlying mating behavior divergence is related to the biogeographic history and the tempo and mode of speciation remains poorly understood. Here, we use quantitative trait locus (QTL) mapping to infer the number, distribution, and effect size of mating song rhythm variations in the crickets Laupala eukolea and Laupala cerasina, which occur on different islands (Maui and Hawaii). We then compare these results with a similar study of an independently evolving species pair that diverged within the same island. Finally, we annotate the L. cerasina transcriptome and test whether the QTL fall in functionally enriched genomic regions. We document a polygenic architecture behind the song rhythm divergence in the inter-island species pair that is remarkably similar to that previously found for an intra-island species pair in the same genus. Importantly, the QTL regions were significantly enriched for potential homologs of the genes involved in pathways that may be modulating the cricket song rhythm. These clusters of loci could constrain the spatial genomic distribution of the genetic variation underlying the cricket song variation and harbor several candidate genes that merit further study. Full article
(This article belongs to the Special Issue Evolutionary Genetics of Reproductive Isolation)
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21 pages, 338 KiB  
Article
A Novel Probability Model for LncRNA–Disease Association Prediction Based on the Naïve Bayesian Classifier
by Jingwen Yu, Pengyao Ping, Lei Wang, Linai Kuang, Xueyong Li and Zhelun Wu
Genes 2018, 9(7), 345; https://doi.org/10.3390/genes9070345 - 8 Jul 2018
Cited by 53 | Viewed by 5832
Abstract
An increasing number of studies have indicated that long-non-coding RNAs (lncRNAs) play crucial roles in biological processes, complex disease diagnoses, prognoses, and treatments. However, experimentally validated associations between lncRNAs and diseases are still very limited. Recently, computational models have been developed to discover [...] Read more.
An increasing number of studies have indicated that long-non-coding RNAs (lncRNAs) play crucial roles in biological processes, complex disease diagnoses, prognoses, and treatments. However, experimentally validated associations between lncRNAs and diseases are still very limited. Recently, computational models have been developed to discover potential associations between lncRNAs and diseases by integrating multiple heterogeneous biological data; this has become a hot topic in biological research. In this article, we constructed a global tripartite network by integrating a variety of biological information including miRNA–disease, miRNA–lncRNA, and lncRNA–disease associations and interactions. Then, we constructed a global quadruple network by appending gene–lncRNA interaction, gene–disease association, and gene–miRNA interaction networks to the global tripartite network. Subsequently, based on these two global networks, a novel approach was proposed based on the naïve Bayesian classifier to predict potential lncRNA–disease associations (NBCLDA). Comparing with the state-of-the-art methods, our new method does not entirely rely on known lncRNA–disease associations, and can achieve a reliable performance with effective area under ROC curve (AUCs)in leave-one-out cross validation. Moreover, in order to further estimate the performance of NBCLDA, case studies of colorectal cancer, prostate cancer, and glioma were implemented in this paper, and the simulation results demonstrated that NBCLDA can be an excellent tool for biomedical research in the future. Full article
(This article belongs to the Special Issue Selected Papers from the Bioinformatics and Intelligent Information Processing Conference (BIIP2018))
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21 pages, 3760 KiB  
Article
Using a Chemical Genetic Screen to Enhance Our Understanding of the Antibacterial Properties of Silver
by Natalie Gugala, Joe Lemire, Kate Chatfield-Reed, Ying Yan, Gordon Chua and Raymond J. Turner
Genes 2018, 9(7), 344; https://doi.org/10.3390/genes9070344 - 6 Jul 2018
Cited by 35 | Viewed by 8251
Abstract
It is essential to understand the mechanisms by which a toxicant is capable of poisoning the bacterial cell. The mechanism of action of many biocides and toxins, including numerous ubiquitous compounds, is not fully understood. For example, despite the widespread clinical and commercial [...] Read more.
It is essential to understand the mechanisms by which a toxicant is capable of poisoning the bacterial cell. The mechanism of action of many biocides and toxins, including numerous ubiquitous compounds, is not fully understood. For example, despite the widespread clinical and commercial use of silver (Ag), the mechanisms describing how this metal poisons bacterial cells remains incomplete. To advance our understanding surrounding the antimicrobial action of Ag, we performed a chemical genetic screen of a mutant library of Escherichia coli—the Keio collection, in order to identify Ag sensitive or resistant deletion strains. Indeed, our findings corroborate many previously established mechanisms that describe the antibacterial effects of Ag, such as the disruption of iron-sulfur clusters containing proteins and certain cellular redox enzymes. However, the data presented here demonstrates that the activity of Ag within the bacterial cell is more extensive, encompassing genes involved in cell wall maintenance, quinone metabolism and sulfur assimilation. Altogether, this study provides further insight into the antimicrobial mechanism of Ag and the physiological adaption of E. coli to this metal. Full article
(This article belongs to the Special Issue Genomics of Bacterial Metal Resistance)
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16 pages, 1235 KiB  
Article
Epistatic Interactions in NS5A of Hepatitis C Virus Suggest Drug Resistance Mechanisms
by Elena Knops, Saleta Sierra, Prabhav Kalaghatgi, Eva Heger, Rolf Kaiser and Olga V. Kalinina
Genes 2018, 9(7), 343; https://doi.org/10.3390/genes9070343 - 6 Jul 2018
Cited by 12 | Viewed by 5553
Abstract
Hepatitis C virus (HCV) causes a major health burden and can be effectively treated by direct-acting antivirals (DAAs). The non-structural protein 5A (NS5A), which plays a role in the viral genome replication, is one of the DAAs’ targets. Resistance-associated viruses (RAVs) harbouring NS5A [...] Read more.
Hepatitis C virus (HCV) causes a major health burden and can be effectively treated by direct-acting antivirals (DAAs). The non-structural protein 5A (NS5A), which plays a role in the viral genome replication, is one of the DAAs’ targets. Resistance-associated viruses (RAVs) harbouring NS5A resistance-associated mutations (RAMs) have been described at baseline and after therapy failure. A mutation from glutamine to arginine at position 30 (Q30R) is a characteristic RAM for the HCV sub/genotype (GT) 1a, but arginine corresponds to the wild type in the GT-1b; still, GT-1b strains are susceptible to NS5A-inhibitors. In this study, we show that GT-1b strains with R30Q often display other specific NS5A substitutions, particularly in positions 24 and 34. We demonstrate that in GT-1b secondary substitutions usually happen after initial R30Q development in the phylogeny, and that the chemical properties of the corresponding amino acids serve to restore the positive charge in this region, acting as compensatory mutations. These findings may have implications for RAVs treatment. Full article
(This article belongs to the Special Issue Evolution and Structure of Proteins and Proteomes)
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20 pages, 3622 KiB  
Article
Gene Regulatory Networks Reconstruction Using the Flooding-Pruning Hill-Climbing Algorithm
by Linlin Xing, Maozu Guo, Xiaoyan Liu, Chunyu Wang and Lei Zhang
Genes 2018, 9(7), 342; https://doi.org/10.3390/genes9070342 - 6 Jul 2018
Cited by 10 | Viewed by 3912
Abstract
The explosion of genomic data provides new opportunities to improve the task of gene regulatory network reconstruction. Because of its inherent probability character, the Bayesian network is one of the most promising methods. However, excessive computation time and the requirements of a large [...] Read more.
The explosion of genomic data provides new opportunities to improve the task of gene regulatory network reconstruction. Because of its inherent probability character, the Bayesian network is one of the most promising methods. However, excessive computation time and the requirements of a large number of biological samples reduce its effectiveness and application to gene regulatory network reconstruction. In this paper, Flooding-Pruning Hill-Climbing algorithm (FPHC) is proposed as a novel hybrid method based on Bayesian networks for gene regulatory networks reconstruction. On the basis of our previous work, we propose the concept of DPI Level based on data processing inequality (DPI) to better identify neighbors of each gene on the lack of enough biological samples. Then, we use the search-and-score approach to learn the final network structure in the restricted search space. We first analyze and validate the effectiveness of FPHC in theory. Then, extensive comparison experiments are carried out on known Bayesian networks and biological networks from the DREAM (Dialogue on Reverse Engineering Assessment and Methods) challenge. The results show that the FPHC algorithm, under recommended parameters, outperforms, on average, the original hill climbing and Max-Min Hill-Climbing (MMHC) methods with respect to the network structure and running time. In addition, our results show that FPHC is more suitable for gene regulatory network reconstruction with limited data. Full article
(This article belongs to the Special Issue Selected Papers from the Bioinformatics and Intelligent Information Processing Conference (BIIP2018))
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17 pages, 1160 KiB  
Review
Emerging Opportunities for Synthetic Biology in Agriculture
by Hugh Douglas Goold, Philip Wright and Deborah Hailstones
Genes 2018, 9(7), 341; https://doi.org/10.3390/genes9070341 - 6 Jul 2018
Cited by 54 | Viewed by 11930
Abstract
Rapid expansion in the emerging field of synthetic biology has to date mainly focused on the microbial sciences and human health. However, the zeitgeist is that synthetic biology will also shortly deliver major outcomes for agriculture. The primary industries of agriculture, fisheries and [...] Read more.
Rapid expansion in the emerging field of synthetic biology has to date mainly focused on the microbial sciences and human health. However, the zeitgeist is that synthetic biology will also shortly deliver major outcomes for agriculture. The primary industries of agriculture, fisheries and forestry, face significant and global challenges; addressing them will be assisted by the sector’s strong history of early adoption of transformative innovation, such as the genetic technologies that underlie synthetic biology. The implementation of synthetic biology within agriculture may, however, be hampered given the industry is dominated by higher plants and mammals, where large and often polyploid genomes and the lack of adequate tools challenge the ability to deliver outcomes in the short term. However, synthetic biology is a rapidly growing field, new techniques in genome design and synthesis, and more efficient molecular tools such as CRISPR/Cas9 may harbor opportunities more broadly than the development of new cultivars and breeds. In particular, the ability to use synthetic biology to engineer biosensors, synthetic speciation, microbial metabolic engineering, mammalian multiplexed CRISPR, novel anti microbials, and projects such as Yeast 2.0 all have significant potential to deliver transformative changes to agriculture in the short, medium and longer term. Specifically, synthetic biology promises to deliver benefits that increase productivity and sustainability across primary industries, underpinning the industry’s prosperity in the face of global challenges. Full article
(This article belongs to the Special Issue Emerging Applications in Synthetic Biology)
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