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Translational genomics

Sabato Santaniello, John T Gale, Sridevi V Sarma
Over the last 30 years, deep brain stimulation (DBS) has been used to treat chronic neurological diseases like dystonia, obsessive-compulsive disorders, essential tremor, Parkinson's disease, and more recently, dementias, depression, cognitive disorders, and epilepsy. Despite its wide use, DBS presents numerous challenges for both clinicians and engineers. One challenge is the design of novel, more efficient DBS therapies, which are hampered by the lack of complete understanding about the cellular mechanisms of therapeutic DBS...
March 20, 2018: Wiley Interdisciplinary Reviews. Systems Biology and Medicine
Apuã C M Paquola, Huma Asif, Carlos Alberto de Bragança Pereira, Bruno César Feltes, Diego Bonatto, Wanessa Cristina Lima, Carlos Frederico Martins Menck
Horizontal gene transfer (HGT) has a major impact on the evolution of prokaryotic genomes, as it allows genes evolved in different contexts to be combined in a single genome, greatly enhancing the ways evolving organisms can explore the gene content space and adapt to the environment. A systematic analysis of HGT in a large number of genomes is of key importance in understanding the impact of HGT in the evolution of prokaryotes. We developed a method for the detection of genes that potentially originated by HGT based on the comparison of BLAST scores between homologous genes to 16S rRNA-based phylogenetic distances between the involved organisms...
March 19, 2018: Journal of Molecular Evolution
Xiangchun Li, Weiqi Xu, Wei Kang, Sunny H Wong, Mengyao Wang, Yong Zhou, Xiaodong Fang, Xiuqing Zhang, Huanming Yang, Chi H Wong, Ka F To, Stephen L Chan, Matthew T V Chan, Joseph J Y Sung, William K K Wu, Jun Yu
Objective: Hepatocellular carcinoma (HCC) is a highly heterogeneous disease with a dismal prognosis. However, driver genes and prognostic markers in HCC remain to be identified. It is hoped that in-depth analysis of HCC genomes in relation to available clinicopathological information will give rise to novel molecular prognostic markers. Methods: We collected genomic data of 1,061 HCC patients from previous studies, and performed integrative analysis to identify significantly mutated genes and molecular prognosticators...
2018: Theranostics
Jorge Ruiz-Orera, Pol Verdaguer-Grau, José Luis Villanueva-Cañas, Xavier Messeguer, M Mar Albà
Accumulating evidence indicates that some protein-coding genes have originated de novo from previously non-coding genomic sequences. However, the processes underlying de novo gene birth are still enigmatic. In particular, the appearance of a new functional protein seems highly improbable unless there is already a pool of neutrally evolving peptides that are translated at significant levels and that can at some point acquire new functions. Here, we use deep ribosome-profiling sequencing data, together with proteomics and single nucleotide polymorphism information, to search for these peptides...
March 19, 2018: Nature ecology & evolution
Harrison C Brown, Philip M Zakas, Stephan N George, Ernest T Parker, H Trent Spencer, Christopher B Doering
Potency is a key optimization parameter for hemophilia A gene therapy product candidates. Optimization strategies include promoter engineering to increase transcription, codon optimization of mRNA to improve translation, and amino-acid substitution to promote secretion. Herein, we describe both rational and empirical design approaches to the development of a minimally sized, highly potent AAV-fVIII vector that incorporates three unique elements: a liver-directed 146-nt transcription regulatory module, a target-cell-specific codon optimization algorithm, and a high-expression bioengineered fVIII variant...
June 15, 2018: Molecular Therapy. Methods & Clinical Development
Sara Villa-Hernández, Rodrigo Bermejo
Proliferating cells need to accurately duplicate and pass their genetic material on to daughter cells. Problems during replication and partition challenge the structural and numerical integrity of chromosomes. Diverse mechanisms, as the DNA replication checkpoint, survey the correct progression of replication and couple it with other cell cycle events to preserve genome integrity. The structural maintenance of chromosomes (SMC) cohesin complex primarily contributes to chromosome duplication by mediating the tethering of newly replicated sister chromatids, thus assisting their equal segregation in mitosis...
March 16, 2018: Current Genetics
Antoine Molaro, Janet M Young, Harmit S Malik
Eukaryotic genomes must accomplish both compact packaging for genome stability and inheritance, as well as accessibility for gene expression. They do so using post-translational modifications of four ancient canonical histone proteins (H2A, H2B, H3, and H4) and by deploying histone variants with specialized chromatin functions. Some histone variants are conserved across all eukaryotes, whereas others are lineage-specific. Here, we performed detailed phylogenomic analyses of "short H2A histone" variants found in mammalian genomes...
March 16, 2018: Genome Research
Panagiotis Galanos, George Pappas, Alexander Polyzos, Athanassios Kotsinas, Ioanna Svolaki, Nickolaos N Giakoumakis, Christina Glytsou, Ioannis S Pateras, Umakanta Swain, Vassilis L Souliotis, Alexandros G Georgakilas, Nicholas Geacintov, Luca Scorrano, Claudia Lukas, Jiri Lukas, Zvi Livneh, Zoi Lygerou, Dipanjan Chowdhury, Claus Storgaard Sørensen, Jiri Bartek, Vassilis G Gorgoulis
BACKGROUND: Genomic instability promotes evolution and heterogeneity of tumors. Unraveling its mechanistic basis is essential for the design of appropriate therapeutic strategies. In a previous study, we reported an unexpected oncogenic property of p21WAF1/Cip1 , showing that its chronic expression in a p53-deficient environment causes genomic instability by deregulation of the replication licensing machinery. RESULTS: We now demonstrate that p21WAF1/Cip1 can further fuel genomic instability by suppressing the repair capacity of low- and high-fidelity pathways that deal with nucleotide abnormalities...
March 16, 2018: Genome Biology
Ajeet K Sharma, Nabeel Ahmed, Edward P O'Brien
Ribosome profiling experiments have found greater than 100-fold variation in ribosome density along mRNA transcripts, indicating that individual codon elongation rates can vary to a similar degree. This wide range of elongation times, coupled with differences in codon usage between transcripts, suggests that the average codon translation-rate per gene can vary widely. Yet, ribosome run-off experiments have found that the average codon translation rate for different groups of transcripts in mouse stem cells is constant at 5...
February 2018: Physical Review. E
Maxime Lamontagne, Jean-Christophe Bérubé, Ma'en Obeidat, Michael H Cho, Brian D Hobbs, Phuwanat Sakornsakolpat, Kim de Jong, H Marike Boezen, David Nickle, Ke Hao, Wim Timens, Maarten van den Berge, Philippe Joubert, Michel Laviolette, Don D Sin, Peter D Paré, Yohan Bossé
Causal genes of chronic obstructive pulmonary disease (COPD) remain elusive. The current study aims at integrating genome-wide association studies (GWAS) and lung expression quantitative loci (eQTL) data to map COPD candidate causal genes and gain biological insights into the recently discovered COPD susceptibility loci. Two complementary genomic datasets on COPD were studied. First, the lung eQTL dataset which included whole-genome gene expression and genotyping data from 1,038 individuals. Second, the largest COPD GWAS to date from the International COPD Genetics Consortium (ICGC) with 13,710 cases and 38,062 controls...
March 14, 2018: Human Molecular Genetics
Zhipeng Zhou, Yunkun Dang, Mian Zhou, Haiyan Yuan, Yi Liu
Codon usage biases are found in all genomes and influence protein expression levels. The codon usage effect on protein expression was thought to be mainly due to its impact on translation. Here we show that transcription termination is an important driving force for codon usage bias in eukaryotes. Using Neurospora crassa as a model organism, we demonstrated that introduction of rare codons results in premature transcription termination (PTT) within open reading frames and the abolishment of full-length mRNA...
March 16, 2018: ELife
Michael Karsy, Jian Guan, L Eric Huang
OBJECTIVE Gliomas are one of the most common types of primary brain tumors. Recent studies have supported the importance of key genetic alterations, including isocitrate dehydrogenase (IDH) mutations and 1p19q codeletion, in glioma prognosis. Mutant IDH produces 2-hydroxyglutarate from α-ketoglutarate, a key metabolite of the Krebs cycle. The mitochondrial pyruvate carrier (MPC) is composed of MPC1 and MPC2 subunits and is functionally essential for the Krebs cycle. The authors sought to explore the impact of MPC1 and MPC2 expression on patient prognosis...
March 16, 2018: Journal of Neurosurgery
Rebecca C Richmond, Gemma C Sharp, Georgia Herbert, Charlotte Atkinson, Caroline Taylor, Sohinee Bhattacharya, Doris Campbell, Marion Hall, Nabila Kazmi, Tom Gaunt, Wendy McArdle, Susan Ring, George Davey Smith, Andy Ness, Caroline L Relton
Background: It has been proposed that maternal folic-acid supplement use may alter the DNA-methylation patterns of the offspring during the in-utero period, which could influence development and later-life health outcomes. Evidence from human studies suggests a role for prenatal folate levels in influencing DNA methylation in early life, but this has not been extended to consider persistent effects into adulthood. Methods: To better elucidate the long-term impact of maternal folic acid in pregnancy on DNA methylation in offspring, we carried out an epigenome-wide association study (EWAS) nested within the Aberdeen Folic Acid Supplementation Trial (AFAST-a trial of two different doses: 0...
March 12, 2018: International Journal of Epidemiology
Maroua Ben Amira, Robin Mom, David Lopez, Hatem Chaar, Ali Khouaja, Valérie Pujade-Renaud, Boris Fumanal, Aurélie Gousset-Dupont, Gisèle Bronner, Philippe Label, Jean-Louis Julien, Mohamed Ali Triki, Daniel Auguin, Jean-Stéphane Venisse
Major intrinsic proteins (MIP) are characterized by a transmembrane pore-type architecture that facilitates transport across biomembranes of water and a variety of low molecular weight solutes. They are found in all parts of life, with remarkable protein diversity. Very little is known about MIP from fungi. And yet, it can legitimately be stated that MIP are pivotal molecular components in the privileged relationships fungi enjoy with plants or soil fauna in various environments. To date, MIP have never been studied in a mycoparasitism situation...
2018: PloS One
Hitoyoshi Yasuo, Alex McDougall
Phallusia mammillata has recently emerged as a new ascidian model. Its unique characteristics, including the optical transparency of eggs and embryos and efficient translation of exogenously introduced mRNA in eggs, make the Phallusia system suitable for fluorescent protein (FP)-based imaging approaches. In addition, genomic and transcriptomic resources are readily available for this ascidian species, facilitating functional gene studies. Microinjection is probably the most versatile technique for introducing exogenous molecules such as plasmids, mRNAs, and proteins into ascidian eggs/embryos...
2018: Advances in Experimental Medicine and Biology
Genki Yoshikawa, Ahmed Askora, Romain Blanc-Mathieu, Takeru Kawasaki, Yanze Li, Miyako Nakano, Hiroyuki Ogata, Takashi Yamada
Xanthomonas virus (phage) XacN1 is a novel jumbo myovirus infecting Xanthomonas citri, the causative agent of Asian citrus canker. Its linear 384,670 bp double-stranded DNA genome encodes 592 proteins and presents the longest (66 kbp) direct terminal repeats (DTRs) among sequenced viral genomes. The DTRs harbor 56 tRNA genes, which correspond to all 20 amino acids and represent the largest number of tRNA genes reported in a viral genome. Codon usage analysis revealed a propensity for the phage encoded tRNAs to target codons that are highly used by the phage but less frequently by its host...
March 14, 2018: Scientific Reports
Changguo Ma, Chunjie Gu, Yongxia Huo, Xiaoyan Li, Xiong-Jian Luo
Genome-wide association studies (GWAS) have identified more than 100 loci that show robust association with schizophrenia risk. However, due to the complexity of linkage disequilibrium and gene regulatory, it is challenging to pinpoint the causal genes at the risk loci and translate the genetic findings from GWAS into disease mechanism and clinical treatment. Here we systematically predicted the plausible candidate causal genes for schizophrenia at genome-wide level. We utilized different approaches and strategies to predict causal genes for schizophrenia, including Sherlock, SMR, DAPPLE, Prix Fixe, NetWAS, and DEPICT...
March 15, 2018: Translational Psychiatry
Christina Pfaff, Hans F Ehrnsberger, Maria Flores-Tornero, Brian B Soerensen, Thomas Schubert, Gernot Längst, Joachim Griesenbeck, Stefanie Sprunck, Marion Grasser, Klaus D Grasser
The regulated transport of mRNAs from the cell nucleus to the cytosol is a critical step linking transcript synthesis and processing with translation. However, in plants, only few of the factors that act in the mRNA export pathway have been functionally characterised. Flowering plant genomes encode several members of the ALY protein family, which function as mRNA export factors in other organisms. Arabidopsis thaliana ALY1-4 are commonly detected in root and leaf cells, but are differentially expressed in reproductive tissue...
March 14, 2018: Plant Physiology
Randall Marcelo Chin, Tadas Panavas, Jeffrey M Brown, Krista K Johnson
Mitochondrial disease may be caused by mutations in the protein-coding genes of the mitochondrial genome. A promising strategy for treating such diseases is allotopic expression-the translation of wild-type copies of these proteins in the cytosol, with subsequent translocation into the mitochondria, resulting in rescue of mitochondrial function. In this paper, we develop an automated, quantitative, and unbiased screening platform to evaluate protein localization and mitochondrial morphology. This platform was used to compare 31 mitochondrial targeting sequences and 15 3' UTRs in their ability to localize up to 9 allotopically expressed proteins to the mitochondria and their subsequent impact on mitochondrial morphology...
March 13, 2018: Cell Reports
Sellappan Selvaraju, Sivashanmugam Parthipan, Lakshminarayana Somashekar, B Krishnan Binsila, Atul P Kolte, Arunachalam Arangasamy, Janivara Parameshwaraiah Ravindra, Stephen A Krawetz
With artificial insemination (AI) and other precision dependent assisted reproductive technologies (ART) being followed in large scale in human and animal reproduction, assessing semen quality and fertilizability is under continuous scrutiny. Various tests have been developed to predict semen quality, but so far no single, highly reliable test is available. In this regard, transcriptomic profiling of spermatozoa assumes significance as it carries the information about spermatogenesis, sperm function, and paternal roles in post-fertilization events...
March 14, 2018: Systems Biology in Reproductive Medicine
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