Deciphering molecular circuits from genetic variation underlying transcriptional responsiveness to stimuli

PubMed Central

Gat-Viks, Irit; Chevrier, Nicolas; Wilentzik, Roni; Eisenhaure, Thomas; Raychowdhury, Raktima; Steuerman, Yael; Shalek, Alex; Hacohen, Nir; Amit, Ido; Regev, Aviv

2013-01-01

Individual genetic variation affects gene expression in response to stimuli, often by influencing complex molecular circuits. Here we combine genomic and intermediate-scale transcriptional profiling with computational methods to identify variants that affect the responsiveness of genes to stimuli (responsiveness QTLs; reQTLs) and to position these variants in molecular circuit diagrams. We apply this approach to study variation in transcriptional responsiveness to pathogen components in dendritic cells from recombinant inbred mouse strains. We identify reQTLs that correlate with particular stimuli and position them in known pathways. For example, in response to a virus-like stimulus, a trans-acting variant acts as an activator of the antiviral response; using RNAi, we identify Rgs16 as the likely causal gene. Our approach charts an experimental and analytic path to decipher the mechanisms underlying genetic variation in circuits that control responses to stimuli. PMID:23503680

A ‘tool box’ for deciphering neuronal circuits in the developing chick spinal cord

PubMed Central

Hadas, Yoav; Etlin, Alex; Falk, Haya; Avraham, Oshri; Kobiler, Oren; Panet, Amos; Lev-Tov, Aharon; Klar, Avihu

2014-01-01

The genetic dissection of spinal circuits is an essential new means for understanding the neural basis of mammalian behavior. Molecular targeting of specific neuronal populations, a key instrument in the genetic dissection of neuronal circuits in the mouse model, is a complex and time-demanding process. Here we present a circuit-deciphering ‘tool box’ for fast, reliable and cheap genetic targeting of neuronal circuits in the developing spinal cord of the chick. We demonstrate targeting of motoneurons and spinal interneurons, mapping of axonal trajectories and synaptic targeting in both single and populations of spinal interneurons, and viral vector-mediated labeling of pre-motoneurons. We also demonstrate fluorescent imaging of the activity pattern of defined spinal neurons during rhythmic motor behavior, and assess the role of channel rhodopsin-targeted population of interneurons in rhythmic behavior using specific photoactivation. PMID:25147209

Deciphering molecular circuits from genetic variation underlying transcriptional responsiveness to stimuli.

PubMed

Gat-Viks, Irit; Chevrier, Nicolas; Wilentzik, Roni; Eisenhaure, Thomas; Raychowdhury, Raktima; Steuerman, Yael; Shalek, Alex K; Hacohen, Nir; Amit, Ido; Regev, Aviv

2013-04-01

Individual genetic variation affects gene responsiveness to stimuli, often by influencing complex molecular circuits. Here we combine genomic and intermediate-scale transcriptional profiling with computational methods to identify variants that affect the responsiveness of genes to stimuli (responsiveness quantitative trait loci or reQTLs) and to position these variants in molecular circuit diagrams. We apply this approach to study variation in transcriptional responsiveness to pathogen components in dendritic cells from recombinant inbred mouse strains. We identify reQTLs that correlate with particular stimuli and position them in known pathways. For example, in response to a virus-like stimulus, a trans-acting variant responds as an activator of the antiviral response; using RNA interference, we identify Rgs16 as the likely causal gene. Our approach charts an experimental and analytic path to decipher the mechanisms underlying genetic variation in circuits that control responses to stimuli.

Mitochondrial DNA haplogroup phylogeny of the dog: Proposal for a cladistic nomenclature.

PubMed

Fregel, Rosa; Suárez, Nicolás M; Betancor, Eva; González, Ana M; Cabrera, Vicente M; Pestano, José

2015-05-01

Canis lupus familiaris mitochondrial DNA analysis has increased in recent years, not only for the purpose of deciphering dog domestication but also for forensic genetic studies or breed characterization. The resultant accumulation of data has increased the need for a normalized and phylogenetic-based nomenclature like those provided for human maternal lineages. Although a standardized classification has been proposed, haplotype names within clades have been assigned gradually without considering the evolutionary history of dog mtDNA. Moreover, this classification is based only on the D-loop region, proven to be insufficient for phylogenetic purposes due to its high number of recurrent mutations and the lack of relevant information present in the coding region. In this study, we design 1) a refined mtDNA cladistic nomenclature from a phylogenetic tree based on complete sequences, classifying dog maternal lineages into haplogroups defined by specific diagnostic mutations, and 2) a coding region SNP analysis that allows a more accurate classification into haplogroups when combined with D-loop sequencing, thus improving the phylogenetic information obtained in dog mitochondrial DNA studies. Copyright © 2015 Elsevier B.V. All rights reserved.

Histone modifications controlling native and induced neural stem cell identity.

PubMed

Broccoli, Vania; Colasante, Gaia; Sessa, Alessandro; Rubio, Alicia

2015-10-01

During development, neural progenitor cells (NPCs) that are capable of self-renewing maintain a proliferative cellular pool while generating all differentiated neural cell components. Although the genetic network of transcription factors (TFs) required for neural specification has been well characterized, the unique set of histone modifications that accompanies this process has only recently started to be investigated. In vitro neural differentiation of pluripotent stem cells is emerging as a powerful system to examine epigenetic programs. Deciphering the histone code and how it shapes the chromatin environment will reveal the intimate link between epigenetic changes and mechanisms for neural fate determination in the developing nervous system. Furthermore, it will offer a molecular framework for a stringent comparison between native and induced neural stem cells (iNSCs) generated by direct neural cell conversion. Copyright © 2015 Elsevier Ltd. All rights reserved.

The Interactions between the Long Non-coding RNA NERDL and Its Target Gene Affect Wood Formation in Populus tomentosa

PubMed Central

Shi, Wan; Quan, Mingyang; Du, Qingzhang; Zhang, Deqiang

2017-01-01

Long non-coding RNAs (lncRNAs) are important regulatory factors for plant growth and development, but little is known about the allelic interactions of lncRNAs with mRNA in perennial plants. Here, we analyzed the interaction of the NERD (Needed for RDR2-independent DNA methylation) Populus tomentosa gene PtoNERD with its putative regulator, the lncRNA NERDL (NERD-related lncRNA), which partially overlaps with the promoter region of this gene. Expression analysis in eight tissues showed a positive correlation between NERDL and PtoNERD (r = 0.62), suggesting that the interaction of NERDL with its putative target might be involved in wood formation. We conducted association mapping in a natural population of P. tomentosa (435 unrelated individuals) to evaluate genetic variation and the interaction of the lncRNA NERDL with PtoNERD. Using additive and dominant models, we identified 30 SNPs (P < 0.01) associated with five tree growth and wood property traits. Each SNP explained 3.90–8.57% of phenotypic variance, suggesting that NERDL and its putative target play a common role in wood formation. Epistasis analysis uncovered nine SNP-SNP association pairs between NERDL and PtoNERD, with an information gain of -7.55 to 2.16%, reflecting the strong interactions between NERDL and its putative target. This analysis provides a powerful method for deciphering the genetic interactions of lncRNAs with mRNA and dissecting the complex genetic network of quantitative traits in trees. PMID:28674544

Genome medicine: gene therapy for the millennium, 30 September-3 October 2001, Rome, Italy.

PubMed

Gruenert, D C; Novelli, G; Dallapiccola, B; Colosimo, A

2002-06-01

The recent surge of DNA sequence information resulting from the efforts of agencies interested in deciphering the human genetic code has facilitated technological developments that have been critical in the identification of genes associated with numerous disease pathologies. In addition, these efforts have opened the door to the opportunity to develop novel genetic therapies to treat a broad range of inherited disorders. Through a joint effort by the University of Vermont, the University of Rome, Tor Vergata, University of Rome, La Sapienza, and the CSS Mendel Institute, Rome, an international meeting, 'Genome Medicine: Gene Therapy for the Millennium' was organized. This meeting provided a forum for the discussion of scientific and clinical advances stimulated by the explosion of sequence information generated by the Human Genome Project and the implications these advances have for gene therapy. The meeting had six sessions that focused on the functional evaluation of specific genes via biochemical analysis and through animal models, the development of novel therapeutic strategies involving gene targeting, artificial chromsomes, DNA delivery systems and non-embryonic stem cells, and on the ethical and social implications of these advances.

Rapid Identification of Genetic Modifications in Bacillus anthracis Using Whole Genome Draft Sequences Generated by 454 Pyrosequencing

DTIC Science & Technology

2010-08-25

or intentional genetic modifications that circumvent the targets of the detection assays or in the case of a biological attack using an antibiotic ...genetic changes conferring antibiotic resistance can be deciphered rapidly and accurately using WGS. We demonstrate the utility of Roche 454...Rapid Identification of Genetic Modifications in Bacillus anthracis Using Whole Genome Draft Sequences Generated by 454 Pyrosequencing Peter E. Chen1

Association analysis of three diverse rice (Oryza sativa L.) germplasm collections for loci regulating grain quality traits

USDA-ARS?s Scientific Manuscript database

In rice (Oryza sativa L.), end-use/cooking quality is vital for producers and millions of consumers worldwide. Grain quality is a complex trait with interacting genetic and environmental factors. Deciphering the complex genetic architecture associated with grain quality, will provide vital informati...

Deciphering the evolutionary history of open and closed mitosis

PubMed Central

Sazer, Shelley; Lynch, Michael; Needleman, Daniel

2014-01-01

Summary The origin of the nucleus at the prokaryote to eukaryote transition represents one of the most important events in the evolution of cellular organization. The nuclear envelope encircles the chromosomes in interphase and is a selectively permeable barrier between the nucleoplasm and cytoplasm and an organizational scaffold for the nucleus. It remains intact in the "closed" mitosis of some yeast but loses its integrity in the "open" mitosis of mammals. Instances of both types of mitosis within two evolutionary clades indicate multiple evolutionary transitions between open and closed mitosis, although the underlying genetic changes that influenced these transitions remain unknown. A survey of the diversity of mitotic nuclei that fall between these extremes is the starting point from which to determine the physiologically relevant characteristics distinguishing open from closed mitosis and to understand how they evolved and why they are retained in present-day organisms. The field is now poised to begin addressing these issues by defining and document patterns of mitotic nuclear variation within and among species and map them onto a phylogenic tree. Deciphering the evolutionary history of open and closed mitosis will complement cell biological and genetic approaches aimed at deciphering the fundamental organizational principles of the nucleus. PMID:25458223

Cryptanalysis in World War II--and Mathematics Education.

ERIC Educational Resources Information Center

Hilton, Peter

1984-01-01

Hilton describes the team of cryptanalysts who tried to decipher German and Japanese codes during the Second World War. The work of Turing, essentially developing the computer, is reported, as well as inferences about pure and applied mathematics. (MNS)

Genetics Home Reference: periventricular heterotopia

MedlinePlus

... Metcalfe KA, Isidor B, Louvier UW, Poduri A, Taylor JC, Tilly P, Poirier K, Saillour Y, Lebrun N, Stemmelen T, Rudolf G, Muraca G, Saintpierre B, Elmorjani A; Deciphering Developmental Disorders study, Moïse M, ...

Applications of RNA Indexes for Precision Oncology in Breast Cancer.

PubMed

Ma, Liming; Liang, Zirui; Zhou, Hui; Qu, Lianghu

2018-05-09

Precision oncology aims to offer the most appropriate treatments to cancer patients mainly based on their individual genetic information. Genomics has provided numerous valuable data on driver mutations and risk loci; however, it remains a formidable challenge to transform these data into therapeutic agents. Transcriptomics describes the multifarious expression patterns of both mRNAs and non-coding RNAs (ncRNAs), which facilitates the deciphering of genomic codes. In this review, we take breast cancer as an example to demonstrate the applications of these rich RNA resources in precision medicine exploration. These include the use of mRNA profiles in triple-negative breast cancer (TNBC) subtyping to inform corresponding candidate targeted therapies; current advancements and achievements of high-throughput RNA interference (RNAi) screening technologies in breast cancer; and microRNAs as functional signatures for defining cell identities and regulating the biological activities of breast cancer cells. We summarize the benefits of transcriptomic analyses in breast cancer management and propose that unscrambling the core signaling networks of cancer may be an important task of multiple-omic data integration for precision oncology. Copyright © 2018 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

The Human Genome Project: An Imperative for International Collaboration.

ERIC Educational Resources Information Center

Allende, J. E.

1989-01-01

Discussed is the Human Genome Project which aims to decipher the totality of the human genetic information. The historical background, the objectives, international cooperation, ethical discussion, and the role of UNESCO are included. (KR)

Reframed Genome-Scale Metabolic Model to Facilitate Genetic Design and Integration with Expression Data.

PubMed

Gu, Deqing; Jian, Xingxing; Zhang, Cheng; Hua, Qiang

2017-01-01

Genome-scale metabolic network models (GEMs) have played important roles in the design of genetically engineered strains and helped biologists to decipher metabolism. However, due to the complex gene-reaction relationships that exist in model systems, most algorithms have limited capabilities with respect to directly predicting accurate genetic design for metabolic engineering. In particular, methods that predict reaction knockout strategies leading to overproduction are often impractical in terms of gene manipulations. Recently, we proposed a method named logical transformation of model (LTM) to simplify the gene-reaction associations by introducing intermediate pseudo reactions, which makes it possible to generate genetic design. Here, we propose an alternative method to relieve researchers from deciphering complex gene-reactions by adding pseudo gene controlling reactions. In comparison to LTM, this new method introduces fewer pseudo reactions and generates a much smaller model system named as gModel. We showed that gModel allows two seldom reported applications: identification of minimal genomes and design of minimal cell factories within a modified OptKnock framework. In addition, gModel could be used to integrate expression data directly and improve the performance of the E-Fmin method for predicting fluxes. In conclusion, the model transformation procedure will facilitate genetic research based on GEMs, extending their applications.

High-density genetic map and identification of QTLs for responses to temperature and salinity stresses in the model brown alga Ectocarpus

PubMed Central

Avia, Komlan; Coelho, Susana M.; Montecinos, Gabriel J.; Cormier, Alexandre; Lerck, Fiona; Mauger, Stéphane; Faugeron, Sylvain; Valero, Myriam; Cock, J. Mark; Boudry, Pierre

2017-01-01

Deciphering the genetic architecture of adaptation of brown algae to environmental stresses such as temperature and salinity is of evolutionary as well as of practical interest. The filamentous brown alga Ectocarpus sp. is a model for the brown algae and its genome has been sequenced. As sessile organisms, brown algae need to be capable of resisting the various abiotic stressors that act in the intertidal zone (e.g. osmotic pressure, temperature, salinity, UV radiation) and previous studies have shown that an important proportion of the expressed genes is regulated in response to hyposaline, hypersaline or oxidative stress conditions. Using the double digest RAD sequencing method, we constructed a dense genetic map with 3,588 SNP markers and identified 39 QTLs for growth-related traits and their plasticity under different temperature and salinity conditions (tolerance to high temperature and low salinity). GO enrichment tests within QTL intervals highlighted membrane transport processes such as ion transporters. Our study represents a significant step towards deciphering the genetic basis of adaptation of Ectocarpus sp. to stress conditions and provides a substantial resource to the increasing list of tools generated for the species. PMID:28256542

MEF2C loss-of-function mutation contributes to congenital heart defects.

PubMed

Qiao, Xiao-Hui; Wang, Fei; Zhang, Xian-Ling; Huang, Ri-Tai; Xue, Song; Wang, Juan; Qiu, Xing-Biao; Liu, Xing-Yuan; Yang, Yi-Qing

2017-01-01

Congenital heart disease (CHD) is the most common type of developmental abnormality in humans, and is a leading cause for substantially increased morbidity and mortality in affected individuals. Increasing studies demonstrates a pivotal role of genetic defects in the pathogenesis of CHD, and presently mutations in more than 60 genes have been associated with CHD. Nevertheless, CHD is of pronounced genetic heterogeneity, and the genetic basis underpinning CHD in a large proportion of patients remains unclear. In the present study, the whole coding exons and splicing donors/acceptors of the MEF2C gene, which codes for a transcription factor essential for normal cardiovascular development, were sequenced in 200 unrelated patients affected with CHD, and a novel heterozygous missense mutation, p.L38P, was identified in an index patient with patent ductus arteriosus (PDA) and ventricular septal defect (VSD). Genetic scan of the mutation carrier's family members available showed that the mutation was present in all affected family members but absent in unaffected family members. Analysis of the proband's pedigree revealed that the mutation co-segregated with PDA, which was transmitted as an autosomal dominant trait with complete penetrance. The mutation changed the amino acid that was completely conserved evolutionarily, and did not exist in 300 unrelated, ethnically-matched healthy individuals used as controls. Functional deciphers by using a dual-luciferase reporter assay system unveiled that the mutant MEF2C protein had a significantly reduced transcriptional activity. Furthermore, the mutation significantly diminished the synergistic activation between MEF2C and GATA4, another cardiac core transcription factor that has been causally linked to CHD. In conclusion, this is the first report on the association of a MEF2C loss-of-function mutation with an increased vulnerability to CHD in humans, which provides novel insight into the molecular mechanisms underlying CHD, implying potential implications for early diagnosis and timely prophylaxis of CHD.

MEF2C loss-of-function mutation contributes to congenital heart defects

PubMed Central

Qiao, Xiao-Hui; Wang, Fei; Zhang, Xian-Ling; Huang, Ri-Tai; Xue, Song; Wang, Juan; Qiu, Xing-Biao; Liu, Xing-Yuan; Yang, Yi-Qing

2017-01-01

Congenital heart disease (CHD) is the most common type of developmental abnormality in humans, and is a leading cause for substantially increased morbidity and mortality in affected individuals. Increasing studies demonstrates a pivotal role of genetic defects in the pathogenesis of CHD, and presently mutations in more than 60 genes have been associated with CHD. Nevertheless, CHD is of pronounced genetic heterogeneity, and the genetic basis underpinning CHD in a large proportion of patients remains unclear. In the present study, the whole coding exons and splicing donors/acceptors of the MEF2C gene, which codes for a transcription factor essential for normal cardiovascular development, were sequenced in 200 unrelated patients affected with CHD, and a novel heterozygous missense mutation, p.L38P, was identified in an index patient with patent ductus arteriosus (PDA) and ventricular septal defect (VSD). Genetic scan of the mutation carrier's family members available showed that the mutation was present in all affected family members but absent in unaffected family members. Analysis of the proband's pedigree revealed that the mutation co-segregated with PDA, which was transmitted as an autosomal dominant trait with complete penetrance. The mutation changed the amino acid that was completely conserved evolutionarily, and did not exist in 300 unrelated, ethnically-matched healthy individuals used as controls. Functional deciphers by using a dual-luciferase reporter assay system unveiled that the mutant MEF2C protein had a significantly reduced transcriptional activity. Furthermore, the mutation significantly diminished the synergistic activation between MEF2C and GATA4, another cardiac core transcription factor that has been causally linked to CHD. In conclusion, this is the first report on the association of a MEF2C loss-of-function mutation with an increased vulnerability to CHD in humans, which provides novel insight into the molecular mechanisms underlying CHD, implying potential implications for early diagnosis and timely prophylaxis of CHD. PMID:29104469

Deciphering the evolutionary history of open and closed mitosis.

PubMed

Sazer, Shelley; Lynch, Michael; Needleman, Daniel

2014-11-17

The origin of the nucleus at the prokaryote-to-eukaryote transition represents one of the most important events in the evolution of cellular organization. The nuclear envelope encircles the chromosomes in interphase and is a selectively permeable barrier between the nucleoplasm and cytoplasm and an organizational scaffold for the nucleus. It remains intact in the 'closed' mitosis of some yeasts, but loses its integrity in the 'open' mitosis of mammals. Instances of both types of mitosis within two evolutionary clades indicate multiple evolutionary transitions between open and closed mitosis, although the underlying genetic changes that influenced these transitions remain unknown. A survey of the diversity of mitotic nuclei that fall between these extremes is the starting point from which to determine the physiologically relevant characteristics distinguishing open from closed mitosis and to understand how they evolved and why they are retained in present-day organisms. The field is now poised to begin addressing these issues by defining and documenting patterns of mitotic nuclear variation within and among species and mapping them onto a phylogenic tree. Deciphering the evolutionary history of open and closed mitosis will complement cell biological and genetic approaches aimed at deciphering the fundamental organizational principles of the nucleus. Copyright © 2014 Elsevier Ltd. All rights reserved.

Metabolomics to Decipher the Chemical Defense of Cereals against Fusarium graminearum and Deoxynivalenol Accumulation

PubMed Central

Gauthier, Léa; Atanasova-Penichon, Vessela; Chéreau, Sylvain; Richard-Forget, Florence

2015-01-01

Fusarium graminearum is the causal agent of Fusarium head blight (FHB) and Gibberella ear rot (GER), two devastating diseases of wheat, barley, and maize. Furthermore, F. graminearum species can produce type B trichothecene mycotoxins that accumulate in grains. Use of FHB and GER resistant cultivars is one of the most promising strategies to reduce damage induced by F. graminearum. Combined with genetic approaches, metabolomic ones can provide powerful opportunities for plant breeding through the identification of resistant biomarker metabolites which have the advantage of integrating the genetic background and the influence of the environment. In the past decade, several metabolomics attempts have been made to decipher the chemical defense that cereals employ to counteract F. graminearum. By covering the major classes of metabolites that have been highlighted and addressing their potential role, this review demonstrates the complex and integrated network of events that cereals can orchestrate to resist to F. graminearum. PMID:26492237

Deciphering the Genome Sequences of the Hydrophobic Cyanobacterium Scytonema tolypothrichoides VB-61278

PubMed Central

Das, Abhishek; Panda, Arijit; Singh, Deeksha; Chandrababunaidu, Mathu Malar; Mishra, Gyan Prakash; Bhan, Sushma

2015-01-01

Scytonema tolypothrichoides VB-61278, a terrestrial cyanobacterium, can be exploited to produce commercially important products. Here, we report for the first time a 10-Mb draft genome assembly of S. tolypothrichoides VB-61278, with 214 scaffolds and 7,148 putative protein-coding genes. PMID:25838486

Harry Potter and the Cryptography with Matrices

ERIC Educational Resources Information Center

Chua, Boon Liang

2006-01-01

This article describes Cryptography, defined as the science of encrypting and deciphering messages written in secret codes, it has played a vital role in securing information since ancient times. There are several cryptographic techniques and many make extensive use of mathematics to secure information. The author discusses an activity built…

BASIC Language Flow Charting Program (BASCHART). Technical Note 3-82.

ERIC Educational Resources Information Center

Johnson, Charles C.; And Others

This document describes BASCHART, a computer aid designed to decipher and automatically flow chart computer program logic; it also provides the computer code necessary for this process. Developed to reduce the labor intensive manual process of producing a flow chart for an undocumented or inadequately documented program, BASCHART will…

Dcode.org anthology of comparative genomic tools.

PubMed

Loots, Gabriela G; Ovcharenko, Ivan

2005-07-01

Comparative genomics provides the means to demarcate functional regions in anonymous DNA sequences. The successful application of this method to identifying novel genes is currently shifting to deciphering the non-coding encryption of gene regulation across genomes. To facilitate the practical application of comparative sequence analysis to genetics and genomics, we have developed several analytical and visualization tools for the analysis of arbitrary sequences and whole genomes. These tools include two alignment tools, zPicture and Mulan; a phylogenetic shadowing tool, eShadow for identifying lineage- and species-specific functional elements; two evolutionary conserved transcription factor analysis tools, rVista and multiTF; a tool for extracting cis-regulatory modules governing the expression of co-regulated genes, Creme 2.0; and a dynamic portal to multiple vertebrate and invertebrate genome alignments, the ECR Browser. Here, we briefly describe each one of these tools and provide specific examples on their practical applications. All the tools are publicly available at the http://www.dcode.org/ website.

Genetic structure of the fungal grapevine pathogen Eutypa lata from four continents

USDA-ARS?s Scientific Manuscript database

Deciphering the geographic origins of pathogens and elucidating the population biology of these microscopic organisms are necessary steps to establish effective disease-control strategies. The generalist ascomycete fungus Eutypa lata causes Eutypa dieback of grapevine (Vitis vinifera) worldwide. To ...

Deciphering the Genome Sequences of the Hydrophobic Cyanobacterium Scytonema tolypothrichoides VB-61278.

PubMed

Das, Abhishek; Panda, Arijit; Singh, Deeksha; Chandrababunaidu, Mathu Malar; Mishra, Gyan Prakash; Bhan, Sushma; Adhikary, Siba Prasad; Tripathy, Sucheta

2015-04-02

Scytonema tolypothrichoides VB-61278, a terrestrial cyanobacterium, can be exploited to produce commercially important products. Here, we report for the first time a 10-Mb draft genome assembly of S. tolypothrichoides VB-61278, with 214 scaffolds and 7,148 putative protein-coding genes. Copyright © 2015 Das et al.

Visual Information Literacy: Reading a Documentary Photograph

ERIC Educational Resources Information Center

Abilock, Debbie

2008-01-01

Like a printed text, an architectural blueprint, a mathematical equation, or a musical score, a visual image is its own language. Visual literacy has three components: (1) learning; (2) thinking; and (3) communicating. A "literate" person is able to decipher the basic code and syntax, interpret the signs and symbols, correctly apply terms from an…

The Structure of Federal Policy: Deciphering the United States Code

ERIC Educational Resources Information Center

Staller, Karen M.

2004-01-01

CSWE mandates the study of social welfare policy, its history, and its evaluation; thus, assignments that require students to select policy for study are common. Educators provide frameworks for analysis but may not address the prerequisite step of locating policy for study, so students flounder in government documents without the tools to…

Odor Coding by a Mammalian Receptor Repertoire

PubMed Central

Saito, Harumi; Chi, Qiuyi; Zhuang, Hanyi; Matsunami, Hiro; Mainland, Joel D.

2009-01-01

Deciphering olfactory encoding requires a thorough description of the ligands that activate each odorant receptor (OR). In mammalian systems, however, ligands are known for fewer than 50 of over 1400 human and mouse ORs, greatly limiting our understanding of olfactory coding. We performed high-throughput screening of 93 odorants against 464 ORs expressed in heterologous cells and identified agonists for 52 mouse and 10 human ORs. We used the resulting interaction profiles to develop a predictive model relating physicochemical odorant properties, OR sequences, and their interactions. Our results provide a basis for translating odorants into receptor neuron responses and unraveling mammalian odor coding. PMID:19261596

Translation regulation of mammalian selenoproteins.

PubMed

Vindry, Caroline; Ohlmann, Théophile; Chavatte, Laurent

2018-05-09

Interest in selenium research has considerably grown over the last decades owing to the association of selenium deficiencies with an increased risk of several human diseases, including cancers, cardiovascular disorders and infectious diseases. The discovery of a genetically encoded 21 st amino acid, selenocysteine, is a fascinating breakthrough in molecular biology as it is the first addition to the genetic code deciphered in the 1960s. Selenocysteine is a structural and functional analog of cysteine, where selenium replaces sulfur, and its presence is critical for the catalytic activity of selenoproteins. The insertion of selenocysteine is a non-canonical translational event, based on the recoding of a UGA codon in selenoprotein mRNAs, normally used as a stop codon in other cellular mRNAs. Two RNA molecules and associated partners are crucial components of the selenocysteine insertion machinery, the Sec-tRNA [Ser]Sec devoted to UGA codon recognition and the SECIS elements located in the 3'UTR of selenoprotein mRNAs. The translational UGA recoding event is a limiting stage of selenoprotein expression and its efficiency is regulated by several factors. The control of selenoproteome expression is crucial for redox homeostasis and antioxidant defense of mammalian organisms. In this review, we summarize current knowledge on the co-translational insertion of selenocysteine into selenoproteins, and its layers of regulation. Copyright © 2018. Published by Elsevier B.V.

[Encryption technique for linkable anonymizing].

PubMed

Okamoto, Etsuji

2004-06-01

Linkage of different records such as health insurance claims or medical records for the purpose of cohort studies or cancer registration usually requires matching with personal names and other personally identifiable data. The present study was conducted to examine the possibility of performing such privacy-sensitive procedures in a "linkable anonymizing" manner using encryption. While bidirectional communication entails encryption and deciphering, necessitating both senders and receivers sharing a common secret "key", record linkage entails only encryption and not deciphering because researchers do not need to know the identity of the linked person. This unidirectional nature relieves researchers from the historical problem of "key sharing" and enables data holders such as municipal governments and insurers to encrypt personal names in a relatively easy manner. The author demonstrates an encryption technique using readily available spread-sheet software, Microsoft Excel in a step-by-step fashion. Encoding Chinese characters into the numeric JIS codes and replacing the codes with a randomly assigned case-sensitive alphabet, all names of Japanese nationals will be encrypted into gibberish strings of alphabet, which can not be deciphered without the secret key. Data holders are able to release personal data without sacrificing privacy, even when accidental leakage occurs and researchers are still able to link records of the same name because encrypted texts, although gibberish, are unique to each name. Such a technical assurance of privacy protection is expected to satisfy the Privacy Protection Act or the Ethical Guidelines for Epidemiological Research and enhance public health research. Traditional encryption techniques, however, cannot be applied to cancer or stroke registration, because the registrar receives reports from numerous unspecified senders. The new public key encryption technique will enable disease registry in a linkable anonymizing manner. However various technical problems such as complexity, difficulties in registrar inquiries and risk of code-breaking make the encryption technique unsuitable for disease registry in the foreseeable future.

Development: facial makeup enhancing our looks.

PubMed

Rohner, Nicolas; Tschopp, Patrick; Tabin, Cliff

2014-01-06

A recent study in mice deciphers the complex genetic regulatory network underlying the morphogenesis of the face. The enhancer landscape underlying craniofacial development provides multiple entry points to understand what makes up the face, in natural variation or pathological conditions. Copyright © 2014 Elsevier Ltd. All rights reserved.

Deciphering genetic diversity and inheritance of tomato fruit weight and composition through a systems biology approach

PubMed Central

Pascual, Laura; Xu, Jiaxin; Causse, Mathilde

2013-01-01

Integrative systems biology proposes new approaches to decipher the variation of phenotypic traits. In an effort to link the genetic variation and the physiological and molecular bases of fruit composition, the proteome (424 protein spots), metabolome (26 compounds), enzymatic profile (26 enzymes), and phenotypes of eight tomato accessions, covering the genetic diversity of the species, and four of their F1 hybrids, were characterized at two fruit developmental stages (cell expansion and orange-red). The contents of metabolites varied among the genetic backgrounds, while enzyme profiles were less variable, particularly at the cell expansion stage. Frequent genotype by stage interactions suggested that the trends observed for one accession at a physiological level may change in another accession. In agreement with this, the inheritance modes varied between crosses and stages. Although additivity was predominant, 40% of the traits were non-additively inherited. Relationships among traits revealed associations between different levels of expression and provided information on several key proteins. Notably, the role of frucktokinase, invertase, and cysteine synthase in the variation of metabolites was highlighted. Several stress-related proteins also appeared related to fruit weight differences. These key proteins might be targets for improving metabolite contents of the fruit. This systems biology approach provides better understanding of networks controlling the genetic variation of tomato fruit composition. In addition, the wide data sets generated provide an ideal framework to develop innovative integrated hypothesis and will be highly valuable for the research community. PMID:24151307

A natural compromise: a moderate solution to the GMO & "natural" labeling disputes.

PubMed

Amaru, Stephanie

2014-01-01

In the United States, genetically modified (GM) foods are labeled no differently from their natural counterparts, leaving consumers with no mechanism for deciphering genetically modified food content. The Food and Drug Administration (FDA) has not formally defined the term "natural," which is frequently used on food labels despite consumer confusion as to what it means. The FDA should initiate a notice and comment rulemaking addressing the narrow issue of whether use of the word "natural" should be permitted oil GM food labels. Prohibition of the use of"natural" on genetically modified foods would mitigate consumer deception regarding genetically modified food content without significantly disadvantaging genetically modified food producers.

Forward and reverse mutagenesis in C. elegans

PubMed Central

Kutscher, Lena M.; Shaham, Shai

2014-01-01

Mutagenesis drives natural selection. In the lab, mutations allow gene function to be deciphered. C. elegans is highly amendable to functional genetics because of its short generation time, ease of use, and wealth of available gene-alteration techniques. Here we provide an overview of historical and contemporary methods for mutagenesis in C. elegans, and discuss principles and strategies for forward (genome-wide mutagenesis) and reverse (target-selected and gene-specific mutagenesis) genetic studies in this animal. PMID:24449699

Applying remote sensing expertise to crop improvement: progress and challenges to scale up high throughput field phenotyping from research to industry

NASA Astrophysics Data System (ADS)

Gouache, David; Beauchêne, Katia; Mini, Agathe; Fournier, Antoine; de Solan, Benoit; Baret, Fred; Comar, Alexis

2016-05-01

Digital and image analysis technologies in greenhouses have become commonplace in plant science research and started to move into the plant breeding industry. However, the core of plant breeding work takes place in fields. We will present successive technological developments that have allowed the migration and application of remote sensing approaches at large into the field of crop genetics and physiology research, with a number of projects that have taken place in France. These projects have allowed us to develop combined sensor plus vector systems, from tractor mounted and UAV (unmanned aerial vehicle) mounted spectroradiometry to autonomous vehicle mounted spectroradiometry, RGB (red-green-blue) imagery and Lidar. We have tested these systems for deciphering the genetics of complex plant improvement targets such as the robustness to nitrogen and water deficiency of wheat and maize. Our results from wheat experiments indicate that these systems can be used both to screen genetic diversity for nitrogen stress tolerance and to decipher the genetics behind this diversity. We will present our view on the next critical steps in terms of technology and data analysis that will be required to reach cost effective implementation in industrial plant breeding programs. If this can be achieved, these technologies will largely contribute to resolving the equation of increasing food supply in the resource limited world that lies ahead.

Use of modern tomato breeding germplasm for deciphering the genetic control of agronomical traits by Genome Wide Association study.

PubMed

Bauchet, Guillaume; Grenier, Stéphane; Samson, Nicolas; Bonnet, Julien; Grivet, Laurent; Causse, Mathilde

2017-05-01

A panel of 300 tomato accessions including breeding materials was built and characterized with >11,000 SNP. A population structure in six subgroups was identified. Strong heterogeneity in linkage disequilibrium and recombination landscape among groups and chromosomes was shown. GWAS identified several associations for fruit weight, earliness and plant growth. Genome-wide association studies (GWAS) have become a method of choice in quantitative trait dissection. First limited to highly polymorphic and outcrossing species, it is now applied in horticultural crops, notably in tomato. Until now GWAS in tomato has been performed on panels of heirloom and wild accessions. Using modern breeding materials would be of direct interest for breeding purpose. To implement GWAS on a large panel of 300 tomato accessions including 168 breeding lines, this study assessed the genetic diversity and linkage disequilibrium decay and revealed the population structure and performed GWA experiment. Genetic diversity and population structure analyses were based on molecular markers (>11,000 SNP) covering the whole genome. Six genetic subgroups were revealed and associated to traits of agronomical interest, such as fruit weight and disease resistance. Estimates of linkage disequilibrium highlighted the heterogeneity of its decay among genetic subgroups. Haplotype definition allowed a fine characterization of the groups and their recombination landscape revealing the patterns of admixture along the genome. Selection footprints showed results in congruence with introgressions. Taken together, all these elements refined our knowledge of the genetic material included in this panel and allowed the identification of several associations for fruit weight, plant growth and earliness, deciphering the genetic architecture of these complex traits and identifying several new loci useful for tomato breeding.

Introducing the Creative Learning Principles: Instructional Tasks Used to Promote Rhizomatic Learning through Creativity

ERIC Educational Resources Information Center

Ellis, Violet Adams

2016-01-01

Proving a child has been adequately educated is manifest through assessments evaluating the recall of facts or the deciphering of codes. How this information is taught and learned is the issue. Webb's depth of knowledge (DOK) and Bloom's taxonomy are cognitive models that drive instruction in today's classrooms. According to these models,…

Is There a Place for Peace Education? Political Education and Citizenship Activism in Israeli Schools

ERIC Educational Resources Information Center

Levy, Gal

2014-01-01

What is wrong with "peace education" in Israel? In this article, I attempt to decipher the cultural codes of Israeli schools in their relation to issues of peace, conflict and citizenship. It combines findings from two studies in order to understand how "school culture" animates "peace education." My main contention…

Deciphering maize genetics and ecology to reduce insect damage and aflatoxin accumulation

USDA-ARS?s Scientific Manuscript database

Ear-colonizing insects and diseases, which reduce yield and impose health threats via mycotoxin contaminations, are critical impediments for maize production in the southern US states. To address this problem a combination of basic and applied research approaches are being conducted by the interdis...

Global genetic structure of the fungal grapevine pathogen Eutypa lata

USDA-ARS?s Scientific Manuscript database

The ascomycete fungus Eutypa lata is a trunk pathogen of cultivated grapevine (Vitis vinifera) in all major grape-growing regions of the world. Throughout its geographic range, it is considered a generalist pathogen that can complete its life cycle on a broad range of hosts. To decipher the cosmopol...

Molecular genetics made simple

PubMed Central

Kassem, Heba Sh.; Girolami, Francesca; Sanoudou, Despina

2012-01-01

Abstract Genetics have undoubtedly become an integral part of biomedical science and clinical practice, with important implications in deciphering disease pathogenesis and progression, identifying diagnostic and prognostic markers, as well as designing better targeted treatments. The exponential growth of our understanding of different genetic concepts is paralleled by a growing list of genetic terminology that can easily intimidate the unfamiliar reader. Rendering genetics incomprehensible to the clinician however, defeats the very essence of genetic research: its utilization for combating disease and improving quality of life. Herein we attempt to correct this notion by presenting the basic genetic concepts along with their usefulness in the cardiology clinic. Bringing genetics closer to the clinician will enable its harmonious incorporation into clinical care, thus not only restoring our perception of its simple and elegant nature, but importantly ensuring the maximal benefit for our patients. PMID:25610837

shiftNMFk 1.1: Robust Nonnegative matrix factorization with kmeans clustering and signal shift, for allocation of unknown physical sources, toy version for open sourcing with publications

DOE Office of Scientific and Technical Information (OSTI.GOV)

Alexandrov, Boian S.; Lliev, Filip L.; Stanev, Valentin G.

This code is a toy (short) version of CODE-2016-83. From a general perspective, the code represents an unsupervised adaptive machine learning algorithm that allows efficient and high performance de-mixing and feature extraction of a multitude of non-negative signals mixed and recorded by a network of uncorrelated sensor arrays. The code identifies the number of the mixed original signals and their locations. Further, the code also allows deciphering of signals that have been delayed in regards to the mixing process in each sensor. This code is high customizable and it can be efficiently used for a fast macro-analyses of data. Themore » code is applicable to a plethora of distinct problems: chemical decomposition, pressure transient decomposition, unknown sources/signal allocation, EM signal decomposition. An additional procedure for allocation of the unknown sources is incorporated in the code.« less

Application of genomics for understanding plant virus-insect vector interactions and insect vector control

USDA-ARS?s Scientific Manuscript database

The ability to decipher DNA sequences provides new insights into the study of plant viruses and their interactions with host plants, including the intricate interactions that allow a virus to be transmitted by an insect vector. Next generation sequencing (NGS) provides a wealth of genetic informati...

Genetic variants associated with physical and mental characteristics of the elite athletes in the Polish population.

PubMed

Peplonska, B; Adamczyk, J G; Siewierski, M; Safranow, K; Maruszak, A; Sozanski, H; Gajewski, A K; Zekanowski, C

2017-08-01

The aim of the study was to assess whether selected genetic variants are associated with elite athlete performance in a group of 413 elite athletes and 451 sedentary controls. Polymorphisms in ACE, ACTN3, AGT, NRF-2, PGC1A, PPARG, and TFAM implicated in physical performance traits were analyzed. Additionally, polymorphisms in CHRNB3 and FAAH coding for proteins modulating activity of brain's emotion centers were included. The results of univariate analyses indicated that the elite athletic performance is associated with four polymorphisms: ACE (rs4341, P = 0.0095), NRF-2 (rs12594956, P = 0.011), TFAM (rs2306604, P = 0.049), and FAAH (rs324420, P = 0.0041). The multivariate analysis adjusted for age and gender confirmed this association. The higher number of ACE D alleles (P = 0.0021) and the presence of NRF-2 rs12594956 A allele (P = 0.0067) are positive predictors, whereas TFAM rs2306604 GG genotype (P = 0.031) and FAAH rs324420 AA genotype (P = 0.0084) negatively affect the elite athletic performance. The CHRNB3 variant (rs4950, G allele) is significantly more frequent in the endurance athletes compared with the power ones (P = 0.025). Multivariate analysis demonstrated that the presence of rs4950 G allele contributes to endurance performance (P = 0.0047). Our results suggest that genetic inheritance of psychological traits should be taken into consideration while trying to decipher a genetic profile of top athletic performance. © 2016 The Authors. Scandinavian Journal of Medicine & Science in Sports published by John Wiley & Sons Ltd.

Shared Sulfur Mobilization Routes for tRNA Thiolation and Molybdenum Cofactor Biosynthesis in Prokaryotes and Eukaryotes

PubMed Central

Leimkühler, Silke; Bühning, Martin; Beilschmidt, Lena

2017-01-01

Modifications of transfer RNA (tRNA) have been shown to play critical roles in the biogenesis, metabolism, structural stability and function of RNA molecules, and the specific modifications of nucleobases with sulfur atoms in tRNA are present in pro- and eukaryotes. Here, especially the thiomodifications xm5s2U at the wobble position 34 in tRNAs for Lys, Gln and Glu, were suggested to have an important role during the translation process by ensuring accurate deciphering of the genetic code and by stabilization of the tRNA structure. The trafficking and delivery of sulfur nucleosides is a complex process carried out by sulfur relay systems involving numerous proteins, which not only deliver sulfur to the specific tRNAs but also to other sulfur-containing molecules including iron–sulfur clusters, thiamin, biotin, lipoic acid and molybdopterin (MPT). Among the biosynthesis of these sulfur-containing molecules, the biosynthesis of the molybdenum cofactor (Moco) and the synthesis of thio-modified tRNAs in particular show a surprising link by sharing protein components for sulfur mobilization in pro- and eukaryotes. PMID:28098827

Deciphering Neural Codes of Memory during Sleep

PubMed Central

Chen, Zhe; Wilson, Matthew A.

2017-01-01

Memories of experiences are stored in the cerebral cortex. Sleep is critical for consolidating hippocampal memory of wake experiences into the neocortex. Understanding representations of neural codes of hippocampal-neocortical networks during sleep would reveal important circuit mechanisms on memory consolidation, and provide novel insights into memory and dreams. Although sleep-associated ensemble spike activity has been investigated, identifying the content of memory in sleep remains challenging. Here, we revisit important experimental findings on sleep-associated memory (i.e., neural activity patterns in sleep that reflect memory processing) and review computational approaches for analyzing sleep-associated neural codes (SANC). We focus on two analysis paradigms for sleep-associated memory, and propose a new unsupervised learning framework (“memory first, meaning later”) for unbiased assessment of SANC. PMID:28390699

Deciphering the transcriptional cis-regulatory code.

PubMed

Yáñez-Cuna, J Omar; Kvon, Evgeny Z; Stark, Alexander

2013-01-01

Information about developmental gene expression resides in defined regulatory elements, called enhancers, in the non-coding part of the genome. Although cells reliably utilize enhancers to orchestrate gene expression, a cis-regulatory code that would allow their interpretation has remained one of the greatest challenges of modern biology. In this review, we summarize studies from the past three decades that describe progress towards revealing the properties of enhancers and discuss how recent approaches are providing unprecedented insights into regulatory elements in animal genomes. Over the next years, we believe that the functional characterization of regulatory sequences in entire genomes, combined with recent computational methods, will provide a comprehensive view of genomic regulatory elements and their building blocks and will enable researchers to begin to understand the sequence basis of the cis-regulatory code. Copyright © 2012 Elsevier Ltd. All rights reserved.

The Vocal Repertoire of the Domesticated Zebra Finch: a Data Driven Approach to Decipher the Information-bearing Acoustic Features of Communication Signals

PubMed Central

Elie, Julie E.; Theunissen, Frédéric E.

2018-01-01

Although a universal code for the acoustic features of animal vocal communication calls may not exist, the thorough analysis of the distinctive acoustical features of vocalization categories is important not only to decipher the acoustical code for a specific species but also to understand the evolution of communication signals and the mechanisms used to produce and understand them. Here, we recorded more than 8,000 examples of almost all the vocalizations of the domesticated zebra finch, Taeniopygia guttata: vocalizations produced to establish contact, to form and maintain pair bonds, to sound an alarm, to communicate distress or to advertise hunger or aggressive intents. We characterized each vocalization type using complete representations that avoided any a priori assumptions on the acoustic code, as well as classical bioacoustics measures that could provide more intuitive interpretations. We then used these acoustical features to rigorously determine the potential information-bearing acoustical features for each vocalization type using both a novel regularized classifier and an unsupervised clustering algorithm. Vocalization categories are discriminated by the shape of their frequency spectrum and by their pitch saliency (noisy to tonal vocalizations) but not particularly by their fundamental frequency. Notably, the spectral shape of zebra finch vocalizations contains peaks or formants that vary systematically across categories and that would be generated by active control of both the vocal organ (source) and the upper vocal tract (filter). PMID:26581377

Some pungent arguments against the physico-chemical theories of the origin of the genetic code and corroborating the coevolution theory.

PubMed

Di Giulio, Massimo

2017-02-07

Whereas it is extremely easy to prove that "if the biosynthetic relationships between amino acids were fundamental in the structuring of the genetic code, then their physico-chemical properties might also be revealed in the genetic code table"; it is, on the contrary, impossible to prove that "if the physico-chemical properties of amino acids were fundamental in the structuring of the genetic code, then the presence of the biosynthetic relationships between amino acids should not be revealed in the genetic code". And, given that in the genetic code table are mirrored both the biosynthetic relationships between amino acids and their physico-chemical properties, all this would be a test that would falsify the physico-chemical theories of the origin of the genetic code. That is to say, if the physico-chemical properties of amino acids had a fundamental role in organizing the genetic code, then we would not have duly revealed the presence - in the genetic code - of the biosynthetic relationships between amino acids, and on the contrary this has been observed. Therefore, this falsifies the physico-chemical theories of genetic code origin. Whereas, the coevolution theory of the origin of the genetic code would be corroborated by this analysis, because it would be able to give a description of evolution of the genetic code more coherent with the indisputable empirical observations that link both the biosynthetic relationships of amino acids and their physico-chemical properties to the evolutionary organization of the genetic code. Copyright © 2016 Elsevier Ltd. All rights reserved.

Deciphering the function and regulation of SbCAD2: A key lignin gene to improve sorghum biomass degradability

USDA-ARS?s Scientific Manuscript database

Genetic modification of lignin biosynthesis in the cell wall of biofuel feedstocks is likely one of the most effective ways to improve the conversion efficiency of cellulosic biomass to biofuel for the bioenergy industry. As a key enzyme that catalyzes the last step of monolignol synthesis, cinnamy...

Trinity: Transcriptome Assembly for Genetic and Functional Analysis of Cancer | Informatics Technology for Cancer Research (ITCR)

Cancer.gov

The cancer transcriptome is shaped by genetic changes, variation in gene transcription, mRNA processing, editing and stability, and the cancer microbiome. Deciphering this variation and understanding its implications on tumorigenesis requires sophisticated computational analyses. Most RNA-Seq analyses rely on methods that first map short reads to a reference genome, and then compare them to annotated transcripts or assemble them. However, this strategy can be limited when the cancer genome is substantially different than the reference or for detecting sequences from the cancer microbiome.

An analysis of the metabolic theory of the origin of the genetic code

NASA Technical Reports Server (NTRS)

Amirnovin, R.; Bada, J. L. (Principal Investigator)

1997-01-01

A computer program was used to test Wong's coevolution theory of the genetic code. The codon correlations between the codons of biosynthetically related amino acids in the universal genetic code and in randomly generated genetic codes were compared. It was determined that many codon correlations are also present within random genetic codes and that among the random codes there are always several which have many more correlations than that found in the universal code. Although the number of correlations depends on the choice of biosynthetically related amino acids, the probability of choosing a random genetic code with the same or greater number of codon correlations as the universal genetic code was found to vary from 0.1% to 34% (with respect to a fairly complete listing of related amino acids). Thus, Wong's theory that the genetic code arose by coevolution with the biosynthetic pathways of amino acids, based on codon correlations between biosynthetically related amino acids, is statistical in nature.

Mistranslation: from adaptations to applications.

PubMed

Hoffman, Kyle S; O'Donoghue, Patrick; Brandl, Christopher J

2017-11-01

The conservation of the genetic code indicates that there was a single origin, but like all genetic material, the cell's interpretation of the code is subject to evolutionary pressure. Single nucleotide variations in tRNA sequences can modulate codon assignments by altering codon-anticodon pairing or tRNA charging. Either can increase translation errors and even change the code. The frozen accident hypothesis argued that changes to the code would destabilize the proteome and reduce fitness. In studies of model organisms, mistranslation often acts as an adaptive response. These studies reveal evolutionary conserved mechanisms to maintain proteostasis even during high rates of mistranslation. This review discusses the evolutionary basis of altered genetic codes, how mistranslation is identified, and how deviations to the genetic code are exploited. We revisit early discoveries of genetic code deviations and provide examples of adaptive mistranslation events in nature. Lastly, we highlight innovations in synthetic biology to expand the genetic code. The genetic code is still evolving. Mistranslation increases proteomic diversity that enables cells to survive stress conditions or suppress a deleterious allele. Genetic code variants have been identified by genome and metagenome sequence analyses, suppressor genetics, and biochemical characterization. Understanding the mechanisms of translation and genetic code deviations enables the design of new codes to produce novel proteins. Engineering the translation machinery and expanding the genetic code to incorporate non-canonical amino acids are valuable tools in synthetic biology that are impacting biomedical research. This article is part of a Special Issue entitled "Biochemistry of Synthetic Biology - Recent Developments" Guest Editor: Dr. Ilka Heinemann and Dr. Patrick O'Donoghue. Copyright © 2017 Elsevier B.V. All rights reserved.

Whole genome annotation and comparative genomic analyses of bio-control fungus Purpureocillium lilacinum.

PubMed

Prasad, Pushplata; Varshney, Deepti; Adholeya, Alok

2015-11-25

The fungus Purpureocillium lilacinum is widely known as a biological control agent against plant parasitic nematodes. This research article consists of genomic annotation of the first draft of whole genome sequence of P. lilacinum. The study aims to decipher the putative genetic components of the fungus involved in nematode pathogenesis by performing comparative genomic analysis with nine closely related fungal species in Hypocreales. de novo genomic assembly was done and a total of 301 scaffolds were constructed for P. lilacinum genomic DNA. By employing structural genome prediction models, 13, 266 genes coding for proteins were predicted in the genome. Approximately 73% of the predicted genes were functionally annotated using Blastp, InterProScan and Gene Ontology. A 14.7% fraction of the predicted genes shared significant homology with genes in the Pathogen Host Interactions (PHI) database. The phylogenomic analysis carried out using maximum likelihood RAxML algorithm provided insight into the evolutionary relationship of P. lilacinum. In congruence with other closely related species in the Hypocreales namely, Metarhizium spp., Pochonia chlamydosporia, Cordyceps militaris, Trichoderma reesei and Fusarium spp., P. lilacinum has large gene sets coding for G-protein coupled receptors (GPCRs), proteases, glycoside hydrolases and carbohydrate esterases that are required for degradation of nematode-egg shell components. Screening of the genome by Antibiotics & Secondary Metabolite Analysis Shell (AntiSMASH) pipeline indicated that the genome potentially codes for a variety of secondary metabolites, possibly required for adaptation to heterogeneous lifestyles reported for P. lilacinum. Significant up-regulation of subtilisin-like serine protease genes in presence of nematode eggs in quantitative real-time analyses suggested potential role of serine proteases in nematode pathogenesis. The data offer a better understanding of Purpureocillium lilacinum genome and will enhance our understanding on the molecular mechanism involved in nematophagy.

Evaluation of coded wire tags for marking lake trout

USGS Publications Warehouse

Elrod, Joseph H.; Schneider, Clifford P.

1986-01-01

Among hatchery-reared lake trout (Salvelinus namaycush) of the 1979-1982 year classes stocked in New York waters of Lake Ontario, more than 3 million fish were marked with a coded wire tag (CWT) plus an adipose fin clip, and 1.5 million with only conventional fin clips. Altogether, 7,640 tags were recovered from fish collected with bottom trawls and gill nets or caught by anglers during 1980-1983. One person was able to extract and decipher 200 or more CWTs per day with about a 1% error rate in reading and recording codes. Presence of the CWT did not affect growth. The adipose fin clip did not regenerate. The occurrence of fish with an adipose fin clip but no CWT resulted primarily from the regeneration of paired fins among fish marked with a combination of the adipose fin and a paired fin. Loss of CWTs between marking and stocking (generally 4-5 months for fish stocked in spring and 1-8 d for fish stocked in fall) declined from nearly 11% for the 1979 year class stocked as fall fingerlings to less than 3% for the 1981 and 1982 year classes - a difference that primarily reflected improvements in instrumentation and tagging technique. The rate of CWT loss after the marked fish were stocked was probably less than 1% per year. The CWT is a reliable method for marking hatchery-reared lake trout. A large number of experimental groups can be uniquely marked, and fish from each group can be accurately identified throughout their life. Use of this technique should greatly facilitate evaluations of genetic strain, hatchery experience, condition at time of stocking, season of stocking, size at stocking, method of stocking and other factors that affect poststocking survival and performance of lake trout stocked in the Great Lakes.

Increasing Nucleosome Occupancy Is Correlated with an Increasing Mutation Rate so Long as DNA Repair Machinery Is Intact

PubMed Central

Taylor, Jared F.; Khattab, Omar S.; Chen, Yu-Han; Chen, Yumay; Jacobsen, Steven E.; Wang, Ping H.

2015-01-01

Deciphering the multitude of epigenomic and genomic factors that influence the mutation rate is an area of great interest in modern biology. Recently, chromatin has been shown to play a part in this process. To elucidate this relationship further, we integrated our own ultra-deep sequenced human nucleosomal DNA data set with a host of published human genomic and cancer genomic data sets. Our results revealed, that differences in nucleosome occupancy are associated with changes in base-specific mutation rates. Increasing nucleosome occupancy is associated with an increasing transition to transversion ratio and an increased germline mutation rate within the human genome. Additionally, cancer single nucleotide variants and microindels are enriched within nucleosomes and both the coding and non-coding cancer mutation rate increases with increasing nucleosome occupancy. There is an enrichment of cancer indels at the theoretical start (74 bp) and end (115 bp) of linker DNA between two nucleosomes. We then hypothesized that increasing nucleosome occupancy decreases access to DNA by DNA repair machinery and could account for the increasing mutation rate. Such a relationship should not exist in DNA repair knockouts, and we thus repeated our analysis in DNA repair machinery knockouts to test our hypothesis. Indeed, our results revealed no correlation between increasing nucleosome occupancy and increasing mutation rate in DNA repair knockouts. Our findings emphasize the linkage of the genome and epigenome through the nucleosome whose properties can affect genome evolution and genetic aberrations such as cancer. PMID:26308346

A genetic scale of reading frame coding.

PubMed

Michel, Christian J

2014-08-21

The reading frame coding (RFC) of codes (sets) of trinucleotides is a genetic concept which has been largely ignored during the last 50 years. A first objective is the definition of a new and simple statistical parameter PrRFC for analysing the probability (efficiency) of reading frame coding (RFC) of any trinucleotide code. A second objective is to reveal different classes and subclasses of trinucleotide codes involved in reading frame coding: the circular codes of 20 trinucleotides and the bijective genetic codes of 20 trinucleotides coding the 20 amino acids. This approach allows us to propose a genetic scale of reading frame coding which ranges from 1/3 with the random codes (RFC probability identical in the three frames) to 1 with the comma-free circular codes (RFC probability maximal in the reading frame and null in the two shifted frames). This genetic scale shows, in particular, the reading frame coding probabilities of the 12,964,440 circular codes (PrRFC=83.2% in average), the 216 C(3) self-complementary circular codes (PrRFC=84.1% in average) including the code X identified in eukaryotic and prokaryotic genes (PrRFC=81.3%) and the 339,738,624 bijective genetic codes (PrRFC=61.5% in average) including the 52 codes without permuted trinucleotides (PrRFC=66.0% in average). Otherwise, the reading frame coding probabilities of each trinucleotide code coding an amino acid with the universal genetic code are also determined. The four amino acids Gly, Lys, Phe and Pro are coded by codes (not circular) with RFC probabilities equal to 2/3, 1/2, 1/2 and 2/3, respectively. The amino acid Leu is coded by a circular code (not comma-free) with a RFC probability equal to 18/19. The 15 other amino acids are coded by comma-free circular codes, i.e. with RFC probabilities equal to 1. The identification of coding properties in some classes of trinucleotide codes studied here may bring new insights in the origin and evolution of the genetic code. Copyright © 2014 Elsevier Ltd. All rights reserved.

Genetic code, hamming distance and stochastic matrices.

PubMed

He, Matthew X; Petoukhov, Sergei V; Ricci, Paolo E

2004-09-01

In this paper we use the Gray code representation of the genetic code C=00, U=10, G=11 and A=01 (C pairs with G, A pairs with U) to generate a sequence of genetic code-based matrices. In connection with these code-based matrices, we use the Hamming distance to generate a sequence of numerical matrices. We then further investigate the properties of the numerical matrices and show that they are doubly stochastic and symmetric. We determine the frequency distributions of the Hamming distances, building blocks of the matrices, decomposition and iterations of matrices. We present an explicit decomposition formula for the genetic code-based matrix in terms of permutation matrices, which provides a hypercube representation of the genetic code. It is also observed that there is a Hamiltonian cycle in a genetic code-based hypercube.

Glocalized New Age Spirituality: A Mental Map of the New Central Bus Station in Tel Aviv, Deciphered through Its Visual Codes and Based on Ethno-Visual Research

ERIC Educational Resources Information Center

Ben-Peshat, Malka; Sitton, Shoshana

2011-01-01

We present here the findings of an ethno-visual research study involving the creation of a mental map of images, artifacts and practices in Tel Aviv's New Central Bus Station. This huge and complex building, part bus station, part shopping mall, has become a stage for multicultural encounters and interactions among diverse communities of users.…

Two Perspectives on the Origin of the Standard Genetic Code

NASA Astrophysics Data System (ADS)

Sengupta, Supratim; Aggarwal, Neha; Bandhu, Ashutosh Vishwa

2014-12-01

The origin of a genetic code made it possible to create ordered sequences of amino acids. In this article we provide two perspectives on code origin by carrying out simulations of code-sequence coevolution in finite populations with the aim of examining how the standard genetic code may have evolved from more primitive code(s) encoding a small number of amino acids. We determine the efficacy of the physico-chemical hypothesis of code origin in the absence and presence of horizontal gene transfer (HGT) by allowing a diverse collection of code-sequence sets to compete with each other. We find that in the absence of horizontal gene transfer, natural selection between competing codes distinguished by differences in the degree of physico-chemical optimization is unable to explain the structure of the standard genetic code. However, for certain probabilities of the horizontal transfer events, a universal code emerges having a structure that is consistent with the standard genetic code.

Trans-oligomerization of duplicated aminoacyl-tRNA synthetases maintains genetic code fidelity under stress.

PubMed

Rubio, Miguel Ángel; Napolitano, Mauro; Ochoa de Alda, Jesús A G; Santamaría-Gómez, Javier; Patterson, Carl J; Foster, Andrew W; Bru-Martínez, Roque; Robinson, Nigel J; Luque, Ignacio

2015-11-16

Aminoacyl-tRNA synthetases (aaRSs) play a key role in deciphering the genetic message by producing charged tRNAs and are equipped with proofreading mechanisms to ensure correct pairing of tRNAs with their cognate amino acid. Duplicated aaRSs are very frequent in Nature, with 25,913 cases observed in 26,837 genomes. The oligomeric nature of many aaRSs raises the question of how the functioning and oligomerization of duplicated enzymes is organized. We characterized this issue in a model prokaryotic organism that expresses two different threonyl-tRNA synthetases, responsible for Thr-tRNA(Thr) synthesis: one accurate and constitutively expressed (T1) and another (T2) with impaired proofreading activity that also generates mischarged Ser-tRNA(Thr). Low zinc promotes dissociation of dimeric T1 into monomers deprived of aminoacylation activity and simultaneous induction of T2, which is active for aminoacylation under low zinc. T2 either forms homodimers or heterodimerizes with T1 subunits that provide essential proofreading activity in trans. These findings evidence that in organisms with duplicated genes, cells can orchestrate the assemblage of aaRSs oligomers that meet the necessities of the cell in each situation. We propose that controlled oligomerization of duplicated aaRSs is an adaptive mechanism that can potentially be expanded to the plethora of organisms with duplicated oligomeric aaRSs. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

Genetic basis and biotechnological manipulation of sexual dimorphism and sex determination in fish.

PubMed

Mei, Jie; Gui, Jian-Fang

2015-02-01

Aquaculture has made an enormous contribution to the world food production, especially to the sustainable supply of animal proteins. The utility of diverse reproduction strategies in fish, such as the exploiting use of unisexual gynogenesis, has created a typical case of fish genetic breeding. A number of fish species show substantial sexual dimorphism that is closely linked to multiple economic traits including growth rate and body size, and the efficient development of sex-linked genetic markers and sex control biotechnologies has provided significant approaches to increase the production and value for commercial purposes. Along with the rapid development of genomics and molecular genetic techniques, the genetic basis of sexual dimorphism has been gradually deciphered, and great progress has been made in the mechanisms of fish sex determination and identification of sex-determining genes. This review summarizes the progress to provide some directive and objective thinking for further research in this field.

Automated design of genetic toggle switches with predetermined bistability.

PubMed

Chen, Shuobing; Zhang, Haoqian; Shi, Handuo; Ji, Weiyue; Feng, Jingchen; Gong, Yan; Yang, Zhenglin; Ouyang, Qi

2012-07-20

Synthetic biology aims to rationally construct biological devices with required functionalities. Methods that automate the design of genetic devices without post-hoc adjustment are therefore highly desired. Here we provide a method to predictably design genetic toggle switches with predetermined bistability. To accomplish this task, a biophysical model that links ribosome binding site (RBS) DNA sequence to toggle switch bistability was first developed by integrating a stochastic model with RBS design method. Then, to parametrize the model, a library of genetic toggle switch mutants was experimentally built, followed by establishing the equivalence between RBS DNA sequences and switch bistability. To test this equivalence, RBS nucleotide sequences for different specified bistabilities were in silico designed and experimentally verified. Results show that the deciphered equivalence is highly predictive for the toggle switch design with predetermined bistability. This method can be generalized to quantitative design of other probabilistic genetic devices in synthetic biology.

Deciphering the genetic control of fruit texture in apple by multiple family-based analysis and genome-wide association

PubMed Central

Di Guardo, Mario; Bink, Marco C.A.M.; Guerra, Walter; Letschka, Thomas; Lozano, Lidia; Busatto, Nicola; Poles, Lara; Tadiello, Alice; Bianco, Luca; Visser, Richard G.F.; van de Weg, Eric

2017-01-01

Abstract Fruit texture is a complex feature composed of mechanical and acoustic properties relying on the modifications occurring in the cell wall throughout fruit development and ripening. Apple is characterized by a large variation in fruit texture behavior that directly impacts both the consumer’s appreciation and post-harvest performance. To decipher the genetic control of fruit texture comprehensively, two complementing quantitative trait locus (QTL) mapping approaches were employed. The first was represented by a pedigree-based analysis (PBA) carried out on six full-sib pedigreed families, while the second was a genome-wide association study (GWAS) performed on a collection of 233 apple accessions. Both plant materials were genotyped with a 20K single nucleotide polymorphism (SNP) array and phenotyped with a sophisticated high-resolution texture analyzer. The overall QTL results indicated the fundamental role of chromosome 10 in controlling the mechanical properties, while chromosomes 2 and 14 were more associated with the acoustic response. The latter QTL, moreover, showed a consistent relationship between the QTL-estimated genotypes and the acoustic performance assessed among seedlings. The in silico annotation of these intervals revealed interesting candidate genes potentially involved in fruit texture regulation, as suggested by the gene expression profile. The joint integration of these approaches sheds light on the specific control of fruit texture, enabling important genetic information to assist in the selection of valuable fruit quality apple varieties. PMID:28338805

Deciphering the genetic control of fruit texture in apple by multiple family-based analysis and genome-wide association.

PubMed

Di Guardo, Mario; Bink, Marco C A M; Guerra, Walter; Letschka, Thomas; Lozano, Lidia; Busatto, Nicola; Poles, Lara; Tadiello, Alice; Bianco, Luca; Visser, Richard G F; van de Weg, Eric; Costa, Fabrizio

2017-03-01

Fruit texture is a complex feature composed of mechanical and acoustic properties relying on the modifications occurring in the cell wall throughout fruit development and ripening. Apple is characterized by a large variation in fruit texture behavior that directly impacts both the consumer's appreciation and post-harvest performance. To decipher the genetic control of fruit texture comprehensively, two complementing quantitative trait locus (QTL) mapping approaches were employed. The first was represented by a pedigree-based analysis (PBA) carried out on six full-sib pedigreed families, while the second was a genome-wide association study (GWAS) performed on a collection of 233 apple accessions. Both plant materials were genotyped with a 20K single nucleotide polymorphism (SNP) array and phenotyped with a sophisticated high-resolution texture analyzer. The overall QTL results indicated the fundamental role of chromosome 10 in controlling the mechanical properties, while chromosomes 2 and 14 were more associated with the acoustic response. The latter QTL, moreover, showed a consistent relationship between the QTL-estimated genotypes and the acoustic performance assessed among seedlings. The in silico annotation of these intervals revealed interesting candidate genes potentially involved in fruit texture regulation, as suggested by the gene expression profile. The joint integration of these approaches sheds light on the specific control of fruit texture, enabling important genetic information to assist in the selection of valuable fruit quality apple varieties. © The Author 2017. Published by Oxford University Press on behalf of the Society for Experimental Biology.

Mechanisms and consequences of alternative polyadenylation

PubMed Central

Di Giammartino, Dafne Campigli; Nishida, Kensei; Manley, James L.

2011-01-01

Summary Alternative polyadenylation (APA) is emerging as a widespread mechanism used to control gene expression. Like alternative splicing, usage of alternative poly(A) sites allows a single gene to encode multiple mRNA transcripts. In some cases, this changes the mRNA coding potential; in other cases, the code remains unchanged but the 3’UTR length is altered, influencing the fate of mRNAs in several ways, for example, by altering the availability of RNA binding protein sites and microRNA binding sites. The mechansims governing both global and gene-specific APA are only starting to be deciphered. Here we review what is known about these mechanisms and the functional consequences of alternative polyadenlyation. PMID:21925375

Deciphering Neural Codes of Memory during Sleep.

PubMed

Chen, Zhe; Wilson, Matthew A

2017-05-01

Memories of experiences are stored in the cerebral cortex. Sleep is critical for the consolidation of hippocampal memory of wake experiences into the neocortex. Understanding representations of neural codes of hippocampal-neocortical networks during sleep would reveal important circuit mechanisms in memory consolidation and provide novel insights into memory and dreams. Although sleep-associated ensemble spike activity has been investigated, identifying the content of memory in sleep remains challenging. Here we revisit important experimental findings on sleep-associated memory (i.e., neural activity patterns in sleep that reflect memory processing) and review computational approaches to the analysis of sleep-associated neural codes (SANCs). We focus on two analysis paradigms for sleep-associated memory and propose a new unsupervised learning framework ('memory first, meaning later') for unbiased assessment of SANCs. Copyright © 2017 Elsevier Ltd. All rights reserved.

An NGS Workflow Blueprint for DNA Sequencing Data and Its Application in Individualized Molecular Oncology

PubMed Central

Li, Jian; Batcha, Aarif Mohamed Nazeer; Grüning, Björn; Mansmann, Ulrich R.

2015-01-01

Next-generation sequencing (NGS) technologies that have advanced rapidly in the past few years possess the potential to classify diseases, decipher the molecular code of related cell processes, identify targets for decision-making on targeted therapy or prevention strategies, and predict clinical treatment response. Thus, NGS is on its way to revolutionize oncology. With the help of NGS, we can draw a finer map for the genetic basis of diseases and can improve our understanding of diagnostic and prognostic applications and therapeutic methods. Despite these advantages and its potential, NGS is facing several critical challenges, including reduction of sequencing cost, enhancement of sequencing quality, improvement of technical simplicity and reliability, and development of semiautomated and integrated analysis workflow. In order to address these challenges, we conducted a literature research and summarized a four-stage NGS workflow for providing a systematic review on NGS-based analysis, explaining the strength and weakness of diverse NGS-based software tools, and elucidating its potential connection to individualized medicine. By presenting this four-stage NGS workflow, we try to provide a minimal structural layout required for NGS data storage and reproducibility. PMID:27081306

Evolution of transcriptional enhancers and animal diversity

PubMed Central

Rubinstein, Marcelo; de Souza, Flávio S. J.

2013-01-01

Deciphering the genetic bases that drive animal diversity is one of the major challenges of modern biology. Although four decades ago it was proposed that animal evolution was mainly driven by changes in cis-regulatory DNA elements controlling gene expression rather than in protein-coding sequences, only now are powerful bioinformatics and experimental approaches available to accelerate studies into how the evolution of transcriptional enhancers contributes to novel forms and functions. In the introduction to this Theme Issue, we start by defining the general properties of transcriptional enhancers, such as modularity and the coexistence of tight sequence conservation with transcription factor-binding site shuffling as different mechanisms that maintain the enhancer grammar over evolutionary time. We discuss past and current methods used to identify cell-type-specific enhancers and provide examples of how enhancers originate de novo, change and are lost in particular lineages. We then focus in the central part of this Theme Issue on analysing examples of how the molecular evolution of enhancers may change form and function. Throughout this introduction, we present the main findings of the articles, reviews and perspectives contributed to this Theme Issue that together illustrate some of the great advances and current frontiers in the field. PMID:24218630

The aminoacyl-tRNA synthetases had only a marginal role in the origin of the organization of the genetic code: Evidence in favor of the coevolution theory.

PubMed

Di Giulio, Massimo

2017-11-07

The coevolution theory of the origin of the genetic code suggests that the organization of the genetic code coevolved with the biosynthetic relationships between amino acids. The mechanism that allowed this coevolution was based on tRNA-like molecules on which-this theory-would postulate the biosynthetic transformations between amino acids to have occurred. This mechanism makes a prediction on how the role conducted by the aminoacyl-tRNA synthetases (ARSs), in the origin of the genetic code, should have been. Indeed, if the biosynthetic transformations between amino acids occurred on tRNA-like molecules, then there was no need to link amino acids to these molecules because amino acids were already charged on tRNA-like molecules, as the coevolution theory suggests. In spite of the fact that ARSs make the genetic code responsible for the first interaction between a component of nucleic acids and that of proteins, for the coevolution theory the role of ARSs should have been entirely marginal in the genetic code origin. Therefore, I have conducted a further analysis of the distribution of the two classes of ARSs and of their subclasses-in the genetic code table-in order to perform a falsification test of the coevolution theory. Indeed, in the case in which the distribution of ARSs within the genetic code would have been highly significant, then the coevolution theory would be falsified since the mechanism on which it is based would not predict a fundamental role of ARSs in the origin of the genetic code. I found that the statistical significance of the distribution of the two classes of ARSs in the table of the genetic code is low or marginal, whereas that of the subclasses of ARSs statistically significant. However, this is in perfect agreement with the postulates of the coevolution theory. Indeed, the only case of statistical significance-regarding the classes of ARSs-is appreciable for the CAG code, whereas for its complement-the UNN/NUN code-only a marginal significance is measurable. These two codes codify roughly for the two ARS classes, in particular, the CAG code for the class II while the UNN/NUN code for the class I. Furthermore, the subclasses of ARSs show a statistical significance of their distribution in the genetic code table. Nevertheless, the more sensible explanation for these observations would be the following. The observation that would link the two classes of ARSs to the CAG and UNN/NUN codes, and the statistical significance of the distribution of the subclasses of ARSs in the genetic code table, would be only a secondary effect due to the highly significant distribution of the polarity of amino acids and their biosynthetic relationships in the genetic code. That is to say, the polarity of amino acids and their biosynthetic relationships would have conditioned the evolution of ARSs so that their presence in the genetic code would have been detectable. Even if the ARSs would not have-on their own-influenced directly the evolutionary organization of the genetic code. In other words, the role that ARSs had in the origin of the genetic code would have been entirely marginal. This conclusion would be in perfect accord with the predictions of the coevolution theory. Conversely, this conclusion would be in contrast-at least partially-with the physicochemical theories of the origin of the genetic code because they would foresee an absolutely more active role of ARSs in the origin of the organization of the genetic code. Copyright © 2017 Elsevier Ltd. All rights reserved.

How Precisely Can Prostate Cancer Be Managed?

PubMed Central

2016-01-01

Progress has been made in applying genetic information to disease management in the postgenomic era, and precision medicine is emerging in prostate cancer management. The prostate health index, the 4-kallikrein (4K) score, and the PCA3, TMPRSS2-ERG, and Prostarix tests have potential for refining prostate cancer screening in conjunction with traditional prostate-specific antigen testing. The Confirm MDx and PCA3 tests have shown promise in identifying men who need be rebiopsied after a primary negative biopsy. Oncotype DX, Prolaris, the biopsy-based Decipher prostate cancer test, and ProMark may improve predictive risk stratification in addition to the traditional Gleason score and tumor stage. Decipher and Prolaris may predict biochemical recurrence and metastasis after radical prostatectomy and possibly help identify patients who need adjuvant therapy. Androgen receptor splice variant 7 appears effective in guiding the selection of second hormonal manipulation with abiraterone or enzalutamide versus chemotherapy when treating metastatic castration-resistant prostate cancer. PMID:27915475

Critical roles for a genetic code alteration in the evolution of the genus Candida.

PubMed

Silva, Raquel M; Paredes, João A; Moura, Gabriela R; Manadas, Bruno; Lima-Costa, Tatiana; Rocha, Rita; Miranda, Isabel; Gomes, Ana C; Koerkamp, Marian J G; Perrot, Michel; Holstege, Frank C P; Boucherie, Hélian; Santos, Manuel A S

2007-10-31

During the last 30 years, several alterations to the standard genetic code have been discovered in various bacterial and eukaryotic species. Sense and nonsense codons have been reassigned or reprogrammed to expand the genetic code to selenocysteine and pyrrolysine. These discoveries highlight unexpected flexibility in the genetic code, but do not elucidate how the organisms survived the proteome chaos generated by codon identity redefinition. In order to shed new light on this question, we have reconstructed a Candida genetic code alteration in Saccharomyces cerevisiae and used a combination of DNA microarrays, proteomics and genetics approaches to evaluate its impact on gene expression, adaptation and sexual reproduction. This genetic manipulation blocked mating, locked yeast in a diploid state, remodelled gene expression and created stress cross-protection that generated adaptive advantages under environmental challenging conditions. This study highlights unanticipated roles for codon identity redefinition during the evolution of the genus Candida, and strongly suggests that genetic code alterations create genetic barriers that speed up speciation.

Arbitrariness is not enough: towards a functional approach to the genetic code.

PubMed

Lacková, Ľudmila; Matlach, Vladimír; Faltýnek, Dan

2017-12-01

Arbitrariness in the genetic code is one of the main reasons for a linguistic approach to molecular biology: the genetic code is usually understood as an arbitrary relation between amino acids and nucleobases. However, from a semiotic point of view, arbitrariness should not be the only condition for definition of a code, consequently it is not completely correct to talk about "code" in this case. Yet we suppose that there exist a code in the process of protein synthesis, but on a higher level than the nucleic bases chains. Semiotically, a code should be always associated with a function and we propose to define the genetic code not only relationally (in basis of relation between nucleobases and amino acids) but also in terms of function (function of a protein as meaning of the code). Even if the functional definition of meaning in the genetic code has been discussed in the field of biosemiotics, its further implications have not been considered. In fact, if the function of a protein represents the meaning of the genetic code (the sign's object), then it is crucial to reconsider the notion of its expression (the sign) as well. In our contribution, we will show that the actual model of the genetic code is not the only possible and we will propose a more appropriate model from a semiotic point of view.

Alignment-based and alignment-free methods converge with experimental data on amino acids coded by stop codons at split between nuclear and mitochondrial genetic codes.

PubMed

Seligmann, Hervé

2018-05-01

Genetic codes mainly evolve by reassigning punctuation codons, starts and stops. Previous analyses assuming that undefined amino acids translate stops showed greater divergence between nuclear and mitochondrial genetic codes. Here, three independent methods converge on which amino acids translated stops at split between nuclear and mitochondrial genetic codes: (a) alignment-free genetic code comparisons inserting different amino acids at stops; (b) alignment-based blast analyses of hypothetical peptides translated from non-coding mitochondrial sequences, inserting different amino acids at stops; (c) biases in amino acid insertions at stops in proteomic data. Hence short-term protein evolution models reconstruct long-term genetic code evolution. Mitochondria reassign stops to amino acids otherwise inserted at stops by codon-anticodon mismatches (near-cognate tRNAs). Hence dual function (translation termination and translation by codon-anticodon mismatch) precedes mitochondrial reassignments of stops to amino acids. Stop ambiguity increases coded information, compensates endocellular mitogenome reduction. Mitochondrial codon reassignments might prevent viral infections. Copyright © 2018 Elsevier B.V. All rights reserved.

Deciphering neuronal population codes for acute thermal pain

NASA Astrophysics Data System (ADS)

Chen, Zhe; Zhang, Qiaosheng; Phuong Sieu Tong, Ai; Manders, Toby R.; Wang, Jing

2017-06-01

Objective. Pain is defined as an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage. Current pain research mostly focuses on molecular and synaptic changes at the spinal and peripheral levels. However, a complete understanding of pain mechanisms requires the physiological study of the neocortex. Our goal is to apply a neural decoding approach to read out the onset of acute thermal pain signals, which can be used for brain-machine interface. Approach. We used micro wire arrays to record ensemble neuronal activities from the primary somatosensory cortex (S1) and anterior cingulate cortex (ACC) in freely behaving rats. We further investigated neural codes for acute thermal pain at both single-cell and population levels. To detect the onset of acute thermal pain signals, we developed a novel latent state-space framework to decipher the sorted or unsorted S1 and ACC ensemble spike activities, which reveal information about the onset of pain signals. Main results. The state space analysis allows us to uncover a latent state process that drives the observed ensemble spike activity, and to further detect the ‘neuronal threshold’ for acute thermal pain on a single-trial basis. Our method achieved good detection performance in sensitivity and specificity. In addition, our results suggested that an optimal strategy for detecting the onset of acute thermal pain signals may be based on combined evidence from S1 and ACC population codes. Significance. Our study is the first to detect the onset of acute pain signals based on neuronal ensemble spike activity. It is important from a mechanistic viewpoint as it relates to the significance of S1 and ACC activities in the regulation of the acute pain onset.

Frequency spectrum might act as communication code between retina and visual cortex I

PubMed Central

Yang, Xu; Gong, Bo; Lu, Jian-Wei

2015-01-01

AIM To explore changes and possible communication relationship of local potential signals recorded simultaneously from retina and visual cortex I (V1). METHODS Fourteen C57BL/6J mice were measured with pattern electroretinogram (PERG) and pattern visually evoked potential (PVEP) and fast Fourier transform has been used to analyze the frequency components of those signals. RESULTS The amplitude of PERG and PVEP was measured at about 36.7 µV and 112.5 µV respectively and the dominant frequency of PERG and PVEP, however, stay unchanged and both signals do not have second, or otherwise, harmonic generation. CONCLUSION The results suggested that retina encodes visual information in the way of frequency spectrum and then transfers it to primary visual cortex. The primary visual cortex accepts and deciphers the input visual information coded from retina. Frequency spectrum may act as communication code between retina and V1. PMID:26682156

Frequency spectrum might act as communication code between retina and visual cortex I.

PubMed

Yang, Xu; Gong, Bo; Lu, Jian-Wei

2015-01-01

To explore changes and possible communication relationship of local potential signals recorded simultaneously from retina and visual cortex I (V1). Fourteen C57BL/6J mice were measured with pattern electroretinogram (PERG) and pattern visually evoked potential (PVEP) and fast Fourier transform has been used to analyze the frequency components of those signals. The amplitude of PERG and PVEP was measured at about 36.7 µV and 112.5 µV respectively and the dominant frequency of PERG and PVEP, however, stay unchanged and both signals do not have second, or otherwise, harmonic generation. The results suggested that retina encodes visual information in the way of frequency spectrum and then transfers it to primary visual cortex. The primary visual cortex accepts and deciphers the input visual information coded from retina. Frequency spectrum may act as communication code between retina and V1.

Random digital encryption secure communication system

NASA Technical Reports Server (NTRS)

Doland, G. D. (Inventor)

1982-01-01

The design of a secure communication system is described. A product code, formed from two pseudorandom sequences of digital bits, is used to encipher or scramble data prior to transmission. The two pseudorandom sequences are periodically changed at intervals before they have had time to repeat. One of the two sequences is transmitted continuously with the scrambled data for synchronization. In the receiver portion of the system, the incoming signal is compared with one of two locally generated pseudorandom sequences until correspondence between the sequences is obtained. At this time, the two locally generated sequences are formed into a product code which deciphers the data from the incoming signal. Provision is made to ensure synchronization of the transmitting and receiving portions of the system.

Genetic Code Analysis Toolkit: A novel tool to explore the coding properties of the genetic code and DNA sequences

NASA Astrophysics Data System (ADS)

Kraljić, K.; Strüngmann, L.; Fimmel, E.; Gumbel, M.

2018-01-01

The genetic code is degenerated and it is assumed that redundancy provides error detection and correction mechanisms in the translation process. However, the biological meaning of the code's structure is still under current research. This paper presents a Genetic Code Analysis Toolkit (GCAT) which provides workflows and algorithms for the analysis of the structure of nucleotide sequences. In particular, sets or sequences of codons can be transformed and tested for circularity, comma-freeness, dichotomic partitions and others. GCAT comes with a fertile editor custom-built to work with the genetic code and a batch mode for multi-sequence processing. With the ability to read FASTA files or load sequences from GenBank, the tool can be used for the mathematical and statistical analysis of existing sequence data. GCAT is Java-based and provides a plug-in concept for extensibility. Availability: Open source Homepage:http://www.gcat.bio/

DECIPHER, a Search-Based Approach to Chimera Identification for 16S rRNA Sequences

PubMed Central

Wright, Erik S.; Yilmaz, L. Safak

2012-01-01

DECIPHER is a new method for finding 16S rRNA chimeric sequences by the use of a search-based approach. The method is based upon detecting short fragments that are uncommon in the phylogenetic group where a query sequence is classified but frequently found in another phylogenetic group. The algorithm was calibrated for full sequences (fs_DECIPHER) and short sequences (ss_DECIPHER) and benchmarked against WigeoN (Pintail), ChimeraSlayer, and Uchime using artificially generated chimeras. Overall, ss_DECIPHER and Uchime provided the highest chimera detection for sequences 100 to 600 nucleotides long (79% and 81%, respectively), but Uchime's performance deteriorated for longer sequences, while ss_DECIPHER maintained a high detection rate (89%). Both methods had low false-positive rates (1.3% and 1.6%). The more conservative fs_DECIPHER, benchmarked only for sequences longer than 600 nucleotides, had an overall detection rate lower than that of ss_DECIPHER (75%) but higher than those of the other programs. In addition, fs_DECIPHER had the lowest false-positive rate among all the benchmarked programs (<0.20%). DECIPHER was outperformed only by ChimeraSlayer and Uchime when chimeras were formed from closely related parents (less than 10% divergence). Given the differences in the programs, it was possible to detect over 89% of all chimeras with just the combination of ss_DECIPHER and Uchime. Using fs_DECIPHER, we detected between 1% and 2% additional chimeras in the RDP, SILVA, and Greengenes databases from which chimeras had already been removed with Pintail or Bellerophon. DECIPHER was implemented in the R programming language and is directly accessible through a webpage or by downloading the program as an R package (http://DECIPHER.cee.wisc.edu). PMID:22101057

Integrating functional genomics to accelerate mechanistic personalized medicine.

PubMed

Tyner, Jeffrey W

2017-03-01

The advent of deep sequencing technologies has resulted in the deciphering of tremendous amounts of genetic information. These data have led to major discoveries, and many anecdotes now exist of individual patients whose clinical outcomes have benefited from novel, genetically guided therapeutic strategies. However, the majority of genetic events in cancer are currently undrugged, leading to a biological gap between understanding of tumor genetic etiology and translation to improved clinical approaches. Functional screening has made tremendous strides in recent years with the development of new experimental approaches to studying ex vivo and in vivo drug sensitivity. Numerous discoveries and anecdotes also exist for translation of functional screening into novel clinical strategies; however, the current clinical application of functional screening remains largely confined to small clinical trials at specific academic centers. The intersection between genomic and functional approaches represents an ideal modality to accelerate our understanding of drug sensitivities as they relate to specific genetic events and further understand the full mechanisms underlying drug sensitivity patterns.

Mathematical fundamentals for the noise immunity of the genetic code.

PubMed

Fimmel, Elena; Strüngmann, Lutz

2018-02-01

Symmetry is one of the essential and most visible patterns that can be seen in nature. Starting from the left-right symmetry of the human body, all types of symmetry can be found in crystals, plants, animals and nature as a whole. Similarly, principals of symmetry are also some of the fundamental and most useful tools in modern mathematical natural science that play a major role in theory and applications. As a consequence, it is not surprising that the desire to understand the origin of life, based on the genetic code, forces us to involve symmetry as a mathematical concept. The genetic code can be seen as a key to biological self-organisation. All living organisms have the same molecular bases - an alphabet consisting of four letters (nitrogenous bases): adenine, cytosine, guanine, and thymine. Linearly ordered sequences of these bases contain the genetic information for synthesis of proteins in all forms of life. Thus, one of the most fascinating riddles of nature is to explain why the genetic code is as it is. Genetic coding possesses noise immunity which is the fundamental feature that allows to pass on the genetic information from parents to their descendants. Hence, since the time of the discovery of the genetic code, scientists have tried to explain the noise immunity of the genetic information. In this chapter we will discuss recent results in mathematical modelling of the genetic code with respect to noise immunity, in particular error-detection and error-correction. We will focus on two central properties: Degeneracy and frameshift correction. Different amino acids are encoded by different quantities of codons and a connection between this degeneracy and the noise immunity of genetic information is a long standing hypothesis. Biological implications of the degeneracy have been intensively studied and whether the natural code is a frozen accident or a highly optimised product of evolution is still controversially discussed. Symmetries in the structure of degeneracy of the genetic code are essential and give evidence of substantial advantages of the natural code over other possible ones. In the present chapter we will present a recent approach to explain the degeneracy of the genetic code by algorithmic methods from bioinformatics, and discuss its biological consequences. The biologists recognised this problem immediately after the detection of the non-overlapping structure of the genetic code, i.e., coding sequences are to be read in a unique way determined by their reading frame. But how does the reading head of the ribosome recognises an error in the grouping of codons, caused by e.g. insertion or deletion of a base, that can be fatal during the translation process and may result in nonfunctional proteins? In this chapter we will discuss possible solutions to the frameshift problem with a focus on the theory of so-called circular codes that were discovered in large gene populations of prokaryotes and eukaryotes in the early 90s. Circular codes allow to detect a frameshift of one or two positions and recently a beautiful theory of such codes has been developed using statistics, group theory and graph theory. Copyright © 2017 Elsevier B.V. All rights reserved.

Listening to Brain Microcircuits for Interfacing With External World—Progress in Wireless Implantable Microelectronic Neuroengineering Devices

PubMed Central

Nurmikko, Arto V.; Donoghue, John P.; Hochberg, Leigh R.; Patterson, William R.; Song, Yoon-Kyu; Bull, Christopher W.; Borton, David A.; Laiwalla, Farah; Park, Sunmee; Ming, Yin; Aceros, Juan

2011-01-01

Acquiring neural signals at high spatial and temporal resolution directly from brain microcircuits and decoding their activity to interpret commands and/or prior planning activity, such as motion of an arm or a leg, is a prime goal of modern neurotechnology. Its practical aims include assistive devices for subjects whose normal neural information pathways are not functioning due to physical damage or disease. On the fundamental side, researchers are striving to decipher the code of multiple neural microcircuits which collectively make up nature’s amazing computing machine, the brain. By implanting biocompatible neural sensor probes directly into the brain, in the form of microelectrode arrays, it is now possible to extract information from interacting populations of neural cells with spatial and temporal resolution at the single cell level. With parallel advances in application of statistical and mathematical techniques tools for deciphering the neural code, extracted populations or correlated neurons, significant understanding has been achieved of those brain commands that control, e.g., the motion of an arm in a primate (monkey or a human subject). These developments are accelerating the work on neural prosthetics where brain derived signals may be employed to bypass, e.g., an injured spinal cord. One key element in achieving the goals for practical and versatile neural prostheses is the development of fully implantable wireless microelectronic “brain-interfaces” within the body, a point of special emphasis of this paper. PMID:21654935

The neutral emergence of error minimized genetic codes superior to the standard genetic code.

PubMed

Massey, Steven E

2016-11-07

The standard genetic code (SGC) assigns amino acids to codons in such a way that the impact of point mutations is reduced, this is termed 'error minimization' (EM). The occurrence of EM has been attributed to the direct action of selection, however it is difficult to explain how the searching of alternative codes for an error minimized code can occur via codon reassignments, given that these are likely to be disruptive to the proteome. An alternative scenario is that EM has arisen via the process of genetic code expansion, facilitated by the duplication of genes encoding charging enzymes and adaptor molecules. This is likely to have led to similar amino acids being assigned to similar codons. Strikingly, we show that if during code expansion the most similar amino acid to the parent amino acid, out of the set of unassigned amino acids, is assigned to codons related to those of the parent amino acid, then genetic codes with EM superior to the SGC easily arise. This scheme mimics code expansion via the gene duplication of charging enzymes and adaptors. The result is obtained for a variety of different schemes of genetic code expansion and provides a mechanistically realistic manner in which EM has arisen in the SGC. These observations might be taken as evidence for self-organization in the earliest stages of life. Copyright © 2016 Elsevier Ltd. All rights reserved.

Functional Evolution of a cis-Regulatory Module

PubMed Central

Palsson, Arnar; Alekseeva, Elena; Bergman, Casey M; Nathan, Janaki; Kreitman, Martin

2005-01-01

Lack of knowledge about how regulatory regions evolve in relation to their structure–function may limit the utility of comparative sequence analysis in deciphering cis-regulatory sequences. To address this we applied reverse genetics to carry out a functional genetic complementation analysis of a eukaryotic cis-regulatory module—the even-skipped stripe 2 enhancer—from four Drosophila species. The evolution of this enhancer is non-clock-like, with important functional differences between closely related species and functional convergence between distantly related species. Functional divergence is attributable to differences in activation levels rather than spatiotemporal control of gene expression. Our findings have implications for understanding enhancer structure–function, mechanisms of speciation and computational identification of regulatory modules. PMID:15757364

Atopic Dermatitis According to GARP: New Mechanistic Insights in Disease Pathogenesis.

PubMed

Nousbeck, Janna; Irvine, Alan D

2016-12-01

In complex disease such as atopic dermatitis, the journey from identification of strong risk loci to profound functional and mechanistic insights can take several years. Here, Manz et al. have elegantly deciphered the mechanistic pathways in the well-established 11q13.5 atopic dermatitis risk locus. Their genetic and functional insights emphasize a role for T regulatory cells in atopic dermatitis pathogenesis. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Genetics of Sleep and Sleep disorders

PubMed Central

Sehgal, Amita; Mignot, Emmanuel

2011-01-01

Sleep remains one of the least understood phenomena in biology – even its role in synaptic plasticity remains debatable. Since sleep was recognized to be regulated genetically, intense research has launched on two fronts: the development of model organisms for deciphering the molecular mechanisms of sleep and attempts to identify genetic underpinnings of human sleep disorders. In this Review, we describe how unbiased, high-throughput screens in model organisms are uncovering sleep regulatory mechanisms and how pathways, such as the circadian clock network and specific neurotransmitter signals, have conserved effects on sleep from Drosophila to humans. At the same time, genome-wide association (GWA) studies have uncovered ~14 loci increasing susceptibility to sleep disorders, such as narcolepsy and restless leg syndrome. To conclude, we discuss how these different strategies will be critical to unambiguously defining the function of sleep. PMID:21784243

Coevolution Theory of the Genetic Code at Age Forty: Pathway to Translation and Synthetic Life

PubMed Central

Wong, J. Tze-Fei; Ng, Siu-Kin; Mat, Wai-Kin; Hu, Taobo; Xue, Hong

2016-01-01

The origins of the components of genetic coding are examined in the present study. Genetic information arose from replicator induction by metabolite in accordance with the metabolic expansion law. Messenger RNA and transfer RNA stemmed from a template for binding the aminoacyl-RNA synthetase ribozymes employed to synthesize peptide prosthetic groups on RNAs in the Peptidated RNA World. Coevolution of the genetic code with amino acid biosynthesis generated tRNA paralogs that identify a last universal common ancestor (LUCA) of extant life close to Methanopyrus, which in turn points to archaeal tRNA introns as the most primitive introns and the anticodon usage of Methanopyrus as an ancient mode of wobble. The prediction of the coevolution theory of the genetic code that the code should be a mutable code has led to the isolation of optional and mandatory synthetic life forms with altered protein alphabets. PMID:26999216

Strategies for high-altitude adaptation revealed from high-quality draft genome of non-violacein producing Janthinobacterium lividum ERGS5:01.

PubMed

Kumar, Rakshak; Acharya, Vishal; Singh, Dharam; Kumar, Sanjay

2018-01-01

A light pink coloured bacterial strain ERGS5:01 isolated from glacial stream water of Sikkim Himalaya was affiliated to Janthinobacterium lividum based on 16S rRNA gene sequence identity and phylogenetic clustering. Whole genome sequencing was performed for the strain to confirm its taxonomy as it lacked the typical violet pigmentation of the genus and also to decipher its survival strategy at the aquatic ecosystem of high elevation. The PacBio RSII sequencing generated genome of 5,168,928 bp with 4575 protein-coding genes and 118 RNA genes. Whole genome-based multilocus sequence analysis clustering, in silico DDH similarity value of 95.1% and, the ANI value of 99.25% established the identity of the strain ERGS5:01 (MCC 2953) as a non-violacein producing J. lividum . The genome comparisons across genus Janthinobacterium revealed an open pan-genome with the scope of the addition of new orthologous cluster to complete the genomic inventory. The genomic insight provided the genetic basis of freezing and frequent freeze-thaw cycle tolerance and, for industrially important enzymes. Extended insight into the genome provided clues of crucial genes associated with adaptation in the harsh aquatic ecosystem of high altitude.

The Transition from a Phytopathogenic Smut Ancestor to an Anamorphic Biocontrol Agent Deciphered by Comparative Whole-Genome Analysis[W][OPEN

PubMed Central

Lefebvre, François; Joly, David L.; Labbé, Caroline; Teichmann, Beate; Linning, Rob; Belzile, François; Bakkeren, Guus; Bélanger, Richard R.

2013-01-01

Pseudozyma flocculosa is related to the model plant pathogen Ustilago maydis yet is not a phytopathogen but rather a biocontrol agent of powdery mildews; this relationship makes it unique for the study of the evolution of plant pathogenicity factors. The P. flocculosa genome of ∼23 Mb includes 6877 predicted protein coding genes. Genome features, including hallmarks of pathogenicity, are very similar in P. flocculosa and U. maydis, Sporisorium reilianum, and Ustilago hordei. Furthermore, P. flocculosa, a strict anamorph, revealed conserved and seemingly intact mating-type and meiosis loci typical of Ustilaginales. By contrast, we observed the loss of a specific subset of candidate secreted effector proteins reported to influence virulence in U. maydis as the singular divergence that could explain its nonpathogenic nature. These results suggest that P. flocculosa could have once been a virulent smut fungus that lost the specific effectors necessary for host compatibility. Interestingly, the biocontrol agent appears to have acquired genes encoding secreted proteins not found in the compared Ustilaginales, including necrosis-inducing-Phytophthora-protein- and Lysin-motif- containing proteins believed to have direct relevance to its lifestyle. The genome sequence should contribute to new insights into the subtle genetic differences that can lead to drastic changes in fungal pathogen lifestyles. PMID:23800965

SG-ADVISER CNV: copy-number variant annotation and interpretation.

PubMed

Erikson, Galina A; Deshpande, Neha; Kesavan, Balachandar G; Torkamani, Ali

2015-09-01

Copy-number variants have been associated with a variety of diseases, especially cancer, autism, schizophrenia, and developmental delay. The majority of clinically relevant events occur de novo, necessitating the interpretation of novel events. In this light, we present the Scripps Genome ADVISER CNV annotation pipeline and Web server, which aims to fill the gap between copy number variant detection and interpretation by performing in-depth annotations and functional predictions for copy number variants. The Scripps Genome ADVISER CNV suite includes a Web server interface to a high-performance computing environment for calculations of annotations and a table-based user interface that allows for the execution of numerous annotation-based variant filtration strategies and statistics. The annotation results include details regarding location, impact on the coding portion of genes, allele frequency information (including allele frequencies from the Scripps Wellderly cohort), and overlap information with other reference data sets (including ClinVar, DGV, DECIPHER). A summary variant classification is produced (ADVISER score) based on the American College of Medical Genetics and Genomics scoring guidelines. We demonstrate >90% sensitivity/specificity for detection of pathogenic events. Scripps Genome ADVISER CNV is designed to allow users with no prior bioinformatics expertise to manipulate large volumes of copy-number variant data. Scripps Genome ADVISER CNV is available at http://genomics.scripps.edu/ADVISER/.

Crucial steps to life: From chemical reactions to code using agents.

PubMed

Witzany, Guenther

2016-02-01

The concepts of the origin of the genetic code and the definitions of life changed dramatically after the RNA world hypothesis. Main narratives in molecular biology and genetics such as the "central dogma," "one gene one protein" and "non-coding DNA is junk" were falsified meanwhile. RNA moved from the transition intermediate molecule into centre stage. Additionally the abundance of empirical data concerning non-random genetic change operators such as the variety of mobile genetic elements, persistent viruses and defectives do not fit with the dominant narrative of error replication events (mutations) as being the main driving forces creating genetic novelty and diversity. The reductionistic and mechanistic views on physico-chemical properties of the genetic code are no longer convincing as appropriate descriptions of the abundance of non-random genetic content operators which are active in natural genetic engineering and natural genome editing. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Invoking adaptation to decipher the genetic legacy of past climate change.

PubMed

de Lafontaine, Guillaume; Napier, Joseph D; Petit, Rémy J; Hu, Feng Sheng

2018-05-05

Persistence of natural populations during periods of climate change is likely to depend on migration (range shifts) or adaptation. These responses were traditionally considered discrete processes and conceptually divided into the realms of ecology and evolution. In a milestone paper, Davis and Shaw (2001) argued that the interplay of adaptation and migration was central to biotic responses to Quaternary climate, but since then there has been no synthesis of efforts made to set up this research program. Here we review some of the salient findings from molecular genetic studies assessing ecological and evolutionary responses to Quaternary climate change. These studies have revolutionized our understanding of population processes associated with past species migration. However, knowledge remains limited about the role of natural selection for local adaptation of populations to Quaternary environmental fluctuations and associated range shifts, and for the footprints this might have left on extant populations. Next-generation sequencing technologies, high-resolution paleoclimate analyses, and advances in population genetic theory offer an unprecedented opportunity to test hypotheses about adaptation through time. Recent population genomics studies have greatly improved our understanding of the role of contemporary adaptation to local environments in shaping spatial patterns of genetic diversity across modern-day landscapes. Advances in this burgeoning field provide important conceptual and methodological bases to decipher the historical role of natural selection and assess adaptation to past environmental variation. We suggest that a process called "temporal conditional neutrality" has taken place: some alleles favored in glacial environments become selectively neutral in modern-day conditions, whereas some alleles that had been neutral during glacial periods become under selection in modern environments. Building on this view, we present a new integrative framework for addressing the interplay of demographic and adaptive evolutionary responses to Quaternary climate dynamics, the research agenda initially envisioned by Davis and Shaw (2001). This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

What to do with a Dead Research Code

NASA Astrophysics Data System (ADS)

Nemiroff, Robert J.

2016-01-01

The project has ended -- should all of the computer codes that enabled the project be deleted? No. Like research papers, research codes typically carry valuable information past project end dates. Several possible end states to the life of research codes are reviewed. Historically, codes are typically left dormant on an increasingly obscure local disk directory until forgotten. These codes will likely become any or all of: lost, impossible to compile and run, difficult to decipher, and likely deleted when the code's proprietor moves on or dies. It is argued here, though, that it would be better for both code authors and astronomy generally if project codes were archived after use in some way. Archiving is advantageous for code authors because archived codes might increase the author's ADS citable publications, while astronomy as a science gains transparency and reproducibility. Paper-specific codes should be included in the publication of the journal papers they support, just like figures and tables. General codes that support multiple papers, possibly written by multiple authors, including their supporting websites, should be registered with a code registry such as the Astrophysics Source Code Library (ASCL). Codes developed on GitHub can be archived with a third party service such as, currently, BackHub. An important code version might be uploaded to a web archiving service like, currently, Zenodo or Figshare, so that this version receives a Digital Object Identifier (DOI), enabling it to found at a stable address into the future. Similar archiving services that are not DOI-dependent include perma.cc and the Internet Archive Wayback Machine at archive.org. Perhaps most simply, copies of important codes with lasting value might be kept on a cloud service like, for example, Google Drive, while activating Google's Inactive Account Manager.

A discriminative test among the different theories proposed to explain the origin of the genetic code: the coevolution theory finds additional support.

PubMed

Giulio, Massimo Di

2018-05-19

A discriminative statistical test among the different theories proposed to explain the origin of the genetic code is presented. Gathering the amino acids into polarity and biosynthetic classes that are the first expression of the physicochemical theory of the origin of the genetic code and the second expression of the coevolution theory, these classes are utilized in the Fisher's exact test to establish their significance within the genetic code table. Linking to the rows and columns of the genetic code of probabilities that express the statistical significance of these classes, I have finally been in the condition to be able to calculate a χ value to link to both the physicochemical theory and to the coevolution theory that would express the corroboration level referred to these theories. The comparison between these two χ values showed that the coevolution theory is able to explain - in this strictly empirical analysis - the origin of the genetic code better than that of the physicochemical theory. Copyright © 2018 Elsevier B.V. All rights reserved.

Unraveling transcriptional control and cis-regulatory codes using the software suite GeneACT

PubMed Central

Cheung, Tom Hiu; Kwan, Yin Lam; Hamady, Micah; Liu, Xuedong

2006-01-01

Deciphering gene regulatory networks requires the systematic identification of functional cis-acting regulatory elements. We present a suite of web-based bioinformatics tools, called GeneACT , that can rapidly detect evolutionarily conserved transcription factor binding sites or microRNA target sites that are either unique or over-represented in differentially expressed genes from DNA microarray data. GeneACT provides graphic visualization and extraction of common regulatory sequence elements in the promoters and 3'-untranslated regions that are conserved across multiple mammalian species. PMID:17064417

Constitutional aneuploidy and cancer predisposition†

PubMed Central

Ganmore, Ithamar; Smooha, Gil; Izraeli, Shai

2009-01-01

Constitutional aneuploidies are rare syndromes associated with multiple developmental abnormalities and the alterations in the risk for specific cancers. Acquired somatic chromosomal aneuploidies are the most common genetic aberrations in sporadic cancers. Thus studies of these rare constitutional aneuploidy syndromes are important not only for patient counseling and clinical management, but also for deciphering the mechanisms by which chromosomal aneuploidy affect cancer initiation and progression. Here we review the major constitutional aneuploidy syndromes and suggest some general mechanisms for the associated cancer predisposition. PMID:19297405

Constitutional aneuploidy and cancer predisposition.

PubMed

Ganmore, Ithamar; Smooha, Gil; Izraeli, Shai

2009-04-15

Constitutional aneuploidies are rare syndromes associated with multiple developmental abnormalities and the alterations in the risk for specific cancers. Acquired somatic chromosomal aneuploidies are the most common genetic aberrations in sporadic cancers. Thus studies of these rare constitutional aneuploidy syndromes are important not only for patient counseling and clinical management, but also for deciphering the mechanisms by which chromosomal aneuploidy affect cancer initiation and progression. Here we review the major constitutional aneuploidy syndromes and suggest some general mechanisms for the associated cancer predisposition.

Inclusion of the fitness sharing technique in an evolutionary algorithm to analyze the fitness landscape of the genetic code adaptability.

PubMed

Santos, José; Monteagudo, Ángel

2017-03-27

The canonical code, although prevailing in complex genomes, is not universal. It was shown the canonical genetic code superior robustness compared to random codes, but it is not clearly determined how it evolved towards its current form. The error minimization theory considers the minimization of point mutation adverse effect as the main selection factor in the evolution of the code. We have used simulated evolution in a computer to search for optimized codes, which helps to obtain information about the optimization level of the canonical code in its evolution. A genetic algorithm searches for efficient codes in a fitness landscape that corresponds with the adaptability of possible hypothetical genetic codes. The lower the effects of errors or mutations in the codon bases of a hypothetical code, the more efficient or optimal is that code. The inclusion of the fitness sharing technique in the evolutionary algorithm allows the extent to which the canonical genetic code is in an area corresponding to a deep local minimum to be easily determined, even in the high dimensional spaces considered. The analyses show that the canonical code is not in a deep local minimum and that the fitness landscape is not a multimodal fitness landscape with deep and separated peaks. Moreover, the canonical code is clearly far away from the areas of higher fitness in the landscape. Given the non-presence of deep local minima in the landscape, although the code could evolve and different forces could shape its structure, the fitness landscape nature considered in the error minimization theory does not explain why the canonical code ended its evolution in a location which is not an area of a localized deep minimum of the huge fitness landscape.

Evolvix BEST Names for semantic reproducibility across code2brain interfaces

PubMed Central

Scheuer, Katherine S.; Keel, Seth A.; Vyas, Vaibhav; Liblit, Ben; Hanlon, Bret; Ferris, Michael C.; Yin, John; Dutra, Inês; Pietsch, Anthony; Javid, Christine G.; Moog, Cecilia L.; Meyer, Jocelyn; Dresel, Jerdon; McLoone, Brian; Loberger, Sonya; Movaghar, Arezoo; Gilchrist‐Scott, Morgaine; Sabri, Yazeed; Sescleifer, Dave; Pereda‐Zorrilla, Ivan; Zietlow, Andrew; Smith, Rodrigo; Pietenpol, Samantha; Goldfinger, Jacob; Atzen, Sarah L.; Freiberg, Erika; Waters, Noah P.; Nusbaum, Claire; Nolan, Erik; Hotz, Alyssa; Kliman, Richard M.; Mentewab, Ayalew; Fregien, Nathan; Loewe, Martha

2016-01-01

Names in programming are vital for understanding the meaning of code and big data. We define code2brain (C2B) interfaces as maps in compilers and brains between meaning and naming syntax, which help to understand executable code. While working toward an Evolvix syntax for general‐purpose programming that makes accurate modeling easy for biologists, we observed how names affect C2B quality. To protect learning and coding investments, C2B interfaces require long‐term backward compatibility and semantic reproducibility (accurate reproduction of computational meaning from coder‐brains to reader‐brains by code alone). Semantic reproducibility is often assumed until confusing synonyms degrade modeling in biology to deciphering exercises. We highlight empirical naming priorities from diverse individuals and roles of names in different modes of computing to show how naming easily becomes impossibly difficult. We present the Evolvix BEST (Brief, Explicit, Summarizing, Technical) Names concept for reducing naming priority conflicts, test it on a real challenge by naming subfolders for the Project Organization Stabilizing Tool system, and provide naming questionnaires designed to facilitate C2B debugging by improving names used as keywords in a stabilizing programming language. Our experiences inspired us to develop Evolvix using a flipped programming language design approach with some unexpected features and BEST Names at its core. PMID:27918836

Pleiotropic roles of Clostridium difficile sin locus

PubMed Central

Ou, Junjun; Dupuy, Bruno

2018-01-01

Clostridium difficile is the primary cause of nosocomial diarrhea and pseudomembranous colitis. It produces dormant spores, which serve as an infectious vehicle responsible for transmission of the disease and persistence of the organism in the environment. In Bacillus subtilis, the sin locus coding SinR (113 aa) and SinI (57 aa) is responsible for sporulation inhibition. In B. subtilis, SinR mainly acts as a repressor of its target genes to control sporulation, biofilm formation, and autolysis. SinI is an inhibitor of SinR, so their interaction determines whether SinR can inhibit its target gene expression. The C. difficile genome carries two sinR homologs in the operon that we named sinR and sinR’, coding for SinR (112 aa) and SinR’ (105 aa), respectively. In this study, we constructed and characterized sin locus mutants in two different C. difficile strains R20291 and JIR8094, to decipher the locus’s role in C. difficile physiology. Transcriptome analysis of the sinRR’ mutants revealed their pleiotropic roles in controlling several pathways including sporulation, toxin production, and motility in C. difficile. Through various genetic and biochemical experiments, we have shown that SinR can regulate transcription of key regulators in these pathways, which includes sigD, spo0A, and codY. We have found that SinR’ acts as an antagonist to SinR by blocking its repressor activity. Using a hamster model, we have also demonstrated that the sin locus is needed for successful C. difficile infection. This study reveals the sin locus as a central link that connects the gene regulatory networks of sporulation, toxin production, and motility; three key pathways that are important for C. difficile pathogenesis. PMID:29529083

Protein-ligand interfaces are polarized: discovery of a strong trend for intermolecular hydrogen bonds to favor donors on the protein side with implications for predicting and designing ligand complexes.

PubMed

Raschka, Sebastian; Wolf, Alex J; Bemister-Buffington, Joseph; Kuhn, Leslie A

2018-04-01

Understanding how proteins encode ligand specificity is fascinating and similar in importance to deciphering the genetic code. For protein-ligand recognition, the combination of an almost infinite variety of interfacial shapes and patterns of chemical groups makes the problem especially challenging. Here we analyze data across non-homologous proteins in complex with small biological ligands to address observations made in our inhibitor discovery projects: that proteins favor donating H-bonds to ligands and avoid using groups with both H-bond donor and acceptor capacity. The resulting clear and significant chemical group matching preferences elucidate the code for protein-native ligand binding, similar to the dominant patterns found in nucleic acid base-pairing. On average, 90% of the keto and carboxylate oxygens occurring in the biological ligands formed direct H-bonds to the protein. A two-fold preference was found for protein atoms to act as H-bond donors and ligand atoms to act as acceptors, and 76% of all intermolecular H-bonds involved an amine donor. Together, the tight chemical and geometric constraints associated with satisfying donor groups generate a hydrogen-bonding lock that can be matched only by ligands bearing the right acceptor-rich key. Measuring an index of H-bond preference based on the observed chemical trends proved sufficient to predict other protein-ligand complexes and can be used to guide molecular design. The resulting Hbind and Protein Recognition Index software packages are being made available for rigorously defining intermolecular H-bonds and measuring the extent to which H-bonding patterns in a given complex match the preference key.

Protein-ligand interfaces are polarized: discovery of a strong trend for intermolecular hydrogen bonds to favor donors on the protein side with implications for predicting and designing ligand complexes

NASA Astrophysics Data System (ADS)

Raschka, Sebastian; Wolf, Alex J.; Bemister-Buffington, Joseph; Kuhn, Leslie A.

2018-02-01

Understanding how proteins encode ligand specificity is fascinating and similar in importance to deciphering the genetic code. For protein-ligand recognition, the combination of an almost infinite variety of interfacial shapes and patterns of chemical groups makes the problem especially challenging. Here we analyze data across non-homologous proteins in complex with small biological ligands to address observations made in our inhibitor discovery projects: that proteins favor donating H-bonds to ligands and avoid using groups with both H-bond donor and acceptor capacity. The resulting clear and significant chemical group matching preferences elucidate the code for protein-native ligand binding, similar to the dominant patterns found in nucleic acid base-pairing. On average, 90% of the keto and carboxylate oxygens occurring in the biological ligands formed direct H-bonds to the protein. A two-fold preference was found for protein atoms to act as H-bond donors and ligand atoms to act as acceptors, and 76% of all intermolecular H-bonds involved an amine donor. Together, the tight chemical and geometric constraints associated with satisfying donor groups generate a hydrogen-bonding lock that can be matched only by ligands bearing the right acceptor-rich key. Measuring an index of H-bond preference based on the observed chemical trends proved sufficient to predict other protein-ligand complexes and can be used to guide molecular design. The resulting Hbind and Protein Recognition Index software packages are being made available for rigorously defining intermolecular H-bonds and measuring the extent to which H-bonding patterns in a given complex match the preference key.

Neuronal functions associated with endo- and exocytotic events-cum-molecular trafficking may be cell maturation-dependent: lessons learned from studies on botulism.

PubMed

Ray, Radharaman; Zhang, Peng; Ray, Prabhati

2011-08-01

The passion in the scientific endeavors of Marshall Warren Nirenberg had been his quest for knowledge regarding the storage, retrieval, and processing of information in the cell. After deciphering the genetic code for which he shared the Nobel Prize in Physiology and Medicine in 1968, Nirenberg devoted his attention to unraveling the mysteries in the most complex cellular organization in the body, i.e., the nervous system, especially those governing neuronal development, plasticity, and synaptogenesis. During the tenure of the primary author (RR) as a postdoctoral Staff Fellow in the Nirenberg laboratory in the late seventies to early eighties, he had the opportunity of working on projects related to what Nirenberg used to broadly define as the "synaptic code." The major aspects of these projects dealt with the functional macromolecules relevant to neuronal growth, organization, lineage, selectivity, stabilization, synaptogenesis, and functions such as neuroexocytosis. This author's emphasis was particularly on voltage-gated calcium channels that regulate stimulus-induced neurotransmitter release. One central as well as crucial theme in these studies was the fact that the neurons had to be mature and differentiated in order to study these entities (Science 222: 794-799, 1983; Cold Spring Harb Symp Quant Biol 48: 707-715, 1983). In this communication, we illustrate how did this basic knowledge, i.e., cell maturation-dependent properties being essential for neuronal functions, led to a successful experimental design and demonstration of the validity of the targeted neurologic therapeutic delivery approach based on recombinant botulinum toxin serotype A (BoNT/A) heavy chain (rHC) serving as a neuron-specific targeting molecule (BMC Pharmacol 9: 12, 2009).

Speciation genetics: current status and evolving approaches

PubMed Central

Wolf, Jochen B. W.; Lindell, Johan; Backström, Niclas

2010-01-01

The view of species as entities subjected to natural selection and amenable to change put forth by Charles Darwin and Alfred Wallace laid the conceptual foundation for understanding speciation. Initially marred by a rudimental understanding of hereditary principles, evolutionists gained appreciation of the mechanistic underpinnings of speciation following the merger of Mendelian genetic principles with Darwinian evolution. Only recently have we entered an era where deciphering the molecular basis of speciation is within reach. Much focus has been devoted to the genetic basis of intrinsic postzygotic isolation in model organisms and several hybrid incompatibility genes have been successfully identified. However, concomitant with the recent technological advancements in genome analysis and a newfound interest in the role of ecology in the differentiation process, speciation genetic research is becoming increasingly open to non-model organisms. This development will expand speciation research beyond the traditional boundaries and unveil the genetic basis of speciation from manifold perspectives and at various stages of the splitting process. This review aims at providing an extensive overview of speciation genetics. Starting from key historical developments and core concepts of speciation genetics, we focus much of our attention on evolving approaches and introduce promising methodological approaches for future research venues. PMID:20439277

Education and personalized genomics: deciphering the public's genetic health report

PubMed Central

Lamb, Neil E; Myers, Richard M; Gunter, Chris

2010-01-01

Where do members of the public turn to understand what genetic tests mean in terms of their own health? Now that genome-wide association studies and complete genome sequencing are widely available, the importance of education in personalized genomics cannot be overstated. Although some media have introduced the concept of genetic testing to better understand health and disease, the public's understanding of the scope and impact of genetic variation has not kept up with the pace of the science or technology. Unfortunately, the likely sources to which the public turn to for guidance – their physician and the media – are often no better prepared. We examine several venues for information, including print and online guides for both lay and health-oriented audiences, and summarize selected resources in multiple formats. We also note on the roadblocks to progress and discuss ways to remove them, as urgent action is needed to connect people with their genomes in a meaningful way. PMID:20161675

Functional wiring of the yeast kinome revealed by global analysis of genetic network motifs

PubMed Central

Sharifpoor, Sara; van Dyk, Dewald; Costanzo, Michael; Baryshnikova, Anastasia; Friesen, Helena; Douglas, Alison C.; Youn, Ji-Young; VanderSluis, Benjamin; Myers, Chad L.; Papp, Balázs; Boone, Charles; Andrews, Brenda J.

2012-01-01

A combinatorial genetic perturbation strategy was applied to interrogate the yeast kinome on a genome-wide scale. We assessed the global effects of gene overexpression or gene deletion to map an integrated genetic interaction network of synthetic dosage lethal (SDL) and loss-of-function genetic interactions (GIs) for 92 kinases, producing a meta-network of 8700 GIs enriched for pathways known to be regulated by cognate kinases. Kinases most sensitive to dosage perturbations had constitutive cell cycle or cell polarity functions under standard growth conditions. Condition-specific screens confirmed that the spectrum of kinase dosage interactions can be expanded substantially in activating conditions. An integrated network composed of systematic SDL, negative and positive loss-of-function GIs, and literature-curated kinase–substrate interactions revealed kinase-dependent regulatory motifs predictive of novel gene-specific phenotypes. Our study provides a valuable resource to unravel novel functional relationships and pathways regulated by kinases and outlines a general strategy for deciphering mutant phenotypes from large-scale GI networks. PMID:22282571

Ecology and genomics of an important crop wild relative as a prelude to agricultural innovation.

PubMed

von Wettberg, Eric J B; Chang, Peter L; Başdemir, Fatma; Carrasquila-Garcia, Noelia; Korbu, Lijalem Balcha; Moenga, Susan M; Bedada, Gashaw; Greenlon, Alex; Moriuchi, Ken S; Singh, Vasantika; Cordeiro, Matilde A; Noujdina, Nina V; Dinegde, Kassaye Negash; Shah Sani, Syed Gul Abbas; Getahun, Tsegaye; Vance, Lisa; Bergmann, Emily; Lindsay, Donna; Mamo, Bullo Erena; Warschefsky, Emily J; Dacosta-Calheiros, Emmanuel; Marques, Edward; Yilmaz, Mustafa Abdullah; Cakmak, Ahmet; Rose, Janna; Migneault, Andrew; Krieg, Christopher P; Saylak, Sevgi; Temel, Hamdi; Friesen, Maren L; Siler, Eleanor; Akhmetov, Zhaslan; Ozcelik, Huseyin; Kholova, Jana; Can, Canan; Gaur, Pooran; Yildirim, Mehmet; Sharma, Hari; Vadez, Vincent; Tesfaye, Kassahun; Woldemedhin, Asnake Fikre; Tar'an, Bunyamin; Aydogan, Abdulkadir; Bukun, Bekir; Penmetsa, R Varma; Berger, Jens; Kahraman, Abdullah; Nuzhdin, Sergey V; Cook, Douglas R

2018-02-13

Domesticated species are impacted in unintended ways during domestication and breeding. Changes in the nature and intensity of selection impart genetic drift, reduce diversity, and increase the frequency of deleterious alleles. Such outcomes constrain our ability to expand the cultivation of crops into environments that differ from those under which domestication occurred. We address this need in chickpea, an important pulse legume, by harnessing the diversity of wild crop relatives. We document an extreme domestication-related genetic bottleneck and decipher the genetic history of wild populations. We provide evidence of ancestral adaptations for seed coat color crypsis, estimate the impact of environment on genetic structure and trait values, and demonstrate variation between wild and cultivated accessions for agronomic properties. A resource of genotyped, association mapping progeny functionally links the wild and cultivated gene pools and is an essential resource chickpea for improvement, while our methods inform collection of other wild crop progenitor species.

A Bayesian network coding scheme for annotating biomedical information presented to genetic counseling clients.

PubMed

Green, Nancy

2005-04-01

We developed a Bayesian network coding scheme for annotating biomedical content in layperson-oriented clinical genetics documents. The coding scheme supports the representation of probabilistic and causal relationships among concepts in this domain, at a high enough level of abstraction to capture commonalities among genetic processes and their relationship to health. We are using the coding scheme to annotate a corpus of genetic counseling patient letters as part of the requirements analysis and knowledge acquisition phase of a natural language generation project. This paper describes the coding scheme and presents an evaluation of intercoder reliability for its tag set. In addition to giving examples of use of the coding scheme for analysis of discourse and linguistic features in this genre, we suggest other uses for it in analysis of layperson-oriented text and dialogue in medical communication.

An algebraic hypothesis about the primeval genetic code architecture.

PubMed

Sánchez, Robersy; Grau, Ricardo

2009-09-01

A plausible architecture of an ancient genetic code is derived from an extended base triplet vector space over the Galois field of the extended base alphabet {D,A,C,G,U}, where symbol D represents one or more hypothetical bases with unspecific pairings. We hypothesized that the high degeneration of a primeval genetic code with five bases and the gradual origin and improvement of a primeval DNA repair system could make possible the transition from ancient to modern genetic codes. Our results suggest that the Watson-Crick base pairing G identical with C and A=U and the non-specific base pairing of the hypothetical ancestral base D used to define the sum and product operations are enough features to determine the coding constraints of the primeval and the modern genetic code, as well as, the transition from the former to the latter. Geometrical and algebraic properties of this vector space reveal that the present codon assignment of the standard genetic code could be induced from a primeval codon assignment. Besides, the Fourier spectrum of the extended DNA genome sequences derived from the multiple sequence alignment suggests that the called period-3 property of the present coding DNA sequences could also exist in the ancient coding DNA sequences. The phylogenetic analyses achieved with metrics defined in the N-dimensional vector space (B(3))(N) of DNA sequences and with the new evolutionary model presented here also suggest that an ancient DNA coding sequence with five or more bases does not contradict the expected evolutionary history.

Reassigning stop codons via translation termination: How a few eukaryotes broke the dogma.

PubMed

Alkalaeva, Elena; Mikhailova, Tatiana

2017-03-01

The genetic code determines how amino acids are encoded within mRNA. It is universal among the vast majority of organisms, although several exceptions are known. Variant genetic codes are found in ciliates, mitochondria, and numerous other organisms. All revealed genetic codes (standard and variant) have at least one codon encoding a translation stop signal. However, recently two new genetic codes with a reassignment of all three stop codons were revealed in studies examining the protozoa transcriptomes. Here, we discuss this finding and the recent studies of variant genetic codes in eukaryotes. We consider the possible molecular mechanisms allowing the use of certain codons as sense and stop signals simultaneously. The results obtained by studying these amazing organisms represent a new and exciting insight into the mechanism of stop codon decoding in eukaryotes. Also see the video abstract here. © 2017 WILEY Periodicals, Inc.

Genetic hotels for the standard genetic code: evolutionary analysis based upon novel three-dimensional algebraic models.

PubMed

José, Marco V; Morgado, Eberto R; Govezensky, Tzipe

2011-07-01

Herein, we rigorously develop novel 3-dimensional algebraic models called Genetic Hotels of the Standard Genetic Code (SGC). We start by considering the primeval RNA genetic code which consists of the 16 codons of type RNY (purine-any base-pyrimidine). Using simple algebraic operations, we show how the RNA code could have evolved toward the current SGC via two different intermediate evolutionary stages called Extended RNA code type I and II. By rotations or translations of the subset RNY, we arrive at the SGC via the former (type I) or via the latter (type II), respectively. Biologically, the Extended RNA code type I, consists of all codons of the type RNY plus codons obtained by considering the RNA code but in the second (NYR type) and third (YRN type) reading frames. The Extended RNA code type II, comprises all codons of the type RNY plus codons that arise from transversions of the RNA code in the first (YNY type) and third (RNR) nucleotide bases. Since the dimensions of remarkable subsets of the Genetic Hotels are not necessarily integer numbers, we also introduce the concept of algebraic fractal dimension. A general decoding function which maps each codon to its corresponding amino acid or the stop signals is also derived. The Phenotypic Hotel of amino acids is also illustrated. The proposed evolutionary paths are discussed in terms of the existing theories of the evolution of the SGC. The adoption of 3-dimensional models of the Genetic and Phenotypic Hotels will facilitate the understanding of the biological properties of the SGC.

Structural Phylogenomics Retrodicts the Origin of the Genetic Code and Uncovers the Evolutionary Impact of Protein Flexibility

PubMed Central

Caetano-Anollés, Gustavo; Wang, Minglei; Caetano-Anollés, Derek

2013-01-01

The genetic code shapes the genetic repository. Its origin has puzzled molecular scientists for over half a century and remains a long-standing mystery. Here we show that the origin of the genetic code is tightly coupled to the history of aminoacyl-tRNA synthetase enzymes and their interactions with tRNA. A timeline of evolutionary appearance of protein domain families derived from a structural census in hundreds of genomes reveals the early emergence of the ‘operational’ RNA code and the late implementation of the standard genetic code. The emergence of codon specificities and amino acid charging involved tight coevolution of aminoacyl-tRNA synthetases and tRNA structures as well as episodes of structural recruitment. Remarkably, amino acid and dipeptide compositions of single-domain proteins appearing before the standard code suggest archaic synthetases with structures homologous to catalytic domains of tyrosyl-tRNA and seryl-tRNA synthetases were capable of peptide bond formation and aminoacylation. Results reveal that genetics arose through coevolutionary interactions between polypeptides and nucleic acid cofactors as an exacting mechanism that favored flexibility and folding of the emergent proteins. These enhancements of phenotypic robustness were likely internalized into the emerging genetic system with the early rise of modern protein structure. PMID:23991065

Reducing the genetic code induces massive rearrangement of the proteome

PubMed Central

O’Donoghue, Patrick; Prat, Laure; Kucklick, Martin; Schäfer, Johannes G.; Riedel, Katharina; Rinehart, Jesse; Söll, Dieter; Heinemann, Ilka U.

2014-01-01

Expanding the genetic code is an important aim of synthetic biology, but some organisms developed naturally expanded genetic codes long ago over the course of evolution. Less than 1% of all sequenced genomes encode an operon that reassigns the stop codon UAG to pyrrolysine (Pyl), a genetic code variant that results from the biosynthesis of Pyl-tRNAPyl. To understand the selective advantage of genetically encoding more than 20 amino acids, we constructed a markerless tRNAPyl deletion strain of Methanosarcina acetivorans (ΔpylT) that cannot decode UAG as Pyl or grow on trimethylamine. Phenotypic defects in the ΔpylT strain were evident in minimal medium containing methanol. Proteomic analyses of wild type (WT) M. acetivorans and ΔpylT cells identified 841 proteins from >7,000 significant peptides detected by MS/MS. Protein production from UAG-containing mRNAs was verified for 19 proteins. Translation of UAG codons was verified by MS/MS for eight proteins, including identification of a Pyl residue in PylB, which catalyzes the first step of Pyl biosynthesis. Deletion of tRNAPyl globally altered the proteome, leading to >300 differentially abundant proteins. Reduction of the genetic code from 21 to 20 amino acids led to significant down-regulation in translation initiation factors, amino acid metabolism, and methanogenesis from methanol, which was offset by a compensatory (100-fold) up-regulation in dimethyl sulfide metabolic enzymes. The data show how a natural proteome adapts to genetic code reduction and indicate that the selective value of an expanded genetic code is related to carbon source range and metabolic efficiency. PMID:25404328

Listening to Brain Microcircuits for Interfacing With External World-Progress in Wireless Implantable Microelectronic Neuroengineering Devices: Experimental systems are described for electrical recording in the brain using multiple microelectrodes and short range implantable or wearable broadcasting units.

PubMed

Nurmikko, Arto V; Donoghue, John P; Hochberg, Leigh R; Patterson, William R; Song, Yoon-Kyu; Bull, Christopher W; Borton, David A; Laiwalla, Farah; Park, Sunmee; Ming, Yin; Aceros, Juan

2010-01-01

Acquiring neural signals at high spatial and temporal resolution directly from brain microcircuits and decoding their activity to interpret commands and/or prior planning activity, such as motion of an arm or a leg, is a prime goal of modern neurotechnology. Its practical aims include assistive devices for subjects whose normal neural information pathways are not functioning due to physical damage or disease. On the fundamental side, researchers are striving to decipher the code of multiple neural microcircuits which collectively make up nature's amazing computing machine, the brain. By implanting biocompatible neural sensor probes directly into the brain, in the form of microelectrode arrays, it is now possible to extract information from interacting populations of neural cells with spatial and temporal resolution at the single cell level. With parallel advances in application of statistical and mathematical techniques tools for deciphering the neural code, extracted populations or correlated neurons, significant understanding has been achieved of those brain commands that control, e.g., the motion of an arm in a primate (monkey or a human subject). These developments are accelerating the work on neural prosthetics where brain derived signals may be employed to bypass, e.g., an injured spinal cord. One key element in achieving the goals for practical and versatile neural prostheses is the development of fully implantable wireless microelectronic "brain-interfaces" within the body, a point of special emphasis of this paper.

Juvenile Moyamoya and Craniosynostosis in a Child with Deletion 1p32p31: Expanding the Clinical Spectrum of 1p32p31 Deletion Syndrome and a Review of the Literature

PubMed Central

Prontera, Paolo; Rogaia, Daniela; Mencarelli, Amedea; Ottaviani, Valentina; Guercini, Giorgio; Bersano, Anna; Stangoni, Gabriela

2017-01-01

Moyamoya angiopathy (MA) is a rare cerebrovascular disorder characterised by the progressive occlusion of the internal carotid artery. Its aetiology is uncertain, but a genetic background seems likely, given the high MA familial rate. To investigate the aetiology of craniosynostosis and juvenile moyamoya in a 14-year-old male patient, we performed an array-comparative genomic hybridisation revealing a de novo interstitial deletion of 8.5 Mb in chromosome region 1p32p31. The deletion involved 34 protein coding genes, including NF1A, whose haploinsufficiency is indicated as being mainly responsible for the 1p32-p31 chromosome deletion syndrome phenotype (OMIM 613735). Our patient also has a deleted FOXD3 of the FOX gene family of transcription factors, which plays an important role in neural crest cell growth and differentiation. As the murine FOXD3−/− model shows craniofacial anomalies and abnormal common carotid artery morphology, it can be hypothesised that FOXD3 is involved in the pathogenesis of the craniofacial and vascular defects observed in our patient. In support of our assumption, we found in the literature another patient with a syndromic form of MA who had a deletion involving another FOX gene (FOXC1). In addition to describing the clinical history of our patient, we have reviewed all of the available literature concerning other patients with a 1p32p31 deletion, including cases from the Decipher database, and we have also reviewed the genetic disorders associated with MA, which is a useful guide for the diagnosis of syndromic form of MA. PMID:28926972

Redox Indicator Mice Stably Expressing Genetically Encoded Neuronal roGFP: Versatile Tools to Decipher Subcellular Redox Dynamics in Neuropathophysiology.

PubMed

Wagener, Kerstin C; Kolbrink, Benedikt; Dietrich, Katharina; Kizina, Kathrin M; Terwitte, Lukas S; Kempkes, Belinda; Bao, Guobin; Müller, Michael

2016-07-01

Reactive oxygen species (ROS) and downstream redox alterations not only mediate physiological signaling but also neuropathology. For long, ROS/redox imaging was hampered by a lack of reliable probes. Genetically encoded redox sensors overcame this gap and revolutionized (sub)cellular redox imaging. Yet, the successful delivery of sensor-coding DNA, which demands transfection/transduction of cultured preparations or stereotaxic microinjections of each subject, remains challenging. By generating transgenic mice, we aimed to overcome limiting cultured preparations, circumvent surgical interventions, and to extend effectively redox imaging to complex and adult preparations. Our redox indicator mice widely express Thy1-driven roGFP1 (reduction-oxidation-sensitive green fluorescent protein 1) in neuronal cytosol or mitochondria. Negative phenotypic effects of roGFP1 were excluded and its proper targeting and functionality confirmed. Redox mapping by ratiometric wide-field imaging reveals most oxidizing conditions in CA3 neurons. Furthermore, mitochondria are more oxidized than cytosol. Cytosolic and mitochondrial roGFP1s reliably report cell endogenous redox dynamics upon metabolic challenge or stimulation. Fluorescence lifetime imaging yields stable, but marginal, response ranges. We therefore developed automated excitation ratiometric 2-photon imaging. It offers superior sensitivity, spatial resolution, and response dynamics. Redox indicator mice enable quantitative analyses of subcellular redox dynamics in a multitude of preparations and at all postnatal stages. This will uncover cell- and compartment-specific cerebral redox signals and their defined alterations during development, maturation, and aging. Cross-breeding with other disease models will reveal molecular details on compartmental redox homeostasis in neuropathology. Combined with ratiometric 2-photon imaging, this will foster our mechanistic understanding of cellular redox signals in their full complexity. Antioxid. Redox Signal. 25, 41-58.

Redox Indicator Mice Stably Expressing Genetically Encoded Neuronal roGFP: Versatile Tools to Decipher Subcellular Redox Dynamics in Neuropathophysiology

PubMed Central

Wagener, Kerstin C.; Kolbrink, Benedikt; Dietrich, Katharina; Kizina, Kathrin M.; Terwitte, Lukas S.; Kempkes, Belinda; Bao, Guobin

2016-01-01

Abstract Aims: Reactive oxygen species (ROS) and downstream redox alterations not only mediate physiological signaling but also neuropathology. For long, ROS/redox imaging was hampered by a lack of reliable probes. Genetically encoded redox sensors overcame this gap and revolutionized (sub)cellular redox imaging. Yet, the successful delivery of sensor-coding DNA, which demands transfection/transduction of cultured preparations or stereotaxic microinjections of each subject, remains challenging. By generating transgenic mice, we aimed to overcome limiting cultured preparations, circumvent surgical interventions, and to extend effectively redox imaging to complex and adult preparations. Results: Our redox indicator mice widely express Thy1-driven roGFP1 (reduction–oxidation-sensitive green fluorescent protein 1) in neuronal cytosol or mitochondria. Negative phenotypic effects of roGFP1 were excluded and its proper targeting and functionality confirmed. Redox mapping by ratiometric wide-field imaging reveals most oxidizing conditions in CA3 neurons. Furthermore, mitochondria are more oxidized than cytosol. Cytosolic and mitochondrial roGFP1s reliably report cell endogenous redox dynamics upon metabolic challenge or stimulation. Fluorescence lifetime imaging yields stable, but marginal, response ranges. We therefore developed automated excitation ratiometric 2-photon imaging. It offers superior sensitivity, spatial resolution, and response dynamics. Innovation and Conclusion: Redox indicator mice enable quantitative analyses of subcellular redox dynamics in a multitude of preparations and at all postnatal stages. This will uncover cell- and compartment-specific cerebral redox signals and their defined alterations during development, maturation, and aging. Cross-breeding with other disease models will reveal molecular details on compartmental redox homeostasis in neuropathology. Combined with ratiometric 2-photon imaging, this will foster our mechanistic understanding of cellular redox signals in their full complexity. Antioxid. Redox Signal. 25, 41–58. PMID:27059697

Adaptive antioxidant methionine accumulation in respiratory chain complexes explains the use of a deviant genetic code in mitochondria.

PubMed

Bender, Aline; Hajieva, Parvana; Moosmann, Bernd

2008-10-28

Humans and most other animals use 2 different genetic codes to translate their hereditary information: the standard code for nuclear-encoded proteins and a modern variant of this code in mitochondria. Despite the pivotal role of the genetic code for cell biology, the functional significance of the deviant mitochondrial code has remained enigmatic since its first description in 1979. Here, we show that profound and functionally beneficial alterations on the encoded protein level were causative for the AUA codon reassignment from isoleucine to methionine observed in most mitochondrial lineages. We demonstrate that this codon reassignment leads to a massive accumulation of the easily oxidized amino acid methionine in the highly oxidative inner mitochondrial membrane. This apparently paradoxical outcome can yet be smoothly settled if the antioxidant surface chemistry of methionine is taken into account, and we present direct experimental evidence that intramembrane accumulation of methionine exhibits antioxidant and cytoprotective properties in living cells. Our results unveil that methionine is an evolutionarily selected antioxidant building block of respiratory chain complexes. Collective protein alterations can thus constitute the selective advantage behind codon reassignments, which authenticates the "ambiguous decoding" hypothesis of genetic code evolution. Oxidative stress has shaped the mitochondrial genetic code.

Stop Codon Reassignment in the Wild

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ivanova, Natalia; Schwientek, Patrick; Tripp, H. James

Since the discovery of the genetic code and protein translation mechanisms (1), a limited number of variations of the standard assignment between unique base triplets (codons) and their encoded amino acids and translational stop signals have been found in bacteria and phages (2-3). Given the apparent ubiquity of the canonical genetic code, the design of genomically recoded organisms with non-canonical codes has been suggested as a means to prevent horizontal gene transfer between laboratory and environmental organisms (4). It is also predicted that genomically recoded organisms are immune to infection by viruses, under the assumption that phages and their hostsmore » must share a common genetic code (5). This paradigm is supported by the observation of increased resistance of genomically recoded bacteria to phages with a canonical code (4). Despite these assumptions and accompanying lines of evidence, it remains unclear whether differential and non-canonical codon usage represents an absolute barrier to phage infection and genetic exchange between organisms. Our knowledge of the diversity of genetic codes and their use by viruses and their hosts is primarily derived from the analysis of cultivated organisms. Advances in single-cell sequencing and metagenome assembly technologies have enabled the reconstruction of genomes of uncultivated bacterial and archaeal lineages (6). These initial findings suggest that large scale systematic studies of uncultivated microorganisms and viruses may reveal the extent and modes of divergence from the canonical genetic code operating in nature. To explore alternative genetic codes, we carried out a systematic analysis of stop codon reassignments from the canonical TAG amber, TGA opal, and TAA ochre codons in assembled metagenomes from environmental and host-associated samples, single-cell genomes of uncultivated bacteria and archaea, and a collection of phage sequences« less

Deciphering the Code of the Cancer Genome: Mechanisms of Chromosome Rearrangement

PubMed Central

Willis, Nicholas A.; Rass, Emilie; Scully, Ralph

2015-01-01

Chromosome rearrangement plays a causal role in tumorigenesis by contributing to the inactivation of tumor suppressor genes, the dysregulated expression or amplification of oncogenes and the generation of novel gene fusions. Chromosome breaks are important intermediates in this process. How, when and where these breaks arise and the specific mechanisms engaged in their repair strongly influence the resulting patterns of chromosome rearrangement. Here, we review recent progress in understanding how certain distinctive features of the cancer genome, including clustered mutagenesis, tandem segmental duplications, complex breakpoints, chromothripsis, chromoplexy and chromoanasynthesis may arise. PMID:26726318

The fourfold way of the genetic code.

PubMed

Jiménez-Montaño, Miguel Angel

2009-11-01

We describe a compact representation of the genetic code that factorizes the table in quartets. It represents a "least grammar" for the genetic language. It is justified by the Klein-4 group structure of RNA bases and codon doublets. The matrix of the outer product between the column-vector of bases and the corresponding row-vector V(T)=(C G U A), considered as signal vectors, has a block structure consisting of the four cosets of the KxK group of base transformations acting on doublet AA. This matrix, translated into weak/strong (W/S) and purine/pyrimidine (R/Y) nucleotide classes, leads to a code table with mixed and unmixed families in separate regions. A basic difference between them is the non-commuting (R/Y) doublets: AC/CA, GU/UG. We describe the degeneracy in the canonical code and the systematic changes in deviant codes in terms of the divisors of 24, employing modulo multiplication groups. We illustrate binary sub-codes characterizing mutations in the quartets. We introduce a decision-tree to predict the mode of tRNA recognition corresponding to each codon, and compare our result with related findings by Jestin and Soulé [Jestin, J.-L., Soulé, C., 2007. Symmetries by base substitutions in the genetic code predict 2' or 3' aminoacylation of tRNAs. J. Theor. Biol. 247, 391-394], and the rearrangements of the table by Delarue [Delarue, M., 2007. An asymmetric underlying rule in the assignment of codons: possible clue to a quick early evolution of the genetic code via successive binary choices. RNA 13, 161-169] and Rodin and Rodin [Rodin, S.N., Rodin, A.S., 2008. On the origin of the genetic code: signatures of its primordial complementarity in tRNAs and aminoacyl-tRNA synthetases. Heredity 100, 341-355], respectively.

On initial Brain Activity Mapping of episodic and semantic memory code in the hippocampus.

PubMed

Tsien, Joe Z; Li, Meng; Osan, Remus; Chen, Guifen; Lin, Longian; Wang, Phillip Lei; Frey, Sabine; Frey, Julietta; Zhu, Dajiang; Liu, Tianming; Zhao, Fang; Kuang, Hui

2013-10-01

It has been widely recognized that the understanding of the brain code would require large-scale recording and decoding of brain activity patterns. In 2007 with support from Georgia Research Alliance, we have launched the Brain Decoding Project Initiative with the basic idea which is now similarly advocated by BRAIN project or Brain Activity Map proposal. As the planning of the BRAIN project is currently underway, we share our insights and lessons from our efforts in mapping real-time episodic memory traces in the hippocampus of freely behaving mice. We show that appropriate large-scale statistical methods are essential to decipher and measure real-time memory traces and neural dynamics. We also provide an example of how the carefully designed, sometime thinking-outside-the-box, behavioral paradigms can be highly instrumental to the unraveling of memory-coding cell assembly organizing principle in the hippocampus. Our observations to date have led us to conclude that the specific-to-general categorical and combinatorial feature-coding cell assembly mechanism represents an emergent property for enabling the neural networks to generate and organize not only episodic memory, but also semantic knowledge and imagination. Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

On Initial Brain Activity Mapping of Associative Memory Code in the Hippocampus

PubMed Central

Tsien, Joe Z.; Li, Meng; Osan, Remus; Chen, Guifen; Lin, Longian; Lei Wang, Phillip; Frey, Sabine; Frey, Julietta; Zhu, Dajiang; Liu, Tianming; Zhao, Fang; Kuang, Hui

2013-01-01

It has been widely recognized that the understanding of the brain code would require large-scale recording and decoding of brain activity patterns. In 2007 with support from Georgia Research Alliance, we have launched the Brain Decoding Project Initiative with the basic idea which is now similarly advocated by BRAIN project or Brain Activity Map proposal. As the planning of the BRAIN project is currently underway, we share our insights and lessons from our efforts in mapping real-time episodic memory traces in the hippocampus of freely behaving mice. We show that appropriate large-scale statistical methods are essential to decipher and measure real-time memory traces and neural dynamics. We also provide an example of how the carefully designed, sometime thinking-outside-the-box, behavioral paradigms can be highly instrumental to the unraveling of memory-coding cell assembly organizing principle in the hippocampus. Our observations to date have led us to conclude that the specific-to-general categorical and combinatorial feature-coding cell assembly mechanism represents an emergent property for enabling the neural networks to generate and organize not only episodic memory, but also semantic knowledge and imagination. PMID:23838072

FOXP2 and the neuroanatomy of speech and language.

PubMed

Vargha-Khadem, Faraneh; Gadian, David G; Copp, Andrew; Mishkin, Mortimer

2005-02-01

That speech and language are innate capacities of the human brain has long been widely accepted, but only recently has an entry point into the genetic basis of these remarkable faculties been found. The discovery of a mutation in FOXP2 in a family with a speech and language disorder has enabled neuroscientists to trace the neural expression of this gene during embryological development, track the effects of this gene mutation on brain structure and function, and so begin to decipher that part of our neural inheritance that culminates in articulate speech.

CMCpy: Genetic Code-Message Coevolution Models in Python

PubMed Central

Becich, Peter J.; Stark, Brian P.; Bhat, Harish S.; Ardell, David H.

2013-01-01

Code-message coevolution (CMC) models represent coevolution of a genetic code and a population of protein-coding genes (“messages”). Formally, CMC models are sets of quasispecies coupled together for fitness through a shared genetic code. Although CMC models display plausible explanations for the origin of multiple genetic code traits by natural selection, useful modern implementations of CMC models are not currently available. To meet this need we present CMCpy, an object-oriented Python API and command-line executable front-end that can reproduce all published results of CMC models. CMCpy implements multiple solvers for leading eigenpairs of quasispecies models. We also present novel analytical results that extend and generalize applications of perturbation theory to quasispecies models and pioneer the application of a homotopy method for quasispecies with non-unique maximally fit genotypes. Our results therefore facilitate the computational and analytical study of a variety of evolutionary systems. CMCpy is free open-source software available from http://pypi.python.org/pypi/CMCpy/. PMID:23532367

The evolution of the genetic code: Impasses and challenges.

PubMed

Kun, Ádám; Radványi, Ádám

2018-02-01

The origin of the genetic code and translation is a "notoriously difficult problem". In this survey we present a list of questions that a full theory of the genetic code needs to answer. We assess the leading hypotheses according to these criteria. The stereochemical, the coding coenzyme handle, the coevolution, the four-column theory, the error minimization and the frozen accident hypotheses are discussed. The integration of these hypotheses can account for the origin of the genetic code. But experiments are badly needed. Thus we suggest a host of experiments that could (in)validate some of the models. We focus especially on the coding coenzyme handle hypothesis (CCH). The CCH suggests that amino acids attached to RNA handles enhanced catalytic activities of ribozymes. Alternatively, amino acids without handles or with a handle consisting of a single adenine, like in contemporary coenzymes could have been employed. All three scenarios can be tested in in vitro compartmentalized systems. Copyright © 2017 Elsevier B.V. All rights reserved.

Genetic coding and gene expression - new Quadruplet genetic coding model

NASA Astrophysics Data System (ADS)

Shankar Singh, Rama

2012-07-01

Successful demonstration of human genome project has opened the door not only for developing personalized medicine and cure for genetic diseases, but it may also answer the complex and difficult question of the origin of life. It may lead to making 21st century, a century of Biological Sciences as well. Based on the central dogma of Biology, genetic codons in conjunction with tRNA play a key role in translating the RNA bases forming sequence of amino acids leading to a synthesized protein. This is the most critical step in synthesizing the right protein needed for personalized medicine and curing genetic diseases. So far, only triplet codons involving three bases of RNA, transcribed from DNA bases, have been used. Since this approach has several inconsistencies and limitations, even the promise of personalized medicine has not been realized. The new Quadruplet genetic coding model proposed and developed here involves all four RNA bases which in conjunction with tRNA will synthesize the right protein. The transcription and translation process used will be the same, but the Quadruplet codons will help overcome most of the inconsistencies and limitations of the triplet codes. Details of this new Quadruplet genetic coding model and its subsequent potential applications including relevance to the origin of life will be presented.

Foreword

NASA Astrophysics Data System (ADS)

Zhuk, A. I.; Ryabov, M. I.

This issue includes articles based on some plenary reports made during the 5th International Gamow Conference and the 15th Gamow conference-school. The Conference was devoted to a number of remarkable events:the 111 year Jubilee of George Gamow, one of the great physicists and cosmologists of the 20th century; the 150th anniversary of the Odessa I.I. Mechnikov National University and the Department of Astronomy; the 100th and 110th anniversaries of the Einstein's general and special relativity; the 50th anniversary of the discovery of cosmic microwave background (CMB) predicted by Gamow. The number 111 (three units!) represents the three major fundamental Gamow's achievements: alpha decay, the hot model of the universe and the prediction of CMB and deciphering of the genetic code. With 120 experts from 13 countries (Ukraine, Russia, Azerbaijan, Georgia, France, Italy, Switzerland, Poland, Egypt, Kazakhstan, Czech Republic, Belarus, USA) delivering 20 plenary talks, 113 contributed talks and 21 posters, both the Conference and the School were very successful. The main topics of the Conference were astrophysics, cosmology, gravity, high energy physics, radioastronomy, solar activity, solar system and astrobiology. Organizing Institutions: Odessa I.I. Mechnikov National University (Astronomical Observatory and Astronomy Department), Radio-Astronomical Institute of the NAS of Ukraine, Odessa Astronomical Society. The conference was held with the support of Ukrainian Astronomical Association, Euroasian Astronomical Society, Department of Physics and Astronomy of the NAS of Ukraine, South Scientific Center of the NAS of Ukraine.

The identification of cis-regulatory elements: A review from a machine learning perspective.

PubMed

Li, Yifeng; Chen, Chih-Yu; Kaye, Alice M; Wasserman, Wyeth W

2015-12-01

The majority of the human genome consists of non-coding regions that have been called junk DNA. However, recent studies have unveiled that these regions contain cis-regulatory elements, such as promoters, enhancers, silencers, insulators, etc. These regulatory elements can play crucial roles in controlling gene expressions in specific cell types, conditions, and developmental stages. Disruption to these regions could contribute to phenotype changes. Precisely identifying regulatory elements is key to deciphering the mechanisms underlying transcriptional regulation. Cis-regulatory events are complex processes that involve chromatin accessibility, transcription factor binding, DNA methylation, histone modifications, and the interactions between them. The development of next-generation sequencing techniques has allowed us to capture these genomic features in depth. Applied analysis of genome sequences for clinical genetics has increased the urgency for detecting these regions. However, the complexity of cis-regulatory events and the deluge of sequencing data require accurate and efficient computational approaches, in particular, machine learning techniques. In this review, we describe machine learning approaches for predicting transcription factor binding sites, enhancers, and promoters, primarily driven by next-generation sequencing data. Data sources are provided in order to facilitate testing of novel methods. The purpose of this review is to attract computational experts and data scientists to advance this field. Crown Copyright © 2015. Published by Elsevier Ireland Ltd. All rights reserved.

Microbial culturomics unravels the halophilic microbiota repertoire of table salt: description of Gracilibacillus massiliensis sp. nov.

PubMed

Diop, Awa; Khelaifia, Saber; Armstrong, Nicholas; Labas, Noémie; Fournier, Pierre-Edouard; Raoult, Didier; Million, Matthieu

2016-01-01

Microbial culturomics represents an ongoing revolution in the characterization of environmental and human microbiome. By using three media containing high salt concentration (100, 150, and 200 g/L), the halophilic microbial culturome of a commercial table salt was determined. Eighteen species belonging to the Terrabacteria group were isolated including eight moderate halophilic and 10 halotolerant bacteria. Gracilibacillus massiliensis sp. nov., type strain Awa-1 T (=CSUR P1441=DSM 29726), is a moderately halophilic gram-positive, non-spore-forming rod, and is motile by using a flagellum. Strain Awa-1 T shows catalase activity but no oxidase activity. It is not only an aerobic bacterium but also able to grow in anaerobic and microaerophilic atmospheres. The draft genome of G. massiliensis is 4,207,226 bp long, composed of 13 scaffolds with 36.05% of G+C content. It contains 3,908 genes (3,839 protein-coding and 69 RNA genes). At least 1,983 (52%) orthologous proteins were not shared with the closest phylogenetic species. Hundred twenty-six genes (3.3%) were identified as ORFans. Microbial culturomics can dramatically improve the characterization of the food and environmental microbiota repertoire, deciphering new bacterial species and new genes. Further studies will clarify the geographic specificity and the putative role of these new microbes and their related functional genetic content in environment, health, and disease.

Carbon source-dependent expansion of the genetic code in bacteria

PubMed Central

Prat, Laure; Heinemann, Ilka U.; Aerni, Hans R.; Rinehart, Jesse; O’Donoghue, Patrick; Söll, Dieter

2012-01-01

Despite the fact that the genetic code is known to vary between organisms in rare cases, it is believed that in the lifetime of a single cell the code is stable. We found Acetohalobium arabaticum cells grown on pyruvate genetically encode 20 amino acids, but in the presence of trimethylamine (TMA), A. arabaticum dynamically expands its genetic code to 21 amino acids including pyrrolysine (Pyl). A. arabaticum is the only known organism that modulates the size of its genetic code in response to its environment and energy source. The gene cassette pylTSBCD, required to biosynthesize and genetically encode UAG codons as Pyl, is present in the genomes of 24 anaerobic archaea and bacteria. Unlike archaeal Pyl-decoding organisms that constitutively encode Pyl, we observed that A. arabaticum controls Pyl encoding by down-regulating transcription of the entire Pyl operon under growth conditions lacking TMA, to the point where no detectable Pyl-tRNAPyl is made in vivo. Pyl-decoding archaea adapted to an expanded genetic code by minimizing TAG codon frequency to typically ∼5% of ORFs, whereas Pyl-decoding bacteria (∼20% of ORFs contain in-frame TAGs) regulate Pyl-tRNAPyl formation and translation of UAG by transcriptional deactivation of genes in the Pyl operon. We further demonstrate that Pyl encoding occurs in a bacterium that naturally encodes the Pyl operon, and identified Pyl residues by mass spectrometry in A. arabaticum proteins including two methylamine methyltransferases. PMID:23185002

Question 6: coevolution theory of the genetic code: a proven theory.

PubMed

Wong, Jeffrey Tze-Fei

2007-10-01

The coevolution theory proposes that primordial proteins consisted only of those amino acids readily obtainable from the prebiotic environment, representing about half the twenty encoded amino acids of today, and the missing amino acids entered the system as the code expanded along with pathways of amino acid biosynthesis. The isolation of genetic code mutants, and the antiquity of pretran synthesis revealed by the comparative genomics of tRNAs and aminoacyl-tRNA synthetases, have combined to provide a rigorous proof of the four fundamental tenets of the theory, thus solving the riddle of the structure of the universal genetic code.

Whole-Genome Sequencing Reveals Genetic Variation in the Asian House Rat.

PubMed

Teng, Huajing; Zhang, Yaohua; Shi, Chengmin; Mao, Fengbiao; Hou, Lingling; Guo, Hongling; Sun, Zhongsheng; Zhang, Jianxu

2016-07-07

Whole-genome sequencing of wild-derived rat species can provide novel genomic resources, which may help decipher the genetics underlying complex phenotypes. As a notorious pest, reservoir of human pathogens, and colonizer, the Asian house rat, Rattus tanezumi, is successfully adapted to its habitat. However, little is known regarding genetic variation in this species. In this study, we identified over 41,000,000 single-nucleotide polymorphisms, plus insertions and deletions, through whole-genome sequencing and bioinformatics analyses. Moreover, we identified over 12,000 structural variants, including 143 chromosomal inversions. Further functional analyses revealed several fixed nonsense mutations associated with infection and immunity-related adaptations, and a number of fixed missense mutations that may be related to anticoagulant resistance. A genome-wide scan for loci under selection identified various genes related to neural activity. Our whole-genome sequencing data provide a genomic resource for future genetic studies of the Asian house rat species and have the potential to facilitate understanding of the molecular adaptations of rats to their ecological niches. Copyright © 2016 Teng et al.

Sporadic and hereditary amyotrophic lateral sclerosis (ALS).

PubMed

Ajroud-Driss, Senda; Siddique, Teepu

2015-04-01

Genetic discoveries in ALS have a significant impact on deciphering molecular mechanisms of motor neuron degeneration. The identification of SOD1 as the first genetic cause of ALS led to the engineering of the SOD1 mouse, the backbone of ALS research, and set the stage for future genetic breakthroughs. In addition, careful analysis of ALS pathology added valuable pieces to the ALS puzzle. From this joint effort, major pathogenic pathways emerged. Whereas the study of TDP43, FUS and C9ORF72 pointed to the possible involvement of RNA biology in motor neuron survival, recent work on P62 and UBQLN2 refocused research on protein degradation pathways. Despite all these efforts, the etiology of most cases of sporadic ALS remains elusive. Newly acquired genomic tools now allow the identification of genetic and epigenetic factors that can either increase ALS risk or modulate disease phenotype. These developments will certainly allow for better disease modeling to identify novel therapeutic targets for ALS. This article is part of a Special Issue entitled: Neuromuscular Diseases: Pathology and Molecular Pathogenesis. Copyright © 2014 Elsevier B.V. All rights reserved.

Phenotypic Graphs and Evolution Unfold the Standard Genetic Code as the Optimal

NASA Astrophysics Data System (ADS)

Zamudio, Gabriel S.; José, Marco V.

2018-03-01

In this work, we explicitly consider the evolution of the Standard Genetic Code (SGC) by assuming two evolutionary stages, to wit, the primeval RNY code and two intermediate codes in between. We used network theory and graph theory to measure the connectivity of each phenotypic graph. The connectivity values are compared to the values of the codes under different randomization scenarios. An error-correcting optimal code is one in which the algebraic connectivity is minimized. We show that the SGC is optimal in regard to its robustness and error-tolerance when compared to all random codes under different assumptions.

An abstract model of rogue code insertion into radio frequency wireless networks. The effects of computer viruses on the Program Management Office

NASA Astrophysics Data System (ADS)

Feudo, Christopher V.

1994-04-01

This dissertation demonstrates that inadequately protected wireless LANs are more vulnerable to rogue program attack than traditional LANs. Wireless LANs not only run the same risks as traditional LANs, but they also run additional risks associated with an open transmission medium. Intruders can scan radio waves and, given enough time and resources, intercept, analyze, decipher, and reinsert data into the transmission medium. This dissertation describes the development and instantiation of an abstract model of the rogue code insertion process into a DOS-based wireless communications system using radio frequency (RF) atmospheric signal transmission. The model is general enough to be applied to widely used target environments such as UNIX, Macintosh, and DOS operating systems. The methodology and three modules, the prober, activator, and trigger modules, to generate rogue code and insert it into a wireless LAN were developed to illustrate the efficacy of the model. Also incorporated into the model are defense measures against remotely introduced rogue programs and a cost-benefit analysis that determined that such defenses for a specific environment were cost-justified.

Genetic validation of bipolar disorder identified by automated phenotyping using electronic health records.

PubMed

Chen, Chia-Yen; Lee, Phil H; Castro, Victor M; Minnier, Jessica; Charney, Alexander W; Stahl, Eli A; Ruderfer, Douglas M; Murphy, Shawn N; Gainer, Vivian; Cai, Tianxi; Jones, Ian; Pato, Carlos N; Pato, Michele T; Landén, Mikael; Sklar, Pamela; Perlis, Roy H; Smoller, Jordan W

2018-04-18

Bipolar disorder (BD) is a heritable mood disorder characterized by episodes of mania and depression. Although genomewide association studies (GWAS) have successfully identified genetic loci contributing to BD risk, sample size has become a rate-limiting obstacle to genetic discovery. Electronic health records (EHRs) represent a vast but relatively untapped resource for high-throughput phenotyping. As part of the International Cohort Collection for Bipolar Disorder (ICCBD), we previously validated automated EHR-based phenotyping algorithms for BD against in-person diagnostic interviews (Castro et al. Am J Psychiatry 172:363-372, 2015). Here, we establish the genetic validity of these phenotypes by determining their genetic correlation with traditionally ascertained samples. Case and control algorithms were derived from structured and narrative text in the Partners Healthcare system comprising more than 4.6 million patients over 20 years. Genomewide genotype data for 3330 BD cases and 3952 controls of European ancestry were used to estimate SNP-based heritability (h 2 g ) and genetic correlation (r g ) between EHR-based phenotype definitions and traditionally ascertained BD cases in GWAS by the ICCBD and Psychiatric Genomics Consortium (PGC) using LD score regression. We evaluated BD cases identified using 4 EHR-based algorithms: an NLP-based algorithm (95-NLP) and three rule-based algorithms using codified EHR with decreasing levels of stringency-"coded-strict", "coded-broad", and "coded-broad based on a single clinical encounter" (coded-broad-SV). The analytic sample comprised 862 95-NLP, 1968 coded-strict, 2581 coded-broad, 408 coded-broad-SV BD cases, and 3 952 controls. The estimated h 2 g were 0.24 (p = 0.015), 0.09 (p = 0.064), 0.13 (p = 0.003), 0.00 (p = 0.591) for 95-NLP, coded-strict, coded-broad and coded-broad-SV BD, respectively. The h 2 g for all EHR-based cases combined except coded-broad-SV (excluded due to 0 h 2 g ) was 0.12 (p = 0.004). These h 2 g were lower or similar to the h 2 g observed by the ICCBD + PGCBD (0.23, p = 3.17E-80, total N = 33,181). However, the r g between ICCBD + PGCBD and the EHR-based cases were high for 95-NLP (0.66, p = 3.69 × 10 -5 ), coded-strict (1.00, p = 2.40 × 10 -4 ), and coded-broad (0.74, p = 8.11 × 10 -7 ). The r g between EHR-based BD definitions ranged from 0.90 to 0.98. These results provide the first genetic validation of automated EHR-based phenotyping for BD and suggest that this approach identifies cases that are highly genetically correlated with those ascertained through conventional methods. High throughput phenotyping using the large data resources available in EHRs represents a viable method for accelerating psychiatric genetic research.

Mutational screening in genes related with porto-pulmonary hypertension: An analysis of 6 cases.

PubMed

Pousada, Guillermo; Baloira, Adolfo; Valverde, Diana

2017-04-07

Portopulmonary hypertension (PPH) is a rare disease with a low incidence and without a clearly-identified genetic component. The aim of this work was to check genes and genetic modifiers related to pulmonary arterial hypertension in patients with PPH in order to clarify the molecular basis of the pathology. We selected a total of 6 patients with PPH and amplified the exonic regions and intronic flanking regions of the relevant genes and regions of interest of the genetic modifiers. Six patients diagnosed with PPH were analyzed and compared to 55 healthy individuals. Potentially-pathogenic mutations were identified in the analyzed genes of 5 patients. None of these mutations, which are highly conserved throughout evolution, were detected in the control patients nor different databases analyzed (1000 Genomes, ExAC and DECIPHER). After analyzing for genetic modifiers, we found different variations that could favor the onset of the disease. The genetic analysis carried out in this small cohort of patients with PPH revealed a large number of mutations, with the ENG gene showing the greatest mutational frequency. Copyright © 2017 Elsevier España, S.L.U. All rights reserved.

Mobilome and genetic modification of bifidobacteria.

PubMed

Guglielmetti, S; Mayo, B; Álvarez-Martín, P

2013-06-01

Until recently, proper development of molecular studies in Bifidobacterium species has been hampered by growth difficulties, because of their exigent nutritive requirements, oxygen sensitivity and lack of efficient genetic tools. These studies, however, are critical to uncover the cross-talk between bifidobacteria and their hosts' cells and to prove unequivocally the supposed beneficial effects provided through the endogenous bifidobacterial populations or after ingestion as probiotics. The genome sequencing projects of different bifidobacterial strains have provided a wealth of genetic data that will be of much help in deciphering the molecular basis of the physiological properties of bifidobacteria. To this end, the purposeful development of stable cloning and expression vectors based on robust replicons - either from temperate phages or resident plasmids - is still needed. This review addresses the current knowledge on the mobile genetic elements of bifidobacteria (prophages, plasmids and transposons) and summarises the different types of vectors already available, together with the transformation procedures for introducing DNA into the cells. It also covers recent molecular studies performed with such vectors and incipient results on the genetic modification of these organisms, establishing the basis that would allow the use of bifidobacteria for future biotechnological applications.

Rooted tRNAomes and evolution of the genetic code

PubMed Central

Pak, Daewoo; Du, Nan; Kim, Yunsoo; Sun, Yanni

2018-01-01

ABSTRACT We advocate for a tRNA- rather than an mRNA-centric model for evolution of the genetic code. The mechanism for evolution of cloverleaf tRNA provides a root sequence for radiation of tRNAs and suggests a simplified understanding of code evolution. To analyze code sectoring, rooted tRNAomes were compared for several archaeal and one bacterial species. Rooting of tRNAome trees reveals conserved structures, indicating how the code was shaped during evolution and suggesting a model for evolution of a LUCA tRNAome tree. We propose the polyglycine hypothesis that the initial product of the genetic code may have been short chain polyglycine to stabilize protocells. In order to describe how anticodons were allotted in evolution, the sectoring-degeneracy hypothesis is proposed. Based on sectoring, a simple stepwise model is developed, in which the code sectors from a 1→4→8→∼16 letter code. At initial stages of code evolution, we posit strong positive selection for wobble base ambiguity, supporting convergence to 4-codon sectors and ∼16 letters. In a later stage, ∼5–6 letters, including stops, were added through innovating at the anticodon wobble position. In archaea and bacteria, tRNA wobble adenine is negatively selected, shrinking the maximum size of the primordial genetic code to 48 anticodons. Because 64 codons are recognized in mRNA, tRNA-mRNA coevolution requires tRNA wobble position ambiguity leading to degeneracy of the code. PMID:29372672

The "periodic table" of the genetic code: A new way to look at the code and the decoding process.

PubMed

Komar, Anton A

2016-01-01

Henri Grosjean and Eric Westhof recently presented an information-rich, alternative view of the genetic code, which takes into account current knowledge of the decoding process, including the complex nature of interactions between mRNA, tRNA and rRNA that take place during protein synthesis on the ribosome, and it also better reflects the evolution of the code. The new asymmetrical circular genetic code has a number of advantages over the traditional codon table and the previous circular diagrams (with a symmetrical/clockwise arrangement of the U, C, A, G bases). Most importantly, all sequence co-variances can be visualized and explained based on the internal logic of the thermodynamics of codon-anticodon interactions.

Deciphering the complete mitochondrial genome and phylogeny of the extinct cave bear in the Paleolithic painted cave of Chauvet.

PubMed

Bon, Céline; Caudy, Nicolas; de Dieuleveult, Maud; Fosse, Philippe; Philippe, Michel; Maksud, Frédéric; Beraud-Colomb, Eliane; Bouzaid, Eric; Kefi, Rym; Laugier, Christelle; Rousseau, Bernard; Casane, Didier; van der Plicht, Johannes; Elalouf, Jean-Marc

2008-11-11

Retrieving a large amount of genetic information from extinct species was demonstrated feasible, but complete mitochondrial genome sequences have only been deciphered for the moa, a bird that became extinct a few hundred years ago, and for Pleistocene species, such as the woolly mammoth and the mastodon, both of which could be studied from animals embedded in permafrost. To enlarge the diversity of mitochondrial genomes available for Pleistocene species, we turned to the cave bear (Ursus spelaeus), whose only remains consist of skeletal elements. We collected bone samples from the Paleolithic painted cave of Chauvet-Pont d'Arc (France), which displays the earliest known human drawings, and contains thousands of bear remains. We selected a cave bear sternebra, radiocarbon dated to 32,000 years before present, from which we generated overlapping DNA fragments assembling into a 16,810-base pair mitochondrial genome. Together with the first mitochondrial genome for the brown bear western lineage, this study provides a statistically secured molecular phylogeny assessing the cave bear as a sister taxon to the brown bear and polar bear clade, with a divergence inferred to 1.6 million years ago. With the first mitochondrial genome for a Pleistocene carnivore to be delivered, our study establishes the Chauvet-Pont d'Arc Cave as a new reservoir for Paleogenetic studies. These molecular data enable establishing the chronology of bear speciation, and provide a helpful resource to rescue for genetic analysis archeological samples initially diagnosed as devoid of amplifiable DNA.

Deciphering the complete mitochondrial genome and phylogeny of the extinct cave bear in the Paleolithic painted cave of Chauvet

PubMed Central

Bon, Céline; Caudy, Nicolas; de Dieuleveult, Maud; Fosse, Philippe; Philippe, Michel; Maksud, Frédéric; Beraud-Colomb, Éliane; Bouzaid, Eric; Kefi, Rym; Laugier, Christelle; Rousseau, Bernard; Casane, Didier; van der Plicht, Johannes; Elalouf, Jean-Marc

2008-01-01

Retrieving a large amount of genetic information from extinct species was demonstrated feasible, but complete mitochondrial genome sequences have only been deciphered for the moa, a bird that became extinct a few hundred years ago, and for Pleistocene species, such as the woolly mammoth and the mastodon, both of which could be studied from animals embedded in permafrost. To enlarge the diversity of mitochondrial genomes available for Pleistocene species, we turned to the cave bear (Ursus spelaeus), whose only remains consist of skeletal elements. We collected bone samples from the Paleolithic painted cave of Chauvet-Pont d'Arc (France), which displays the earliest known human drawings, and contains thousands of bear remains. We selected a cave bear sternebra, radiocarbon dated to 32,000 years before present, from which we generated overlapping DNA fragments assembling into a 16,810-base pair mitochondrial genome. Together with the first mitochondrial genome for the brown bear western lineage, this study provides a statistically secured molecular phylogeny assessing the cave bear as a sister taxon to the brown bear and polar bear clade, with a divergence inferred to 1.6 million years ago. With the first mitochondrial genome for a Pleistocene carnivore to be delivered, our study establishes the Chauvet-Pont d'Arc Cave as a new reservoir for Paleogenetic studies. These molecular data enable establishing the chronology of bear speciation, and provide a helpful resource to rescue for genetic analysis archeological samples initially diagnosed as devoid of amplifiable DNA. PMID:18955696

A median third eye: pineal gland retraces evolution of vertebrate photoreceptive organs.

PubMed

Mano, Hiroaki; Fukada, Yoshitaka

2007-01-01

In many vertebrates, the pineal gland serves as a photoreceptive neuroendocrine organ. Morphological and functional similarities between the pineal and retinal photoreceptor cells indicate their close evolutionary relationship, and hence the comparative studies on the pineal gland and the retina are the keys to deciphering the evolutionary traces of the vertebrate photoreceptive organs. Several studies have suggested common genetic and molecular mechanisms responsible for their similarities, but largely unknown are those underlying pineal-specific development and physiological functions. Recent studies have identified several cis-acting DNA elements that participate in transcriptional control of the pineal-specific genes. Genetic approaches in the zebrafish have also contributed to elucidating the genetic network regulating the pineal development and neurogenesis. These efforts toward elucidating the molecular instrumentation intrinsic to the pineal gland, back to back with those to the retina, should lead to a comprehensive understanding of the evolutionary history of the vertebrate photoreceptive structures. This article summarizes the current status of research on these topics.

Cole Disease Results from Mutations in ENPP1.

PubMed

Eytan, Ori; Morice-Picard, Fanny; Sarig, Ofer; Ezzedine, Khaled; Isakov, Ofer; Li, Qiaoli; Ishida-Yamamoto, Akemi; Shomron, Noam; Goldsmith, Tomer; Fuchs-Telem, Dana; Adir, Noam; Uitto, Jouni; Orlow, Seth J; Taieb, Alain; Sprecher, Eli

2013-10-03

The coexistence of abnormal keratinization and aberrant pigmentation in a number of cornification disorders has long suggested a mechanistic link between these two processes. Here, we deciphered the genetic basis of Cole disease, a rare autosomal-dominant genodermatosis featuring punctate keratoderma, patchy hypopigmentation, and uncommonly, cutaneous calcifications. Using a combination of exome and direct sequencing, we showed complete cosegregation of the disease phenotype with three heterozygous ENPP1 mutations in three unrelated families. All mutations were found to affect cysteine residues in the somatomedin-B-like 2 (SMB2) domain in the encoded protein, which has been implicated in insulin signaling. ENPP1 encodes ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), which is responsible for the generation of inorganic pyrophosphate, a natural inhibitor of mineralization. Previously, biallelic mutations in ENPP1 were shown to underlie a number of recessive conditions characterized by ectopic calcification, thus providing evidence of profound phenotypic heterogeneity in ENPP1-associated genetic diseases. Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Severe Cutaneous Adverse Reactions: The Pharmacogenomics from Research to Clinical Implementation

PubMed Central

Su, Shih-Chi; Hung, Shuen-Iu; Fan, Wen-Lang; Dao, Ro-Lan; Chung, Wen-Hung

2016-01-01

Severe cutaneous adverse reactions (SCARs), previously thought to be idiosyncratic or unpredictable, are a deadly form of adverse drug reactions with skin manifestations. Current pharmacogenomic studies of SCARs have made important strides, as the prevention of SCARs, to some extent, appears attainable with the identification of genetic variants for genes encoding drug-metabolizing enzymes and human leukocyte antigens (HLAs). Despite the improvement of incidence, a treatment guideline for this devastating condition is still unavailable, highlighting the inadequacy of contemporary accepted therapeutic interventions. As such, prompt withdrawal of causative drugs is believed to be a priority of patient management. In this review, we discuss recent cutting-edge findings concerning the discovery of biomarkers for SCARs and their clinical utilities in the better prediction and early diagnosis of this disease. The knowledge compiled herein provides clues for future investigations on deciphering additional genetic markers for SCARs and the design of clinical trials for the prospective identification of subjects at genetic risk for this condition, ultimately personalizing the medicine. PMID:27854302

Unraveling the mechanisms of synapse formation and axon regeneration: the awesome power of C. elegans genetics.

PubMed

Jin, YiShi

2015-11-01

Since Caenorhabditis elegans was chosen as a model organism by Sydney Brenner in 1960's, genetic studies in this organism have been instrumental in discovering the function of genes and in deciphering molecular signaling network. The small size of the organism and the simple nervous system enable the complete reconstruction of the first connectome. The stereotypic developmental program and the anatomical reproducibility of synaptic connections provide a blueprint to dissect the mechanisms underlying synapse formation. Recent technological innovation using laser surgery of single axons and in vivo imaging has also made C. elegans a new model for axon regeneration. Importantly, genes regulating synaptogenesis and axon regeneration are highly conserved in function across animal phyla. This mini-review will summarize the main approaches and the key findings in understanding the mechanisms underlying the development and maintenance of the nervous system. The impact of such findings underscores the awesome power of C. elegans genetics.

Impact of genetic features on treatment decisions in AML.

PubMed

Döhner, Hartmut; Gaidzik, Verena I

2011-01-01

In recent years, research in molecular genetics has been instrumental in deciphering the molecular pathogenesis of acute myeloid leukemia (AML). With the advent of the novel genomics technologies such as next-generation sequencing, it is expected that virtually all genetic lesions in AML will soon be identified. Gene mutations or deregulated expression of genes or sets of genes now allow us to explore the enormous diversity among cytogenetically defined subsets of AML, in particular the large subset of cytogenetically normal AML. Nonetheless, there are several challenges, such as discriminating driver from passenger mutations, evaluating the prognostic and predictive value of a specific mutation in the concert of the various concurrent mutations, or translating findings from molecular disease pathogenesis into novel therapies. Progress is unlikely to be fast in developing molecular targeted therapies. Contrary to the initial assumption, the development of molecular targeted therapies is slow and the various reports of promising new compounds will need to be put into perspective because many of these drugs did not show the expected effects.

Toward Molecular Level of the “Salmonella-Victim” Ecology, Genetics, and Evolution

PubMed Central

Rumyantsev, S.N.

2004-01-01

Bacteria of the Salmonella genus are polypathogenic agents that can affect both men and animals, causing devastating and fatal illness. Despite considerable immunological, epidemiological, and genetic efforts, and increased understanding of how the Salmonella infection develops, many key questions concerning Salmonella infection remain unanswered. Salmonella can be carried as harmless commensals in some sectors of the population. In some individuals, however, the same microbes cause illness while others display immunity to primary Salmonella infection. Nothing is known about the molecular base of the Salmonella pathogenicity. Even the ability of Salmonella to destroy the victims cells has been the subject of century-long discussions. In this article, some key findings concerning ecology, molecular ecology, and cell level of the Salmonella infection genetics are summarized and interpreted from the viewpoint of evolutionary theory with certitude that this approach can help to decipher the undiscovered secrets of Salmonella infections epidemiology and pathogenesis, as well as the clinical course and severity, and to select ways for fighting against Salmonella. PMID:15105959

Reconstruction of DNA sequences using genetic algorithms and cellular automata: towards mutation prediction?

PubMed

Mizas, Ch; Sirakoulis, G Ch; Mardiris, V; Karafyllidis, I; Glykos, N; Sandaltzopoulos, R

2008-04-01

Change of DNA sequence that fuels evolution is, to a certain extent, a deterministic process because mutagenesis does not occur in an absolutely random manner. So far, it has not been possible to decipher the rules that govern DNA sequence evolution due to the extreme complexity of the entire process. In our attempt to approach this issue we focus solely on the mechanisms of mutagenesis and deliberately disregard the role of natural selection. Hence, in this analysis, evolution refers to the accumulation of genetic alterations that originate from mutations and are transmitted through generations without being subjected to natural selection. We have developed a software tool that allows modelling of a DNA sequence as a one-dimensional cellular automaton (CA) with four states per cell which correspond to the four DNA bases, i.e. A, C, T and G. The four states are represented by numbers of the quaternary number system. Moreover, we have developed genetic algorithms (GAs) in order to determine the rules of CA evolution that simulate the DNA evolution process. Linear evolution rules were considered and square matrices were used to represent them. If DNA sequences of different evolution steps are available, our approach allows the determination of the underlying evolution rule(s). Conversely, once the evolution rules are deciphered, our tool may reconstruct the DNA sequence in any previous evolution step for which the exact sequence information was unknown. The developed tool may be used to test various parameters that could influence evolution. We describe a paradigm relying on the assumption that mutagenesis is governed by a near-neighbour-dependent mechanism. Based on the satisfactory performance of our system in the deliberately simplified example, we propose that our approach could offer a starting point for future attempts to understand the mechanisms that govern evolution. The developed software is open-source and has a user-friendly graphical input interface.

Synthetic alienation of microbial organisms by using genetic code engineering: Why and how?

PubMed

Kubyshkin, Vladimir; Budisa, Nediljko

2017-08-01

The main goal of synthetic biology (SB) is the creation of biodiversity applicable for biotechnological needs, while xenobiology (XB) aims to expand the framework of natural chemistries with the non-natural building blocks in living cells to accomplish artificial biodiversity. Protein and proteome engineering, which overcome limitation of the canonical amino acid repertoire of 20 (+2) prescribed by the genetic code by using non-canonic amino acids (ncAAs), is one of the main focuses of XB research. Ideally, estranging the genetic code from its current form via systematic introduction of ncAAs should enable the development of bio-containment mechanisms in synthetic cells potentially endowing them with a "genetic firewall" i.e. orthogonality which prevents genetic information transfer to natural systems. Despite rapid progress over the past two decades, it is not yet possible to completely alienate an organism that would use and maintain different genetic code associations permanently. In order to engineer robust bio-contained life forms, the chemical logic behind the amino acid repertoire establishment should be considered. Starting from recent proposal of Hartman and Smith about the genetic code establishment in the RNA world, here the authors mapped possible biotechnological invasion points for engineering of bio-contained synthetic cells equipped with non-canonical functionalities. Copyright © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Problem-Based Test: An "In Vitro" Experiment to Analyze the Genetic Code

ERIC Educational Resources Information Center

Szeberenyi, Jozsef

2010-01-01

Terms to be familiar with before you start to solve the test: genetic code, translation, synthetic polynucleotide, leucine, serine, filter precipitation, radioactivity measurement, template, mRNA, tRNA, rRNA, aminoacyl-tRNA synthesis, ribosomes, degeneration of the code, wobble, initiation, and elongation of protein synthesis, initiation codon.…

Deciphering the glycosaminoglycan code with the help of microarrays.

PubMed

de Paz, Jose L; Seeberger, Peter H

2008-07-01

Carbohydrate microarrays have become a powerful tool to elucidate the biological role of complex sugars. Microarrays are particularly useful for the study of glycosaminoglycans (GAGs), a key class of carbohydrates. The high-throughput chip format enables rapid screening of large numbers of potential GAG sequences produced via a complex biosynthesis while consuming very little sample. Here, we briefly highlight the most recent advances involving GAG microarrays built with synthetic or naturally derived oligosaccharides. These chips are powerful tools for characterizing GAG-protein interactions and determining structure-activity relationships for specific sequences. Thereby, they contribute to decoding the information contained in specific GAG sequences.

Tests of various colorants for application of a Fourier transform infrared imaging system to deciphering obliterated writings

NASA Astrophysics Data System (ADS)

Sugawara, Shigeru

2015-10-01

Obliterated writing is writing that has been obscured by different-colored materials. There are obliterated writings that cannot be detected by conventional methods. A method for deciphering such obliterated writings was developed in this study. Mid-infrared spectroscopic imaging in the wavelength range of 2.5-14 μm was used for deciphering because the infrared spectrum differs among different brands of colorants. Obliterated writings were made by pressing information protection stamps onto characters written by 4 kinds of colorants. The samples were tested for deciphering by the Fourier-transform infrared imaging system. Two peak areas of two specific wavenumber regions of each reflectance spectrum were calculated and the ratio of the two values is displayed as a unique gray scale in the spectroscopic image. As a result, the absorption peak at various wavenumbers could be used to decipher obliterated writings that could not be detected by the conventional methods. Ten different parameters for deciphering obliterated writing were found in this study.

An extension of the coevolution theory of the origin of the genetic code

PubMed Central

Di Giulio, Massimo

2008-01-01

Background The coevolution theory of the origin of the genetic code suggests that the genetic code is an imprint of the biosynthetic relationships between amino acids. However, this theory does not seem to attribute a role to the biosynthetic relationships between the earliest amino acids that evolved along the pathways of energetic metabolism. As a result, the coevolution theory is unable to clearly define the very earliest phases of genetic code origin. In order to remove this difficulty, I here suggest an extension of the coevolution theory that attributes a crucial role to the first amino acids that evolved along these biosynthetic pathways and to their biosynthetic relationships, even when defined by the non-amino acid molecules that are their precursors. Results It is re-observed that the first amino acids to evolve along these biosynthetic pathways are predominantly those codified by codons of the type GNN, and this observation is found to be statistically significant. Furthermore, the close biosynthetic relationships between the sibling amino acids Ala-Ser, Ser-Gly, Asp-Glu, and Ala-Val are not random in the genetic code table and reinforce the hypothesis that the biosynthetic relationships between these six amino acids played a crucial role in defining the very earliest phases of genetic code origin. Conclusion All this leads to the hypothesis that there existed a code, GNS, reflecting the biosynthetic relationships between these six amino acids which, as it defines the very earliest phases of genetic code origin, removes the main difficulty of the coevolution theory. Furthermore, it is here discussed how this code might have naturally led to the code codifying only for the domains of the codons of precursor amino acids, as predicted by the coevolution theory. Finally, the hypothesis here suggested also removes other problems of the coevolution theory, such as the existence for certain pairs of amino acids with an unclear biosynthetic relationship between the precursor and product amino acids and the collocation of Ala between the amino acids Val and Leu belonging to the pyruvate biosynthetic family, which the coevolution theory considered as belonging to different biosyntheses. Reviewers This article was reviewed by Rob Knight, Paul Higgs (nominated by Laura Landweber), and Eugene Koonin. PMID:18775066

Evolvix BEST Names for semantic reproducibility across code2brain interfaces.

PubMed

Loewe, Laurence; Scheuer, Katherine S; Keel, Seth A; Vyas, Vaibhav; Liblit, Ben; Hanlon, Bret; Ferris, Michael C; Yin, John; Dutra, Inês; Pietsch, Anthony; Javid, Christine G; Moog, Cecilia L; Meyer, Jocelyn; Dresel, Jerdon; McLoone, Brian; Loberger, Sonya; Movaghar, Arezoo; Gilchrist-Scott, Morgaine; Sabri, Yazeed; Sescleifer, Dave; Pereda-Zorrilla, Ivan; Zietlow, Andrew; Smith, Rodrigo; Pietenpol, Samantha; Goldfinger, Jacob; Atzen, Sarah L; Freiberg, Erika; Waters, Noah P; Nusbaum, Claire; Nolan, Erik; Hotz, Alyssa; Kliman, Richard M; Mentewab, Ayalew; Fregien, Nathan; Loewe, Martha

2017-01-01

Names in programming are vital for understanding the meaning of code and big data. We define code2brain (C2B) interfaces as maps in compilers and brains between meaning and naming syntax, which help to understand executable code. While working toward an Evolvix syntax for general-purpose programming that makes accurate modeling easy for biologists, we observed how names affect C2B quality. To protect learning and coding investments, C2B interfaces require long-term backward compatibility and semantic reproducibility (accurate reproduction of computational meaning from coder-brains to reader-brains by code alone). Semantic reproducibility is often assumed until confusing synonyms degrade modeling in biology to deciphering exercises. We highlight empirical naming priorities from diverse individuals and roles of names in different modes of computing to show how naming easily becomes impossibly difficult. We present the Evolvix BEST (Brief, Explicit, Summarizing, Technical) Names concept for reducing naming priority conflicts, test it on a real challenge by naming subfolders for the Project Organization Stabilizing Tool system, and provide naming questionnaires designed to facilitate C2B debugging by improving names used as keywords in a stabilizing programming language. Our experiences inspired us to develop Evolvix using a flipped programming language design approach with some unexpected features and BEST Names at its core. © 2016 The Authors. Annals of the New York Academy of Sciences published by Wiley Periodicals, Inc. on behalf of New York Academy of Sciences.

Refactoring the Genetic Code for Increased Evolvability

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pines, Gur; Winkler, James D.; Pines, Assaf

ABSTRACT The standard genetic code is robust to mutations during transcription and translation. Point mutations are likely to be synonymous or to preserve the chemical properties of the original amino acid. Saturation mutagenesis experiments suggest that in some cases the best-performing mutant requires replacement of more than a single nucleotide within a codon. These replacements are essentially inaccessible to common error-based laboratory engineering techniques that alter a single nucleotide per mutation event, due to the extreme rarity of adjacent mutations. In this theoretical study, we suggest a radical reordering of the genetic code that maximizes the mutagenic potential of singlemore » nucleotide replacements. We explore several possible genetic codes that allow a greater degree of accessibility to the mutational landscape and may result in a hyperevolvable organism that could serve as an ideal platform for directed evolution experiments. We then conclude by evaluating the challenges of constructing such recoded organisms and their potential applications within the field of synthetic biology. IMPORTANCE The conservative nature of the genetic code prevents bioengineers from efficiently accessing the full mutational landscape of a gene via common error-prone methods. Here, we present two computational approaches to generate alternative genetic codes with increased accessibility. These new codes allow mutational transitions to a larger pool of amino acids and with a greater extent of chemical differences, based on a single nucleotide replacement within the codon, thus increasing evolvability both at the single-gene and at the genome levels. Given the widespread use of these techniques for strain and protein improvement, along with more fundamental evolutionary biology questions, the use of recoded organisms that maximize evolvability should significantly improve the efficiency of directed evolution, library generation, and fitness maximization.« less

Refactoring the Genetic Code for Increased Evolvability

DOE PAGES

Pines, Gur; Winkler, James D.; Pines, Assaf; ...

2017-11-14

ABSTRACT The standard genetic code is robust to mutations during transcription and translation. Point mutations are likely to be synonymous or to preserve the chemical properties of the original amino acid. Saturation mutagenesis experiments suggest that in some cases the best-performing mutant requires replacement of more than a single nucleotide within a codon. These replacements are essentially inaccessible to common error-based laboratory engineering techniques that alter a single nucleotide per mutation event, due to the extreme rarity of adjacent mutations. In this theoretical study, we suggest a radical reordering of the genetic code that maximizes the mutagenic potential of singlemore » nucleotide replacements. We explore several possible genetic codes that allow a greater degree of accessibility to the mutational landscape and may result in a hyperevolvable organism that could serve as an ideal platform for directed evolution experiments. We then conclude by evaluating the challenges of constructing such recoded organisms and their potential applications within the field of synthetic biology. IMPORTANCE The conservative nature of the genetic code prevents bioengineers from efficiently accessing the full mutational landscape of a gene via common error-prone methods. Here, we present two computational approaches to generate alternative genetic codes with increased accessibility. These new codes allow mutational transitions to a larger pool of amino acids and with a greater extent of chemical differences, based on a single nucleotide replacement within the codon, thus increasing evolvability both at the single-gene and at the genome levels. Given the widespread use of these techniques for strain and protein improvement, along with more fundamental evolutionary biology questions, the use of recoded organisms that maximize evolvability should significantly improve the efficiency of directed evolution, library generation, and fitness maximization.« less

From gene engineering to gene modulation and manipulation: can we prevent or detect gene doping in sports?

PubMed

Fischetto, Giuseppe; Bermon, Stéphane

2013-10-01

During the last 2 decades, progress in deciphering the human gene map as well as the discovery of specific defective genes encoding particular proteins in some serious human diseases have resulted in attempts to treat sick patients with gene therapy. There has been considerable focus on human recombinant proteins which were gene-engineered and produced in vitro (insulin, growth hormone, insulin-like growth factor-1, erythropoietin). Unfortunately, these substances and methods also became improper tools for unscrupulous athletes. Biomedical research has focused on the possible direct insertion of gene material into the body, in order to replace some defective genes in vivo and/or to promote long-lasting endogenous synthesis of deficient proteins. Theoretically, diabetes, anaemia, muscular dystrophies, immune deficiency, cardiovascular diseases and numerous other illnesses could benefit from such innovative biomedical research, though much work remains to be done. Considering recent findings linking specific genotypes and physical performance, it is tempting to submit the young athletic population to genetic screening or, alternatively, to artificial gene expression modulation. Much research is already being conducted in order to achieve a safe transfer of genetic material to humans. This is of critical importance since uncontrolled production of the specifically coded protein, with serious secondary adverse effects (polycythaemia, acute cardiovascular problems, cancer, etc.), could occur. Other unpredictable reactions (immunogenicity of vectors or DNA-vector complex, autoimmune anaemia, production of wild genetic material) also remain possible at the individual level. Some new substances (myostatin blockers or anti-myostatin antibodies), although not gene material, might represent a useful and well-tolerated treatment to prevent progression of muscular dystrophies. Similarly, other molecules, in the roles of gene or metabolic activators [5-aminoimidazole-4-carboxamide 1-β-D-ribofuranoside (AICAR), GW1516], might concomitantly improve endurance exercise capacity in ischaemic conditions but also in normal conditions. Undoubtedly, some athletes will attempt to take advantage of these new molecules to increase strength or endurance. Antidoping laboratories are improving detection methods. These are based both on direct identification of new substances or their metabolites and on indirect evaluation of changes in gene, protein or metabolite patterns (genomics, proteomics or metabolomics).

A comparative genomics perspective on the genetic content of the alkaliphilic haloarchaeon Natrialba magadii ATCC 43099T

PubMed Central

2012-01-01

Background Natrialba magadii is an aerobic chemoorganotrophic member of the Euryarchaeota and is a dual extremophile requiring alkaline conditions and hypersalinity for optimal growth. The genome sequence of Nab. magadii type strain ATCC 43099 was deciphered to obtain a comprehensive insight into the genetic content of this haloarchaeon and to understand the basis of some of the cellular functions necessary for its survival. Results The genome of Nab. magadii consists of four replicons with a total sequence of 4,443,643 bp and encodes 4,212 putative proteins, some of which contain peptide repeats of various lengths. Comparative genome analyses facilitated the identification of genes encoding putative proteins involved in adaptation to hypersalinity, stress response, glycosylation, and polysaccharide biosynthesis. A proton-driven ATP synthase and a variety of putative cytochromes and other proteins supporting aerobic respiration and electron transfer were encoded by one or more of Nab. magadii replicons. The genome encodes a number of putative proteases/peptidases as well as protein secretion functions. Genes encoding putative transcriptional regulators, basal transcription factors, signal perception/transduction proteins, and chemotaxis/phototaxis proteins were abundant in the genome. Pathways for the biosynthesis of thiamine, riboflavin, heme, cobalamin, coenzyme F420 and other essential co-factors were deduced by in depth sequence analyses. However, approximately 36% of Nab. magadii protein coding genes could not be assigned a function based on Blast analysis and have been annotated as encoding hypothetical or conserved hypothetical proteins. Furthermore, despite extensive comparative genomic analyses, genes necessary for survival in alkaline conditions could not be identified in Nab. magadii. Conclusions Based on genomic analyses, Nab. magadii is predicted to be metabolically versatile and it could use different carbon and energy sources to sustain growth. Nab. magadii has the genetic potential to adapt to its milieu by intracellular accumulation of inorganic cations and/or neutral organic compounds. The identification of Nab. magadii genes involved in coenzyme biosynthesis is a necessary step toward further reconstruction of the metabolic pathways in halophilic archaea and other extremophiles. The knowledge gained from the genome sequence of this haloalkaliphilic archaeon is highly valuable in advancing the applications of extremophiles and their enzymes. PMID:22559199

Deciphering mechanisms underlying the genetic variation of general production and liver quality traits in the overfed mule duck by pQTL analyses.

PubMed

François, Yoannah; Vignal, Alain; Molette, Caroline; Marty-Gasset, Nathalie; Davail, Stéphane; Liaubet, Laurence; Marie-Etancelin, Christel

2017-04-19

The aim of this study was to analyse the mechanisms that underlie phenotypic quantitative trait loci (QTL) in overfed mule ducks by identifying co-localized proteomic QTL (pQTL). The QTL design consisted of three families of common ducks that were progeny-tested by using 294 male mule ducks. This population of common ducks was genotyped using a genetic map that included 334 genetic markers located across 28 APL chromosomes (APL for Anas platyrhynchos). Mule ducks were phenotyped for 49 traits related to growth, metabolism, overfeeding ability and meat and fatty liver quality, and 326 soluble fatty liver proteins were quantified. One hundred and seventy-six pQTL and 80 phenotypic QTL were detected at the 5% chromosome-wide significance threshold. The great majority of the identified pQTL were trans-acting and localized on a chromosome other than that carrying the coding gene. The most significant pQTL (1% genome-wide significance) were found for alpha-enolase on APL18 and fatty acid synthase on APL24. Some proteins were associated with numerous pQTL (for example, 17 and 14 pQTL were detected for alpha-enolase and apolipoprotein A1, respectively) and pQTL hotspots were observed on some chromosomes (APL18, 24, 25 and 29). We detected 66 co-localized phenotypic QTL and pQTL for which the significance of the two-trait QTL (2t-QTL) analysis was higher than that of the strongest QTL using a single-trait approach. Among these, 16 2t-QTL were pleiotropic. For example, on APL15, melting rate and abundance of two alpha-enolase spots appeared to be impacted by a single locus that is involved in the glycolytic process. On APLZ, we identified a pleiotropic QTL that modified both the blood level of glucose at the beginning of the force-feeding period and the concentration of glutamate dehydrogenase, which, in humans, is involved in increased glucose absorption by the liver when the glutamate dehydrogenase 1 gene is mutated. We identified pleiotropic loci that affect metabolic pathways linked to glycolysis or lipogenesis, and in the end to fatty liver quality. Further investigation, via transcriptomics and metabolomics approaches, is required to confirm the biomarkers that were found to impact the genetic variability of these phenotypic traits.

Mitochondrial genetic codes evolve to match amino acid requirements of proteins.

PubMed

Swire, Jonathan; Judson, Olivia P; Burt, Austin

2005-01-01

Mitochondria often use genetic codes different from the standard genetic code. Now that many mitochondrial genomes have been sequenced, these variant codes provide the first opportunity to examine empirically the processes that produce new genetic codes. The key question is: Are codon reassignments the sole result of mutation and genetic drift? Or are they the result of natural selection? Here we present an analysis of 24 phylogenetically independent codon reassignments in mitochondria. Although the mutation-drift hypothesis can explain reassignments from stop to an amino acid, we found that it cannot explain reassignments from one amino acid to another. In particular--and contrary to the predictions of the mutation-drift hypothesis--the codon involved in such a reassignment was not rare in the ancestral genome. Instead, such reassignments appear to take place while the codon is in use at an appreciable frequency. Moreover, the comparison of inferred amino acid usage in the ancestral genome with the neutral expectation shows that the amino acid gaining the codon was selectively favored over the amino acid losing the codon. These results are consistent with a simple model of weak selection on the amino acid composition of proteins in which codon reassignments are selected because they compensate for multiple slightly deleterious mutations throughout the mitochondrial genome. We propose that the selection pressure is for reduced protein synthesis cost: most reassignments give amino acids that are less expensive to synthesize. Taken together, our results strongly suggest that mitochondrial genetic codes evolve to match the amino acid requirements of proteins.

PheProb: probabilistic phenotyping using diagnosis codes to improve power for genetic association studies.

PubMed

Sinnott, Jennifer A; Cai, Fiona; Yu, Sheng; Hejblum, Boris P; Hong, Chuan; Kohane, Isaac S; Liao, Katherine P

2018-05-17

Standard approaches for large scale phenotypic screens using electronic health record (EHR) data apply thresholds, such as ≥2 diagnosis codes, to define subjects as having a phenotype. However, the variation in the accuracy of diagnosis codes can impair the power of such screens. Our objective was to develop and evaluate an approach which converts diagnosis codes into a probability of a phenotype (PheProb). We hypothesized that this alternate approach for defining phenotypes would improve power for genetic association studies. The PheProb approach employs unsupervised clustering to separate patients into 2 groups based on diagnosis codes. Subjects are assigned a probability of having the phenotype based on the number of diagnosis codes. This approach was developed using simulated EHR data and tested in a real world EHR cohort. In the latter, we tested the association between low density lipoprotein cholesterol (LDL-C) genetic risk alleles known for association with hyperlipidemia and hyperlipidemia codes (ICD-9 272.x). PheProb and thresholding approaches were compared. Among n = 1462 subjects in the real world EHR cohort, the threshold-based p-values for association between the genetic risk score (GRS) and hyperlipidemia were 0.126 (≥1 code), 0.123 (≥2 codes), and 0.142 (≥3 codes). The PheProb approach produced the expected significant association between the GRS and hyperlipidemia: p = .001. PheProb improves statistical power for association studies relative to standard thresholding approaches by leveraging information about the phenotype in the billing code counts. The PheProb approach has direct applications where efficient approaches are required, such as in Phenome-Wide Association Studies.

Experimental studies related to the origin of the genetic code and the process of protein synthesis - A review

NASA Technical Reports Server (NTRS)

Lacey, J. C., Jr.; Mullins, D. W., Jr.

1983-01-01

A survey is presented of the literature on the experimental evidence for the genetic code assignments and the chemical reactions involved in the process of protein synthesis. In view of the enormous number of theoretical models that have been advanced to explain the origin of the genetic code, attention is confined to experimental studies. Since genetic coding has significance only within the context of protein synthesis, it is believed that the problem of the origin of the code must be dealt with in terms of the origin of the process of protein synthesis. It is contended that the answers must lie in the nature of the molecules, amino acids and nucleotides, the affinities they might have for one another, and the effect that those affinities must have on the chemical reactions that are related to primitive protein synthesis. The survey establishes that for the bulk of amino acids, there is a direct and significant correlation between the hydrophobicity rank of the amino acids and the hydrophobicity rank of their anticodonic dinucleotides.

The role of crossover operator in evolutionary-based approach to the problem of genetic code optimization.

PubMed

Błażej, Paweł; Wnȩtrzak, Małgorzata; Mackiewicz, Paweł

2016-12-01

One of theories explaining the present structure of canonical genetic code assumes that it was optimized to minimize harmful effects of amino acid replacements resulting from nucleotide substitutions and translational errors. A way to testify this concept is to find the optimal code under given criteria and compare it with the canonical genetic code. Unfortunately, the huge number of possible alternatives makes it impossible to find the optimal code using exhaustive methods in sensible time. Therefore, heuristic methods should be applied to search the space of possible solutions. Evolutionary algorithms (EA) seem to be ones of such promising approaches. This class of methods is founded both on mutation and crossover operators, which are responsible for creating and maintaining the diversity of candidate solutions. These operators possess dissimilar characteristics and consequently play different roles in the process of finding the best solutions under given criteria. Therefore, the effective searching for the potential solutions can be improved by applying both of them, especially when these operators are devised specifically for a given problem. To study this subject, we analyze the effectiveness of algorithms for various combinations of mutation and crossover probabilities under three models of the genetic code assuming different restrictions on its structure. To achieve that, we adapt the position based crossover operator for the most restricted model and develop a new type of crossover operator for the more general models. The applied fitness function describes costs of amino acid replacement regarding their polarity. Our results indicate that the usage of crossover operators can significantly improve the quality of the solutions. Moreover, the simulations with the crossover operator optimize the fitness function in the smaller number of generations than simulations without this operator. The optimal genetic codes without restrictions on their structure minimize the costs about 2.7 times better than the canonical genetic code. Interestingly, the optimal codes are dominated by amino acids characterized by polarity close to its average value for all amino acids. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Genome-wide SNPs reveal the drivers of gene flow in an urban population of the Asian Tiger Mosquito, Aedes albopictus.

PubMed

Schmidt, Thomas L; Rašić, Gordana; Zhang, Dongjing; Zheng, Xiaoying; Xi, Zhiyong; Hoffmann, Ary A

2017-10-01

Aedes albopictus is a highly invasive disease vector with an expanding worldwide distribution. Genetic assays using low to medium resolution markers have found little evidence of spatial genetic structure even at broad geographic scales, suggesting frequent passive movement along human transportation networks. Here we analysed genetic structure of Aedes albopictus collected from 12 sample sites in Guangzhou, China, using thousands of genome-wide single nucleotide polymorphisms (SNPs). We found evidence for passive gene flow, with distance from shipping terminals being the strongest predictor of genetic distance among mosquitoes. As further evidence of passive dispersal, we found multiple pairs of full-siblings distributed between two sample sites 3.7 km apart. After accounting for geographical variability, we also found evidence for isolation by distance, previously undetectable in Ae. albopictus. These findings demonstrate how large SNP datasets and spatially-explicit hypothesis testing can be used to decipher processes at finer geographic scales than formerly possible. Our approach can be used to help predict new invasion pathways of Ae. albopictus and to refine strategies for vector control that involve the transformation or suppression of mosquito populations.

Genetic Markers of Cardiovascular Disease in Rheumatoid Arthritis

PubMed Central

Rodríguez-Rodríguez, Luis; López-Mejías, Raquel; García-Bermúdez, Mercedes; González-Juanatey, Carlos; González-Gay, Miguel A.; Martín, Javier

2012-01-01

Cardiovascular (CV) disease is the most common cause of premature mortality in patients with rheumatoid arthritis (RA). It is the result of an accelerated atherosclerotic process. Both RA and atherosclerosis are complex polygenic diseases. Besides traditional CV risk factors and chronic inflammation, a number of studies have confirmed the role of genetic factors in the development of the atherogenesis observed in RA. In this regard, besides a strong association between the HLA-DRB1∗04 shared epitope alleles and both endothelial dysfunction, an early step in the atherosclerotic process, and clinically evident CV disease, other polymorphisms belonging to genes implicated in inflammatory and metabolic pathways, located inside and outside the HLA region, such as the 308 variant (G > A, rs1800629) of the TNFA locus, the rs1801131 polymorphism (A > C; position + 1298) of the MTHFR locus, or a deletion of 32 base pairs on the CCR5 gene, seem to be associated with the risk of CV disease in patients with RA. Despite considerable effort to decipher the genetic basis of CV disease in RA, further studies are required to better establish the genetic influence in the increased risk of CV events observed in patients with RA. PMID:22927710

Real coded genetic algorithm for fuzzy time series prediction

NASA Astrophysics Data System (ADS)

Jain, Shilpa; Bisht, Dinesh C. S.; Singh, Phool; Mathpal, Prakash C.

2017-10-01

Genetic Algorithm (GA) forms a subset of evolutionary computing, rapidly growing area of Artificial Intelligence (A.I.). Some variants of GA are binary GA, real GA, messy GA, micro GA, saw tooth GA, differential evolution GA. This research article presents a real coded GA for predicting enrollments of University of Alabama. Data of Alabama University is a fuzzy time series. Here, fuzzy logic is used to predict enrollments of Alabama University and genetic algorithm optimizes fuzzy intervals. Results are compared to other eminent author works and found satisfactory, and states that real coded GA are fast and accurate.

CRISPR/Cas9-loxP-Mediated Gene Editing as a Novel Site-Specific Genetic Manipulation Tool.

PubMed

Yang, Fayu; Liu, Changbao; Chen, Ding; Tu, Mengjun; Xie, Haihua; Sun, Huihui; Ge, Xianglian; Tang, Lianchao; Li, Jin; Zheng, Jiayong; Song, Zongming; Qu, Jia; Gu, Feng

2017-06-16

Cre-loxP, as one of the site-specific genetic manipulation tools, offers a method to study the spatial and temporal regulation of gene expression/inactivation in order to decipher gene function. CRISPR/Cas9-mediated targeted genome engineering technologies are sparking a new revolution in biological research. Whether the traditional site-specific genetic manipulation tool and CRISPR/Cas9 could be combined to create a novel genetic tool for highly specific gene editing is not clear. Here, we successfully generated a CRISPR/Cas9-loxP system to perform gene editing in human cells, providing the proof of principle that these two technologies can be used together for the first time. We also showed that distinct non-homologous end-joining (NHEJ) patterns from CRISPR/Cas9-mediated gene editing of the targeting sequence locates at the level of plasmids (episomal) and chromosomes. Specially, the CRISPR/Cas9-mediated NHEJ pattern in the nuclear genome favors deletions (64%-68% at the human AAVS1 locus versus 4%-28% plasmid DNA). CRISPR/Cas9-loxP, a novel site-specific genetic manipulation tool, offers a platform for the dissection of gene function and molecular insights into DNA-repair pathways. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

The genetic regulatory network centered on Pto-Wuschela and its targets involved in wood formation revealed by association studies.

PubMed

Yang, Xiaohui; Wei, Zunzheng; Du, Qingzhang; Chen, Jinhui; Wang, Qingshi; Quan, Mingyang; Song, Yuepeng; Xie, Jianbo; Zhang, Deqiang

2015-11-09

Transcription factors (TFs) regulate gene expression and can strongly affect phenotypes. However, few studies have examined TF variants and TF interactions with their targets in plants. Here, we used genetic association in 435 unrelated individuals of Populus tomentosa to explore the variants in Pto-Wuschela and its targets to decipher the genetic regulatory network of Pto-Wuschela. Our bioinformatics and co-expression analysis identified 53 genes with the motif TCACGTGA as putative targets of Pto-Wuschela. Single-marker association analysis showed that Pto-Wuschela was associated with wood properties, which is in agreement with the observation that it has higher expression in stem vascular tissues in Populus. Also, SNPs in the 53 targets were associated with growth or wood properties under additive or dominance effects, suggesting these genes and Pto-Wuschela may act in the same genetic pathways that affect variation in these quantitative traits. Epistasis analysis indicated that 75.5% of these genes directly or indirectly interacted Pto-Wuschela, revealing the coordinated genetic regulatory network formed by Pto-Wuschela and its targets. Thus, our study provides an alternative method for dissection of the interactions between a TF and its targets, which will strength our understanding of the regulatory roles of TFs in complex traits in plants.

Defragged Binary I Ching Genetic Code Chromosomes Compared to Nirenberg’s and Transformed into Rotating 2D Circles and Squares and into a 3D 100% Symmetrical Tetrahedron Coupled to a Functional One to Discern Start From Non-Start Methionines through a Stella Octangula

PubMed Central

Castro-Chavez, Fernando

2012-01-01

Background Three binary representations of the genetic code according to the ancient I Ching of Fu-Xi will be presented, depending on their defragging capabilities by pairing based on three biochemical properties of the nucleic acids: H-bonds, Purine/Pyrimidine rings, and the Keto-enol/Amino-imino tautomerism, yielding the last pair a 32/32 single-strand self-annealed genetic code and I Ching tables. Methods Our working tool is the ancient binary I Ching's resulting genetic code chromosomes defragged by vertical and by horizontal pairing, reverse engineered into non-binaries of 2D rotating 4×4×4 circles and 8×8 squares and into one 3D 100% symmetrical 16×4 tetrahedron coupled to a functional tetrahedron with apical signaling and central hydrophobicity (codon formula: 4[1(1)+1(3)+1(4)+4(2)]; 5:5, 6:6 in man) forming a stella octangula, and compared to Nirenberg's 16×4 codon table (1965) pairing the first two nucleotides of the 64 codons in axis y. Results One horizontal and one vertical defragging had the start Met at the center. Two, both horizontal and vertical pairings produced two pairs of 2×8×4 genetic code chromosomes naturally arranged (M and I), rearranged by semi-introversion of central purines or pyrimidines (M' and I') and by clustering hydrophobic amino acids; their quasi-identity was disrupted by amino acids with odd codons (Met and Tyr pairing to Ile and TGA Stop); in all instances, the 64-grid 90° rotational ability was restored. Conclusions We defragged three I Ching representations of the genetic code while emphasizing Nirenberg's historical finding. The synthetic genetic code chromosomes obtained reflect the protective strategy of enzymes with a similar function, having both humans and mammals a biased G-C dominance of three H-bonds in the third nucleotide of their most used codons per amino acid, as seen in one chromosome of the i, M and M' genetic codes, while a two H-bond A-T dominance was found in their complementary chromosome, as seen in invertebrates and plants. The reverse engineering of chromosome I' into 2D rotating circles and squares was undertaken, yielding a 100% symmetrical 3D geometry which was coupled to a previously obtained genetic code tetrahedron in order to differentiate the start methionine from the methionine that is acting as a codifying non-start codon. PMID:23431415

Spatial and temporal patterns of neutral and adaptive genetic variation in the endangered African wild dog (Lycaon pictus).

PubMed

Marsden, Clare D; Woodroffe, Rosie; Mills, Michael G L; McNutt, J Weldon; Creel, Scott; Groom, Rosemary; Emmanuel, Masenga; Cleaveland, Sarah; Kat, Pieter; Rasmussen, Gregory S A; Ginsberg, Joshua; Lines, Robin; André, Jean-Marc; Begg, Colleen; Wayne, Robert K; Mable, Barbara K

2012-03-01

Deciphering patterns of genetic variation within a species is essential for understanding population structure, local adaptation and differences in diversity between populations. Whilst neutrally evolving genetic markers can be used to elucidate demographic processes and genetic structure, they are not subject to selection and therefore are not informative about patterns of adaptive variation. As such, assessments of pertinent adaptive loci, such as the immunity genes of the major histocompatibility complex (MHC), are increasingly being incorporated into genetic studies. In this study, we combined neutral (microsatellite, mtDNA) and adaptive (MHC class II DLA-DRB1 locus) markers to elucidate the factors influencing patterns of genetic variation in the African wild dog (Lycaon pictus); an endangered canid that has suffered extensive declines in distribution and abundance. Our genetic analyses found all extant wild dog populations to be relatively small (N(e)  < 30). Furthermore, through coalescent modelling, we detected a genetic signature of a recent and substantial demographic decline, which correlates with human expansion, but contrasts with findings in some other African mammals. We found strong structuring of wild dog populations, indicating the negative influence of extensive habitat fragmentation and loss of gene flow between habitat patches. Across populations, we found that the spatial and temporal structure of microsatellite diversity and MHC diversity were correlated and strongly influenced by demographic stability and population size, indicating the effects of genetic drift in these small populations. Despite this correlation, we detected signatures of selection at the MHC, implying that selection has not been completely overwhelmed by genetic drift. © 2012 Blackwell Publishing Ltd.

Deciphering the genetic blueprint behind Holstein milk proteins and production.

PubMed

Lee, Hyun-Jeong; Kim, Jaemin; Lee, Taeheon; Son, Jun Kyu; Yoon, Ho-Baek; Baek, Kwang-Soo; Jeong, Jin Young; Cho, Yong-Min; Lee, Kyung-Tai; Yang, Byoung-Chul; Lim, Hyun-Joo; Cho, Kwanghyeon; Kim, Tae-Hun; Kwon, Eung Gi; Nam, Jungrye; Kwak, Woori; Cho, Seoae; Kim, Heebal

2014-05-14

Holstein is known to provide higher milk yields than most other cattle breeds, and the dominant position of Holstein today is the result of various selection pressures. Holstein cattle have undergone intensive selection for milk production in recent decades, which has left genome-wide footprints of domestication. To further characterize the bovine genome, we performed whole-genome resequencing analysis of 10 Holstein and 11 Hanwoo cattle to identify regions containing genes as outliers in Holstein, including CSN1S1, CSN2, CSN3, and KIT whose products are likely involved in the yield and proteins of milk and their distinctive black-and-white markings. In addition, genes indicative of positive selection were associated with cardiovascular disease, which is related to simultaneous propagation of genetic defects, also known as inbreeding depression in Holstein. © The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

Deciphering the evolution of herbicide resistance in weeds.

PubMed

Délye, Christophe; Jasieniuk, Marie; Le Corre, Valérie

2013-11-01

Resistance to herbicides in arable weeds is increasing rapidly worldwide and threatening global food security. Resistance has now been reported to all major herbicide modes of action despite the development of resistance management strategies in the 1990s. We review here recent advances in understanding the genetic bases and evolutionary drivers of herbicide resistance that highlight the complex nature of selection for this adaptive trait. Whereas early studied cases of resistance were highly herbicide-specific and largely under monogenic control, cases of greatest concern today generally involve resistance to multiple modes of action, are under polygenic control, and are derived from pre-existing stress response pathways. Although 'omics' approaches should enable unraveling the genetic bases of complex resistances, the appearance, selection, and spread of herbicide resistance in weed populations can only be fully elucidated by focusing on evolutionary dynamics and implementing integrative modeling efforts. Copyright © 2013 Elsevier Ltd. All rights reserved.

Emerging Imaging and Genomic Tools for Developmental Systems Biology.

PubMed

Liu, Zhe; Keller, Philipp J

2016-03-21

Animal development is a complex and dynamic process orchestrated by exquisitely timed cell lineage commitment, divisions, migration, and morphological changes at the single-cell level. In the past decade, extensive genetic, stem cell, and genomic studies provided crucial insights into molecular underpinnings and the functional importance of genetic pathways governing various cellular differentiation processes. However, it is still largely unknown how the precise coordination of these pathways is achieved at the whole-organism level and how the highly regulated spatiotemporal choreography of development is established in turn. Here, we discuss the latest technological advances in imaging and single-cell genomics that hold great promise for advancing our understanding of this intricate process. We propose an integrated approach that combines such methods to quantitatively decipher in vivo cellular dynamic behaviors and their underlying molecular mechanisms at the systems level with single-cell, single-molecule resolution. Copyright © 2016 Elsevier Inc. All rights reserved.

Rise of Microbial Culturomics: Noncontiguous Finished Genome Sequence and Description of Beduini massiliensis gen. nov., sp. nov.

PubMed Central

Mourembou, Gaël; Yasir, Muhammad; Azhar, Esam Ibraheem; Lagier, Jean Christophe; Bibi, Fehmida; Jiman-Fatani, Asif Ahmad; Helmy, Nayel; Robert, Catherine; Rathored, Jaishriram; Fournier, Pierre-Edouard; Raoult, Didier

2015-01-01

Abstract Microbial culturomics is a new field of omics sciences that examines the bacterial diversity of human gut coupled with a taxono-genomic strategy. Using microbial culturomics, we report here for the first time a novel Gram negative, catalase- and oxidase-negative, strict anaerobic bacilli named Beduini massiliensis gen. nov., sp nov. strain GM1 (= CSUR P1440 = DSM 100188), isolated from the stools of a female nomadic Bedouin from Saudi Arabia. With a length of 2,850,586 bp, the Beduini massiliensis genome exhibits a G + C content of 35.9%, and contains 2819 genes (2744 protein-coding and 75 RNA genes including 57 tRNA and 18 rRNA genes). It is composed of 6 scaffolds (composed of 6 contigs). A total of 1859 genes (67.75%) were assigned a putative function (by COGs or by NR blast). At least 1457 (53%) orthologous proteins were not shared with the closest phylogenetic species. 274 genes (10.0%) were identified as ORFans. These results show that microbial culturomics can dramatically improve the characterization of the human microbiota repertoire, deciphering new bacterial species and new genes. Further studies will clarify the geographic specificity and the putative role of these new microbes and their related functional genetic content in health and disease. Microbial culturomics is an emerging frontier of omics systems sciences and integrative biology and thus, warrants further consideration as part of the postgenomics methodology toolbox. PMID:26669711

Rise of Microbial Culturomics: Noncontiguous Finished Genome Sequence and Description of Beduini massiliensis gen. nov., sp. nov.

PubMed

Mourembou, Gaël; Yasir, Muhammad; Azhar, Esam Ibraheem; Lagier, Jean Christophe; Bibi, Fehmida; Jiman-Fatani, Asif Ahmad; Helmy, Nayel; Robert, Catherine; Rathored, Jaishriram; Fournier, Pierre-Edouard; Raoult, Didier; Million, Matthieu

2015-12-01

Microbial culturomics is a new field of omics sciences that examines the bacterial diversity of human gut coupled with a taxono-genomic strategy. Using microbial culturomics, we report here for the first time a novel Gram negative, catalase- and oxidase-negative, strict anaerobic bacilli named Beduini massiliensis gen. nov., sp nov. strain GM1 (= CSUR P1440 = DSM 100188), isolated from the stools of a female nomadic Bedouin from Saudi Arabia. With a length of 2,850,586 bp, the Beduini massiliensis genome exhibits a G + C content of 35.9%, and contains 2819 genes (2744 protein-coding and 75 RNA genes including 57 tRNA and 18 rRNA genes). It is composed of 6 scaffolds (composed of 6 contigs). A total of 1859 genes (67.75%) were assigned a putative function (by COGs or by NR blast). At least 1457 (53%) orthologous proteins were not shared with the closest phylogenetic species. 274 genes (10.0%) were identified as ORFans. These results show that microbial culturomics can dramatically improve the characterization of the human microbiota repertoire, deciphering new bacterial species and new genes. Further studies will clarify the geographic specificity and the putative role of these new microbes and their related functional genetic content in health and disease. Microbial culturomics is an emerging frontier of omics systems sciences and integrative biology and thus, warrants further consideration as part of the postgenomics methodology toolbox.

Quaternionic representation of the genetic code.

PubMed

Carlevaro, C Manuel; Irastorza, Ramiro M; Vericat, Fernando

2016-03-01

A heuristic diagram of the evolution of the standard genetic code is presented. It incorporates, in a way that resembles the energy levels of an atom, the physical notion of broken symmetry and it is consistent with original ideas by Crick on the origin and evolution of the code as well as with the chronological order of appearance of the amino acids along the evolution as inferred from work that mixtures known experimental results with theoretical speculations. Suggested by the diagram we propose a Hamilton quaternions based mathematical representation of the code as it stands now-a-days. The central object in the description is a codon function that assigns to each amino acid an integer quaternion in such a way that the observed code degeneration is preserved. We emphasize the advantages of a quaternionic representation of amino acids taking as an example the folding of proteins. With this aim we propose an algorithm to go from the quaternions sequence to the protein three dimensional structure which can be compared with the corresponding experimental one stored at the Protein Data Bank. In our criterion the mathematical representation of the genetic code in terms of quaternions merits to be taken into account because it describes not only most of the known properties of the genetic code but also opens new perspectives that are mainly derived from the close relationship between quaternions and rotations. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

A mirror code for protein-cholesterol interactions in the two leaflets of biological membranes

NASA Astrophysics Data System (ADS)

Fantini, Jacques; di Scala, Coralie; Evans, Luke S.; Williamson, Philip T. F.; Barrantes, Francisco J.

2016-02-01

Cholesterol controls the activity of a wide range of membrane receptors through specific interactions and identifying cholesterol recognition motifs is therefore critical for understanding signaling receptor function. The membrane-spanning domains of the paradigm neurotransmitter receptor for acetylcholine (AChR) display a series of cholesterol consensus domains (referred to as “CARC”). Here we use a combination of molecular modeling, lipid monolayer/mutational approaches and NMR spectroscopy to study the binding of cholesterol to a synthetic CARC peptide. The CARC-cholesterol interaction is of high affinity, lipid-specific, concentration-dependent, and sensitive to single-point mutations. The CARC motif is generally located in the outer membrane leaflet and its reverse sequence CRAC in the inner one. Their simultaneous presence within the same transmembrane domain obeys a “mirror code” controlling protein-cholesterol interactions in the outer and inner membrane leaflets. Deciphering this code enabled us to elaborate guidelines for the detection of cholesterol-binding motifs in any membrane protein. Several representative examples of neurotransmitter receptors and ABC transporters with the dual CARC/CRAC motifs are presented. The biological significance and potential clinical applications of the mirror code are discussed.

Introduction to the Natural Anticipator and the Artificial Anticipator

NASA Astrophysics Data System (ADS)

Dubois, Daniel M.

2010-11-01

This short communication deals with the introduction of the concept of anticipator, which is one who anticipates, in the framework of computing anticipatory systems. The definition of anticipation deals with the concept of program. Indeed, the word program, comes from "pro-gram" meaning "to write before" by anticipation, and means a plan for the programming of a mechanism, or a sequence of coded instructions that can be inserted into a mechanism, or a sequence of coded instructions, as genes or behavioural responses, that is part of an organism. Any natural or artificial programs are thus related to anticipatory rewriting systems, as shown in this paper. All the cells in the body, and the neurons in the brain, are programmed by the anticipatory genetic code, DNA, in a low-level language with four signs. The programs in computers are also computing anticipatory systems. It will be shown, at one hand, that the genetic code DNA is a natural anticipator. As demonstrated by Nobel laureate McClintock [8], genomes are programmed. The fundamental program deals with the DNA genetic code. The properties of the DNA consist in self-replication and self-modification. The self-replicating process leads to reproduction of the species, while the self-modifying process leads to new species or evolution and adaptation in existing ones. The genetic code DNA keeps its instructions in memory in the DNA coding molecule. The genetic code DNA is a rewriting system, from DNA coding to DNA template molecule. The DNA template molecule is a rewriting system to the Messenger RNA molecule. The information is not destroyed during the execution of the rewriting program. On the other hand, it will be demonstrated that Turing machine is an artificial anticipator. The Turing machine is a rewriting system. The head reads and writes, modifying the content of the tape. The information is destroyed during the execution of the program. This is an irreversible process. The input data are lost.

Biosemiotics: a new understanding of life.

PubMed

Barbieri, Marcello

2008-07-01

Biosemiotics is the idea that life is based on semiosis, i.e., on signs and codes. This idea has been strongly suggested by the discovery of the genetic code, but so far it has made little impact in the scientific world and is largely regarded as a philosophy rather than a science. The main reason for this is that modern biology assumes that signs and meanings do not exist at the molecular level, and that the genetic code was not followed by any other organic code for almost four billion years, which implies that it was an utterly isolated exception in the history of life. These ideas have effectively ruled out the existence of semiosis in the organic world, and yet there are experimental facts against all of them. If we look at the evidence of life without the preconditions of the present paradigm, we discover that semiosis is there, in every single cell, and that it has been there since the very beginning. This is what biosemiotics is really about. It is not a philosophy. It is a new scientific paradigm that is rigorously based on experimental facts. Biosemiotics claims that the genetic code (1) is a real code and (2) has been the first of a long series of organic codes that have shaped the history of life on our planet. The reality of the genetic code and the existence of other organic codes imply that life is based on two fundamental processes--copying and coding--and this in turn implies that evolution took place by two distinct mechanisms, i.e., by natural selection (based on copying) and by natural conventions (based on coding). It also implies that the copying of genes works on individual molecules, whereas the coding of proteins operates on collections of molecules, which means that different mechanisms of evolution exist at different levels of organization. This review intends to underline the scientific nature of biosemiotics, and to this purpose, it aims to prove (1) that the cell is a real semiotic system, (2) that the genetic code is a real code, (3) that evolution took place by natural selection and by natural conventions, and (4) that it was natural conventions, i.e., organic codes, that gave origin to the great novelties of macroevolution. Biological semiosis, in other words, is a scientific reality because the codes of life are experimental realities. The time has come, therefore, to acknowledge this fact of life, even if that means abandoning the present theoretical framework in favor of a more general one where biology and semiotics finally come together and become biosemiotics.

Reduced representation genome sequencing reveals patterns of genetic diversity and selection in apple.

PubMed

Ma, Baiquan; Liao, Liao; Peng, Qian; Fang, Ting; Zhou, Hui; Korban, Schuyler S; Han, Yuepeng

2017-03-01

Identifying DNA sequence variations is a fundamental step towards deciphering the genetic basis of traits of interest. Here, a total of 20 cultivated and 10 wild apples were genotyped using specific-locus amplified fragment sequencing, and 39,635 single nucleotide polymorphisms with no missing genotypes and evenly distributed along the genome were selected to investigate patterns of genome-wide genetic variations between cultivated and wild apples. Overall, wild apples displayed higher levels of genetic diversity than cultivated apples. Linkage disequilibrium (LD) decays were observed quite rapidly in cultivated and wild apples, with an r 2 -value below 0.2 at 440 and 280 bp, respectively. Moreover, bidirectional gene flow and different distribution patterns of LD blocks were detected between domesticated and wild apples. Most LD blocks unique to cultivated apples were located within QTL regions controlling fruit quality, thus suggesting that fruit quality had probably undergone selection during apple domestication. The genome of the earliest cultivated apple in China, Nai, was highly similar to that of Malus sieversii, and contained a small portion of genetic material from other wild apple species. This suggested that introgression could have been an important driving force during initial domestication of apple. These findings will facilitate future breeding and genetic dissection of complex traits in apple. © 2017 Institute of Botany, Chinese Academy of Sciences.

Changes in mitochondrial genetic codes as phylogenetic characters: Two examples from the flatworms

PubMed Central

Telford, Maximilian J.; Herniou, Elisabeth A.; Russell, Robert B.; Littlewood, D. Timothy J.

2000-01-01

Shared molecular genetic characteristics other than DNA and protein sequences can provide excellent sources of phylogenetic information, particularly if they are complex and rare and are consequently unlikely to have arisen by chance convergence. We have used two such characters, arising from changes in mitochondrial genetic code, to define a clade within the Platyhelminthes (flatworms), the Rhabditophora. We have sampled 10 distinct classes within the Rhabditophora and find that all have the codon AAA coding for the amino acid Asn rather than the usual Lys and AUA for Ile rather than the usual Met. We find no evidence to support claims that the codon UAA codes for Tyr in the Platyhelminthes rather than the standard stop codon. The Rhabditophora are a very diverse group comprising the majority of the free-living turbellarian taxa and the parasitic Neodermata. In contrast, three other classes of turbellarian flatworm, the Acoela, Nemertodermatida, and Catenulida, have the standard invertebrate assignments for these codons and so are convincingly excluded from the rhabditophoran clade. We have developed a rapid computerized method for analyzing genetic codes and demonstrate the wide phylogenetic distribution of the standard invertebrate code as well as confirming already known metazoan deviations from it (ascidian, vertebrate, echinoderm/hemichordate). PMID:11027335

Complete genome sequence of Streptosporangium roseum type strain (NI 9100T)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nolan, Matt; Sikorski, Johannes; Jando, Marlen

2010-01-01

Streptosporangium roseum Crauch 1955 is the type strain of the species which is the type species of the genus Streptosporangium. The pinkish coiled Streptomyces-like organism with a spore case was isolated from vegetable garden soil in 1955. Here we describe the features of this organism, together with the complete genome sequence and annotation. This is the first completed genome sequence of a member of the family Streptosporangiaceae, and the second largest microbial genome sequence ever deciphered. The 10,369,518 bp long genome with its 9421 protein-coding and 80 RNA genes is a part of the Genomic Encyclopedia of Bacteria and Archaeamore » project.« less

Personalised Medicine: Genome Maintenance Lessons Learned from Studies in Yeast as a Model Organism.

PubMed

Abugable, Arwa A; Awwad, Dahlia A; Fleifel, Dalia; Ali, Mohamed M; El-Khamisy, Sherif; Elserafy, Menattallah

2017-01-01

Yeast research has been tremendously contributing to the understanding of a variety of molecular pathways due to the ease of its genetic manipulation, fast doubling time as well as being cost-effective. The understanding of these pathways did not only help scientists learn more about the cellular functions but also assisted in deciphering the genetic and cellular defects behind multiple diseases. Hence, yeast research not only opened the doors for transforming basic research into applied research, but also paved the roads for improving diagnosis and innovating personalized therapy of different diseases. In this chapter, we discuss how yeast research has contributed to understanding major genome maintenance pathways such as the S-phase checkpoint activation pathways, repair via homologous recombination and non-homologous end joining as well as topoisomerases-induced protein linked DNA breaks repair. Defects in these pathways lead to neurodegenerative diseases and cancer. Thus, the understanding of the exact genetic defects underlying these diseases allowed the development of personalized medicine, improving the diagnosis and treatment and overcoming the detriments of current conventional therapies such as the side effects, toxicity as well as drug resistance.

DNA mutations of the cat: the good, the bad and the ugly.

PubMed

Lyons, Leslie A

2015-03-01

The health of the cat is a complex interaction between its environment (nurture) and its genetics (nature). Over 70 genetic mutations (variants) have been defined in the cat, many involving diseases, structural abnormalities and clinically relevant health concerns. As more of the cat's genome is deciphered, less commonly will the term 'idiopathic' be used regarding the diagnosis of diseases and unique health conditions. State-of-the-art health care will include DNA profiling of the individual cat, and perhaps its tumor, to establish the best treatment approaches. Genetic testing and eventually whole genome sequencing should become routine diagnostics for feline health care. Cat breeds have disseminated around the world. Thus, practitioners should be aware of the breeds common to their region and the mutations found in those regional populations. Specific random-bred populations can also have defined genetic characteristics and mutations. This review of 'the good, the bad and the ugly' DNA variants provides the current state of knowledge for genetic testing and genetic health management for cats. It is aimed at feline and general practitioners wanting to update and review the basics of genetics, what tests are available for cats and sources for genetic testing. The tables are intended to be used as references in the clinic. Practitioners with a high proportion of cat breeder clientele will especially benefit from the review. The data presented is extracted from peer-reviewed publications pertaining to mutation identification, and relevant articles concerning the heritable trait and/or disease. The author also draws upon personal experience and expertise in feline genetics. © ISFM and AAFP 2015.

Biosemiotics: a new understanding of life

NASA Astrophysics Data System (ADS)

Barbieri, Marcello

2008-07-01

Biosemiotics is the idea that life is based on semiosis, i.e., on signs and codes. This idea has been strongly suggested by the discovery of the genetic code, but so far it has made little impact in the scientific world and is largely regarded as a philosophy rather than a science. The main reason for this is that modern biology assumes that signs and meanings do not exist at the molecular level, and that the genetic code was not followed by any other organic code for almost four billion years, which implies that it was an utterly isolated exception in the history of life. These ideas have effectively ruled out the existence of semiosis in the organic world, and yet there are experimental facts against all of them. If we look at the evidence of life without the preconditions of the present paradigm, we discover that semiosis is there, in every single cell, and that it has been there since the very beginning. This is what biosemiotics is really about. It is not a philosophy. It is a new scientific paradigm that is rigorously based on experimental facts. Biosemiotics claims that the genetic code (1) is a real code and (2) has been the first of a long series of organic codes that have shaped the history of life on our planet. The reality of the genetic code and the existence of other organic codes imply that life is based on two fundamental processes—copying and coding—and this in turn implies that evolution took place by two distinct mechanisms, i.e., by natural selection (based on copying) and by natural conventions (based on coding). It also implies that the copying of genes works on individual molecules, whereas the coding of proteins operates on collections of molecules, which means that different mechanisms of evolution exist at different levels of organization. This review intends to underline the scientific nature of biosemiotics, and to this purpose, it aims to prove (1) that the cell is a real semiotic system, (2) that the genetic code is a real code, (3) that evolution took place by natural selection and by natural conventions, and (4) that it was natural conventions, i.e., organic codes, that gave origin to the great novelties of macroevolution. Biological semiosis, in other words, is a scientific reality because the codes of life are experimental realities. The time has come, therefore, to acknowledge this fact of life, even if that means abandoning the present theoretical framework in favor of a more general one where biology and semiotics finally come together and become biosemiotics.

File Compression and Expansion of the Genetic Code by the use of the Yin/Yang Directions to find its Sphered Cube

PubMed Central

Castro-Chavez, Fernando

2014-01-01

Objective The objective of this article is to demonstrate that the genetic code can be studied and represented in a 3-D Sphered Cube for bioinformatics and for education by using the graphical help of the ancient “Book of Changes” or I Ching for the comparison, pair by pair, of the three basic characteristics of nucleotides: H-bonds, molecular structure, and their tautomerism. Methods The source of natural biodiversity is the high plasticity of the genetic code, analyzable with a reverse engineering of its 2-D and 3-D representations (here illustrated), but also through the classical 64-hexagrams of the ancient I Ching, as if they were the 64-codons or words of the genetic code. Results In this article, the four elements of the Yin/Yang were found by correlating the 3×2=6 sets of Cartesian comparisons of the mentioned properties of nucleic acids, to the directionality of their resulting blocks of codons grouped according to their resulting amino acids and/or functions, integrating a 384-codon Sphered Cube whose function is illustrated by comparing six brain peptides and a promoter of osteoblasts from Humans versus Neanderthal, as well as to Negadi’s work on the importance of the number 384 within the genetic code. Conclusions Starting with the codon/anticodon correlation of Nirenberg, published in full here for the first time, and by studying the genetic code and its 3-D display, the buffers of reiteration within codons codifying for the same amino acid, displayed the two long (binary number one) and older Yin/Yang arrows that travel in opposite directions, mimicking the parental DNA strands, while annealing to the two younger and broken (binary number zero) Yin/Yang arrows, mimicking the new DNA strands; the graphic analysis of the of the genetic code and its plasticity was helpful to compare compatible sequences (human compatible to human versus neanderthal compatible to neanderthal), while further exploring the wondrous biodiversity of nature for educational purposes. PMID:25340175

Deciphering evolutionary strata on plant sex chromosomes and fungal mating-type chromosomes through compositional segmentation.

PubMed

Pandey, Ravi S; Azad, Rajeev K

2016-03-01

Sex chromosomes have evolved from a pair of homologous autosomes which differentiated into sex determination systems, such as XY or ZW system, as a consequence of successive recombination suppression between the gametologous chromosomes. Identifying the regions of recombination suppression, namely, the "evolutionary strata", is central to understanding the history and dynamics of sex chromosome evolution. Evolution of sex chromosomes as a consequence of serial recombination suppressions is well-studied for mammals and birds, but not for plants, although 48 dioecious plants have already been reported. Only two plants Silene latifolia and papaya have been studied until now for the presence of evolutionary strata on their X chromosomes, made possible by the sequencing of sex-linked genes on both the X and Y chromosomes, which is a requirement of all current methods that determine stratum structure based on the comparison of gametologous sex chromosomes. To circumvent this limitation and detect strata even if only the sequence of sex chromosome in the homogametic sex (i.e. X or Z chromosome) is available, we have developed an integrated segmentation and clustering method. In application to gene sequences on the papaya X chromosome and protein-coding sequences on the S. latifolia X chromosome, our method could decipher all known evolutionary strata, as reported by previous studies. Our method, after validating on known strata on the papaya and S. latifolia X chromosome, was applied to the chromosome 19 of Populus trichocarpa, an incipient sex chromosome, deciphering two, yet unknown, evolutionary strata. In addition, we applied this approach to the recently sequenced sex chromosome V of the brown alga Ectocarpus sp. that has a haploid sex determination system (UV system) recovering the sex determining and pseudoautosomal regions, and then to the mating-type chromosomes of an anther-smut fungus Microbotryum lychnidis-dioicae predicting five strata in the non-recombining region of both the chromosomes.

Genetic Code Expansion of Mammalian Cells with Unnatural Amino Acids.

PubMed

Brown, Kalyn A; Deiters, Alexander

2015-09-01

The expansion of the genetic code of mammalian cells enables the incorporation of unnatural amino acids into proteins. This is achieved by adding components to the protein biosynthetic machinery, specifically an engineered aminoacyl-tRNA synthetase/tRNA pair. The unnatural amino acids are chemically synthesized and supplemented to the growth medium. Using this methodology, fundamental new chemistries can be added to the functional repertoire of the genetic code of mammalian cells. This protocol outlines the steps necessary to incorporate a photocaged lysine into proteins and showcases its application in the optical triggering of protein translocation to the nucleus. Copyright © 2015 John Wiley & Sons, Inc.

Postglacial recolonization history of the European crabapple (Malus sylvestris Mill.), a wild contributor to the domesticated apple.

PubMed

Cornille, A; Giraud, T; Bellard, C; Tellier, A; Le Cam, B; Smulders, M J M; Kleinschmit, J; Roldan-Ruiz, I; Gladieux, P

2013-04-01

Understanding the way in which the climatic oscillations of the Quaternary Period have shaped the distribution and genetic structure of extant tree species provides insight into the processes driving species diversification, distribution and survival. Deciphering the genetic consequences of past climatic change is also critical for the conservation and sustainable management of forest and tree genetic resources, a timely endeavour as the Earth heads into a period of fast climate change. We used a combination of genetic data and ecological niche models to investigate the historical patterns of biogeographic range expansion of a wild fruit tree, the European crabapple (Malus sylvestris), a wild contributor to the domesticated apple. Both climatic predictions for the last glacial maximum and analyses of microsatellite variation indicated that M. sylvestris experienced range contraction and fragmentation. Bayesian clustering analyses revealed a clear pattern of genetic structure, with one genetic cluster spanning a large area in Western Europe and two other genetic clusters with a more limited distribution range in Eastern Europe, one around the Carpathian Mountains and the other restricted to the Balkan Peninsula. Approximate Bayesian computation appeared to be a powerful technique for inferring the history of these clusters, supporting a scenario of simultaneous differentiation of three separate glacial refugia. Admixture between these three populations was found in their suture zones. A weak isolation by distance pattern was detected within each population, indicating a high extent of historical gene flow for the European crabapple. © 2013 Blackwell Publishing Ltd.

The evolution of vision.

PubMed

Gehring, Walter J

2014-01-01

In this review, the evolution of vision is retraced from its putative origins in cyanobacteria to humans. Circadian oscillatory clocks, phototropism, and phototaxis require the capability to detect light. Photosensory proteins allow us to reconstruct molecular phylogenetic trees. The evolution of animal eyes leading from an ancestral prototype to highly complex image forming eyes can be deciphered on the basis of evolutionary developmental genetic experiments and comparative genomics. As all bilaterian animals share the same master control gene, Pax6, and the same retinal and pigment cell determination genes, we conclude that the different eye-types originated monophyletically and subsequently diversified by divergent, parallel, or convergent evolution. © 2012 Wiley Periodicals, Inc.

Chlamydia cell biology and pathogenesis.

PubMed

Elwell, Cherilyn; Mirrashidi, Kathleen; Engel, Joanne

2016-06-01

Chlamydia spp. are important causes of human disease for which no effective vaccine exists. These obligate intracellular pathogens replicate in a specialized membrane compartment and use a large arsenal of secreted effectors to survive in the hostile intracellular environment of the host. In this Review, we summarize the progress in decoding the interactions between Chlamydia spp. and their hosts that has been made possible by recent technological advances in chlamydial proteomics and genetics. The field is now poised to decipher the molecular mechanisms that underlie the intimate interactions between Chlamydia spp. and their hosts, which will open up many exciting avenues of research for these medically important pathogens.

Chlamydia cell biology and pathogenesis

PubMed Central

Elwell, Cherilyn; Mirrashidi, Kathleen; Engel, Joanne

2016-01-01

Chlamydia spp. are important causes of human disease for which no effective vaccine exists. These obligate intracellular pathogens replicate in a specialized membrane compartment and use a large arsenal of secreted effectors to survive in the hostile intracellular environment of the host. In this Review, we summarize the progress in decoding the interactions between Chlamydia spp. and their hosts that has been made possible by recent technological advances in chlamydial proteomics and genetics. The field is now poised to decipher the molecular mechanisms that underlie the intimate interactions between Chlamydia spp. and their hosts, which will open up many exciting avenues of research for these medically important pathogens. PMID:27108705

From integrative genomics to systems genetics in the rat to link genotypes to phenotypes

PubMed Central

Moreno-Moral, Aida

2016-01-01

ABSTRACT Complementary to traditional gene mapping approaches used to identify the hereditary components of complex diseases, integrative genomics and systems genetics have emerged as powerful strategies to decipher the key genetic drivers of molecular pathways that underlie disease. Broadly speaking, integrative genomics aims to link cellular-level traits (such as mRNA expression) to the genome to identify their genetic determinants. With the characterization of several cellular-level traits within the same system, the integrative genomics approach evolved into a more comprehensive study design, called systems genetics, which aims to unravel the complex biological networks and pathways involved in disease, and in turn map their genetic control points. The first fully integrated systems genetics study was carried out in rats, and the results, which revealed conserved trans-acting genetic regulation of a pro-inflammatory network relevant to type 1 diabetes, were translated to humans. Many studies using different organisms subsequently stemmed from this example. The aim of this Review is to describe the most recent advances in the fields of integrative genomics and systems genetics applied in the rat, with a focus on studies of complex diseases ranging from inflammatory to cardiometabolic disorders. We aim to provide the genetics community with a comprehensive insight into how the systems genetics approach came to life, starting from the first integrative genomics strategies [such as expression quantitative trait loci (eQTLs) mapping] and concluding with the most sophisticated gene network-based analyses in multiple systems and disease states. Although not limited to studies that have been directly translated to humans, we will focus particularly on the successful investigations in the rat that have led to primary discoveries of genes and pathways relevant to human disease. PMID:27736746

From integrative genomics to systems genetics in the rat to link genotypes to phenotypes.

PubMed

Moreno-Moral, Aida; Petretto, Enrico

2016-10-01

Complementary to traditional gene mapping approaches used to identify the hereditary components of complex diseases, integrative genomics and systems genetics have emerged as powerful strategies to decipher the key genetic drivers of molecular pathways that underlie disease. Broadly speaking, integrative genomics aims to link cellular-level traits (such as mRNA expression) to the genome to identify their genetic determinants. With the characterization of several cellular-level traits within the same system, the integrative genomics approach evolved into a more comprehensive study design, called systems genetics, which aims to unravel the complex biological networks and pathways involved in disease, and in turn map their genetic control points. The first fully integrated systems genetics study was carried out in rats, and the results, which revealed conserved trans-acting genetic regulation of a pro-inflammatory network relevant to type 1 diabetes, were translated to humans. Many studies using different organisms subsequently stemmed from this example. The aim of this Review is to describe the most recent advances in the fields of integrative genomics and systems genetics applied in the rat, with a focus on studies of complex diseases ranging from inflammatory to cardiometabolic disorders. We aim to provide the genetics community with a comprehensive insight into how the systems genetics approach came to life, starting from the first integrative genomics strategies [such as expression quantitative trait loci (eQTLs) mapping] and concluding with the most sophisticated gene network-based analyses in multiple systems and disease states. Although not limited to studies that have been directly translated to humans, we will focus particularly on the successful investigations in the rat that have led to primary discoveries of genes and pathways relevant to human disease. © 2016. Published by The Company of Biologists Ltd.

Possibilities for the evolution of the genetic code from a preceding form

NASA Technical Reports Server (NTRS)

Jukes, T. H.

1973-01-01

Analysis of the interaction between mRNA codons and tRNA anticodons suggests a model for the evolution of the genetic code. Modification of the nucleic acid following the anticodon is at present essential in both eukaryotes and prokaryotes to ensure fidelity of translation of codons starting with A, and the amino acids which could be coded for before the evolution of the modifying enzymes can be deduced.

I-Ching, dyadic groups of binary numbers and the geno-logic coding in living bodies.

PubMed

Hu, Zhengbing; Petoukhov, Sergey V; Petukhova, Elena S

2017-12-01

The ancient Chinese book I-Ching was written a few thousand years ago. It introduces the system of symbols Yin and Yang (equivalents of 0 and 1). It had a powerful impact on culture, medicine and science of ancient China and several other countries. From the modern standpoint, I-Ching declares the importance of dyadic groups of binary numbers for the Nature. The system of I-Ching is represented by the tables with dyadic groups of 4 bigrams, 8 trigrams and 64 hexagrams, which were declared as fundamental archetypes of the Nature. The ancient Chinese did not know about the genetic code of protein sequences of amino acids but this code is organized in accordance with the I-Ching: in particularly, the genetic code is constructed on DNA molecules using 4 nitrogenous bases, 16 doublets, and 64 triplets. The article also describes the usage of dyadic groups as a foundation of the bio-mathematical doctrine of the geno-logic code, which exists in parallel with the known genetic code of amino acids but serves for a different goal: to code the inherited algorithmic processes using the logical holography and the spectral logic of systems of genetic Boolean functions. Some relations of this doctrine with the I-Ching are discussed. In addition, the ratios of musical harmony that can be revealed in the parameters of DNA structure are also represented in the I-Ching book. Copyright © 2017 Elsevier Ltd. All rights reserved.

On the possible origin and evolution of the genetic code

NASA Technical Reports Server (NTRS)

Jukes, T. H.

1974-01-01

The genetic code is examined for indications of possible preceding codes that existed during early evolution. Eight of the 20 amino acids are coded by 'quartets' of codons with fourfold degeneracy, and 16 such quartets can exist, so that an earlier code could have provided for 15 or 16 amino acids, rather than 20. If twofold degeneracy is postulated for the first position of the codon, there could have been ten amino acids in the code. It is speculated that these may have been phenylalanine, valine, proline, alanine, histidine, glutamine, glutanic acid, aspartic acid, cysteine and glycine. There is a notable deficiency of arginine in proteins, despite the fact that it has six codons. Simultaneously, there is more lysine in proteins than would be expected from its two codons, if the four bases in mRNA are equiprobable and are arranged randomly. It is speculated that arginine is an 'intruder' into the genetic code, and that it may have displayed another amino acid such as ornithine, or may even have displayed lysine from some of its previous codon assignments. As a result, natural selection has favored lysine against the fact that it has only two codons.

Evidence of translation efficiency adaptation of the coding regions of the bacteriophage lambda.

PubMed

Goz, Eli; Mioduser, Oriah; Diament, Alon; Tuller, Tamir

2017-08-01

Deciphering the way gene expression regulatory aspects are encoded in viral genomes is a challenging mission with ramifications related to all biomedical disciplines. Here, we aimed to understand how the evolution shapes the bacteriophage lambda genes by performing a high resolution analysis of ribosomal profiling data and gene expression related synonymous/silent information encoded in bacteriophage coding regions.We demonstrated evidence of selection for distinct compositions of synonymous codons in early and late viral genes related to the adaptation of translation efficiency to different bacteriophage developmental stages. Specifically, we showed that evolution of viral coding regions is driven, among others, by selection for codons with higher decoding rates; during the initial/progressive stages of infection the decoding rates in early/late genes were found to be superior to those in late/early genes, respectively. Moreover, we argued that selection for translation efficiency could be partially explained by adaptation to Escherichia coli tRNA pool and the fact that it can change during the bacteriophage life cycle.An analysis of additional aspects related to the expression of viral genes, such as mRNA folding and more complex/longer regulatory signals in the coding regions, is also reported. The reported conclusions are likely to be relevant also to additional viruses. © The Author 2017. Published by Oxford University Press on behalf of Kazusa DNA Research Institute.

Deciphering the landscape of host barriers to Listeria monocytogenes infection.

PubMed

Zhang, Ting; Abel, Sören; Abel Zur Wiesch, Pia; Sasabe, Jumpei; Davis, Brigid M; Higgins, Darren E; Waldor, Matthew K

2017-06-13

Listeria monocytogenes is a common food-borne pathogen that can disseminate from the intestine and infect multiple organs. Here, we used sequence tag-based analysis of microbial populations (STAMP) to investigate L monocytogenes population dynamics during infection. We created a genetically barcoded library of murinized L monocytogenes and then used deep sequencing to track the pathogen's dissemination routes and quantify its founding population ( N b ) sizes in different organs. We found that the pathogen disseminates from the gastrointestinal tract to distal sites through multiple independent routes and that N b sizes vary greatly among tissues, indicative of diverse host barriers to infection. Unexpectedly, comparative analyses of sequence tags revealed that fecally excreted organisms are largely derived from the very small number of L. monocytogenes cells that colonize the gallbladder. Immune depletion studies suggest that distinct innate immune cells restrict the pathogen's capacity to establish replicative niches in the spleen and liver. Finally, studies in germ-free mice suggest that the microbiota plays a critical role in the development of the splenic, but not the hepatic, barriers that prevent L. monocytogenes from seeding these organs. Collectively, these observations illustrate the potency of the STAMP approach to decipher the impact of host factors on population dynamics of pathogens during infection.

Peeling off the genetics of atopic dermatitis-like congenital disorders.

PubMed

Samuelov, Liat; Sprecher, Eli

2014-10-01

The epidermis forms during the course of a complex differentiation process known as cornification, which culminates with the formation of the epidermal barrier. The epidermal barrier serves as a vital line of defense against the environment and mainly consists of 3 elements: intracellular keratin filaments, intercellular lipids, and the cornified cell envelope. Adequate epidermal barrier function is also critically dependent on normal shedding of terminally differentiated keratinocytes, a process termed desquamation, which requires the dissolution of cell-cell junctions in the upper granular layers. Although much has been learned about epidermal differentiation through the deciphering of the molecular basis of various cornification disorders, less is currently known about the mechanisms regulating epidermal desquamation and disorders resulting from disruption of this process. Netherton syndrome, peeling skin syndrome type B, and skin dermatitis--multiple severe allergies--metabolic wasting syndrome are 3 autosomal recessive conditions resulting from aberrant regulation of epidermal desquamation. The deciphering of their pathogenesis has not only broadened our understanding of this process but has also shed new light on clinical and mechanistic links between allergic reactions and abnormal desquamation, substantiating the notion that allergic manifestations might, under some circumstances, be the sole consequence of a primary epidermal defect. Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Deciphering the landscape of host barriers to Listeria monocytogenes infection

PubMed Central

Zhang, Ting; Abel, Sören; Abel zur Wiesch, Pia; Sasabe, Jumpei; Davis, Brigid M.; Higgins, Darren E.; Waldor, Matthew K.

2017-01-01

Listeria monocytogenes is a common food-borne pathogen that can disseminate from the intestine and infect multiple organs. Here, we used sequence tag-based analysis of microbial populations (STAMP) to investigate L. monocytogenes population dynamics during infection. We created a genetically barcoded library of murinized L. monocytogenes and then used deep sequencing to track the pathogen’s dissemination routes and quantify its founding population (Nb) sizes in different organs. We found that the pathogen disseminates from the gastrointestinal tract to distal sites through multiple independent routes and that Nb sizes vary greatly among tissues, indicative of diverse host barriers to infection. Unexpectedly, comparative analyses of sequence tags revealed that fecally excreted organisms are largely derived from the very small number of L. monocytogenes cells that colonize the gallbladder. Immune depletion studies suggest that distinct innate immune cells restrict the pathogen’s capacity to establish replicative niches in the spleen and liver. Finally, studies in germ-free mice suggest that the microbiota plays a critical role in the development of the splenic, but not the hepatic, barriers that prevent L. monocytogenes from seeding these organs. Collectively, these observations illustrate the potency of the STAMP approach to decipher the impact of host factors on population dynamics of pathogens during infection. PMID:28559314

Ancient DNA sequence revealed by error-correcting codes.

PubMed

Brandão, Marcelo M; Spoladore, Larissa; Faria, Luzinete C B; Rocha, Andréa S L; Silva-Filho, Marcio C; Palazzo, Reginaldo

2015-07-10

A previously described DNA sequence generator algorithm (DNA-SGA) using error-correcting codes has been employed as a computational tool to address the evolutionary pathway of the genetic code. The code-generated sequence alignment demonstrated that a residue mutation revealed by the code can be found in the same position in sequences of distantly related taxa. Furthermore, the code-generated sequences do not promote amino acid changes in the deviant genomes through codon reassignment. A Bayesian evolutionary analysis of both code-generated and homologous sequences of the Arabidopsis thaliana malate dehydrogenase gene indicates an approximately 1 MYA divergence time from the MDH code-generated sequence node to its paralogous sequences. The DNA-SGA helps to determine the plesiomorphic state of DNA sequences because a single nucleotide alteration often occurs in distantly related taxa and can be found in the alternative codon patterns of noncanonical genetic codes. As a consequence, the algorithm may reveal an earlier stage of the evolution of the standard code.

Ancient DNA sequence revealed by error-correcting codes

PubMed Central

Brandão, Marcelo M.; Spoladore, Larissa; Faria, Luzinete C. B.; Rocha, Andréa S. L.; Silva-Filho, Marcio C.; Palazzo, Reginaldo

2015-01-01

A previously described DNA sequence generator algorithm (DNA-SGA) using error-correcting codes has been employed as a computational tool to address the evolutionary pathway of the genetic code. The code-generated sequence alignment demonstrated that a residue mutation revealed by the code can be found in the same position in sequences of distantly related taxa. Furthermore, the code-generated sequences do not promote amino acid changes in the deviant genomes through codon reassignment. A Bayesian evolutionary analysis of both code-generated and homologous sequences of the Arabidopsis thaliana malate dehydrogenase gene indicates an approximately 1 MYA divergence time from the MDH code-generated sequence node to its paralogous sequences. The DNA-SGA helps to determine the plesiomorphic state of DNA sequences because a single nucleotide alteration often occurs in distantly related taxa and can be found in the alternative codon patterns of noncanonical genetic codes. As a consequence, the algorithm may reveal an earlier stage of the evolution of the standard code. PMID:26159228

Summary of evidence for an anticodonic basis for the origin of the genetic code

NASA Technical Reports Server (NTRS)

Lacey, J. C., Jr.; Mullins, D. W., Jr.

1981-01-01

This article summarizes data supporting the hypothesis that the genetic code origin was based on relationships (probably affinities) between amino acids and their anticodon nucleotides. Selective activation seems to follow from selective affinity and consequently, incorporation of amino acids into peptides can also be selective. It is suggested that these selectivities in affinity and activation, coupled with the base pairing specificities, allowed the origin of the code and the process of translation.

Nuclear fuel management optimization using genetic algorithms

DOE Office of Scientific and Technical Information (OSTI.GOV)

DeChaine, M.D.; Feltus, M.A.

1995-07-01

The code independent genetic algorithm reactor optimization (CIGARO) system has been developed to optimize nuclear reactor loading patterns. It uses genetic algorithms (GAs) and a code-independent interface, so any reactor physics code (e.g., CASMO-3/SIMULATE-3) can be used to evaluate the loading patterns. The system is compared to other GA-based loading pattern optimizers. Tests were carried out to maximize the beginning of cycle k{sub eff} for a pressurized water reactor core loading with a penalty function to limit power peaking. The CIGARO system performed well, increasing the k{sub eff} after lowering the peak power. Tests of a prototype parallel evaluation methodmore » showed the potential for a significant speedup.« less

Clinical application of antenatal genetic diagnosis of osteogenesis imperfecta type IV.

PubMed

Yuan, Jing; Li, Song; Xu, YeYe; Cong, Lin

2015-04-02

Clinical analysis and genetic testing of a family with osteogenesis imperfecta type IV were conducted, aiming to discuss antenatal genetic diagnosis of osteogenesis imperfecta type IV. Preliminary genotyping was performed based on clinical characteristics of the family members and then high-throughput sequencing was applied to rapidly and accurately detect the changes in candidate genes. Genetic testing of the III5 fetus and other family members revealed missense mutation in c.2746G>A, pGly916Arg in COL1A2 gene coding region and missense and synonymous mutation in COL1A1 gene coding region. Application of antenatal genetic diagnosis provides fast and accurate genetic counseling and eugenics suggestions for patients with osteogenesis imperfecta type IV and their families.

Fitting Analysis using Differential evolution Optimization (FADO):. Spectral population synthesis through genetic optimization under self-consistency boundary conditions

NASA Astrophysics Data System (ADS)

Gomes, J. M.; Papaderos, P.

2017-07-01

The goal of population spectral synthesis (pss; also referred to as inverse, semi-empirical evolutionary- or fossil record approach) is to decipher from the spectrum of a galaxy the mass, age and metallicity of its constituent stellar populations. This technique, which is the reverse of but complementary to evolutionary synthesis, has been established as fundamental tool in extragalactic research. It has been extensively applied to large spectroscopic data sets, notably the SDSS, leading to important insights into the galaxy assembly history. However, despite significant improvements over the past decade, all current pss codes suffer from two major deficiencies that inhibit us from gaining sharp insights into the star-formation history (SFH) of galaxies and potentially introduce substantial biases in studies of their physical properties (e.g., stellar mass, mass-weighted stellar age and specific star formation rate). These are I) the neglect of nebular emission in spectral fits, consequently; II) the lack of a mechanism that ensures consistency between the best-fitting SFH and the observed nebular emission characteristics of a star-forming (SF) galaxy (e.g., hydrogen Balmer-line luminosities and equivalent widths-EWs, shape of the continuum in the region around the Balmer and Paschen jump). In this article, we present fado (Fitting Analysis using Differential evolution Optimization) - a conceptually novel, publicly available pss tool with the distinctive capability of permitting identification of the SFH that reproduces the observed nebular characteristics of a SF galaxy. This so-far unique self-consistency concept allows us to significantly alleviate degeneracies in current spectral synthesis, thereby opening a new avenue to the exploration of the assembly history of galaxies. The innovative character of fado is further augmented by its mathematical foundation: fado is the first pss code employing genetic differential evolution optimization. This, in conjunction with various other currently unique elements in its mathematical concept and numerical realization (e.g., mid-analysis optimization of the spectral library using artificial intelligence, test for convergence through a procedure inspired by Markov chain Monte Carlo techniques, quasi-parallelization embedded within a modular architecture) results in key improvements with respect to computational efficiency and uniqueness of the best-fitting SFHs. Furthermore, fado incorporates within a single code the entire chain of pre-processing, modeling, post-processing, storage and graphical representation of the relevant output from pss, including emission-line measurements and estimates of uncertainties for all primary and secondary products from spectral synthesis (e.g., mass contributions of individual stellar populations, mass- and luminosity-weighted stellar ages and metallicities). This integrated concept greatly simplifies and accelerates a lengthy sequence of individual time-consuming steps that are generally involved in pss modeling, further enhancing the overall efficiency of the code and inviting to its automated application to large spectroscopic data sets. The distribution package of the FADO v.1 tool contains the binary and its auxiliary files. FADO v.1 is only available at the CDS via anonymous ftp to http://cdsarc.u-strasbg.fr (http://130.79.128.5) or via http://cdsarc.u-strasbg.fr/viz-bin/qcat?J/A+A/603/A63

Identification of small non-coding RNA classes expressed in swine whole blood during HP-PRRSV infection

USDA-ARS?s Scientific Manuscript database

It has been established that reduced susceptibility to porcine reproductive and respiratory syndrome virus (PRRSV) has a genetic component. This genetic component may take the form of small non-coding RNAs (sncRNA), which are molecules that function as regulators of gene expression. Various sncRNAs ...

Genome survey and high-density genetic map construction provide genomic and genetic resources for the Pacific White Shrimp Litopenaeus vannamei

PubMed Central

Yu, Yang; Zhang, Xiaojun; Yuan, Jianbo; Li, Fuhua; Chen, Xiaohan; Zhao, Yongzhen; Huang, Long; Zheng, Hongkun; Xiang, Jianhai

2015-01-01

The Pacific white shrimp Litopenaeus vannamei is the dominant crustacean species in global seafood mariculture. Understanding the genome and genetic architecture is useful for deciphering complex traits and accelerating the breeding program in shrimp. In this study, a genome survey was conducted and a high-density linkage map was constructed using a next-generation sequencing approach. The genome survey was used to identify preliminary genome characteristics and to generate a rough reference for linkage map construction. De novo SNP discovery resulted in 25,140 polymorphic markers. A total of 6,359 high-quality markers were selected for linkage map construction based on marker coverage among individuals and read depths. For the linkage map, a total of 6,146 markers spanning 4,271.43 cM were mapped to 44 sex-averaged linkage groups, with an average marker distance of 0.7 cM. An integration analysis linked 5,885 genome scaffolds and 1,504 BAC clones to the linkage map. Based on the high-density linkage map, several QTLs for body weight and body length were detected. This high-density genetic linkage map reveals basic genomic architecture and will be useful for comparative genomics research, genome assembly and genetic improvement of L. vannamei and other penaeid shrimp species. PMID:26503227

Identification of successive flowering phases highlights a new genetic control of the flowering pattern in strawberry

PubMed Central

Perrotte, Justine; Guédon, Yann; Gaston, Amèlia; Denoyes, Béatrice

2016-01-01

The genetic control of the switch between seasonal and perpetual flowering has been deciphered in various perennial species. However, little is known about the genetic control of the dynamics of perpetual flowering, which changes abruptly at well-defined time instants during the growing season. Here, we characterize the perpetual flowering pattern and identify new genetic controls of this pattern in the cultivated strawberry. Twenty-one perpetual flowering strawberry genotypes were phenotyped at the macroscopic scale for their course of emergence of inflorescences and stolons during the growing season. A longitudinal analysis based on the segmentation of flowering rate profiles using multiple change-point models was conducted. The flowering pattern of perpetual flowering genotypes takes the form of three or four successive phases: an autumn-initiated flowering phase, a flowering pause, and a single stationary perpetual flowering phase or two perpetual flowering phases, the second one being more intense. The genetic control of flowering was analysed by quantitative trait locus mapping of flowering traits based on these flowering phases. We showed that the occurrence of a fourth phase of intense flowering is controlled by a newly identified locus, different from the locus FaPFRU, controlling the switch between seasonal and perpetual flowering behaviour. The role of this locus was validated by the analysis of data obtained previously during six consecutive years. PMID:27664957

X exceptionalism in Caenorhabditis speciation.

PubMed

Cutter, Asher D

2017-11-13

Speciation genetics research in diverse organisms shows the X-chromosome to be exceptional in how it contributes to "rules" of speciation. Until recently, however, the nematode phylum has been nearly silent on this issue, despite the model organism Caenorhabditis elegans having touched most other topics in biology. Studies of speciation with Caenorhabditis accelerated with the recent discovery of species pairs showing partial interfertility. The resulting genetic analyses of reproductive isolation in nematodes demonstrate key roles for the X-chromosome in hybrid male sterility and inviability, opening up new understanding of the genetic causes of Haldane's rule, Darwin's corollary to Haldane's rule, and enabling tests of the large-X effect hypothesis. Studies to date implicate improper chromatin regulation of the X-chromosome by small RNA pathways as integral to hybrid male dysfunction. Sexual transitions in reproductive mode to self-fertilizing hermaphroditism inject distinctive molecular evolutionary features into the speciation process for some species. Caenorhabditis also provides unique opportunities for analysis in a system with XO sex determination that lacks a Y-chromosome, sex chromosome-dependent sperm competition differences and mechanisms of gametic isolation, exceptional accessibility to the development process and rapid experimental evolution. As genetic analysis of reproductive isolation matures with investigation of multiple pairs of Caenorhabditis species and new species discovery, nematodes will provide a powerful complement to more established study organisms for deciphering the genetic basis of and rules to speciation. © 2017 John Wiley & Sons Ltd.

[Direct genetic manipulation and criminal code in Venezuela: absolute criminal law void?].

PubMed

Cermeño Zambrano, Fernando G De J

2002-01-01

The judicial regulation of genetic biotechnology applied to the human genome is of big relevance currently in Venezuela due to the drafting of an innovative bioethical law in the country's parliament. This article will highlight the constitutional normative of Venezuela's 1999 Constitution regarding this subject, as it establishes the framework from which this matter will be legally regulated. The approach this article makes towards the genetic biotechnology applied to the human genome is made taking into account the Venezuelan penal law and by highlighting the violent genetic manipulations that have criminal relevance. The genetic biotechnology applied to the human genome has another important relevance as a consequence of the reformulation of the Venezuelan Penal Code discussed by the country's National Assembly. Therefore, a concise study of the country's penal code will be made in this article to better understand what judicial-penal properties have been protected by the Venezuelan penal legislation. This last step will enable us to identify the penal tools Venezuela counts on to face direct genetic manipulations. We will equally indicate the existing punitive loophole and that should be covered by the penal legislator. In conclusion, this essay concerns criminal policy, referred to the direct genetic manipulations on the human genome that haven't been typified in Venezuelan law, thus discovering a genetic biotechnology paradise.

Decoding the genome beyond sequencing: the new phase of genomic research.

PubMed

Heng, Henry H Q; Liu, Guo; Stevens, Joshua B; Bremer, Steven W; Ye, Karen J; Abdallah, Batoul Y; Horne, Steven D; Ye, Christine J

2011-10-01

While our understanding of gene-based biology has greatly improved, it is clear that the function of the genome and most diseases cannot be fully explained by genes and other regulatory elements. Genes and the genome represent distinct levels of genetic organization with their own coding systems; Genes code parts like protein and RNA, but the genome codes the structure of genetic networks, which are defined by the whole set of genes, chromosomes and their topological interactions within a cell. Accordingly, the genetic code of DNA offers limited understanding of genome functions. In this perspective, we introduce the genome theory which calls for the departure of gene-centric genomic research. To make this transition for the next phase of genomic research, it is essential to acknowledge the importance of new genome-based biological concepts and to establish new technology platforms to decode the genome beyond sequencing. Copyright © 2011 Elsevier Inc. All rights reserved.

Use of fluorescent proteins and color-coded imaging to visualize cancer cells with different genetic properties.

PubMed

Hoffman, Robert M

2016-03-01

Fluorescent proteins are very bright and available in spectrally-distinct colors, enable the imaging of color-coded cancer cells growing in vivo and therefore the distinction of cancer cells with different genetic properties. Non-invasive and intravital imaging of cancer cells with fluorescent proteins allows the visualization of distinct genetic variants of cancer cells down to the cellular level in vivo. Cancer cells with increased or decreased ability to metastasize can be distinguished in vivo. Gene exchange in vivo which enables low metastatic cancer cells to convert to high metastatic can be color-coded imaged in vivo. Cancer stem-like and non-stem cells can be distinguished in vivo by color-coded imaging. These properties also demonstrate the vast superiority of imaging cancer cells in vivo with fluorescent proteins over photon counting of luciferase-labeled cancer cells.

Was Wright Right? The Canonical Genetic Code is an Empirical Example of an Adaptive Peak in Nature; Deviant Genetic Codes Evolved Using Adaptive Bridges

PubMed Central

2010-01-01

The canonical genetic code is on a sub-optimal adaptive peak with respect to its ability to minimize errors, and is close to, but not quite, optimal. This is demonstrated by the near-total adjacency of synonymous codons, the similarity of adjacent codons, and comparisons of frequency of amino acid usage with number of codons in the code for each amino acid. As a rare empirical example of an adaptive peak in nature, it shows adaptive peaks are real, not merely theoretical. The evolution of deviant genetic codes illustrates how populations move from a lower to a higher adaptive peak. This is done by the use of “adaptive bridges,” neutral pathways that cross over maladaptive valleys by virtue of masking of the phenotypic expression of some maladaptive aspects in the genotype. This appears to be the general mechanism by which populations travel from one adaptive peak to another. There are multiple routes a population can follow to cross from one adaptive peak to another. These routes vary in the probability that they will be used, and this probability is determined by the number and nature of the mutations that happen along each of the routes. A modification of the depiction of adaptive landscapes showing genetic distances and probabilities of travel along their multiple possible routes would throw light on this important concept. PMID:20711776

A PQL (protein quantity loci) analysis of mature pea seed proteins identifies loci determining seed protein composition.

PubMed

Bourgeois, Michael; Jacquin, Françoise; Cassecuelle, Florence; Savois, Vincent; Belghazi, Maya; Aubert, Grégoire; Quillien, Laurence; Huart, Myriam; Marget, Pascal; Burstin, Judith

2011-05-01

Legume seeds are a major source of dietary proteins for humans and animals. Deciphering the genetic control of their accumulation is thus of primary significance towards their improvement. At first, we analysed the genetic variability of the pea seed proteome of three genotypes over 3 years of cultivation. This revealed that seed protein composition variability was under predominant genetic control, with as much as 60% of the spots varying quantitatively among the three genotypes. Then, by combining proteomic and quantitative trait loci (QTL) mapping approaches, we uncovered the genetic architecture of seed proteome variability. Protein quantity loci (PQL) were searched for 525 spots detected on 2-D gels obtained for 157 recombinant inbred lines. Most protein quantity loci mapped in clusters, suggesting that the accumulation of the major storage protein families was under the control of a limited number of loci. While convicilin accumulation was mainly under the control of cis-regulatory regions, vicilins and legumins were controlled by both cis- and trans-regulatory regions. Some loci controlled both seed protein composition and protein content and a locus on LGIIa appears to be a major regulator of protein composition and of protein in vitro digestibility. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Computation of the Genetic Code

NASA Astrophysics Data System (ADS)

Kozlov, Nicolay N.; Kozlova, Olga N.

2018-03-01

One of the problems in the development of mathematical theory of the genetic code (summary is presented in [1], the detailed -to [2]) is the problem of the calculation of the genetic code. Similar problems in the world is unknown and could be delivered only in the 21st century. One approach to solving this problem is devoted to this work. For the first time provides a detailed description of the method of calculation of the genetic code, the idea of which was first published earlier [3]), and the choice of one of the most important sets for the calculation was based on an article [4]. Such a set of amino acid corresponds to a complete set of representations of the plurality of overlapping triple gene belonging to the same DNA strand. A separate issue was the initial point, triggering an iterative search process all codes submitted by the initial data. Mathematical analysis has shown that the said set contains some ambiguities, which have been founded because of our proposed compressed representation of the set. As a result, the developed method of calculation was limited to the two main stages of research, where the first stage only the of the area were used in the calculations. The proposed approach will significantly reduce the amount of computations at each step in this complex discrete structure.

Coding of Class I and II aminoacyl-tRNA synthetases

PubMed Central

Carter, Charles W.

2018-01-01

SUMMARY The aminoacyl-tRNA synthetases and their cognate transfer RNAs translate the universal genetic code. The twenty canonical amino acids are sufficiently diverse to create a selective advantage for dividing amino acid activation between two distinct, apparently unrelated superfamilies of synthetases, Class I amino acids being generally larger and less polar, Class II amino acids smaller and more polar. Biochemical, bioinformatic, and protein engineering experiments support the hypothesis that the two Classes descended from opposite strands of the same ancestral gene. Parallel experimental deconstructions of Class I and II synthetases reveal parallel losses in catalytic proficiency at two novel modular levels—protozymes and Urzymes—associated with the evolution of catalytic activity. Bi-directional coding supports an important unification of the proteome; affords a genetic relatedness metric—middle base-pairing frequencies in sense/antisense alignments—that probes more deeply into the evolutionary history of translation than do single multiple sequence alignments; and has facilitated the analysis of hitherto unknown coding relationships in tRNA sequences. Reconstruction of native synthetases by modular thermodynamic cycles facilitated by domain engineering emphasizes the subtlety associated with achieving high specificity, shedding new light on allosteric relationships in contemporary synthetases. Synthetase Urzyme structural biology suggests that they are catalytically active molten globules, broadening the potential manifold of polypeptide catalysts accessible to primitive genetic coding and motivating revisions of the origins of catalysis. Finally, bi-directional genetic coding of some of the oldest genes in the proteome places major limitations on the likelihood that any RNA World preceded the origins of coded proteins. PMID:28828732

The lack of foundation in the mechanism on which are based the physico-chemical theories for the origin of the genetic code is counterposed to the credible and natural mechanism suggested by the coevolution theory.

PubMed

Di Giulio, Massimo

2016-06-21

I analyze the mechanism on which are based the majority of theories that put to the center of the origin of the genetic code the physico-chemical properties of amino acids. As this mechanism is based on excessive mutational steps, I conclude that it could not have been operative or if operative it would not have allowed a full realization of predictions of these theories, because this mechanism contained, evidently, a high indeterminacy. I make that disapproving the four-column theory of the origin of the genetic code (Higgs, 2009) and reply to the criticism that was directed towards the coevolution theory of the origin of the genetic code. In this context, I suggest a new hypothesis that clarifies the mechanism by which the domains of codons of the precursor amino acids would have evolved, as predicted by the coevolution theory. This mechanism would have used particular elongation factors that would have constrained the evolution of all amino acids belonging to a given biosynthetic family to the progenitor pre-tRNA, that for first recognized, the first codons that evolved in a certain codon domain of a determined precursor amino acid. This happened because the elongation factors recognized two characteristics of the progenitor pre-tRNAs of precursor amino acids, which prevented the elongation factors from recognizing the pre-tRNAs belonging to biosynthetic families of different precursor amino acids. Finally, I analyze by means of Fisher's exact test, the distribution, within the genetic code, of the biosynthetic classes of amino acids and the ones of polarity values of amino acids. This analysis would seem to support the biosynthetic classes of amino acids over the ones of polarity values, as the main factor that led to the structuring of the genetic code, with the physico-chemical properties of amino acids playing only a subsidiary role in this evolution. As a whole, the full analysis brings to the conclusion that the coevolution theory of the origin of the genetic code would be a theory highly corroborated. Copyright © 2016 Elsevier Ltd. All rights reserved.

Comparative use of InDel and SSR markers in deciphering the interspecific structure of cultivated citrus genetic diversity: a perspective for genetic association studies.

PubMed

García-Lor, Andrés; Luro, François; Navarro, Luis; Ollitrault, Patrick

2012-01-01

Genetic stratification associated with domestication history is a key parameter for estimating the pertinence of genetic association study within a gene pool. Previous molecular and phenotypic studies have shown that most of the diversity of cultivated citrus results from recombination between three main species: C. medica (citron), C. reticulata (mandarin) and C. maxima (pummelo). However, the precise contribution of each of these basic species to the genomes of secondary cultivated species, such as C. sinensis (sweet orange), C. limon (lemon), C. aurantium (sour orange), C. paradisi (grapefruit) and recent hybrids is unknown. Our study focused on: (1) the development of insertion-deletion (InDel) markers and their comparison with SSR markers for use in genetic diversity and phylogenetic studies; (2) the analysis of the contributions of basic taxa to the genomes of secondary species and modern cultivars and (3) the description of the organisation of the Citrus gene pool, to evaluate how genetic association studies should be done at the cultivated Citrus gene pool level. InDel markers appear to be better phylogenetic markers for tracing the contributions of the three ancestral species, whereas SSR markers are more useful for intraspecific diversity analysis. Most of the genetic organisation of the Citrus gene pool is related to the differentiation between C. reticulata, C. maxima and C. medica. High and generalised LD was observed, probably due to the initial differentiation between the basic species and a limited number of interspecific recombinations. This structure precludes association genetic studies at the genus level without developing additional recombinant populations from interspecific hybrids. Association genetic studies should also be affordable at intraspecific level in a less structured pool such as C. reticulata.

Genetic Recombination Between Stromal and Cancer Cells Results in Highly Malignant Cells Identified by Color-Coded Imaging in a Mouse Lymphoma Model.

PubMed

Nakamura, Miki; Suetsugu, Atsushi; Hasegawa, Kousuke; Matsumoto, Takuro; Aoki, Hitomi; Kunisada, Takahiro; Shimizu, Masahito; Saji, Shigetoyo; Moriwaki, Hisataka; Hoffman, Robert M

2017-12-01

The tumor microenvironment (TME) promotes tumor growth and metastasis. We previously established the color-coded EL4 lymphoma TME model with red fluorescent protein (RFP) expressing EL4 implanted in transgenic C57BL/6 green fluorescent protein (GFP) mice. Color-coded imaging of the lymphoma TME suggested an important role of stromal cells in lymphoma progression and metastasis. In the present study, we used color-coded imaging of RFP-lymphoma cells and GFP stromal cells to identify yellow-fluorescent genetically recombinant cells appearing only during metastasis. The EL4-RFP lymphoma cells were injected subcutaneously in C57BL/6-GFP transgenic mice and formed subcutaneous tumors 14 days after cell transplantation. The subcutaneous tumors were harvested and transplanted to the abdominal cavity of nude mice. Metastases to the liver, perigastric lymph node, ascites, bone marrow, and primary tumor were imaged. In addition to EL4-RFP cells and GFP-host cells, genetically recombinant yellow-fluorescent cells, were observed only in the ascites and bone marrow. These results indicate genetic exchange between the stromal and cancer cells. Possible mechanisms of genetic exchange are discussed as well as its ramifications for metastasis. J. Cell. Biochem. 118: 4216-4221, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Using Supercomputers to Probe the Early Universe

DOE Office of Scientific and Technical Information (OSTI.GOV)

Giorgi, Elena Edi

For decades physicists have been trying to decipher the first moments after the Big Bang. Using very large telescopes, for example, scientists scan the skies and look at how fast galaxies move. Satellites study the relic radiation left from the Big Bang, called the cosmic microwave background radiation. And finally, particle colliders, like the Large Hadron Collider at CERN, allow researchers to smash protons together and analyze the debris left behind by such collisions. Physicists at Los Alamos National Laboratory, however, are taking a different approach: they are using computers. In collaboration with colleagues at University of California San Diego,more » the Los Alamos researchers developed a computer code, called BURST, that can simulate conditions during the first few minutes of cosmological evolution.« less

New strategies to improve the efficacy of colorectal cancer vaccines: from bench to bedside.

PubMed

Mocellin, Simone

2006-12-01

By exploiting a naturally occurring defense system, anticancer vaccination embodies an ideal non-toxic treatment capable of evoking tumor-specific immune responses that can ultimately recognize and kill colorectal cancer (CRC) cells. Despite the enormous theoretical potential of active specific immunotherapy, no vaccination regimen has achieved sufficient therapeutic efficacy necessary for clinical implementation. Nevertheless, several immunological advances have opened new avenues of research to decipher the biological code governing tumor immune responsiveness, and this is leading to the design of potentially more effective immunotherapeutic protocols. This review briefly summarizes the principles behind anti-CRC vaccination and describes the most promising immunological strategies that have been developed, which are expected to renew interest in this molecularly targeted anticancer approach.

A new coding system for metabolic disorders demonstrates gaps in the international disease classifications ICD-10 and SNOMED-CT, which can be barriers to genotype-phenotype data sharing.

PubMed

Sollie, Annet; Sijmons, Rolf H; Lindhout, Dick; van der Ploeg, Ans T; Rubio Gozalbo, M Estela; Smit, G Peter A; Verheijen, Frans; Waterham, Hans R; van Weely, Sonja; Wijburg, Frits A; Wijburg, Rudolph; Visser, Gepke

2013-07-01

Data sharing is essential for a better understanding of genetic disorders. Good phenotype coding plays a key role in this process. Unfortunately, the two most widely used coding systems in medicine, ICD-10 and SNOMED-CT, lack information necessary for the detailed classification and annotation of rare and genetic disorders. This prevents the optimal registration of such patients in databases and thus data-sharing efforts. To improve care and to facilitate research for patients with metabolic disorders, we developed a new coding system for metabolic diseases with a dedicated group of clinical specialists. Next, we compared the resulting codes with those in ICD and SNOMED-CT. No matches were found in 76% of cases in ICD-10 and in 54% in SNOMED-CT. We conclude that there are sizable gaps in the SNOMED-CT and ICD coding systems for metabolic disorders. There may be similar gaps for other classes of rare and genetic disorders. We have demonstrated that expert groups can help in addressing such coding issues. Our coding system has been made available to the ICD and SNOMED-CT organizations as well as to the Orphanet and HPO organizations for further public application and updates will be published online (www.ddrmd.nl and www.cineas.org). © 2013 WILEY PERIODICALS, INC.

Expanding the genetic code for site-specific labelling of tobacco mosaic virus coat protein and building biotin-functionalized virus-like particles.

PubMed

Wu, F C; Zhang, H; Zhou, Q; Wu, M; Ballard, Z; Tian, Y; Wang, J Y; Niu, Z W; Huang, Y

2014-04-18

A method for site-specific and high yield modification of tobacco mosaic virus coat protein (TMVCP) utilizing a genetic code expanding technology and copper free cycloaddition reaction has been established, and biotin-functionalized virus-like particles were built by the self-assembly of the protein monomers.

On origin of genetic code and tRNA before translation

PubMed Central

2011-01-01

Background Synthesis of proteins is based on the genetic code - a nearly universal assignment of codons to amino acids (aas). A major challenge to the understanding of the origins of this assignment is the archetypal "key-lock vs. frozen accident" dilemma. Here we re-examine this dilemma in light of 1) the fundamental veto on "foresight evolution", 2) modular structures of tRNAs and aminoacyl-tRNA synthetases, and 3) the updated library of aa-binding sites in RNA aptamers successfully selected in vitro for eight amino acids. Results The aa-binding sites of arginine, isoleucine and tyrosine contain both their cognate triplets, anticodons and codons. We have noticed that these cases might be associated with palindrome-dinucleotides. For example, one-base shift to the left brings arginine codons CGN, with CG at 1-2 positions, to the respective anticodons NCG, with CG at 2-3 positions. Formally, the concomitant presence of codons and anticodons is also expected in the reverse situation, with codons containing palindrome-dinucleotides at their 2-3 positions, and anticodons exhibiting them at 1-2 positions. A closer analysis reveals that, surprisingly, RNA binding sites for Arg, Ile and Tyr "prefer" (exactly as in the actual genetic code) the anticodon(2-3)/codon(1-2) tetramers to their anticodon(1-2)/codon(2-3) counterparts, despite the seemingly perfect symmetry of the latter. However, since in vitro selection of aa-specific RNA aptamers apparently had nothing to do with translation, this striking preference provides a new strong support to the notion of the genetic code emerging before translation, in response to catalytic (and possibly other) needs of ancient RNA life. Consistently with the pre-translation origin of the code, we propose here a new model of tRNA origin by the gradual, Fibonacci process-like, elongation of a tRNA molecule from a primordial coding triplet and 5'DCCA3' quadruplet (D is a base-determinator) to the eventual 76 base-long cloverleaf-shaped molecule. Conclusion Taken together, our findings necessarily imply that primordial tRNAs, tRNA aminoacylating ribozymes, and (later) the translation machinery in general have been co-evolving to ''fit'' the (likely already defined) genetic code, rather than the opposite way around. Coding triplets in this primal pre-translational code were likely similar to the anticodons, with second and third nucleotides being more important than the less specific first one. Later, when the code was expanding in co-evolution with the translation apparatus, the importance of 2-3 nucleotides of coding triplets "transferred" to the 1-2 nucleotides of their complements, thus distinguishing anticodons from codons. This evolutionary primacy of anticodons in genetic coding makes the hypothesis of primal stereo-chemical affinity between amino acids and cognate triplets, the hypothesis of coding coenzyme handles for amino acids, the hypothesis of tRNA-like genomic 3' tags suggesting that tRNAs originated in replication, and the hypothesis of ancient ribozymes-mediated operational code of tRNA aminoacylation not mutually contradicting but rather co-existing in harmony. Reviewers This article was reviewed by Eugene V. Koonin, Wentao Ma (nominated by Juergen Brosius) and Anthony Poole. PMID:21342520

Genetic code mutations: the breaking of a three billion year invariance.

PubMed

Mat, Wai-Kin; Xue, Hong; Wong, J Tze-Fei

2010-08-20

The genetic code has been unchanging for some three billion years in its canonical ensemble of encoded amino acids, as indicated by the universal adoption of this ensemble by all known organisms. Code mutations beginning with the encoding of 4-fluoro-Trp by Bacillus subtilis, initially replacing and eventually displacing Trp from the ensemble, first revealed the intrinsic mutability of the code. This has since been confirmed by a spectrum of other experimental code alterations in both prokaryotes and eukaryotes. To shed light on the experimental conversion of a rigidly invariant code to a mutating code, the present study examined code mutations determining the propagation of Bacillus subtilis on Trp and 4-, 5- and 6-fluoro-tryptophans. The results obtained with the mutants with respect to cross-inhibitions between the different indole amino acids, and the growth effects of individual nutrient withdrawals rendering essential their biosynthetic pathways, suggested that oligogenic barriers comprising sensitive proteins which malfunction with amino acid analogues provide effective mechanisms for preserving the invariance of the code through immemorial time, and mutations of these barriers open up the code to continuous change.

Macrophage–Microbe Interactions: Lessons from the Zebrafish Model

PubMed Central

Yoshida, Nagisa; Frickel, Eva-Maria; Mostowy, Serge

2017-01-01

Macrophages provide front line defense against infections. The study of macrophage–microbe interplay is thus crucial for understanding pathogenesis and infection control. Zebrafish (Danio rerio) larvae provide a unique platform to study macrophage–microbe interactions in vivo, from the level of the single cell to the whole organism. Studies using zebrafish allow non-invasive, real-time visualization of macrophage recruitment and phagocytosis. Furthermore, the chemical and genetic tractability of zebrafish has been central to decipher the complex role of macrophages during infection. Here, we discuss the latest developments using zebrafish models of bacterial and fungal infection. We also review novel aspects of macrophage biology revealed by zebrafish, which can potentiate development of new therapeutic strategies for humans. PMID:29250076

[Diagnosis of a case with Williams-Beuren syndrome with nephrocalcinosis using chromosome microarray analysis].

PubMed

Jin, S J; Liu, M; Long, W J; Luo, X P

2016-12-02

Objective: To explore the clinical phenotypes and the genetic cause for a boy with unexplained growth retardation, nephrocalcinosis, auditory anomalies and multi-organ/system developmental disorders. Method: Routine G-banding and chromosome microarray analysis were applied to a child with unexplained growth retardation, nephrocalcinosis, auditory anomalies and multi-organ/system developmental disorders treated in the Department of Pediatrics of Tongji Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology in September 2015 and his parents to conduct the chromosomal karyotype analysis and the whole genome scanning. Deleted genes were searched in the Decipher and NCBI databases, and their relationships with the clinical phenotypes were analyzed. Result: A six-month-old boy was refered to us because of unexplained growth retardation and feeding intolerance.The affected child presented with abnormal manifestation such as special face, umbilical hernia, growth retardation, hypothyroidism, congenital heart disease, right ear sensorineural deafness, hypercalcemia and nephrocalcinosis. The child's karyotype was 46, XY, 16qh + , and his parents' karyotypes were normal. Chromosome microarray analysis revealed a 1 436 kb deletion on the 7q11.23(72701098_74136633) region of the child. This region included 23 protein-coding genes, which were reported to be corresponding to Williams-Beuren syndrome and its certain clinical phenotypes. His parents' results of chromosome microarray analysis were normal. Conclusion: A boy with characteristic manifestation of Williams-Beuren syndrome and rare nephrocalcinosis was diagnosed using chromosome microarray analysis. The deletion on the 7q11.23 might be related to the clinical phenotypes of Williams-Beuren syndrome, yet further studies are needed.

Genome sequence of the small brown planthopper, Laodelphax striatellus.

PubMed

Zhu, Junjie; Jiang, Feng; Wang, Xianhui; Yang, Pengcheng; Bao, Yanyuan; Zhao, Wan; Wang, Wei; Lu, Hong; Wang, Qianshuo; Cui, Na; Li, Jing; Chen, Xiaofang; Luo, Lan; Yu, Jinting; Kang, Le; Cui, Feng

2017-12-01

Laodelphax striatellus Fallén (Hemiptera: Delphacidae) is one of the most destructive rice pests. L. striatellus is different from 2 other rice planthoppers with a released genome sequence, Sogatella furcifera and Nilaparvata lugens, in many biological characteristics, such as host range, dispersal capacity, and vectoring plant viruses. Deciphering the genome of L. striatellus will further the understanding of the genetic basis of the biological differences among the 3 rice planthoppers. A total of 190 Gb of Illumina data and 32.4 Gb of Pacbio data were generated and used to assemble a high-quality L. striatellus genome sequence, which is 541 Mb in length and has a contig N50 of 118 Kb and a scaffold N50 of 1.08 Mb. Annotated repetitive elements account for 25.7% of the genome. A total of 17 736 protein-coding genes were annotated, capturing 97.6% and 98% of the BUSCO eukaryote and arthropoda genes, respectively. Compared with N. lugens and S. furcifera, L. striatellus has the smallest genome and the lowest gene number. Gene family expansion and transcriptomic analyses provided hints to the genomic basis of the differences in important traits such as host range, migratory habit, and plant virus transmission between L. striatellus and the other 2 planthoppers. We report a high-quality genome assembly of L. striatellus, which is an important genomic resource not only for the study of the biology of L. striatellus and its interactions with plant hosts and plant viruses, but also for comparison with other planthoppers. © The Authors 2017. Published by Oxford University Press.

Genome sequence of the small brown planthopper, Laodelphax striatellus

PubMed Central

Zhu, Junjie; Jiang, Feng; Wang, Xianhui; Yang, Pengcheng; Bao, Yanyuan; Zhao, Wan; Wang, Wei; Lu, Hong; Wang, Qianshuo; Cui, Na; Li, Jing; Chen, Xiaofang; Luo, Lan; Yu, Jinting

2017-01-01

Abstract Background Laodelphax striatellus Fallén (Hemiptera: Delphacidae) is one of the most destructive rice pests. L. striatellus is different from 2 other rice planthoppers with a released genome sequence, Sogatella furcifera and Nilaparvata lugens, in many biological characteristics, such as host range, dispersal capacity, and vectoring plant viruses. Deciphering the genome of L. striatellus will further the understanding of the genetic basis of the biological differences among the 3 rice planthoppers. Findings A total of 190 Gb of Illumina data and 32.4 Gb of Pacbio data were generated and used to assemble a high-quality L. striatellus genome sequence, which is 541 Mb in length and has a contig N50 of 118 Kb and a scaffold N50 of 1.08 Mb. Annotated repetitive elements account for 25.7% of the genome. A total of 17 736 protein-coding genes were annotated, capturing 97.6% and 98% of the BUSCO eukaryote and arthropoda genes, respectively. Compared with N. lugens and S. furcifera, L. striatellus has the smallest genome and the lowest gene number. Gene family expansion and transcriptomic analyses provided hints to the genomic basis of the differences in important traits such as host range, migratory habit, and plant virus transmission between L. striatellus and the other 2 planthoppers. Conclusions We report a high-quality genome assembly of L. striatellus, which is an important genomic resource not only for the study of the biology of L. striatellus and its interactions with plant hosts and plant viruses, but also for comparison with other planthoppers. PMID:29136191

On the Evolution of the Standard Genetic Code: Vestiges of Critical Scale Invariance from the RNA World in Current Prokaryote Genomes

PubMed Central

José, Marco V.; Govezensky, Tzipe; García, José A.; Bobadilla, Juan R.

2009-01-01

Herein two genetic codes from which the primeval RNA code could have originated the standard genetic code (SGC) are derived. One of them, called extended RNA code type I, consists of all codons of the type RNY (purine-any base-pyrimidine) plus codons obtained by considering the RNA code but in the second (NYR type) and third (YRN type) reading frames. The extended RNA code type II, comprises all codons of the type RNY plus codons that arise from transversions of the RNA code in the first (YNY type) and third (RNR) nucleotide bases. In order to test if putative nucleotide sequences in the RNA World and in both extended RNA codes, share the same scaling and statistical properties to those encountered in current prokaryotes, we used the genomes of four Eubacteria and three Archaeas. For each prokaryote, we obtained their respective genomes obeying the RNA code or the extended RNA codes types I and II. In each case, we estimated the scaling properties of triplet sequences via a renormalization group approach, and we calculated the frequency distributions of distances for each codon. Remarkably, the scaling properties of the distance series of some codons from the RNA code and most codons from both extended RNA codes turned out to be identical or very close to the scaling properties of codons of the SGC. To test for the robustness of these results, we show, via computer simulation experiments, that random mutations of current genomes, at the rates of 10−10 per site per year during three billions of years, were not enough for destroying the observed patterns. Therefore, we conclude that most current prokaryotes may still contain relics of the primeval RNA World and that both extended RNA codes may well represent two plausible evolutionary paths between the RNA code and the current SGC. PMID:19183813

Pathomechanisms of polycystic ovary syndrome: Multidimensional approaches.

PubMed

Sagvekar, Pooja; Dadachanji, Roshan; Patil, Krutika; Mukherjee, Srabani

2018-03-01

Polycystic ovary syndrome is a complex endocrine disorder affecting numerous women of reproductive age across the globe. Characterized mainly by irregular menses, hirsutism, skewed LH: FSH ratios and bulky polycystic ovaries, this multifactorial endocrinopathy results in unfavorable reproductive and metabolic sequelae, including anovulatory infertility, type 2 diabetes, metabolic syndrome and cardiovascular disease in later years. Increasing evidence has shown that the manifestation of polycystic ovary syndrome (PCOS) is attributable to a cumulative impact of altered genetic, epigenetic and protein profiles which bring about a systemic dysfunction. While genetic approaches help ascertain role of causal variants in its etiology, tissue-specific epigenetic patterns help in deciphering the auxiliary role of environmental, nutritional and behavioral factors. Proteomics is advantageous, linking both genotype and phenotype and contributing to biomarker discovery. Investigating molecular mechanism underlying PCOS is imperative in order to gain insight into the pathophysiology of PCOS and formulate novel diagnostic and treatment strategies. In this review we have summarized these three aspects, which have been successfully utilized to delineate the pathomechanisms of PCOS.

Congenital adrenal hyperplasia due to 11-beta-hydroxylase deficiency: description of a new mutation, R384X.

PubMed

Matallana-Rhoades, Audrey Mary; Corredor-Castro, Juan David; Bonilla-Escobar, Francisco Javier; Mecias-Cruz, Bony Valentina; Mejia de Beldjena, Liliana

2016-09-30

It is presented the phenotype of a new compound heterozygous mutation of the genes R384X and Q356X encoding the enzyme of 11-beta-hydroxylase. Severe virilization, peripheral hypertension, and early puberty. Managed with hormone replacement therapy (corticosteroid) and antihypertensive therapy (beta-blocker), resulting in the control of physical changes and levels of arterial tension. According to the phenotypic characteristics of the patient, it is inferred that the R384X mutation carries an additional burden on the Q356X mutation, with the latter previously described as a cause of 11-beta-hydroxylase deficiency. The description of a new genotype, as in this case, expands the understanding of the hereditary burden and deciphers the various factors that lead to this pathology as well as the other forms of congenital adrenal hyperplasia (CAH), presenting with a broad spectrum of clinical presentations. This study highlights the importance of a complete description of the patient's CAH genetic profile as well as their parents' genetic profile.

Outbred genome sequencing and CRISPR/Cas9 gene editing in butterflies

PubMed Central

Li, Xueyan; Fan, Dingding; Zhang, Wei; Liu, Guichun; Zhang, Lu; Zhao, Li; Fang, Xiaodong; Chen, Lei; Dong, Yang; Chen, Yuan; Ding, Yun; Zhao, Ruoping; Feng, Mingji; Zhu, Yabing; Feng, Yue; Jiang, Xuanting; Zhu, Deying; Xiang, Hui; Feng, Xikan; Li, Shuaicheng; Wang, Jun; Zhang, Guojie; Kronforst, Marcus R.; Wang, Wen

2015-01-01

Butterflies are exceptionally diverse but their potential as an experimental system has been limited by the difficulty of deciphering heterozygous genomes and a lack of genetic manipulation technology. Here we use a hybrid assembly approach to construct high-quality reference genomes for Papilio xuthus (contig and scaffold N50: 492 kb, 3.4 Mb) and Papilio machaon (contig and scaffold N50: 81 kb, 1.15 Mb), highly heterozygous species that differ in host plant affiliations, and adult and larval colour patterns. Integrating comparative genomics and analyses of gene expression yields multiple insights into butterfly evolution, including potential roles of specific genes in recent diversification. To functionally test gene function, we develop an efficient (up to 92.5%) CRISPR/Cas9 gene editing method that yields obvious phenotypes with three genes, Abdominal-B, ebony and frizzled. Our results provide valuable genomic and technological resources for butterflies and unlock their potential as a genetic model system. PMID:26354079

Ancient Egyptian mummy genomes suggest an increase of Sub-Saharan African ancestry in post-Roman periods.

PubMed

Schuenemann, Verena J; Peltzer, Alexander; Welte, Beatrix; van Pelt, W Paul; Molak, Martyna; Wang, Chuan-Chao; Furtwängler, Anja; Urban, Christian; Reiter, Ella; Nieselt, Kay; Teßmann, Barbara; Francken, Michael; Harvati, Katerina; Haak, Wolfgang; Schiffels, Stephan; Krause, Johannes

2017-05-30

Egypt, located on the isthmus of Africa, is an ideal region to study historical population dynamics due to its geographic location and documented interactions with ancient civilizations in Africa, Asia and Europe. Particularly, in the first millennium BCE Egypt endured foreign domination leading to growing numbers of foreigners living within its borders possibly contributing genetically to the local population. Here we present 90 mitochondrial genomes as well as genome-wide data sets from three individuals obtained from Egyptian mummies. The samples recovered from Middle Egypt span around 1,300 years of ancient Egyptian history from the New Kingdom to the Roman Period. Our analyses reveal that ancient Egyptians shared more ancestry with Near Easterners than present-day Egyptians, who received additional sub-Saharan admixture in more recent times. This analysis establishes ancient Egyptian mummies as a genetic source to study ancient human history and offers the perspective of deciphering Egypt's past at a genome-wide level.

Genetics and Molecular Pathogenesis of Gastric Adenocarcinoma.

PubMed

Tan, Patrick; Yeoh, Khay-Guan

2015-10-01

Gastric cancer (GC) is globally the fifth most common cancer and third leading cause of cancer death. A complex disease arising from the interaction of environmental and host-associated factors, key contributors to GC's high mortality include its silent nature, late clinical presentation, and underlying biological and genetic heterogeneity. Achieving a detailed molecular understanding of the various genomic aberrations associated with GC will be critical to improving patient outcomes. The recent years has seen considerable progress in deciphering the genomic landscape of GC, identifying new molecular components such as ARID1A and RHOA, cellular pathways, and tissue populations associated with gastric malignancy and progression. The Cancer Genome Atlas (TCGA) project is a landmark in the molecular characterization of GC. Key challenges for the future will involve the translation of these molecular findings to clinical utility, by enabling novel strategies for early GC detection, and precision therapies for individual GC patients. Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.

Importance of Resolving Fungal Nomenclature: the Case of Multiple Pathogenic Species in the Cryptococcus Genus.

PubMed

Hagen, Ferry; Lumbsch, H Thorsten; Arsic Arsenijevic, Valentina; Badali, Hamid; Bertout, Sebastien; Billmyre, R Blake; Bragulat, M Rosa; Cabañes, F Javier; Carbia, Mauricio; Chakrabarti, Arunaloke; Chaturvedi, Sudha; Chaturvedi, Vishnu; Chen, Min; Chowdhary, Anuradha; Colom, Maria-Francisca; Cornely, Oliver A; Crous, Pedro W; Cuétara, Maria S; Diaz, Mara R; Espinel-Ingroff, Ana; Fakhim, Hamed; Falk, Rama; Fang, Wenjie; Herkert, Patricia F; Ferrer Rodríguez, Consuelo; Fraser, James A; Gené, Josepa; Guarro, Josep; Idnurm, Alexander; Illnait-Zaragozi, María-Teresa; Khan, Ziauddin; Khayhan, Kantarawee; Kolecka, Anna; Kurtzman, Cletus P; Lagrou, Katrien; Liao, Wanqing; Linares, Carlos; Meis, Jacques F; Nielsen, Kirsten; Nyazika, Tinashe K; Pan, Weihua; Pekmezovic, Marina; Polacheck, Itzhack; Posteraro, Brunella; de Queiroz Telles, Flavio; Romeo, Orazio; Sánchez, Manuel; Sampaio, Ana; Sanguinetti, Maurizio; Sriburee, Pojana; Sugita, Takashi; Taj-Aldeen, Saad J; Takashima, Masako; Taylor, John W; Theelen, Bart; Tomazin, Rok; Verweij, Paul E; Wahyuningsih, Retno; Wang, Ping; Boekhout, Teun

2017-01-01

Cryptococcosis is a major fungal disease caused by members of the Cryptococcus gattii and Cryptococcus neoformans species complexes. After more than 15 years of molecular genetic and phenotypic studies and much debate, a proposal for a taxonomic revision was made. The two varieties within C. neoformans were raised to species level, and the same was done for five genotypes within C. gattii . In a recent perspective (K. J. Kwon-Chung et al., mSphere 2:e00357-16, 2017, https://doi.org/10.1128/mSphere.00357-16), it was argued that this taxonomic proposal was premature and without consensus in the community. Although the authors of the perspective recognized the existence of genetic diversity, they preferred the use of the informal nomenclature " C. neoformans species complex" and " C. gattii species complex." Here we highlight the advantage of recognizing these seven species, as ignoring these species will impede deciphering further biologically and clinically relevant differences between them, which may in turn delay future clinical advances.

Ancient Egyptian mummy genomes suggest an increase of Sub-Saharan African ancestry in post-Roman periods

PubMed Central

Schuenemann, Verena J.; Peltzer, Alexander; Welte, Beatrix; van Pelt, W. Paul; Molak, Martyna; Wang, Chuan-Chao; Furtwängler, Anja; Urban, Christian; Reiter, Ella; Nieselt, Kay; Teßmann, Barbara; Francken, Michael; Harvati, Katerina; Haak, Wolfgang; Schiffels, Stephan; Krause, Johannes

2017-01-01

Egypt, located on the isthmus of Africa, is an ideal region to study historical population dynamics due to its geographic location and documented interactions with ancient civilizations in Africa, Asia and Europe. Particularly, in the first millennium BCE Egypt endured foreign domination leading to growing numbers of foreigners living within its borders possibly contributing genetically to the local population. Here we present 90 mitochondrial genomes as well as genome-wide data sets from three individuals obtained from Egyptian mummies. The samples recovered from Middle Egypt span around 1,300 years of ancient Egyptian history from the New Kingdom to the Roman Period. Our analyses reveal that ancient Egyptians shared more ancestry with Near Easterners than present-day Egyptians, who received additional sub-Saharan admixture in more recent times. This analysis establishes ancient Egyptian mummies as a genetic source to study ancient human history and offers the perspective of deciphering Egypt's past at a genome-wide level. PMID:28556824

Genetics, Molecular, and Proteomics Advances in Filamentous Fungi.

PubMed

Sharma Ghimire, Prakriti; Jin, Cheng

2017-10-01

Filamentous fungi play a dynamic role in health and the environment. In addition, their unique and complex hyphal structures are involved in their morphogenesis, integrity, synthesis, and degradation, according to environmental and physiological conditions and resource availability. However, in biotechnology, it has a great value in the production of enzymes, pharmaceuticals, and food ingredients. The beginning of nomenclature of overall fungi started in early 1990 after which the categorization, interior and exterior mechanism, function, molecular and genetics study took pace. This mini-review has emphasized some of the important aspects of filamentous fungi, their pattern of life cycle, history, and development of different strategic methods applied to exploit this unique organism. New trends and concepts that have been applied to overcome obstacle because of their basic structure related to genomics and systems biology has been presented. Furthermore, the future aspects and challenges that need to be deciphered to get a bigger and better picture of filamentous fungi have been discussed.

Mining for Murder-Suicide: An Approach to Identifying Cases of Murder-Suicide in the National Violent Death Reporting System Restricted Access Database.

PubMed

McNally, Matthew R; Patton, Christina L; Fremouw, William J

2016-01-01

The National Violent Death Reporting System (NVDRS) is a United States Centers for Disease Control and Prevention (CDC) database of violent deaths from 2003 to the present. The NVDRS collects information from 32 states on several types of violent deaths, including suicides, homicides, homicides followed by suicides, and deaths resulting from child maltreatment or intimate partner violence, as well as legal intervention and accidental firearm deaths. Despite the availability of data from police narratives, medical examiner reports, and other sources, reliably finding the cases of murder-suicide in the NVDRS has proven problematic due to the lack of a unique code for murder-suicide incidents and outdated descriptions of case-finding procedures from previous researchers. By providing a description of the methods used to access to the NVDRS and coding procedures used to decipher these data, the authors seek to assist future researchers in correctly identifying cases of murder-suicide deaths while avoiding false positives. © 2015 American Academy of Forensic Sciences.

Improving salinity tolerance of plants through conventional breeding and genetic engineering: An analytical comparison.

PubMed

Ashraf, Muhammad; Akram, Nudrat Aisha

2009-01-01

The last century has witnessed a substantial improvement in yield potential, quality and disease resistance in crops. This was indeed the outcome of conventional breeding, which was achieved with little or no knowledge of underlying physiological and biochemical phenomena related to a trait. Also the resources utilized on programs involving conventional breeding were not of great magnitude. Plant breeders have also been successful during the last century in producing a few salt-tolerant cultivars/lines of some potential crops through conventional breeding, but this again has utilized modest resources. However, this approach seems now inefficient due to a number of reasons, and alternatively, genetic engineering for improving crop salt tolerance is being actively followed these days by the plant scientists, world-over. A large number of transgenic lines with enhanced salt tolerance of different crops can be deciphered from the literature but up to now only a very few field-tested cultivars/lines are known despite the fact that considerable resources have been expended on the sophisticated protocols employed for generating such transgenics. This review analytically compares the achievements made so far in terms of producing salt-tolerant lines/cultivars through conventional breeding or genetic engineering.

QTL Dissection of Lag Phase in Wine Fermentation Reveals a New Translocation Responsible for Saccharomyces cerevisiae Adaptation to Sulfite

PubMed Central

Zimmer, Adrien; Durand, Cécile; Loira, Nicolás; Durrens, Pascal; Sherman, David James; Marullo, Philippe

2014-01-01

Quantitative genetics and QTL mapping are efficient strategies for deciphering the genetic polymorphisms that explain the phenotypic differences of individuals within the same species. Since a decade, this approach has been applied to eukaryotic microbes such as Saccharomyces cerevisiae in order to find natural genetic variations conferring adaptation of individuals to their environment. In this work, a QTL responsible for lag phase duration in the alcoholic fermentation of grape juice was dissected by reciprocal hemizygosity analysis. After invalidating the effect of some candidate genes, a chromosomal translocation affecting the lag phase was brought to light using de novo assembly of parental genomes. This newly described translocation (XV-t-XVI) involves the promoter region of ADH1 and the gene SSU1 and confers an increased expression of the sulfite pump during the first hours of alcoholic fermentation. This translocation constitutes another adaptation route of wine yeast to sulfites in addition to the translocation VIII-t-XVI previously described. A population survey of both translocation forms in a panel of domesticated yeast strains suggests that the translocation XV-t-XVI has been empirically selected by human activity. PMID:24489712

[Genetic diversity analysis of Andrographis paniculata in China based on SRAP and SNP].

PubMed

Chen, Rong; Wang, Xiao-Yun; Song, Yu-Ning; Zhu, Yun-feng; Wang, Peng-liang; Li, Min; Zhong, Guo-Yue

2014-12-01

In order to reveal genetic diversity of domestic Andrographis paniculata and its impact on quality, genetic backgrounds of 103 samples from 7 provinces in China were analyzed using SRAP marker and SNP marker. Genetic structures of the A. paniculata populations were estimated with Powermarker V 3.25 and Mega 6.0 software, and polymorphic SNPs were identified with CodonCode Aligner software. The results showed that the genetic distances of domestic A. paniculata germplasm ranged from 0. 01 to 0.09, and no polymorphic SNPs were discovered in coding sequence fragments of ent-copalyl diphosphate synthase. A. paniculata germplasm from various regions in China had poor genetic diversity. This phenomenon was closely related to strict self-fertilization and earlier introduction from the same origin. Therefore, genetic background had little impact on variable qualities of A. paniculata in domestic market. Mutation breeding, polyploid breeding and molecular breeding were proposed as promising strategies in germplasm innovation.

Optimization of algorithm of coding of genetic information of Chlamydia

NASA Astrophysics Data System (ADS)

Feodorova, Valentina A.; Ulyanov, Sergey S.; Zaytsev, Sergey S.; Saltykov, Yury V.; Ulianova, Onega V.

2018-04-01

New method of coding of genetic information using coherent optical fields is developed. Universal technique of transformation of nucleotide sequences of bacterial gene into laser speckle pattern is suggested. Reference speckle patterns of the nucleotide sequences of omp1 gene of typical wild strains of Chlamydia trachomatis of genovars D, E, F, G, J and K and Chlamydia psittaci serovar I as well are generated. Algorithm of coding of gene information into speckle pattern is optimized. Fully developed speckles with Gaussian statistics for gene-based speckles have been used as criterion of optimization.

Xenomicrobiology: a roadmap for genetic code engineering.

PubMed

Acevedo-Rocha, Carlos G; Budisa, Nediljko

2016-09-01

Biology is an analytical and informational science that is becoming increasingly dependent on chemical synthesis. One example is the high-throughput and low-cost synthesis of DNA, which is a foundation for the research field of synthetic biology (SB). The aim of SB is to provide biotechnological solutions to health, energy and environmental issues as well as unsustainable manufacturing processes in the frame of naturally existing chemical building blocks. Xenobiology (XB) goes a step further by implementing non-natural building blocks in living cells. In this context, genetic code engineering respectively enables the re-design of genes/genomes and proteins/proteomes with non-canonical nucleic (XNAs) and amino (ncAAs) acids. Besides studying information flow and evolutionary innovation in living systems, XB allows the development of new-to-nature therapeutic proteins/peptides, new biocatalysts for potential applications in synthetic organic chemistry and biocontainment strategies for enhanced biosafety. In this perspective, we provide a brief history and evolution of the genetic code in the context of XB. We then discuss the latest efforts and challenges ahead for engineering the genetic code with focus on substitutions and additions of ncAAs as well as standard amino acid reductions. Finally, we present a roadmap for the directed evolution of artificial microbes for emancipating rare sense codons that could be used to introduce novel building blocks. The development of such xenomicroorganisms endowed with a 'genetic firewall' will also allow to study and understand the relation between code evolution and horizontal gene transfer. © 2016 The Authors. Microbial Biotechnology published by John Wiley & Sons Ltd and Society for Applied Microbiology.

mRNA changes in nucleus accumbens related to methamphetamine addiction in mice

NASA Astrophysics Data System (ADS)

Zhu, Li; Li, Jiaqi; Dong, Nan; Guan, Fanglin; Liu, Yufeng; Ma, Dongliang; Goh, Eyleen L. K.; Chen, Teng

2016-11-01

Methamphetamine (METH) is a highly addictive psychostimulant that elicits aberrant changes in the expression of microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) in the nucleus accumbens of mice, indicating a potential role of METH in post-transcriptional regulations. To decipher the potential consequences of these post-transcriptional regulations in response to METH, we performed strand-specific RNA sequencing (ssRNA-Seq) to identify alterations in mRNA expression and their alternative splicing in the nucleus accumbens of mice following exposure to METH. METH-mediated changes in mRNAs were analyzed and correlated with previously reported changes in non-coding RNAs (miRNAs and lncRNAs) to determine the potential functions of these mRNA changes observed here and how non-coding RNAs are involved. A total of 2171 mRNAs were differentially expressed in response to METH with functions involved in synaptic plasticity, mitochondrial energy metabolism and immune response. 309 and 589 of these mRNAs are potential targets of miRNAs and lncRNAs respectively. In addition, METH treatment decreases mRNA alternative splicing, and there are 818 METH-specific events not observed in saline-treated mice. Our results suggest that METH-mediated addiction could be attributed by changes in miRNAs and lncRNAs and consequently, changes in mRNA alternative splicing and expression. In conclusion, our study reported a methamphetamine-modified nucleus accumbens transcriptome and provided non-coding RNA-mRNA interaction networks possibly involved in METH addiction.

Color Code: Using Hair Color to Make a Clear Connection between Genotype and Phenotype

ERIC Educational Resources Information Center

Bonner, J. Jose

2011-01-01

Students may wonder why they look the way they do. The answer lies in genetics, the branch of biology that deals with heredity and the variation of inherited traits. However, understanding how an organism's genetic code (i.e., genotype) affects its characteristics (i.e., phenotype) is more than a matter of idle curiosity: It's essential for…

Small non-coding RNAs (sncRNA) regulate gene silencing and modify homeostatic status in animals faced with porcine reproductive and respiratory syndrome virus (PRRSV)

USDA-ARS?s Scientific Manuscript database

It has been established that reduced susceptibility to porcine reproductive and respiratory syndrome virus (PRRSV) has a genetic component. This genetic component may take the form of small non-coding RNAs (sncRNA), which are molecules that function as regulators of gene expression. Various sncRNAs ...

The chemical basis for the origin of the genetic code and the process of protein synthesis

NASA Technical Reports Server (NTRS)

1982-01-01

The major thrust is to understand just how the process of protein synthesis, including that very important aspect, genetic coding, came to be. Two aspects of the problem: the chemistry of active aminoacyl species; and affinities between amino acids and nucleotides, and specifically, how these affinities might affect the chemistry between the two are stressed.

The impact of rare variation on gene expression across tissues.

PubMed

Li, Xin; Kim, Yungil; Tsang, Emily K; Davis, Joe R; Damani, Farhan N; Chiang, Colby; Hess, Gaelen T; Zappala, Zachary; Strober, Benjamin J; Scott, Alexandra J; Li, Amy; Ganna, Andrea; Bassik, Michael C; Merker, Jason D; Hall, Ira M; Battle, Alexis; Montgomery, Stephen B

2017-10-11

Rare genetic variants are abundant in humans and are expected to contribute to individual disease risk. While genetic association studies have successfully identified common genetic variants associated with susceptibility, these studies are not practical for identifying rare variants. Efforts to distinguish pathogenic variants from benign rare variants have leveraged the genetic code to identify deleterious protein-coding alleles, but no analogous code exists for non-coding variants. Therefore, ascertaining which rare variants have phenotypic effects remains a major challenge. Rare non-coding variants have been associated with extreme gene expression in studies using single tissues, but their effects across tissues are unknown. Here we identify gene expression outliers, or individuals showing extreme expression levels for a particular gene, across 44 human tissues by using combined analyses of whole genomes and multi-tissue RNA-sequencing data from the Genotype-Tissue Expression (GTEx) project v6p release. We find that 58% of underexpression and 28% of overexpression outliers have nearby conserved rare variants compared to 8% of non-outliers. Additionally, we developed RIVER (RNA-informed variant effect on regulation), a Bayesian statistical model that incorporates expression data to predict a regulatory effect for rare variants with higher accuracy than models using genomic annotations alone. Overall, we demonstrate that rare variants contribute to large gene expression changes across tissues and provide an integrative method for interpretation of rare variants in individual genomes.

On the evolution of primitive genetic codes.

PubMed

Weberndorfer, Günter; Hofacker, Ivo L; Stadler, Peter F

2003-10-01

The primordial genetic code probably has been a drastically simplified ancestor of the canonical code that is used by contemporary cells. In order to understand how the present-day code came about we first need to explain how the language of the building plan can change without destroying the encoded information. In this work we introduce a minimal organism model that is based on biophysically reasonable descriptions of RNA and protein, namely secondary structure folding and knowledge based potentials. The evolution of a population of such organism under competition for a common resource is simulated explicitly at the level of individual replication events. Starting with very simple codes, and hence greatly reduced amino acid alphabets, we observe a diversification of the codes in most simulation runs. The driving force behind this effect is the possibility to produce fitter proteins when the repertoire of amino acids is enlarged.

Genetics of Inflammatory Bowel Diseases

PubMed Central

McGovern, Dermot; Kugathasan, Subra; Cho, Judy H.

2015-01-01

In this Review, we provide an update on genome-wide association studies (GWAS) in inflammatory bowel disease (IBD). In addition, we summarize progress in defining the functional consequences of associated alleles for coding and non-coding genetic variation. In the small minority of loci where major association signals correspond to non-synonymous variation, we summarize studies defining their functional effects and implications for therapeutic targeting. Importantly, the large majority of GWAS-associated loci involve non-coding variation, many of which modulate levels of gene expression. Recent expression quantitative trait loci (eQTL) studies have established that expression of the large majority of human genes is regulated by non-coding genetic variation. Significant advances in defining the epigenetic landscape have demonstrated that IBD GWAS signals are highly enriched within cell-specific active enhancer marks. Studies in European ancestry populations have dominated the landscape of IBD genetics studies, but increasingly, studies in Asian and African-American populations are being reported. Common variation accounts for only a modest fraction of the predicted heritability and the role of rare genetic variation of higher effects (i.e. odds ratios markedly deviating from one) is increasingly being identified through sequencing efforts. These sequencing studies have been particularly productive in very-early onset, more severe cases. A major challenge in IBD genetics will be harnessing the vast array of genetic discovery for clinical utility, through emerging precision medicine initiatives. We discuss the rapidly evolving area of direct to consumer genetic testing, as well as the current utility of clinical exome sequencing, especially in very early onset, severe IBD cases. We summarize recent progress in the pharmacogenetics of IBD with respect of partitioning patient responses to anti-TNF and thiopurine therapies. Highly collaborative studies across research centers and across subspecialties and disciplines will be required to fully realize the promise of genetic discovery in IBD. PMID:26255561

Modeling the Volcanic Source at Long Valley, CA, Using a Genetic Algorithm Technique

NASA Technical Reports Server (NTRS)

Tiampo, Kristy F.

1999-01-01

In this project, we attempted to model the deformation pattern due to the magmatic source at Long Valley caldera using a real-value coded genetic algorithm (GA) inversion similar to that found in Michalewicz, 1992. The project has been both successful and rewarding. The genetic algorithm, coded in the C programming language, performs stable inversions over repeated trials, with varying initial and boundary conditions. The original model used a GA in which the geophysical information was coded into the fitness function through the computation of surface displacements for a Mogi point source in an elastic half-space. The program was designed to invert for a spherical magmatic source - its depth, horizontal location and volume - using the known surface deformations. It also included the capability of inverting for multiple sources.

Saturation of recognition elements blocks evolution of new tRNA identities

PubMed Central

Saint-Léger, Adélaïde; Bello, Carla; Dans, Pablo D.; Torres, Adrian Gabriel; Novoa, Eva Maria; Camacho, Noelia; Orozco, Modesto; Kondrashov, Fyodor A.; Ribas de Pouplana, Lluís

2016-01-01

Understanding the principles that led to the current complexity of the genetic code is a central question in evolution. Expansion of the genetic code required the selection of new transfer RNAs (tRNAs) with specific recognition signals that allowed them to be matured, modified, aminoacylated, and processed by the ribosome without compromising the fidelity or efficiency of protein synthesis. We show that saturation of recognition signals blocks the emergence of new tRNA identities and that the rate of nucleotide substitutions in tRNAs is higher in species with fewer tRNA genes. We propose that the growth of the genetic code stalled because a limit was reached in the number of identity elements that can be effectively used in the tRNA structure. PMID:27386510

ActiveDriverDB: human disease mutations and genome variation in post-translational modification sites of proteins

PubMed Central

Krassowski, Michal; Paczkowska, Marta; Cullion, Kim; Huang, Tina; Dzneladze, Irakli; Ouellette, B F Francis; Yamada, Joseph T; Fradet-Turcotte, Amelie

2018-01-01

Abstract Interpretation of genetic variation is needed for deciphering genotype-phenotype associations, mechanisms of inherited disease, and cancer driver mutations. Millions of single nucleotide variants (SNVs) in human genomes are known and thousands are associated with disease. An estimated 21% of disease-associated amino acid substitutions corresponding to missense SNVs are located in protein sites of post-translational modifications (PTMs), chemical modifications of amino acids that extend protein function. ActiveDriverDB is a comprehensive human proteo-genomics database that annotates disease mutations and population variants through the lens of PTMs. We integrated >385,000 published PTM sites with ∼3.6 million substitutions from The Cancer Genome Atlas (TCGA), the ClinVar database of disease genes, and human genome sequencing projects. The database includes site-specific interaction networks of proteins, upstream enzymes such as kinases, and drugs targeting these enzymes. We also predicted network-rewiring impact of mutations by analyzing gains and losses of kinase-bound sequence motifs. ActiveDriverDB provides detailed visualization, filtering, browsing and searching options for studying PTM-associated mutations. Users can upload mutation datasets interactively and use our application programming interface in pipelines. Integrative analysis of mutations and PTMs may help decipher molecular mechanisms of phenotypes and disease, as exemplified by case studies of TP53, BRCA2 and VHL. The open-source database is available at https://www.ActiveDriverDB.org. PMID:29126202

Deciphering the Structural Requirements of Nucleoside Bisubstrate Analogues for Inhibition of MbtA in Mycobacterium tuberculosis: A FB-QSAR Study and Combinatorial Library Generation for Identifying Potential Hits.

PubMed

Maganti, Lakshmi; Das, Sanjit Kumar; Mascarenhas, Nahren Manuel; Ghoshal, Nanda

2011-10-01

The re-emergence of tuberculosis infections, which are resistant to conventional drug therapy, has steadily risen in the last decade. Inhibitors of aryl acid adenylating enzyme known as MbtA, involved in siderophore biosynthesis in Mycobacterium tuberculosis, are being explored as potential antitubercular agents. The ability to identify fragments that interact with a biological target is a key step in fragment based drug design (FBDD). To expand the boundaries of quantitative structure activity relationship (QSAR) paradigm, we have proposed a Fragment Based QSAR methodology, referred here in as FB-QSAR, for deciphering the structural requirements of a series of nucleoside bisubstrate analogs for inhibition of MbtA, a key enzyme involved in siderophore biosynthetic pathway. For the development of FB-QSAR models, statistical techniques such as stepwise multiple linear regression (SMLR), genetic function approximation (GFA) and GFAspline were used. The predictive ability of the generated models was validated using different statistical metrics, and similarity-based coverage estimation was carried out to define applicability boundaries. To aid the creation of novel antituberculosis compounds, a bioisosteric database was enumerated using the combichem approach endorsed mining in a lead-like chemical space. The generated library was screened using an integrated in-silico approach and potential hits identified. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Evidence-Based Reading and Writing Assessment for Dyslexia in Adolescents and Young Adults

PubMed Central

Nielsen, Kathleen; Abbott, Robert; Griffin, Whitney; Lott, Joe; Raskind, Wendy; Berninger, Virginia W.

2016-01-01

The same working memory and reading and writing achievement phenotypes (behavioral markers of genetic variants) validated in prior research with younger children and older adults in a multi-generational family genetics study of dyslexia were used to study 81 adolescent and young adults (ages 16 to 25) from that study. Dyslexia is impaired word reading and spelling skills below the population mean and ability to use oral language to express thinking. These working memory predictor measures were given and used to predict reading and writing achievement: Coding (storing and processing) heard and spoken words (phonological coding), read and written words (orthographic coding), base words and affixes (morphological coding), and accumulating words over time (syntax coding); Cross-Code Integration (phonological loop for linking phonological name and orthographic letter codes and orthographic loop for linking orthographic letter codes and finger sequencing codes), and Supervisory Attention (focused and switching attention and self-monitoring during written word finding). Multiple regressions showed that most predictors explained individual difference in at least one reading or writing outcome, but which predictors explained unique variance beyond shared variance depended on outcome. ANOVAs confirmed that research-supported criteria for dyslexia validated for younger children and their parents could be used to diagnose which adolescents and young adults did (n=31) or did not (n=50) meet research criteria for dyslexia. Findings are discussed in reference to the heterogeneity of phenotypes (behavioral markers of genetic variables) and their application to assessment for accommodations and ongoing instruction for adolescents and young adults with dyslexia. PMID:26855554

Whole genome sequencing of 35 individuals provides insights into the genetic architecture of Korean population.

PubMed

Zhang, Wenqian; Meehan, Joe; Su, Zhenqiang; Ng, Hui Wen; Shu, Mao; Luo, Heng; Ge, Weigong; Perkins, Roger; Tong, Weida; Hong, Huixiao

2014-01-01

Due to a significant decline in the costs associated with next-generation sequencing, it has become possible to decipher the genetic architecture of a population by sequencing a large number of individuals to a deep coverage. The Korean Personal Genomes Project (KPGP) recently sequenced 35 Korean genomes at high coverage using the Illumina Hiseq platform and made the deep sequencing data publicly available, providing the scientific community opportunities to decipher the genetic architecture of the Korean population. In this study, we used two single nucleotide variant (SNV) calling pipelines: mapping the raw reads obtained from whole genome sequencing of 35 Korean individuals in KPGP using BWA and SOAP2 followed by SNV calling using SAMtools and SOAPsnp, respectively. The consensus SNVs obtained from the two SNV pipelines were used to represent the SNVs of the Korean population. We compared these SNVs to those from 17 other populations provided by the HapMap consortium and the 1000 Genomes Project (1KGP) and identified SNVs that were only present in the Korean population. We studied the mutation spectrum and analyzed the genes of non-synonymous SNVs only detected in the Korean population. We detected a total of 8,555,726 SNVs in the 35 Korean individuals and identified 1,213,613 SNVs detected in at least one Korean individual (SNV-1) and 12,640 in all of 35 Korean individuals (SNV-35) but not in 17 other populations. In contrast with the SNVs common to other populations in HapMap and 1KGP, the Korean only SNVs had high percentages of non-silent variants, emphasizing the unique roles of these Korean only SNVs in the Korean population. Specifically, we identified 8,361 non-synonymous Korean only SNVs, of which 58 SNVs existed in all 35 Korean individuals. The 5,754 genes of non-synonymous Korean only SNVs were highly enriched in some metabolic pathways. We found adhesion is the top disease term associated with SNV-1 and Nelson syndrome is the only disease term associated with SNV-35. We found that a significant number of Korean only SNVs are in genes that are associated with the drug term of adenosine. We identified the SNVs that were found in the Korean population but not seen in other populations, and explored the corresponding genes and pathways as well as the associated disease terms and drug terms. The results expand our knowledge of the genetic architecture of the Korean population, which will benefit the implementation of personalized medicine for the Korean population.

On models of the genetic code generated by binary dichotomic algorithms.

PubMed

Gumbel, Markus; Fimmel, Elena; Danielli, Alberto; Strüngmann, Lutz

2015-02-01

In this paper we introduce the concept of a BDA-generated model of the genetic code which is based on binary dichotomic algorithms (BDAs). A BDA-generated model is based on binary dichotomic algorithms (BDAs). Such a BDA partitions the set of 64 codons into two disjoint classes of size 32 each and provides a generalization of known partitions like the Rumer dichotomy. We investigate what partitions can be generated when a set of different BDAs is applied sequentially to the set of codons. The search revealed that these models are able to generate code tables with very different numbers of classes ranging from 2 to 64. We have analyzed whether there are models that map the codons to their amino acids. A perfect matching is not possible. However, we present models that describe the standard genetic code with only few errors. There are also models that map all 64 codons uniquely to 64 classes showing that BDAs can be used to identify codons precisely. This could serve as a basis for further mathematical analysis using coding theory, for example. The hypothesis that BDAs might reflect a molecular mechanism taking place in the decoding center of the ribosome is discussed. The scan demonstrated that binary dichotomic partitions are able to model different aspects of the genetic code very well. The search was performed with our tool Beady-A. This software is freely available at http://mi.informatik.hs-mannheim.de/beady-a. It requires a JVM version 6 or higher. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Clonal evolution of acute myeloid leukemia highlighted by latest genome sequencing studies.

PubMed

Zhang, Xuehong; Lv, Dekang; Zhang, Yu; Liu, Quentin; Li, Zhiguang

2016-09-06

Decades of years might be required for an initiated cell to become a fully-pledged, metastasized tumor. DNA mutations are accumulated during this process including background mutations that emerge scholastically, as well as driver mutations that selectively occur in a handful of cancer genes and confer the cell a growth advantage over its neighbors. A clone of tumor cells could be superseded by another clone that acquires new mutations and grows more aggressively. Tumor evolutional patterns have been studied for years using conventional approaches that focus on the investigation of a single or a couple of genes. Latest deep sequencing technology enables a global view of tumor evolution by deciphering almost all genome aberrations in a tumor. Tumor clones and the fate of each clone during tumor evolution can be depicted with the help of the concept of variant allele frequency. Here, we summarize the new insights of cancer evolutional progression in acute myeloid leukemia. Cancer evolution is currently thought to start from a clone that has accumulated the requisite somatically-acquired genetic aberrations through a series of increasingly disordered clinical and pathological phases, eventually leading to malignant transformation [1-3]. The observations in invasive colorectal cancer that usually emerges from an antecedent benign adenomatous polyp and in cervical cancer that proceeds through intraepithelial neoplasia support the idea of stepwise or linear cancerous progression [3-5]. Genetically, such progression is achieved by successive waves of clonal expansion during which cells acquire novel genomic alterations including single nucleotide variants (SNVs), small insertions and deletions (indels), and/or copy number variations (CNVs) [6]. The latest improvement in sequencing technology has allowed the deciphering of the whole exome or genome in different types of tumor and normal tissue pairs, providing detailed catalogue about genome aberrations during tumor initiation and progression, which have been reviewed in several papers [7-10]. Here, we focus on demonstrating the cancer clonal evolution pattern revealed by recent deep sequencing studies of samples from acute myeloid leukemia (AML) patients.

Economic evaluation of Cardio inCode®, a clinical-genetic function for coronary heart disease risk assessment.

PubMed

Ramírez de Arellano, A; Coca, A; de la Figuera, M; Rubio-Terrés, C; Rubio-Rodríguez, D; Gracia, A; Boldeanu, A; Puig-Gilberte, J; Salas, E

2013-10-01

A clinical–genetic function (Cardio inCode®) was generated using genetic variants associated with coronary heart disease (CHD), but not with classical CHD risk factors, to achieve a more precise estimation of the CHD risk of individuals by incorporating genetics into risk equations [Framingham and REGICOR (Registre Gironí del Cor)]. The objective of this study was to conduct an economic analysis of the CHD risk assessment with Cardio inCode®, which incorporates the patient’s genetic risk into the functions of REGICOR and Framingham, compared with the standard method (using only the functions). A Markov model was developed with seven states of health (low CHD risk, moderate CHD risk, high CHD risk, CHD event, recurrent CHD, chronic CHD, and death). The reclassification of CHD risk derived from genetic information and transition probabilities between states was obtained from a validation study conducted in cohorts of REGICOR (Spain) and Framingham (USA). It was assumed that patients classified as at moderate risk by the standard method were the best candidates to test the risk reclassification with Cardio inCode®. The utilities and costs (€; year 2011 values) of Markov states were obtained from the literature and Spanish sources. The analysis was performed from the perspective of the Spanish National Health System, for a life expectancy of 82 years in Spain. An annual discount rate of 3.5 % for costs and benefits was applied. For a Cardio inCode® price of €400, the cost per QALY gained compared with the standard method [incremental cost-effectiveness ratio (ICER)] would be €12,969 and €21,385 in REGICOR and Framingham cohorts, respectively. The threshold price of Cardio inCode® to reach the ICER threshold generally accepted in Spain (€30,000/QALY) would range between €668 and €836. The greatest benefit occurred in the subgroup of patients with moderate–high risk, with a high-risk reclassification of 22.8 % and 12 % of patients and an ICER of €1,652/QALY and €5,884/QALY in the REGICOR and Framingham cohorts, respectively. Sensitivity analyses confirmed the stability of the study results. Cardio inCode® is a cost-effective risk score option in CHD risk assessment compared with the standard method.

Genetic Programming-based Phononic Bandgap Structure Design

DTIC Science & Technology

2011-09-01

derivative-based methods is that they require a good starting location to find the global minimum of a function. As can be seen from figure 2, there are many... FRANCHI CODE 7100 M H ORR CODE 7120 J A BUCARO CODE 7130 G J ORRIS 7140 J S PERKINS CODE 7140 S A CHIN BING CODE 7180 4555 OVERLOOK AVE SW WASHINGTON DC

Inter-individual variation in expression: a missing link in biomarker biology?

PubMed

Little, Peter F R; Williams, Rohan B H; Wilkins, Marc R

2009-01-01

The past decade has seen an explosion of variation data demonstrating that diversity of both protein-coding sequences and of regulatory elements of protein-coding genes is common and of functional importance. In this article, we argue that genetic diversity can no longer be ignored in studies of human biology, even research projects without explicit genetic experimental design, and that this knowledge can, and must, inform research. By way of illustration, we focus on the potential role of genetic data in case-control studies to identify and validate cancer protein biomarkers. We argue that a consideration of genetics, in conjunction with proteomic biomarker discovery projects, should improve the proportion of biomarkers that can accurately classify patients.

Evaluation of Bovine High-Density SNP Genotyping Array in Indigenous Dairy Cattle Breeds.

PubMed

Dash, S; Singh, A; Bhatia, A K; Jayakumar, S; Sharma, A; Singh, S; Ganguly, I; Dixit, S P

2018-04-03

In total 52 samples of Sahiwal ( 19 ), Tharparkar ( 17 ), and Gir ( 16 ) were genotyped by using BovineHD SNP chip to analyze minor allele frequency (MAF), genetic diversity, and linkage disequilibrium among these cattle. The common SNPs of BovineHD and 54K SNP Chips were also extracted and evaluated for their performance. Only 40%-50% SNPs of these arrays was found informative for genetic analysis in these cattle breeds. The overall mean of MAF for SNPs of BovineHD SNPChip was 0.248 ± 0.006, 0.241 ± 0.007, and 0.242 ± 0.009 in Sahiwal, Tharparkar and Gir, respectively, while that for 54K SNPs was on lower side. The average Reynold's genetic distance between breeds ranged from 0.042 to 0.055 based on BovineHD Beadchip, and from 0.052 to 0.084 based on 54K SNP Chip. The estimates of genetic diversity based on HD and 54K chips were almost same and, hence, low density chip seems to be good enough to decipher genetic diversity of these cattle breeds. The linkage disequilibrium started decaying (r 2  < 0.2) at 140 kb inter-marker distance and, hence, a 20K low density customized SNP array from HD chip could be designed for genomic selection in these cattle else the 54K Bead Chip as such will be useful.

Mapping heritability and molecular genetic associations with cortical features using probabilistic brain atlases: methods and applications to schizophrenia.

PubMed

Cannon, Tyrone D; Thompson, Paul M; van Erp, Theo G M; Huttunen, Matti; Lonnqvist, Jouko; Kaprio, Jaakko; Toga, Arthur W

2006-01-01

There is an urgent need to decipher the complex nature of genotype-phenotype relationships within the multiple dimensions of brain structure and function that are compromised in neuropsychiatric syndromes such as schizophrenia. Doing so requires sophisticated methodologies to represent population variability in neural traits and to probe their heritable and molecular genetic bases. We have recently developed and applied computational algorithms to map the heritability of, as well as genetic linkage and association to, neural features encoded using brain imaging in the context of three-dimensional (3D), populationbased, statistical brain atlases. One set of algorithms builds on our prior work using classical twin study methods to estimate heritability by fitting biometrical models for additive genetic, unique, and common environmental influences. Another set of algorithms performs regression-based (Haseman-Elston) identical-bydescent linkage analysis and genetic association analysis of DNA polymorphisms in relation to neural traits of interest in the same 3D population-based brain atlas format. We demonstrate these approaches using samples of healthy monozygotic (MZ) and dizygotic (DZ) twin pairs, as well as MZ and DZ twin pairs discordant for schizophrenia, but the methods can be generalized to other classes of relatives and to other diseases. The results confirm prior evidence of genetic influences on gray matter density in frontal brain regions. They also provide converging evidence that the chromosome 1q42 region is relevant to schizophrenia by demonstrating linkage and association of markers of the Transelin-Associated-Factor-X and Disrupted-In- Schizophrenia-1 genes with prefrontal cortical gray matter deficits in twins discordant for schizophrenia.

Deciphering the BAR code of membrane modulators.

PubMed

Salzer, Ulrich; Kostan, Julius; Djinović-Carugo, Kristina

2017-07-01

The BAR domain is the eponymous domain of the "BAR-domain protein superfamily", a large and diverse set of mostly multi-domain proteins that play eminent roles at the membrane cytoskeleton interface. BAR domain homodimers are the functional units that peripherally associate with lipid membranes and are involved in membrane sculpting activities. Differences in their intrinsic curvatures and lipid-binding properties account for a large variety in membrane modulating properties. Membrane activities of BAR domains are further modified and regulated by intramolecular or inter-subunit domains, by intermolecular protein interactions, and by posttranslational modifications. Rather than providing detailed cell biological information on single members of this superfamily, this review focuses on biochemical, biophysical, and structural aspects and on recent findings that paradigmatically promote our understanding of processes driven and modulated by BAR domains.

A SNP panel and online tool for checking genotype concordance through comparing QR codes.

PubMed

Du, Yonghong; Martin, Joshua S; McGee, John; Yang, Yuchen; Liu, Eric Yi; Sun, Yingrui; Geihs, Matthias; Kong, Xuejun; Zhou, Eric Lingfeng; Li, Yun; Huang, Jie

2017-01-01

In the current precision medicine era, more and more samples get genotyped and sequenced. Both researchers and commercial companies expend significant time and resources to reduce the error rate. However, it has been reported that there is a sample mix-up rate of between 0.1% and 1%, not to mention the possibly higher mix-up rate during the down-stream genetic reporting processes. Even on the low end of this estimate, this translates to a significant number of mislabeled samples, especially over the projected one billion people that will be sequenced within the next decade. Here, we first describe a method to identify a small set of Single nucleotide polymorphisms (SNPs) that can uniquely identify a personal genome, which utilizes allele frequencies of five major continental populations reported in the 1000 genomes project and the ExAC Consortium. To make this panel more informative, we added four SNPs that are commonly used to predict ABO blood type, and another two SNPs that are capable of predicting sex. We then implement a web interface (http://qrcme.tech), nicknamed QRC (for QR code based Concordance check), which is capable of extracting the relevant ID SNPs from a raw genetic data, coding its genotype as a quick response (QR) code, and comparing QR codes to report the concordance of underlying genetic datasets. The resulting 80 fingerprinting SNPs represent a significant decrease in complexity and the number of markers used for genetic data labelling and tracking. Our method and web tool is easily accessible to both researchers and the general public who consider the accuracy of complex genetic data as a prerequisite towards precision medicine.

A SNP panel and online tool for checking genotype concordance through comparing QR codes

PubMed Central

Du, Yonghong; Martin, Joshua S.; McGee, John; Yang, Yuchen; Liu, Eric Yi; Sun, Yingrui; Geihs, Matthias; Kong, Xuejun; Zhou, Eric Lingfeng; Li, Yun

2017-01-01

In the current precision medicine era, more and more samples get genotyped and sequenced. Both researchers and commercial companies expend significant time and resources to reduce the error rate. However, it has been reported that there is a sample mix-up rate of between 0.1% and 1%, not to mention the possibly higher mix-up rate during the down-stream genetic reporting processes. Even on the low end of this estimate, this translates to a significant number of mislabeled samples, especially over the projected one billion people that will be sequenced within the next decade. Here, we first describe a method to identify a small set of Single nucleotide polymorphisms (SNPs) that can uniquely identify a personal genome, which utilizes allele frequencies of five major continental populations reported in the 1000 genomes project and the ExAC Consortium. To make this panel more informative, we added four SNPs that are commonly used to predict ABO blood type, and another two SNPs that are capable of predicting sex. We then implement a web interface (http://qrcme.tech), nicknamed QRC (for QR code based Concordance check), which is capable of extracting the relevant ID SNPs from a raw genetic data, coding its genotype as a quick response (QR) code, and comparing QR codes to report the concordance of underlying genetic datasets. The resulting 80 fingerprinting SNPs represent a significant decrease in complexity and the number of markers used for genetic data labelling and tracking. Our method and web tool is easily accessible to both researchers and the general public who consider the accuracy of complex genetic data as a prerequisite towards precision medicine. PMID:28926565

Interdependence, Reflexivity, Fidelity, Impedance Matching, and the Evolution of Genetic Coding

PubMed Central

Carter, Charles W; Wills, Peter R

2018-01-01

Abstract Genetic coding is generally thought to have required ribozymes whose functions were taken over by polypeptide aminoacyl-tRNA synthetases (aaRS). Two discoveries about aaRS and their interactions with tRNA substrates now furnish a unifying rationale for the opposite conclusion: that the key processes of the Central Dogma of molecular biology emerged simultaneously and naturally from simple origins in a peptide•RNA partnership, eliminating the epistemological utility of a prior RNA world. First, the two aaRS classes likely arose from opposite strands of the same ancestral gene, implying a simple genetic alphabet. The resulting inversion symmetries in aaRS structural biology would have stabilized the initial and subsequent differentiation of coding specificities, rapidly promoting diversity in the proteome. Second, amino acid physical chemistry maps onto tRNA identity elements, establishing reflexive, nanoenvironmental sensing in protein aaRS. Bootstrapping of increasingly detailed coding is thus intrinsic to polypeptide aaRS, but impossible in an RNA world. These notions underline the following concepts that contradict gradual replacement of ribozymal aaRS by polypeptide aaRS: 1) aaRS enzymes must be interdependent; 2) reflexivity intrinsic to polypeptide aaRS production dynamics promotes bootstrapping; 3) takeover of RNA-catalyzed aminoacylation by enzymes will necessarily degrade specificity; and 4) the Central Dogma’s emergence is most probable when replication and translation error rates remain comparable. These characteristics are necessary and sufficient for the essentially de novo emergence of a coupled gene–replicase–translatase system of genetic coding that would have continuously preserved the functional meaning of genetically encoded protein genes whose phylogenetic relationships match those observed today. PMID:29077934

Genomic Editing of Non-Coding RNA Genes with CRISPR/Cas9 Ushers in a Potential Novel Approach to Study and Treat Schizophrenia

PubMed Central

Zhuo, Chuanjun; Hou, Weihong; Hu, Lirong; Lin, Chongguang; Chen, Ce; Lin, Xiaodong

2017-01-01

Schizophrenia is a genetically related mental illness, in which the majority of genetic alterations occur in the non-coding regions of the human genome. In the past decade, a growing number of regulatory non-coding RNAs (ncRNAs) including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) have been identified to be strongly associated with schizophrenia. However, the studies of these ncRNAs in the pathophysiology of schizophrenia and the reverting of their genetic defects in restoration of the normal phenotype have been hampered by insufficient technology to manipulate these ncRNA genes effectively as well as a lack of appropriate animal models. Most recently, a revolutionary gene editing technology known as Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRISPR-associated nuclease 9 (Cas9; CRISPR/Cas9) has been developed that enable researchers to overcome these challenges. In this review article, we mainly focus on the schizophrenia-related ncRNAs and the use of CRISPR/Cas9-mediated editing on the non-coding regions of the genomic DNA in proving causal relationship between the genetic defects and the pathophysiology of schizophrenia. We subsequently discuss the potential of translating this advanced technology into a clinical therapy for schizophrenia, although the CRISPR/Cas9 technology is currently still in its infancy and immature to put into use in the treatment of diseases. Furthermore, we suggest strategies to accelerate the pace from the bench to the bedside. This review describes the application of the powerful and feasible CRISPR/Cas9 technology to manipulate schizophrenia-associated ncRNA genes. This technology could help researchers tackle this complex health problem and perhaps other genetically related mental disorders due to the overlapping genetic alterations of schizophrenia with other mental illnesses. PMID:28217082

Multispectral airborne imagery in the field reveals genetic determinisms of morphological and transpiration traits of an apple tree hybrid population in response to water deficit

PubMed Central

Virlet, Nicolas; Costes, Evelyne; Martinez, Sébastien; Kelner, Jean-Jacques; Regnard, Jean-Luc

2015-01-01

Genetic studies of response to water deficit in adult trees are limited by low throughput of the usual phenotyping methods in the field. Here, we aimed at overcoming this bottleneck, applying a new methodology using airborne multispectral imagery and in planta measurements to compare a high number of individuals. An apple tree population, grafted on the same rootstock, was submitted to contrasting summer water regimes over two years. Aerial images acquired in visible, near- and thermal-infrared at three dates each year allowed calculation of vegetation and water stress indices. Tree vigour and fruit production were also assessed. Linear mixed models were built accounting for date and year effects on several variables and including the differential response of genotypes between control and drought conditions. Broad-sense heritability of most variables was high and 18 quantitative trait loci (QTLs) independent of the dates were detected on nine linkage groups of the consensus apple genetic map. For vegetation and stress indices, QTLs were related to the means, the intra-crown heterogeneity, and differences induced by water regimes. Most QTLs explained 15−20% of variance. Airborne multispectral imaging proved relevant to acquire simultaneous information on a whole tree population and to decipher genetic determinisms involved in response to water deficit. PMID:26208644

dbWGFP: a database and web server of human whole-genome single nucleotide variants and their functional predictions.

PubMed

Wu, Jiaxin; Wu, Mengmeng; Li, Lianshuo; Liu, Zhuo; Zeng, Wanwen; Jiang, Rui

2016-01-01

The recent advancement of the next generation sequencing technology has enabled the fast and low-cost detection of all genetic variants spreading across the entire human genome, making the application of whole-genome sequencing a tendency in the study of disease-causing genetic variants. Nevertheless, there still lacks a repository that collects predictions of functionally damaging effects of human genetic variants, though it has been well recognized that such predictions play a central role in the analysis of whole-genome sequencing data. To fill this gap, we developed a database named dbWGFP (a database and web server of human whole-genome single nucleotide variants and their functional predictions) that contains functional predictions and annotations of nearly 8.58 billion possible human whole-genome single nucleotide variants. Specifically, this database integrates 48 functional predictions calculated by 17 popular computational methods and 44 valuable annotations obtained from various data sources. Standalone software, user-friendly query services and free downloads of this database are available at http://bioinfo.au.tsinghua.edu.cn/dbwgfp. dbWGFP provides a valuable resource for the analysis of whole-genome sequencing, exome sequencing and SNP array data, thereby complementing existing data sources and computational resources in deciphering genetic bases of human inherited diseases. © The Author(s) 2016. Published by Oxford University Press.

Whole-Exome Sequencing to Decipher the Genetic Heterogeneity of Hearing Loss in a Chinese Family with Deaf by Deaf Mating

PubMed Central

Qing, Jie; Yan, Denise; Zhou, Yuan; Liu, Qiong; Wu, Weijing; Xiao, Zian; Liu, Yuyuan; Liu, Jia; Du, Lilin; Xie, Dinghua; Liu, Xue Zhong

2014-01-01

Inherited deafness has been shown to have high genetic heterogeneity. For many decades, linkage analysis and candidate gene approaches have been the main tools to elucidate the genetics of hearing loss. However, this associated study design is costly, time-consuming, and unsuitable for small families. This is mainly due to the inadequate numbers of available affected individuals, locus heterogeneity, and assortative mating. Exome sequencing has now become technically feasible and a cost-effective method for detection of disease variants underlying Mendelian disorders due to the recent advances in next-generation sequencing (NGS) technologies. In the present study, we have combined both the Deafness Gene Mutation Detection Array and exome sequencing to identify deafness causative variants in a large Chinese composite family with deaf by deaf mating. The simultaneous screening of the 9 common deafness mutations using the allele-specific PCR based universal array, resulted in the identification of the 1555A>G in the mitochondrial DNA (mtDNA) 12S rRNA in affected individuals in one branch of the family. We then subjected the mutation-negative cases to exome sequencing and identified novel causative variants in the MYH14 and WFS1 genes. This report confirms the effective use of a NGS technique to detect pathogenic mutations in affected individuals who were not candidates for classical genetic studies. PMID:25289672

Mapping and Deciphering Neural Codes of NMDA Receptor-Dependent Fear Memory Engrams in the Hippocampus

PubMed Central

Tsien, Joe Z.

2013-01-01

Mapping and decoding brain activity patterns underlying learning and memory represents both great interest and immense challenge. At present, very little is known regarding many of the very basic questions regarding the neural codes of memory: are fear memories retrieved during the freezing state or non-freezing state of the animals? How do individual memory traces give arise to a holistic, real-time associative memory engram? How are memory codes regulated by synaptic plasticity? Here, by applying high-density electrode arrays and dimensionality-reduction decoding algorithms, we investigate hippocampal CA1 activity patterns of trace fear conditioning memory code in inducible NMDA receptor knockout mice and their control littermates. Our analyses showed that the conditioned tone (CS) and unconditioned foot-shock (US) can evoke hippocampal ensemble responses in control and mutant mice. Yet, temporal formats and contents of CA1 fear memory engrams differ significantly between the genotypes. The mutant mice with disabled NMDA receptor plasticity failed to generate CS-to-US or US-to-CS associative memory traces. Moreover, the mutant CA1 region lacked memory traces for “what at when” information that predicts the timing relationship between the conditioned tone and the foot shock. The degraded associative fear memory engram is further manifested in its lack of intertwined and alternating temporal association between CS and US memory traces that are characteristic to the holistic memory recall in the wild-type animals. Therefore, our study has decoded real-time memory contents, timing relationship between CS and US, and temporal organizing patterns of fear memory engrams and demonstrated how hippocampal memory codes are regulated by NMDA receptor synaptic plasticity. PMID:24302990

A novel nuclear genetic code alteration in yeasts and the evolution of codon reassignment in eukaryotes

PubMed Central

Mühlhausen, Stefanie; Findeisen, Peggy; Plessmann, Uwe; Urlaub, Henning; Kollmar, Martin

2016-01-01

The genetic code is the cellular translation table for the conversion of nucleotide sequences into amino acid sequences. Changes to the meaning of sense codons would introduce errors into almost every translated message and are expected to be highly detrimental. However, reassignment of single or multiple codons in mitochondria and nuclear genomes, although extremely rare, demonstrates that the code can evolve. Several models for the mechanism of alteration of nuclear genetic codes have been proposed (including “codon capture,” “genome streamlining,” and “ambiguous intermediate” theories), but with little resolution. Here, we report a novel sense codon reassignment in Pachysolen tannophilus, a yeast related to the Pichiaceae. By generating proteomics data and using tRNA sequence comparisons, we show that Pachysolen translates CUG codons as alanine and not as the more usual leucine. The Pachysolen tRNACAG is an anticodon-mutated tRNAAla containing all major alanine tRNA recognition sites. The polyphyly of the CUG-decoding tRNAs in yeasts is best explained by a tRNA loss driven codon reassignment mechanism. Loss of the CUG-tRNA in the ancient yeast is followed by gradual decrease of respective codons and subsequent codon capture by tRNAs whose anticodon is not part of the aminoacyl-tRNA synthetase recognition region. Our hypothesis applies to all nuclear genetic code alterations and provides several testable predictions. We anticipate more codon reassignments to be uncovered in existing and upcoming genome projects. PMID:27197221

TIP: protein backtranslation aided by genetic algorithms.

PubMed

Moreira, Andrés; Maass, Alejandro

2004-09-01

Several applications require the backtranslation of a protein sequence into a nucleic acid sequence. The degeneracy of the genetic code makes this process ambiguous; moreover, not every translation is equally viable. The usual answer is to mimic the codon usage of the target species; however, this does not capture all the relevant features of the 'genomic styles' from different taxa. The program TIP ' Traducción Inversa de Proteínas') applies genetic algorithms to improve the backtranslation, by minimizing the difference of some coding statistics with respect to their average value in the target. http://www.cmm.uchile.cl/genoma/tip/

Expanding and reprogramming the genetic code.

PubMed

Chin, Jason W

2017-10-04

Nature uses a limited, conservative set of amino acids to synthesize proteins. The ability to genetically encode an expanded set of building blocks with new chemical and physical properties is transforming the study, manipulation and evolution of proteins, and is enabling diverse applications, including approaches to probe, image and control protein function, and to precisely engineer therapeutics. Underpinning this transformation are strategies to engineer and rewire translation. Emerging strategies aim to reprogram the genetic code so that noncanonical biopolymers can be synthesized and evolved, and to test the limits of our ability to engineer the translational machinery and systematically recode genomes.

Genetic and genomic glimpses of the elusive arbuscular mycorrhizal fungi.

PubMed

Lanfranco, Luisa; Young, J Peter W

2012-08-01

Arbuscular mycorrhizal fungi (AMF), which form an ancient and widespread mutualistic symbiosis with plants, are a crucial but still enigmatic component of the plant microbiome. Nowadays, their obligate biotrophy is no longer an obstacle to deciphering the role played by AMF in this fascinating symbiosis. The first genome-wide transcriptomic analysis of an AMF showed a metabolic complexity with no sign of massive gene loss, and the presence of genes for meiotic recombination suggests that AMF are not simple clonal organisms, as originally thought. New findings on suppression of host defenses and nutrient exchange processes have shed light on the mechanisms that contribute to such an intimate and long-lasting integration between living plant and fungal cells. Copyright © 2012 Elsevier Ltd. All rights reserved.

Hearing regulates Drosophila aggression.

PubMed

Versteven, Marijke; Vanden Broeck, Lies; Geurten, Bart; Zwarts, Liesbeth; Decraecker, Lisse; Beelen, Melissa; Göpfert, Martin C; Heinrich, Ralf; Callaerts, Patrick

2017-02-21

Aggression is a universal social behavior important for the acquisition of food, mates, territory, and social status. Aggression in Drosophila is context-dependent and can thus be expected to involve inputs from multiple sensory modalities. Here, we use mechanical disruption and genetic approaches in Drosophila melanogaster to identify hearing as an important sensory modality in the context of intermale aggressive behavior. We demonstrate that neuronal silencing and targeted knockdown of hearing genes in the fly's auditory organ elicit abnormal aggression. Further, we show that exposure to courtship or aggression song has opposite effects on aggression. Our data define the importance of hearing in the control of Drosophila intermale aggression and open perspectives to decipher how hearing and other sensory modalities are integrated at the neural circuit level.

Hearing regulates Drosophila aggression

PubMed Central

Versteven, Marijke; Vanden Broeck, Lies; Geurten, Bart; Zwarts, Liesbeth; Decraecker, Lisse; Beelen, Melissa; Göpfert, Martin C.; Heinrich, Ralf; Callaerts, Patrick

2017-01-01

Aggression is a universal social behavior important for the acquisition of food, mates, territory, and social status. Aggression in Drosophila is context-dependent and can thus be expected to involve inputs from multiple sensory modalities. Here, we use mechanical disruption and genetic approaches in Drosophila melanogaster to identify hearing as an important sensory modality in the context of intermale aggressive behavior. We demonstrate that neuronal silencing and targeted knockdown of hearing genes in the fly’s auditory organ elicit abnormal aggression. Further, we show that exposure to courtship or aggression song has opposite effects on aggression. Our data define the importance of hearing in the control of Drosophila intermale aggression and open perspectives to decipher how hearing and other sensory modalities are integrated at the neural circuit level. PMID:28115690

It is all about location: how to pinpoint microorganisms and their functions in multispecies biofilms.

PubMed

Costa, Angela M; Mergulhão, Filipe J; Briandet, Romain; Azevedo, Nuno F

2017-09-01

Multispecies biofilms represent the dominant mode of life for the vast majority of microorganisms. Bacterial spatial localization in such biostructures governs ecological interactions between different populations and triggers the overall community functions. Here, we discuss the pros and cons of fluorescence-based techniques used to decipher bacterial species patterns in biofilms at single cell level, including fluorescence in situ hybridization and the use of genetically modified bacteria that express fluorescent proteins, reporting the significant improvements of those techniques. The development of tools for spatial and temporal study of multispecies biofilms will allow live imaging and spatial localization of cells in naturally occurring biofilms coupled with metabolic information, increasing insight of microbial community and the relation between its structure and functions.

Simulating Electrophoresis.

ERIC Educational Resources Information Center

Moertel, Cheryl; Frutiger, Bruce

1996-01-01

Describes a DNA fingerprinting simulation that uses vegetable food coloring and plastic food containers instead of DNA and expensive gel electrophoresis chambers. Allows students to decipher unknown combinations of dyes in a method similar to that used to decipher samples of DNA in DNA fingerprint techniques. (JRH)

PCR-free quantitative detection of genetically modified organism from raw materials. An electrochemiluminescence-based bio bar code method.

PubMed

Zhu, Debin; Tang, Yabing; Xing, Da; Chen, Wei R

2008-05-15

A bio bar code assay based on oligonucleotide-modified gold nanoparticles (Au-NPs) provides a PCR-free method for quantitative detection of nucleic acid targets. However, the current bio bar code assay requires lengthy experimental procedures including the preparation and release of bar code DNA probes from the target-nanoparticle complex and immobilization and hybridization of the probes for quantification. Herein, we report a novel PCR-free electrochemiluminescence (ECL)-based bio bar code assay for the quantitative detection of genetically modified organism (GMO) from raw materials. It consists of tris-(2,2'-bipyridyl) ruthenium (TBR)-labeled bar code DNA, nucleic acid hybridization using Au-NPs and biotin-labeled probes, and selective capture of the hybridization complex by streptavidin-coated paramagnetic beads. The detection of target DNA is realized by direct measurement of ECL emission of TBR. It can quantitatively detect target nucleic acids with high speed and sensitivity. This method can be used to quantitatively detect GMO fragments from real GMO products.

A unified model of the standard genetic code.

PubMed

José, Marco V; Zamudio, Gabriel S; Morgado, Eberto R

2017-03-01

The Rodin-Ohno (RO) and the Delarue models divide the table of the genetic code into two classes of aminoacyl-tRNA synthetases (aaRSs I and II) with recognition from the minor or major groove sides of the tRNA acceptor stem, respectively. These models are asymmetric but they are biologically meaningful. On the other hand, the standard genetic code (SGC) can be derived from the primeval RNY code (R stands for purines, Y for pyrimidines and N any of them). In this work, the RO-model is derived by means of group actions, namely, symmetries represented by automorphisms, assuming that the SGC originated from a primeval RNY code. It turns out that the RO-model is symmetric in a six-dimensional (6D) hypercube. Conversely, using the same automorphisms, we show that the RO-model can lead to the SGC. In addition, the asymmetric Delarue model becomes symmetric by means of quotient group operations. We formulate isometric functions that convert the class aaRS I into the class aaRS II and vice versa. We show that the four polar requirement categories display a symmetrical arrangement in our 6D hypercube. Altogether these results cannot be attained, neither in two nor in three dimensions. We discuss the present unified 6D algebraic model, which is compatible with both the SGC (based upon the primeval RNY code) and the RO-model.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Vassilevska, Tanya

This is the first code, designed to run on a desktop, which models the intracellular replication and the cell-to-cell infection and demonstrates virus evolution at the molecular level. This code simulates the infection of a population of "idealized biological cells" (represented as objects that do not divide or have metabolism) with "virus" (represented by its genetic sequence), the replication and simultaneous mutation of the virus which leads to evolution of the population of genetically diverse viruses. The code is built to simulate single-stranded RNA viruses. The input for the code is 1. the number of biological cells in the culture,more » 2. the initial composition of the virus population, 3. the reference genome of the RNA virus, 4. the coordinates of the genome regions and their significance and, 5. parameters determining the dynamics of virus replication, such as the mutation rate. The simulation ends when all cells have been infected or when no more infections occurs after a given number of attempts. The code has the ability to simulate the evolution of the virus in serial passage of cell "cultures", i.e. after the end of a simulation, a new one is immediately scheduled with a new culture of infected cells. The code outputs characteristics of the resulting virus population dynamics and genetic composition of the virus population, such as the top dominant genomes, percentage of a genome with specific characteristics.« less

The "Wow! signal" of the terrestrial genetic code

NASA Astrophysics Data System (ADS)

shCherbak, Vladimir I.; Makukov, Maxim A.

2013-05-01

It has been repeatedly proposed to expand the scope for SETI, and one of the suggested alternatives to radio is the biological media. Genomic DNA is already used on Earth to store non-biological information. Though smaller in capacity, but stronger in noise immunity is the genetic code. The code is a flexible mapping between codons and amino acids, and this flexibility allows modifying the code artificially. But once fixed, the code might stay unchanged over cosmological timescales; in fact, it is the most durable construct known. Therefore it represents an exceptionally reliable storage for an intelligent signature, if that conforms to biological and thermodynamic requirements. As the actual scenario for the origin of terrestrial life is far from being settled, the proposal that it might have been seeded intentionally cannot be ruled out. A statistically strong intelligent-like "signal" in the genetic code is then a testable consequence of such scenario. Here we show that the terrestrial code displays a thorough precision-type orderliness matching the criteria to be considered an informational signal. Simple arrangements of the code reveal an ensemble of arithmetical and ideographical patterns of the same symbolic language. Accurate and systematic, these underlying patterns appear as a product of precision logic and nontrivial computing rather than of stochastic processes (the null hypothesis that they are due to chance coupled with presumable evolutionary pathways is rejected with P-value < 10-13). The patterns are profound to the extent that the code mapping itself is uniquely deduced from their algebraic representation. The signal displays readily recognizable hallmarks of artificiality, among which are the symbol of zero, the privileged decimal syntax and semantical symmetries. Besides, extraction of the signal involves logically straightforward but abstract operations, making the patterns essentially irreducible to any natural origin. Plausible ways of embedding the signal into the code and possible interpretation of its content are discussed. Overall, while the code is nearly optimized biologically, its limited capacity is used extremely efficiently to pass non-biological information.

DECIPHERING NATURALLY-OCCURRING PB CONTAMINATION IMPACTING DRINKING WATER WELLS: SHAKER VILLAGE CATCHMENT, MAINE.

EPA Science Inventory

Trace Pb concentrations in groundwater within glacial deposits across Maine fluctuate considerably. Deciphering the distribution and sources of naturally occurring Pb in groundwater with only the use of conventional anomaly identification techniques presents a challenge. In a rep...

SETI in vivo: testing the we-are-them hypothesis

NASA Astrophysics Data System (ADS)

Makukov, Maxim A.; Shcherbak, Vladimir I.

2018-04-01

After it was proposed that life on Earth might descend from seeding by an earlier extraterrestrial civilization motivated to secure and spread life, some authors noted that this alternative offers a testable implication: microbial seeds could be intentionally supplied with a durable signature that might be found in extant organisms. In particular, it was suggested that the optimal location for such an artefact is the genetic code, as the least evolving part of cells. However, as the mainstream view goes, this scenario is too speculative and cannot be meaningfully tested because encoding/decoding a signature within the genetic code is something ill-defined, so any retrieval attempt is doomed to guesswork. Here we refresh the seeded-Earth hypothesis in light of recent observations, and discuss the motivation for inserting a signature. We then show that `biological SETI' involves even weaker assumptions than traditional SETI and admits a well-defined methodological framework. After assessing the possibility in terms of molecular and evolutionary biology, we formalize the approach and, adopting the standard guideline of SETI that encoding/decoding should follow from first principles and be convention-free, develop a universal retrieval strategy. Applied to the canonical genetic code, it reveals a non-trivial precision structure of interlocked logical and numerical attributes of systematic character (previously we found these heuristically). To assess this result in view of the initial assumption, we perform statistical, comparison, interdependence and semiotic analyses. Statistical analysis reveals no causal connection of the result to evolutionary models of the genetic code, interdependence analysis precludes overinterpretation, and comparison analysis shows that known variations of the code lack any precision-logic structures, in agreement with these variations being post-LUCA (i.e. post-seeding) evolutionary deviations from the canonical code. Finally, semiotic analysis shows that not only the found attributes are consistent with the initial assumption, but that they make perfect sense from SETI perspective, as they ultimately maintain some of the most universal codes of culture.

The chemical basis for the origin of the genetic code and the process of protein synthesis

NASA Technical Reports Server (NTRS)

1981-01-01

The principles upon which the process of protein synthesis and the genetic code were established are elucidated. Extensive work on nuclear magnetic resonance studies of both monomermonomer and monoamino acid polynucleotide interactions is included. A new method of general utility for studying any amino acid interacting with any polynucleotide was developed. This system involves the use of methyl esters of amino acids interacting with polynucleotides.

The genetic code as a periodic table: algebraic aspects.

PubMed

Bashford, J D; Jarvis, P D

2000-01-01

The systematics of indices of physico-chemical properties of codons and amino acids across the genetic code are examined. Using a simple numerical labelling scheme for nucleic acid bases, A=(-1,0), C=(0,-1), G=(0,1), U=(1,0), data can be fitted as low order polynomials of the six coordinates in the 64-dimensional codon weight space. The work confirms and extends the recent studies by Siemion et al. (1995. BioSystems 36, 231-238) of the conformational parameters. Fundamental patterns in the data such as codon periodicities, and related harmonics and reflection symmetries, are here associated with the structure of the set of basis monomials chosen for fitting. Results are plotted using the Siemion one-step mutation ring scheme, and variants thereof. The connections between the present work, and recent studies of the genetic code structure using dynamical symmetry algebras, are pointed out.

Emergence of Coding and its Specificity as a Physico-Informatic Problem

NASA Astrophysics Data System (ADS)

Wills, Peter R.; Nieselt, Kay; McCaskill, John S.

2015-06-01

We explore the origin-of-life consequences of the view that biological systems are demarcated from inanimate matter by their possession of referential information, which is processed computationally to control choices of specific physico-chemical events. Cells are cybernetic: they use genetic information in processes of communication and control, subjecting physical events to a system of integrated governance. The genetic code is the most obvious example of how cells use information computationally, but the historical origin of the usefulness of molecular information is not well understood. Genetic coding made information useful because it imposed a modular metric on the evolutionary search and thereby offered a general solution to the problem of finding catalysts of any specificity. We use the term "quasispecies symmetry breaking" to describe the iterated process of self-organisation whereby the alphabets of distinguishable codons and amino acids increased, step by step.

The Hypothesis that the Genetic Code Originated in Coupled Synthesis of Proteins and the Evolutionary Predecessors of Nucleic Acids in Primitive Cells

PubMed Central

Francis, Brian R.

2015-01-01

Although analysis of the genetic code has allowed explanations for its evolution to be proposed, little evidence exists in biochemistry and molecular biology to offer an explanation for the origin of the genetic code. In particular, two features of biology make the origin of the genetic code difficult to understand. First, nucleic acids are highly complicated polymers requiring numerous enzymes for biosynthesis. Secondly, proteins have a simple backbone with a set of 20 different amino acid side chains synthesized by a highly complicated ribosomal process in which mRNA sequences are read in triplets. Apparently, both nucleic acid and protein syntheses have extensive evolutionary histories. Supporting these processes is a complex metabolism and at the hub of metabolism are the carboxylic acid cycles. This paper advances the hypothesis that the earliest predecessor of the nucleic acids was a β-linked polyester made from malic acid, a highly conserved metabolite in the carboxylic acid cycles. In the β-linked polyester, the side chains are carboxylic acid groups capable of forming interstrand double hydrogen bonds. Evolution of the nucleic acids involved changes to the backbone and side chain of poly(β-d-malic acid). Conversion of the side chain carboxylic acid into a carboxamide or a longer side chain bearing a carboxamide group, allowed information polymers to form amide pairs between polyester chains. Aminoacylation of the hydroxyl groups of malic acid and its derivatives with simple amino acids such as glycine and alanine allowed coupling of polyester synthesis and protein synthesis. Use of polypeptides containing glycine and l-alanine for activation of two different monomers with either glycine or l-alanine allowed simple coded autocatalytic synthesis of polyesters and polypeptides and established the first genetic code. A primitive cell capable of supporting electron transport, thioester synthesis, reduction reactions, and synthesis of polyesters and polypeptides is proposed. The cell consists of an iron-sulfide particle enclosed by tholin, a heterogeneous organic material that is produced by Miller-Urey type experiments that simulate conditions on the early Earth. As the synthesis of nucleic acids evolved from β-linked polyesters, the singlet coding system for replication evolved into a four nucleotide/four amino acid process (AMP = aspartic acid, GMP = glycine, UMP = valine, CMP = alanine) and then into the triplet ribosomal process that permitted multiple copies of protein to be synthesized independent of replication. This hypothesis reconciles the “genetics first” and “metabolism first” approaches to the origin of life and explains why there are four bases in the genetic alphabet. PMID:25679748

EDGE 2017 R&D 100 Entry with Appendix

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chain, Patrick Sam Guy; Davenport, Karen Walston; Li, Po-E

Diabetes, infertility, cancer, and Alzheimer’s disease—the key to one day preventing or even curing such afflictions and diseases (both infectious and genetically driven) may be locked in our own genetic code and the code of microorganisms that inhabit our bodies. The study of this code, known as genomics, has recently become much more promising as a result of two things: (1) vast improvements in high-throughput, nextgeneration sequencing (NSG), and (2) an exponential decrease in the cost of such sequencing. For example, it originally cost approximately $3 billion to sequence the human genome; today, this genome could be resequenced for lessmore » than $1,000.« less

Genetic Code Expansion as a Tool to Study Regulatory Processes of Transcription

NASA Astrophysics Data System (ADS)

Schmidt, Moritz; Summerer, Daniel

2014-02-01

The expansion of the genetic code with noncanonical amino acids (ncAA) enables the chemical and biophysical properties of proteins to be tailored, inside cells, with a previously unattainable level of precision. A wide range of ncAA with functions not found in canonical amino acids have been genetically encoded in recent years and have delivered insights into biological processes that would be difficult to access with traditional approaches of molecular biology. A major field for the development and application of novel ncAA-functions has been transcription and its regulation. This is particularly attractive, since advanced DNA sequencing- and proteomics-techniques continue to deliver vast information on these processes on a global level, but complementing methodologies to study them on a detailed, molecular level and in living cells have been comparably scarce. In a growing number of studies, genetic code expansion has now been applied to precisely control the chemical properties of transcription factors, RNA polymerases and histones, and this has enabled new insights into their interactions, conformational changes, cellular localizations and the functional roles of posttranslational modifications.

Extraordinarily Adaptive Properties of the Genetically Encoded Amino Acids

PubMed Central

Ilardo, Melissa; Meringer, Markus; Freeland, Stephen; Rasulev, Bakhtiyor; Cleaves II, H. James

2015-01-01

Using novel advances in computational chemistry, we demonstrate that the set of 20 genetically encoded amino acids, used nearly universally to construct all coded terrestrial proteins, has been highly influenced by natural selection. We defined an adaptive set of amino acids as one whose members thoroughly cover relevant physico-chemical properties, or “chemistry space.” Using this metric, we compared the encoded amino acid alphabet to random sets of amino acids. These random sets were drawn from a computationally generated compound library containing 1913 alternative amino acids that lie within the molecular weight range of the encoded amino acids. Sets that cover chemistry space better than the genetically encoded alphabet are extremely rare and energetically costly. Further analysis of more adaptive sets reveals common features and anomalies, and we explore their implications for synthetic biology. We present these computations as evidence that the set of 20 amino acids found within the standard genetic code is the result of considerable natural selection. The amino acids used for constructing coded proteins may represent a largely global optimum, such that any aqueous biochemistry would use a very similar set. PMID:25802223

77 FR 24554 - Culturally Significant Objects Imported for Exhibition; Determinations: “Quay Brothers: On...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-04-24

... DEPARTMENT OF STATE [Public Notice 7855] Culturally Significant Objects Imported for Exhibition; Determinations: ``Quay Brothers: On Deciphering the Pharmacist's Prescription for Lip-Reading Puppets'' AGENCY...: On Deciphering the Pharmacist's Prescription for Lip-Reading Puppets'' imported from abroad for...

Unravelling migrations in the steppe: mitochondrial DNA sequences from ancient central Asians.

PubMed Central

Lalueza-Fox, C.; Sampietro, M. L.; Gilbert, M. T. P.; Castri, L.; Facchini, F.; Pettener, D.; Bertranpetit, J.

2004-01-01

This study helps to clarify the debate on the Western and Eastern genetic influences in Central Asia. Thirty-six skeletal remains from Kazakhstan (Central Asia), excavated from different sites dating between the fifteenth century BC to the fifth century AD, have been analysed for the hypervariable control region (HVR-I) and haplogroup diagnostic single nucleotide polymorphisms (SNPs) of the mitochondrial DNA genome. Standard authentication criteria for ancient DNA studies, including multiple extractions, cloning of PCR products and independent replication, have been followed. The distribution of east and west Eurasian lineages through time in the region is concordant with the available archaeological information: prior to the thirteenth-seventh century BC, all Kazakh samples belong to European lineages; while later an arrival of east Eurasian sequences that coexisted with the previous west Eurasian genetic substratum can be detected. The presence of an ancient genetic substratum of European origin in West Asia may be related to the discovery of ancient mummies with European features in Xinjiang and to the existence of an extinct Indo-European language, Tocharian. This study demonstrates the usefulness of the ancient DNA in unravelling complex patterns of past human migrations so as to help decipher the origin of present-day admixed populations. PMID:15255049

Childhood Acute Lymphoblastic Leukemia: Progress Through Collaboration

PubMed Central

Yang, Jun J.; Hunger, Stephen P.; Pieters, Rob; Schrappe, Martin; Biondi, Andrea; Vora, Ajay; Baruchel, André; Silverman, Lewis B.; Schmiegelow, Kjeld; Escherich, Gabriele; Horibe, Keizo; Benoit, Yves C.M.; Izraeli, Shai; Yeoh, Allen Eng Juh; Liang, Der-Cherng; Downing, James R.; Evans, William E.; Relling, Mary V.; Mullighan, Charles G.

2015-01-01

Purpose To review the impact of collaborative studies on advances in the biology and treatment of acute lymphoblastic leukemia (ALL) in children and adolescents. Methods A review of English literature on childhood ALL focusing on collaborative studies was performed. The resulting article was reviewed and revised by the committee chairs of the major ALL study groups. Results With long-term survival rates for ALL approaching 90% and the advent of high-resolution genome-wide analyses, several international study groups or consortia were established to conduct collaborative research to further improve outcome. As a result, treatment strategies have been improved for several subtypes of ALL, such as infant, MLL-rearranged, Philadelphia chromosome–positive, and Philadelphia chromosome–like ALL. Many recurrent genetic abnormalities that respond to tyrosine kinase inhibitors and multiple genetic determinants of drug resistance and toxicities have been identified to help develop targeted therapy. Several genetic polymorphisms have been recognized that show susceptibility to developing ALL and that help explain the racial/ethnic differences in the incidence of ALL. Conclusion The information gained from collaborative studies has helped decipher the heterogeneity of ALL to help improve personalized treatment, which will further advance the current high cure rate and the quality of life for children and adolescents with ALL. PMID:26304874

Deciphering the fine-structure of tribal admixture in the Bedouin population using genomic data

PubMed Central

Markus, B; Alshafee, I; Birk, O S

2014-01-01

The Bedouin Israeli population is highly inbred and structured with a very high prevalence of recessive diseases. Many studies in the past two decades focused on linkage analysis in large, multiple consanguineous pedigrees of this population. The advent of high-throughput technologies motivated researchers to search for rare variants shared between smaller pedigrees, integrating data from clinically similar yet seemingly non-related sporadic cases. However, such analyses are challenging because, without pedigree data, there is no prior knowledge regarding possible relatedness between the sporadic cases. Here, we describe models and techniques for the study of relationships between pedigrees and use them for the inference of tribal co-ancestry, delineating the complex social interactions between different tribes in the Negev Bedouins of southern Israel. Through our analysis, we differentiate between tribes that share many yet small genomic segments because of co-ancestry versus tribes that share larger segments because of recent admixture. The emergent pattern is well correlated with the prevalence of rare mutations in the different tribes. Tribes that do not intermarry, mostly because of social restrictions, hold private mutations, whereas tribes that do intermarry demonstrate a genetic flow of mutations between them. Thus, social structure within an inbred community can be delineated through genomic data, with implications to genetic counseling and genetic mapping. PMID:24084643

Deciphering the fine-structure of tribal admixture in the Bedouin population using genomic data.

PubMed

Markus, B; Alshafee, I; Birk, O S

2014-02-01

The Bedouin Israeli population is highly inbred and structured with a very high prevalence of recessive diseases. Many studies in the past two decades focused on linkage analysis in large, multiple consanguineous pedigrees of this population. The advent of high-throughput technologies motivated researchers to search for rare variants shared between smaller pedigrees, integrating data from clinically similar yet seemingly non-related sporadic cases. However, such analyses are challenging because, without pedigree data, there is no prior knowledge regarding possible relatedness between the sporadic cases. Here, we describe models and techniques for the study of relationships between pedigrees and use them for the inference of tribal co-ancestry, delineating the complex social interactions between different tribes in the Negev Bedouins of southern Israel. Through our analysis, we differentiate between tribes that share many yet small genomic segments because of co-ancestry versus tribes that share larger segments because of recent admixture. The emergent pattern is well correlated with the prevalence of rare mutations in the different tribes. Tribes that do not intermarry, mostly because of social restrictions, hold private mutations, whereas tribes that do intermarry demonstrate a genetic flow of mutations between them. Thus, social structure within an inbred community can be delineated through genomic data, with implications to genetic counseling and genetic mapping.

Childhood Acute Lymphoblastic Leukemia: Progress Through Collaboration.

PubMed

Pui, Ching-Hon; Yang, Jun J; Hunger, Stephen P; Pieters, Rob; Schrappe, Martin; Biondi, Andrea; Vora, Ajay; Baruchel, André; Silverman, Lewis B; Schmiegelow, Kjeld; Escherich, Gabriele; Horibe, Keizo; Benoit, Yves C M; Izraeli, Shai; Yeoh, Allen Eng Juh; Liang, Der-Cherng; Downing, James R; Evans, William E; Relling, Mary V; Mullighan, Charles G

2015-09-20

To review the impact of collaborative studies on advances in the biology and treatment of acute lymphoblastic leukemia (ALL) in children and adolescents. A review of English literature on childhood ALL focusing on collaborative studies was performed. The resulting article was reviewed and revised by the committee chairs of the major ALL study groups. With long-term survival rates for ALL approaching 90% and the advent of high-resolution genome-wide analyses, several international study groups or consortia were established to conduct collaborative research to further improve outcome. As a result, treatment strategies have been improved for several subtypes of ALL, such as infant, MLL-rearranged, Philadelphia chromosome-positive, and Philadelphia chromosome-like ALL. Many recurrent genetic abnormalities that respond to tyrosine kinase inhibitors and multiple genetic determinants of drug resistance and toxicities have been identified to help develop targeted therapy. Several genetic polymorphisms have been recognized that show susceptibility to developing ALL and that help explain the racial/ethnic differences in the incidence of ALL. The information gained from collaborative studies has helped decipher the heterogeneity of ALL to help improve personalized treatment, which will further advance the current high cure rate and the quality of life for children and adolescents with ALL. © 2015 by American Society of Clinical Oncology.

Exome Sequencing Frequently Reveals the Cause of Early-Onset Chronic Kidney Disease

PubMed Central

Vivante, Asaf; Hildebrandt, Friedhelm

2016-01-01

The primary causes of chronic kidney disease (CKD) in children differ from those of adult onset CKD. In the United States the most common diagnostic groups of CKD that manifests before 25 years of age are: i) congenital anomalies of the kidneys and urinary tract (CAKUT) (49.1%), ii) steroid-resistant nephrotic syndrome (SRNS) (10.4%), iii) chronic glomerulonephritis (8.1%), and iv) renal cystic ciliopathies (5.3 %), encompassing >70% of CKD together. Recent findings suggest that early-onset CKD is caused by mutations in any one of over 200 different monogenic genes. High-throughput sequencing has very recently rendered identification of causative mutations in this high number of genes feasible. Molecular genetic diagnostics in early onset-CKD (before the age of 25 years) will, i) provide patients and families with a molecular genetic diagnosis, ii) generate new insights into diseases mechanisms, iii) allow etiology-based classification of patient cohorts for clinical studies and, iv) may have consequences for personalized treatment and prevention of CKD. In this review, we will discuss the implications of next-generation sequencing for clinical genetic diagnostics and discovery of novel genes in early-onset CKD. We also delineate the resulting opportunities for deciphering disease mechanisms and therapeutic implications. PMID:26750453

Epigenetics: a new frontier in dentistry.

PubMed

Williams, S D; Hughes, T E; Adler, C J; Brook, A H; Townsend, G C

2014-06-01

In 2007, only four years after the completion of the Human Genome Project, the journal Science announced that epigenetics was the 'breakthrough of the year'. Time magazine placed it second in the top 10 discoveries of 2009. While our genetic code (i.e. our DNA) contains all of the information to produce the elements we require to function, our epigenetic code determines when and where genes in the genetic code are expressed. Without the epigenetic code, the genetic code is like an orchestra without a conductor. Although there is now a substantial amount of published research on epigenetics in medicine and biology, epigenetics in dental research is in its infancy. However, epigenetics promises to become increasingly relevant to dentistry because of the role it plays in gene expression during development and subsequently potentially influencing oral disease susceptibility. This paper provides a review of the field of epigenetics aimed specifically at oral health professionals. It defines epigenetics, addresses the underlying concepts and provides details about specific epigenetic molecular mechanisms. Further, we discuss some of the key areas where epigenetics is implicated, and review the literature on epigenetics research in dentistry, including its relevance to clinical disciplines. This review considers some implications of epigenetics for the future of dental practice, including a 'personalized medicine' approach to the management of common oral diseases. © 2014 Australian Dental Association.

GLADIATOR: a global approach for elucidating disease modules.

PubMed

Silberberg, Yael; Kupiec, Martin; Sharan, Roded

2017-05-26

Understanding the genetic basis of disease is an important challenge in biology and medicine. The observation that disease-related proteins often interact with one another has motivated numerous network-based approaches for deciphering disease mechanisms. In particular, protein-protein interaction networks were successfully used to illuminate disease modules, i.e., interacting proteins working in concert to drive a disease. The identification of these modules can further our understanding of disease mechanisms. We devised a global method for the prediction of multiple disease modules simultaneously named GLADIATOR (GLobal Approach for DIsease AssociaTed mOdule Reconstruction). GLADIATOR relies on a gold-standard disease phenotypic similarity to obtain a pan-disease view of the underlying modules. To traverse the search space of potential disease modules, we applied a simulated annealing algorithm aimed at maximizing the correlation between module similarity and the gold-standard phenotypic similarity. Importantly, this optimization is employed over hundreds of diseases simultaneously. GLADIATOR's predicted modules highly agree with current knowledge about disease-related proteins. Furthermore, the modules exhibit high coherence with respect to functional annotations and are highly enriched with known curated pathways, outperforming previous methods. Examination of the predicted proteins shared by similar diseases demonstrates the diverse role of these proteins in mediating related processes across similar diseases. Last, we provide a detailed analysis of the suggested molecular mechanism predicted by GLADIATOR for hyperinsulinism, suggesting novel proteins involved in its pathology. GLADIATOR predicts disease modules by integrating knowledge of disease-related proteins and phenotypes across multiple diseases. The predicted modules are functionally coherent and are more in line with current biological knowledge compared to modules obtained using previous disease-centric methods. The source code for GLADIATOR can be downloaded from http://www.cs.tau.ac.il/~roded/GLADIATOR.zip .

Long-term genomic and epigenomic dysregulation as a consequence of prenatal alcohol exposure: a model for fetal alcohol spectrum disorders.

PubMed

Kleiber, Morgan L; Diehl, Eric J; Laufer, Benjamin I; Mantha, Katarzyna; Chokroborty-Hoque, Aniruddho; Alberry, Bonnie; Singh, Shiva M

2014-01-01

There is abundant evidence that prenatal alcohol exposure leads to a range of behavioral and cognitive impairments, categorized under the term fetal alcohol spectrum disorders (FASDs). These disorders are pervasive in Western cultures and represent the most common preventable source of neurodevelopmental disabilities. The genetic and epigenetic etiology of these phenotypes, including those factors that may maintain these phenotypes throughout the lifetime of an affected individual, has become a recent topic of investigation. This review integrates recent data that has progressed our understanding FASD as a continuum of molecular events, beginning with cellular stress response and ending with a long-term "footprint" of epigenetic dysregulation across the genome. It reports on data from multiple ethanol-treatment paradigms in mouse models that identify changes in gene expression that occur with respect to neurodevelopmental timing of exposure and ethanol dose. These studies have identified patterns of genomic alteration that are dependent on the biological processes occurring at the time of ethanol exposure. This review also adds to evidence that epigenetic processes such as DNA methylation, histone modifications, and non-coding RNA regulation may underlie long-term changes to gene expression patterns. These may be initiated by ethanol-induced alterations to DNA and histone methylation, particularly in imprinted regions of the genome, affecting transcription which is further fine-tuned by altered microRNA expression. These processes are likely complex, genome-wide, and interrelated. The proposed model suggests a potential for intervention, given that epigenetic changes are malleable and may be altered by postnatal environment. This review accentuates the value of mouse models in deciphering the molecular etiology of FASD, including those processes that may provide a target for the ammelioration of this common yet entirely preventable disorder.

Long-term genomic and epigenomic dysregulation as a consequence of prenatal alcohol exposure: a model for fetal alcohol spectrum disorders

PubMed Central

Kleiber, Morgan L.; Diehl, Eric J.; Laufer, Benjamin I.; Mantha, Katarzyna; Chokroborty-Hoque, Aniruddho; Alberry, Bonnie; Singh, Shiva M.

2014-01-01

There is abundant evidence that prenatal alcohol exposure leads to a range of behavioral and cognitive impairments, categorized under the term fetal alcohol spectrum disorders (FASDs). These disorders are pervasive in Western cultures and represent the most common preventable source of neurodevelopmental disabilities. The genetic and epigenetic etiology of these phenotypes, including those factors that may maintain these phenotypes throughout the lifetime of an affected individual, has become a recent topic of investigation. This review integrates recent data that has progressed our understanding FASD as a continuum of molecular events, beginning with cellular stress response and ending with a long-term “footprint” of epigenetic dysregulation across the genome. It reports on data from multiple ethanol-treatment paradigms in mouse models that identify changes in gene expression that occur with respect to neurodevelopmental timing of exposure and ethanol dose. These studies have identified patterns of genomic alteration that are dependent on the biological processes occurring at the time of ethanol exposure. This review also adds to evidence that epigenetic processes such as DNA methylation, histone modifications, and non-coding RNA regulation may underlie long-term changes to gene expression patterns. These may be initiated by ethanol-induced alterations to DNA and histone methylation, particularly in imprinted regions of the genome, affecting transcription which is further fine-tuned by altered microRNA expression. These processes are likely complex, genome-wide, and interrelated. The proposed model suggests a potential for intervention, given that epigenetic changes are malleable and may be altered by postnatal environment. This review accentuates the value of mouse models in deciphering the molecular etiology of FASD, including those processes that may provide a target for the ammelioration of this common yet entirely preventable disorder. PMID:24917881

Comprehensive Insights in the Mycobacterium avium subsp. paratuberculosis Genome Using New WGS Data of Sheep Strain JIII-386 from Germany

PubMed Central

Möbius, Petra; Hölzer, Martin; Felder, Marius; Nordsiek, Gabriele; Groth, Marco; Köhler, Heike; Reichwald, Kathrin; Platzer, Matthias; Marz, Manja

2015-01-01

Mycobacterium avium (M. a.) subsp. paratuberculosis (MAP)—the etiologic agent of Johne’s disease—affects cattle, sheep, and other ruminants worldwide. To decipher phenotypic differences among sheep and cattle strains (belonging to MAP-S [Type-I/III], respectively, MAP-C [Type-II]), comparative genome analysis needs data from diverse isolates originating from different geographic regions of the world. This study presents the so far best assembled genome of a MAP-S-strain: Sheep isolate JIII-386 from Germany. One newly sequenced cattle isolate (JII-1961, Germany), four published MAP strains of MAP-C and MAP-S from the United States and Australia, and M. a. subsp. hominissuis (MAH) strain 104 were used for assembly improvement and comparisons. All genomes were annotated by BacProt and results compared with NCBI (National Center for Biotechnology Information) annotation. Corresponding protein-coding sequences (CDSs) were detected, but also CDSs that were exclusively determined by either NCBI or BacProt. A new Shine–Dalgarno sequence motif (5′-AGCTGG-3′) was extracted. Novel CDSs including PE-PGRS family protein genes and about 80 noncoding RNAs exhibiting high sequence conservation are presented. Previously found genetic differences between MAP-types are partially revised. Four of ten assumed MAP-S-specific large sequence polymorphism regions (LSPSs) are still present in MAP-C strains; new LSPSs were identified. Independently of the regional origin of the strains, the number of individual CDSs and single nucleotide variants confirms the strong similarity of MAP-C strains and shows higher diversity among MAP-S strains. This study gives ambiguous results regarding the hypothesis that MAP-S is the evolutionary intermediate between MAH and MAP-C, but it clearly shows a higher similarity of MAP to MAH than to Mycobacterium intracellulare. PMID:26384038

A novel reverse genetics system for production of infectious West Nile virus using homologous recombination in mammalian cells.

PubMed

Kobayashi, Shintaro; Yoshii, Kentaro; Hirano, Minato; Muto, Memi; Kariwa, Hiroaki

2017-02-01

Reverse genetics systems facilitate investigation of many aspects of the life cycle and pathogenesis of viruses. However, genetic instability in Escherichia coli has hampered development of a reverse genetics system for West Nile virus (WNV). In this study, we developed a novel reverse genetics system for WNV based on homologous recombination in mammalian cells. Introduction of the DNA fragment coding for the WNV structural protein together with a DNA-based replicon resulted in the release of infectious WNV. The growth rate and plaque size of the recombinant virus were almost identical to those of the parent WNV. Furthermore, chimeric WNV was produced by introducing the DNA fragment coding for the structural protein and replicon plasmid derived from various strains. Here, we report development of a novel system that will facilitate research into WNV infection. Copyright © 2016 Elsevier B.V. All rights reserved.

The Human Proteome Project: Unlocking the Mysteries of Human Life and Unleashing Its Potential

DTIC Science & Technology

2011-02-16

Australasian Genetics Resource Book. June 2007. Accessed September 27, 2010. www.genetics.com.au/pdf/factsheets/fs24.pdf. 2 White House, Office of...Project and Beyond." The Australasian Genetics Resource Book. June 2007. Accessed September 27, 2010. www.genetics.com.au/pdf/factsheets/fs24.pdf...9 Centre for Genetics Education. "The Human Genetic Code – The Human Genome Project and Beyond." The Australasian Genetics Resource Book. June

A novel nuclear genetic code alteration in yeasts and the evolution of codon reassignment in eukaryotes.

PubMed

Mühlhausen, Stefanie; Findeisen, Peggy; Plessmann, Uwe; Urlaub, Henning; Kollmar, Martin

2016-07-01

The genetic code is the cellular translation table for the conversion of nucleotide sequences into amino acid sequences. Changes to the meaning of sense codons would introduce errors into almost every translated message and are expected to be highly detrimental. However, reassignment of single or multiple codons in mitochondria and nuclear genomes, although extremely rare, demonstrates that the code can evolve. Several models for the mechanism of alteration of nuclear genetic codes have been proposed (including "codon capture," "genome streamlining," and "ambiguous intermediate" theories), but with little resolution. Here, we report a novel sense codon reassignment in Pachysolen tannophilus, a yeast related to the Pichiaceae. By generating proteomics data and using tRNA sequence comparisons, we show that Pachysolen translates CUG codons as alanine and not as the more usual leucine. The Pachysolen tRNACAG is an anticodon-mutated tRNA(Ala) containing all major alanine tRNA recognition sites. The polyphyly of the CUG-decoding tRNAs in yeasts is best explained by a tRNA loss driven codon reassignment mechanism. Loss of the CUG-tRNA in the ancient yeast is followed by gradual decrease of respective codons and subsequent codon capture by tRNAs whose anticodon is not part of the aminoacyl-tRNA synthetase recognition region. Our hypothesis applies to all nuclear genetic code alterations and provides several testable predictions. We anticipate more codon reassignments to be uncovered in existing and upcoming genome projects. © 2016 Mühlhausen et al.; Published by Cold Spring Harbor Laboratory Press.

Does the Genetic Code Have A Eukaryotic Origin?

PubMed Central

Zhang, Zhang; Yu, Jun

2013-01-01

In the RNA world, RNA is assumed to be the dominant macromolecule performing most, if not all, core “house-keeping” functions. The ribo-cell hypothesis suggests that the genetic code and the translation machinery may both be born of the RNA world, and the introduction of DNA to ribo-cells may take over the informational role of RNA gradually, such as a mature set of genetic code and mechanism enabling stable inheritance of sequence and its variation. In this context, we modeled the genetic code in two content variables—GC and purine contents—of protein-coding sequences and measured the purine content sensitivities for each codon when the sensitivity (% usage) is plotted as a function of GC content variation. The analysis leads to a new pattern—the symmetric pattern—where the sensitivity of purine content variation shows diagonally symmetry in the codon table more significantly in the two GC content invariable quarters in addition to the two existing patterns where the table is divided into either four GC content sensitivity quarters or two amino acid diversity halves. The most insensitive codon sets are GUN (valine) and CAN (CAR for asparagine and CAY for aspartic acid) and the most biased amino acid is valine (always over-estimated) followed by alanine (always under-estimated). The unique position of valine and its codons suggests its key roles in the final recruitment of the complete codon set of the canonical table. The distinct choice may only be attributable to sequence signatures or signals of splice sites for spliceosomal introns shared by all extant eukaryotes. PMID:23402863

Xenobiology: State-of-the-Art, Ethics, and Philosophy of New-to-Nature Organisms.

PubMed

Schmidt, Markus; Pei, Lei; Budisa, Nediljko

The basic chemical constitution of all living organisms in the context of carbon-based chemistry consists of a limited number of small molecules and polymers. Until the twenty-first century, biology was mainly an analytical science and has now reached a point where it merges with engineering science, paving the way for synthetic biology. One of the objectives of synthetic biology is to try to change the chemical compositions of living cells, that is, to create an artificial biological diversity, which in turn fosters a new sub-field of synthetic biology, xenobiology. In particular, the genetic code in living systems is based on highly standardized chemistry composed of the same "letters" or nucleotides as informational polymers (DNA, RNA) and the 20 amino acids which serve as basic building blocks for proteins. The universality of the genetic code enables not only vertical gene transfer within the same species but also horizontal gene transfer across biological taxa, which require a high degree of standardization and interconnectivity. Although some minor alterations of the standard genetic code are found in nature (e.g., proteins containing non-conical amino acids exist in nature, and some organisms use alternated coding systems), all structurally deep chemistry changes within living systems are generally lethal, making the creation of artificial biological system an extremely difficult challenge.In this context, one of the great challenges for bioscience is the development of a strategy for expanding the standard basic chemical repertoire of living cells. Attempts to alter the meaning of the genetic information stored in DNA as an informational polymer by changing the chemistry of the polymer (i.e., xeno-nucleic acids) or by changes in the genetic code have already yielded successful results. In the future this should enable the partial or full redirection of the biological information flow to generate "new" version(s) of the genetic code derived from the "old" biological world.In addition to the scientific challenges, the attempt to increase biochemical diversity also raises important ethical and philosophical issues. Although promotors of this branch of synthetic biology highlight the many potential applications to come (e.g., novel tools for diagnostics and fighting infection diseases), such developments could also bring risks affecting social, political, and other structures of nearly all societies.

Mapping lupus susceptibility genes in the NZM2410 mouse model.

PubMed

Morel, Laurence

2012-01-01

Considerable efforts have been deployed over the years to decipher the genetic basis of systemic lupus erythematosus (SLE). The NZM2410 strain is murine model in which the genetic analysis of SLE is the most advanced. NZM2410 studies have shown that, as in SLE patients, lupus susceptibility is achieved by the coexpression of many susceptibility alleles, each of which with a small contribution to the overall disease phenotype. This mouse model has also revealed the critical role played by gene-gene interactions, which are believed to be an essential contribution to human SLE heritability, although it has been much more difficult to characterize. We have now reached a phase in which NZM2410 susceptibility genes have been identified, all them novel in their association with lupus or even with immune functions. Ongoing studies geared at understanding how these genes impact immune tolerance and interact with each other in the mouse, and their impact on the human immune system or target organs, will undoubtedly lead to important discovery for a better understanding on the disease and potential identification of therapeutic targets. Copyright © 2012 Elsevier Inc. All rights reserved.

Synthetic biology for pharmaceutical drug discovery

PubMed Central

Trosset, Jean-Yves; Carbonell, Pablo

2015-01-01

Synthetic biology (SB) is an emerging discipline, which is slowly reorienting the field of drug discovery. For thousands of years, living organisms such as plants were the major source of human medicines. The difficulty in resynthesizing natural products, however, often turned pharmaceutical industries away from this rich source for human medicine. More recently, progress on transformation through genetic manipulation of biosynthetic units in microorganisms has opened the possibility of in-depth exploration of the large chemical space of natural products derivatives. Success of SB in drug synthesis culminated with the bioproduction of artemisinin by microorganisms, a tour de force in protein and metabolic engineering. Today, synthetic cells are not only used as biofactories but also used as cell-based screening platforms for both target-based and phenotypic-based approaches. Engineered genetic circuits in synthetic cells are also used to decipher disease mechanisms or drug mechanism of actions and to study cell–cell communication within bacteria consortia. This review presents latest developments of SB in the field of drug discovery, including some challenging issues such as drug resistance and drug toxicity. PMID:26673570

Transcriptomic and epigenomic characterization of the developing bat wing

PubMed Central

Eckalbar, Walter L.; Schlebusch, Stephen A.; Mason, Mandy K.; Gill, Zoe; Parker, Ash V.; Booker, Betty M.; Nishizaki, Sierra; Muswamba-Nday, Christiane; Terhune, Elizabeth; Nevonen, Kimberly; Makki, Nadja; Friedrich, Tara; VanderMeer, Julia E.; Pollard, Katherine S.; Carbone, Lucia; Wall, Jeff D.; Illing, Nicola; Ahituv, Nadav

2016-01-01

Bats are the only mammals capable of powered flight, but little is known about the genetic determinants that shape their wings. Here, we generated a genome for Miniopterus natalensis and performed RNA-seq and ChIP-seq (H3K27ac, H3K27me3) on its developing forelimb and hindlimb autopods at sequential embryonic stages to decipher the molecular events that underlie bat wing development. Over 7,000 genes and several lncRNAs, including Tbx5-as1 and Hottip, were differentially expressed between forelimb, hindlimb and different stages. ChIP-seq identified thousands of regions that are differentially modified in forelimb versus hindlimb. Comparative genomics found 2,796 bat-accelerated regions within H3K27ac peaks, several of which cluster near limb-associated genes. Pathway analyses revealed multiple ribosomal proteins and known limb patterning signaling pathways as differentially regulated, and implicated increased forelimb mesenchymal condensations with differential growth. Combined, our work outlines multiple genetic components that contribute to bat wing formation, providing a genomic blueprint for this morphological innovation. PMID:27019111

A platform for rapid prototyping of synthetic gene networks in mammalian cells

PubMed Central

Duportet, Xavier; Wroblewska, Liliana; Guye, Patrick; Li, Yinqing; Eyquem, Justin; Rieders, Julianne; Rimchala, Tharathorn; Batt, Gregory; Weiss, Ron

2014-01-01

Mammalian synthetic biology may provide novel therapeutic strategies, help decipher new paths for drug discovery and facilitate synthesis of valuable molecules. Yet, our capacity to genetically program cells is currently hampered by the lack of efficient approaches to streamline the design, construction and screening of synthetic gene networks. To address this problem, here we present a framework for modular and combinatorial assembly of functional (multi)gene expression vectors and their efficient and specific targeted integration into a well-defined chromosomal context in mammalian cells. We demonstrate the potential of this framework by assembling and integrating different functional mammalian regulatory networks including the largest gene circuit built and chromosomally integrated to date (6 transcription units, 27kb) encoding an inducible memory device. Using a library of 18 different circuits as a proof of concept, we also demonstrate that our method enables one-pot/single-flask chromosomal integration and screening of circuit libraries. This rapid and powerful prototyping platform is well suited for comparative studies of genetic regulatory elements, genes and multi-gene circuits as well as facile development of libraries of isogenic engineered cell lines. PMID:25378321

Integration of the blaNDM-1 carbapenemase gene into Proteus genomic island 1 (PGI1-PmPEL) in a Proteus mirabilis clinical isolate.

PubMed

Girlich, Delphine; Dortet, Laurent; Poirel, Laurent; Nordmann, Patrice

2015-01-01

To decipher the mechanisms and their associated genetic determinants responsible for β-lactam resistance in a Proteus mirabilis clinical isolate. The entire genetic structure surrounding the β-lactam resistance genes was characterized by PCR, gene walking and DNA sequencing. Genes encoding the carbapenemase NDM-1 and the ESBL VEB-6 were located in a 38.5 kb MDR structure, which itself was inserted into a new variant of the Proteus genomic island 1 (PGI1). This new PGI1-PmPEL variant of 64.4 kb was chromosomally located, as an external circular form in the P. mirabilis isolate, suggesting potential mobility. This is the first known description of the bla(NDM-1) gene in a genomic island structure, which might further enhance the spread of the bla(NDM-1) carbapenemase gene among enteric pathogens. © The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Microbiota and innate immunity in intestinal inflammation and neoplasia.

PubMed

Cario, Elke

2013-01-01

This review focuses on recent advances and novel insights into the mechanistic events that may link commensal microbiota and host innate immunity in the pathophysiology of intestinal inflammation and neoplasia. Unanswered questions are discussed and future perspectives in the field are highlighted. Commensal microbiota, host innate immunity, and genetics form a multidimensional network that controls homeostasis of the mucosal barrier in the intestine. Large-scale sequencing projects have begun to catalog the healthy human microbiome. Converging evidence suggests that alterations in the regulation of the complex host environment [e.g., dysbiosis and overgrowth of select commensal bacterial species, dietary factors, copresence of facultative pathogens (including viruses), and changes in mucus characteristics] may trigger aberrant innate immune signaling, thereby contributing to the development of intestinal inflammation and associated colon cancer in the susceptible individual. Genetically determined innate immune malfunction may create an inflammatory environment that promotes tumor progression (such as the TLR4-D299G mutation). The next challenging steps to be taken are to decipher changes in the human microbiome (and virome) during well defined diseased states, and relate them to intestinal mucosal immune functions and host genotypes.

Human Genome Sequencing in Health and Disease

PubMed Central

Gonzaga-Jauregui, Claudia; Lupski, James R.; Gibbs, Richard A.

2013-01-01

Following the “finished,” euchromatic, haploid human reference genome sequence, the rapid development of novel, faster, and cheaper sequencing technologies is making possible the era of personalized human genomics. Personal diploid human genome sequences have been generated, and each has contributed to our better understanding of variation in the human genome. We have consequently begun to appreciate the vastness of individual genetic variation from single nucleotide to structural variants. Translation of genome-scale variation into medically useful information is, however, in its infancy. This review summarizes the initial steps undertaken in clinical implementation of personal genome information, and describes the application of whole-genome and exome sequencing to identify the cause of genetic diseases and to suggest adjuvant therapies. Better analysis tools and a deeper understanding of the biology of our genome are necessary in order to decipher, interpret, and optimize clinical utility of what the variation in the human genome can teach us. Personal genome sequencing may eventually become an instrument of common medical practice, providing information that assists in the formulation of a differential diagnosis. We outline herein some of the remaining challenges. PMID:22248320

Natural killer cell biology illuminated by primary immunodeficiency syndromes in humans.

PubMed

Voss, Matthias; Bryceson, Yenan T

2017-04-01

Natural killer (NK) cells are innate immune cytotoxic effector cells well known for their role in antiviral immunity and tumor immunosurveillance. In parts, this knowledge stems from rare inherited immunodeficiency disorders in humans that abrogate NK cell function leading to immune impairments, most notably associated with a high susceptibility to viral infections. Phenotypically, these disorders range from deficiencies selectively affecting NK cells to complex general immune defects that affect NK cells but also other immune cell subsets. Moreover, deficiencies may be associated with reduced NK cell numbers or rather impair specific NK cell effector functions. In recent years, genetic defects underlying the various NK cell deficiencies have been uncovered and have triggered investigative efforts to decipher the molecular mechanisms underlying these disorders. Here we review the associations between inherited human diseases and NK cell development as well as function, with a particular focus on defects in NK cell exocytosis and cytotoxicity. Furthermore we outline how reports of diverse genetic defects have shaped our understanding of NK cell biology. Copyright © 2015. Published by Elsevier Inc.

Chemotaxonomic Study of Citrus, Poncirus and Fortunella Genotypes Based on Peel Oil Volatile Compounds - Deciphering the Genetic Origin of Mangshanyegan (Citrus nobilis Lauriro)

PubMed Central

Liu, Cuihua; Jiang, Dong; Cheng, Yunjiang; Deng, Xiuxin; Chen, Feng; Fang, Liu; Ma, Zhaocheng; Xu, Juan

2013-01-01

Volatile profiles yielded from gas chromatography-mass spectrometry (GC-MS) analysis provide abundant information not only for metabolism-related research, but also for chemotaxonomy. To study the chemotaxonomy of Mangshanyegan, its volatile profiles of fruit and leaf and those of 29 other genotypes of Citrus, Poncirus, and Fortunella were subjected to phylogenetic analyses. Results showed that 145 identified (including 64 tentatively identified) and 15 unidentified volatile compounds were detected from their peel oils. The phylogenetic analysis of peel oils based on hierarchical cluster analysis (HCA) demonstrated a good agreement with the Swingle taxonomy system, in which the three genera of Citrus, Poncirus, and Fortunella were almost completely separated. As to Citrus, HCA indicated that Citrophorum, Cephalocitrus, and Sinocitrus fell into three subgroups, respectively. Also, it revealed that Mangshanyegan contain volatile compounds similar to those from pummelo, though it is genetically believed to be a mandarin. These results were further supported by the principal component analysis of the peel oils and the HCA results of volatile profiles of leaves in the study. PMID:23516475

Application of NMR-based metabolomics to the study of gut microbiota in obesity.

PubMed

Calvani, Riccardo; Brasili, Elisa; Praticò, Giulia; Sciubba, Fabio; Roselli, Marianna; Finamore, Alberto; Marini, Federico; Marzetti, Emanuele; Miccheli, Alfredo

2014-01-01

Lifestyle habits, host gene repertoire, and alterations in the intestinal microbiota concur to the development of obesity. A great deal of research has recently been focused on investigating the role gut microbiota plays in the pathogenesis of metabolic dysfunctions and increased adiposity. Altered microbiota can affect host physiology through several pathways, including enhanced energy harvest, and perturbations in immunity, metabolic signaling, and inflammatory pathways. A broad range of "omics" technologies is now available to help decipher the interactions between the host and the gut microbiota at detailed genetic and functional levels. In particular, metabolomics--the comprehensive analysis of metabolite composition of biological fluids and tissues--could provide breakthrough insights into the links among the gut microbiota, host genetic repertoire, and diet during the development and progression of obesity. Here, we briefly review the most insightful findings on the involvement of gut microbiota in the pathogenesis of obesity. We also discuss how metabolomic approaches based on nuclear magnetic resonance spectroscopy could help understand the activity of gut microbiota in relation to obesity, and assess the effects of gut microbiota modulation in the treatment of this condition.

Latexin Inactivation Enhances Survival and Long-Term Engraftment of Hematopoietic Stem Cells and Expands the Entire Hematopoietic System in Mice.

PubMed

Liu, Yi; Zhang, Cuiping; Li, Zhenyu; Wang, Chi; Jia, Jianhang; Gao, Tianyan; Hildebrandt, Gerhard; Zhou, Daohong; Bondada, Subbarao; Ji, Peng; St Clair, Daret; Liu, Jinze; Zhan, Changguo; Geiger, Hartmut; Wang, Shuxia; Liang, Ying

2017-04-11

Natural genetic diversity offers an important yet largely untapped resource to decipher the molecular mechanisms regulating hematopoietic stem cell (HSC) function. Latexin (Lxn) is a negative stem cell regulatory gene identified on the basis of genetic diversity. By using an Lxn knockout mouse model, we found that Lxn inactivation in vivo led to the physiological expansion of the entire hematopoietic hierarchy. Loss of Lxn enhanced the competitive repopulation capacity and survival of HSCs in a cell-intrinsic manner. Gene profiling of Lxn-null HSCs showed altered expression of genes enriched in cell-matrix and cell-cell interactions. Thrombospondin 1 (Thbs1) was a potential downstream target with a dramatic downregulation in Lxn-null HSCs. Enforced expression of Thbs1 restored the Lxn inactivation-mediated HSC phenotypes. This study reveals that Lxn plays an important role in the maintenance of homeostatic hematopoiesis, and it may lead to development of safe and effective approaches to manipulate HSCs for clinical benefit. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Zebrafish Craniofacial Development: A Window into Early Patterning

PubMed Central

Mork, Lindsey; Crump, Gage

2016-01-01

The formation of the face and skull involves a complex series of developmental events mediated by cells derived from the neural crest, endoderm, mesoderm, and ectoderm. Although vertebrates boast an enormous diversity of adult facial morphologies, the fundamental signaling pathways and cellular events that sculpt the nascent craniofacial skeleton in the embryo have proven to be highly conserved from fish to man. The zebrafish Danio rerio, a small freshwater cyprinid fish from eastern India, has served as a popular model of craniofacial development since the 1990s. Unique strengths of the zebrafish model include a simplified skeleton during larval stages, access to rapidly developing embryos for live imaging, and amenability to transgenesis and complex genetics. In this chapter, we describe the anatomy of the zebrafish craniofacial skeleton; its applications as models for the mammalian jaw, middle ear, palate, and cranial sutures; the superior imaging technology available in fish that has provided unprecedented insights into the dynamics of facial morphogenesis; the use of the zebrafish to decipher the genetic underpinnings of craniofacial biology; and finally a glimpse into the most promising future applications of zebrafish craniofacial research. PMID:26589928

PineElm_SSRdb: a microsatellite marker database identified from genomic, chloroplast, mitochondrial and EST sequences of pineapple (Ananas comosus (L.) Merrill).

PubMed

Chaudhary, Sakshi; Mishra, Bharat Kumar; Vivek, Thiruvettai; Magadum, Santoshkumar; Yasin, Jeshima Khan

2016-01-01

Simple Sequence Repeats or microsatellites are resourceful molecular genetic markers. There are only few reports of SSR identification and development in pineapple. Complete genome sequence of pineapple available in the public domain can be used to develop numerous novel SSRs. Therefore, an attempt was made to identify SSRs from genomic, chloroplast, mitochondrial and EST sequences of pineapple which will help in deciphering genetic makeup of its germplasm resources. A total of 359511 SSRs were identified in pineapple (356385 from genome sequence, 45 from chloroplast sequence, 249 in mitochondrial sequence and 2832 from EST sequences). The list of EST-SSR markers and their details are available in the database. PineElm_SSRdb is an open source database available for non-commercial academic purpose at http://app.bioelm.com/ with a mapping tool which can develop circular maps of selected marker set. This database will be of immense use to breeders, researchers and graduates working on Ananas spp. and to others working on cross-species transferability of markers, investigating diversity, mapping and DNA fingerprinting.

Importance of Resolving Fungal Nomenclature: the Case of Multiple Pathogenic Species in the Cryptococcus Genus

PubMed Central

Lumbsch, H. Thorsten; Bertout, Sebastien; Cabañes, F. Javier; Carbia, Mauricio; Chen, Min; Cuétara, Maria S.; Espinel-Ingroff, Ana; Falk, Rama; Ferrer Rodríguez, Consuelo; Fraser, James A.; Khan, Ziauddin; Kurtzman, Cletus P.; Lagrou, Katrien; Liao, Wanqing; Linares, Carlos; Nielsen, Kirsten; Pan, Weihua; Pekmezovic, Marina; Romeo, Orazio; Sánchez, Manuel; Sampaio, Ana; Sriburee, Pojana; Sugita, Takashi; Takashima, Masako; Taylor, John W.; Theelen, Bart; Tomazin, Rok; Verweij, Paul E.; Wahyuningsih, Retno

2017-01-01

ABSTRACT Cryptococcosis is a major fungal disease caused by members of the Cryptococcus gattii and Cryptococcus neoformans species complexes. After more than 15 years of molecular genetic and phenotypic studies and much debate, a proposal for a taxonomic revision was made. The two varieties within C. neoformans were raised to species level, and the same was done for five genotypes within C. gattii. In a recent perspective (K. J. Kwon-Chung et al., mSphere 2:e00357-16, 2017, https://doi.org/10.1128/mSphere.00357-16), it was argued that this taxonomic proposal was premature and without consensus in the community. Although the authors of the perspective recognized the existence of genetic diversity, they preferred the use of the informal nomenclature “C. neoformans species complex” and “C. gattii species complex.” Here we highlight the advantage of recognizing these seven species, as ignoring these species will impede deciphering further biologically and clinically relevant differences between them, which may in turn delay future clinical advances. PMID:28875175

The power of fission: yeast as a tool for understanding complex splicing.

PubMed

Fair, Benjamin Jung; Pleiss, Jeffrey A

2017-06-01

Pre-mRNA splicing is an essential component of eukaryotic gene expression. Many metazoans, including humans, regulate alternative splicing patterns to generate expansions of their proteome from a limited number of genes. Importantly, a considerable fraction of human disease causing mutations manifest themselves through altering the sequences that shape the splicing patterns of genes. Thus, understanding the mechanistic bases of this complex pathway will be an essential component of combating these diseases. Dating almost to the initial discovery of splicing, researchers have taken advantage of the genetic tractability of budding yeast to identify the components and decipher the mechanisms of splicing. However, budding yeast lacks the complex splicing machinery and alternative splicing patterns most relevant to humans. More recently, many researchers have turned their efforts to study the fission yeast, Schizosaccharomyces pombe, which has retained many features of complex splicing, including degenerate splice site sequences, the usage of exonic splicing enhancers, and SR proteins. Here, we review recent work using fission yeast genetics to examine pre-mRNA splicing, highlighting its promise for modeling the complex splicing seen in higher eukaryotes.

Bayesian Ising approximation for learning dictionaries of multispike timing patterns in premotor neurons

NASA Astrophysics Data System (ADS)

Hernandez Lahme, Damian; Sober, Samuel; Nemenman, Ilya

Important questions in computational neuroscience are whether, how much, and how information is encoded in the precise timing of neural action potentials. We recently demonstrated that, in the premotor cortex during vocal control in songbirds, spike timing is far more informative about upcoming behavior than is spike rate (Tang et al, 2014). However, identification of complete dictionaries that relate spike timing patterns with the controled behavior remains an elusive problem. Here we present a computational approach to deciphering such codes for individual neurons in the songbird premotor area RA, an analog of mammalian primary motor cortex. Specifically, we analyze which multispike patterns of neural activity predict features of the upcoming vocalization, and hence are important codewords. We use a recently introduced Bayesian Ising Approximation, which properly accounts for the fact that many codewords overlap and hence are not independent. Our results show which complex, temporally precise multispike combinations are used by individual neurons to control acoustic features of the produced song, and that these code words are different across individual neurons and across different acoustic features. This work was supported, in part, by JSMF Grant 220020321, NSF Grant 1208126, NIH Grant NS084844 and NIH Grant 1 R01 EB022872.

Fractional optical cryptographic protocol for data containers in a noise-free multiuser environment

NASA Astrophysics Data System (ADS)

Jaramillo, Alexis; Barrera, John Fredy; Zea, Alejandro Vélez; Torroba, Roberto

2018-03-01

Optical encryption systems have great potential for flexible and high-performance data protection, making them an area of rapid development. However, most approaches present two main issues, namely, the presence of speckle noise, and the degree of security they offer. Here we introduce an experimental implementation of an optical encrypting protocol that tackles these issues by taking advantage of recent developments in the field. These developments include the introduction of information containers for noise free information retrieval, the use of multiplexing to allow for a multiple user environment and an architecture based on the Joint fractional Fourier transform that allows increased degrees of freedom and simplifies the experimental requirements. Thus, data handling via QR code containers involving multiple users processed in a fractional joint transform correlator produce coded information with increased security and ease of use. In this way, we can guarantee that only the user with the correct combination of encryption key and security parameters can achieve noise free information after deciphering. We analyze the performance of the system when the order of the fractional Fourier transform is changed during decryption. We show experimental results that confirm the validity of our proposal.

Sensory and Working Memory Representations of Small and Large Numerosities in the Crow Endbrain.

PubMed

Ditz, Helen M; Nieder, Andreas

2016-11-23

Neurons in the avian nidopallium caudolaterale (NCL), an endbrain structure that originated independently from the mammalian neocortex, process visual numerosities. To clarify the code for number in this anatomically distinct endbrain area in birds, neuronal responses to a broad range of numerosities were analyzed. We recorded single-neuron activity from the NCL of crows performing a delayed match-to-sample task with visual numerosities as discriminanda. The responses of >20% of randomly selected neurons were modulated significantly by numerosities ranging from one to 30 items. Numerosity-selective neurons showed bell-shaped tuning curves with one of the presented numerosities as preferred numerosity regardless of the physical appearance of the items. The resulting labeled-line code exhibited logarithmic compression obeying the Weber-Fechner law for magnitudes. Comparable proportions of selective neurons were found, not only during stimulus presentation, but also in the delay phase, indicating a dominant role of the NCL in numerical working memory. Both during sensory encoding and memorization of numerosities in working memory, NCL activity predicted the crows' number discrimination performance. These neuronal data reveal striking similarities across vertebrate taxa in their code for number despite convergently evolved and anatomically distinct endbrain structures. Birds are known for their capabilities to process numerical quantity. However, birds lack a six-layered neocortex that enables primates with numerical competence. We aimed to decipher the neuronal code for numerical quantity in the independently and distinctly evolved endbrain of birds. We recorded the activity of neurons in an endbrain association area termed nidopallium caudolaterale (NCL) from crows that assessed and briefly memorized numerosities from one to 30 dots. We report a neuronal code for sensory representation and working memory of numerosities in the crow NCL exhibiting several characteristics that are surprisingly similar to the ones found in primates. Our data suggest a common code for number in two different vertebrate taxa that has evolved based on convergent evolution. Copyright © 2016 the authors 0270-6474/16/3612044-09$15.00/0.

A meta-analysis of Th2 pathway genetic variants and risk for allergic rhinitis.

PubMed

Bunyavanich, Supinda; Shargorodsky, Josef; Celedón, Juan C

2011-06-01

There is a significant genetic contribution to allergic rhinitis (AR). Genetic association studies for AR have been performed, but varying results make it challenging to decipher the overall potential effect of specific variants. The Th2 pathway plays an important role in the immunological development of AR. We performed meta-analyses of genetic association studies of variants in Th2 pathway genes and AR. PubMed and Phenopedia were searched by double extraction for original studies on Th2 pathway-related genetic polymorphisms and their associations with AR. A meta-analysis was conducted on each genetic polymorphism with data meeting our predetermined selection criteria. Analyses were performed using both fixed and random effects models, with stratification by age group, ethnicity, and AR definition where appropriate. Heterogeneity and publication bias were assessed. Six independent studies analyzing three candidate polymorphisms and involving a total of 1596 cases and 2892 controls met our inclusion criteria. Overall, the A allele of IL13 single nucleotide polymorphism (SNP) rs20541 was associated with increased odds of AR (estimated OR=1.2; 95% CI 1.1-1.3, p-value 0.004 in fixed effects model, 95% CI 1.0-1.5, p-value 0.056 in random effects model). The A allele of rs20541 was associated with increased odds of AR in mixed age groups using both fixed effects and random effects modeling. IL13 SNP rs1800925 and IL4R SNP 1801275 did not demonstrate overall associations with AR. We conclude that there is evidence for an overall association between IL13 SNP rs20541 and increased risk of AR, especially in mixed-age populations. © 2011 John Wiley & Sons A/S.

Methylphenidate and Atomoxetine-Responsive Prefrontal Cortical Genetic Overlaps in "Impulsive" SHR/NCrl and Wistar Rats.

PubMed

Dela Peña, Ike; Dela Peña, Irene Joy; de la Peña, June Bryan; Kim, Hee Jin; Shin, Chan Young; Han, Doug Hyun; Kim, Bung-Nyun; Ryu, Jong Hoon; Cheong, Jae Hoon

2017-09-01

Impulsivity, the predisposition to act prematurely without foresight, is associated with a number of neuropsychiatric disorders, including attention-deficit/hyperactivity disorder (ADHD). Identifying genetic underpinnings of impulsive behavior may help decipher the complex etiology and neurobiological factors of disorders marked by impulsivity. To identify potential genetic factors of impulsivity, we examined common differentially expressed genes (DEGs) in the prefrontal cortex (PFC) of adolescent SHR/NCrl and Wistar rats, which showed marked decrease in preference for the large but delayed reward, compared with WKY/NCrl rats, in the delay discounting task. Of these DEGs, we examined drug-responsive transcripts whose mRNA levels were altered following treatment (in SHR/NCrl and Wistar rats) with drugs that alleviate impulsivity, namely, the ADHD medications methylphenidate and atomoxetine. Prefrontal cortical genetic overlaps between SHR/NCrl and Wistar rats in comparison with WKY/NCrl included genes associated with transcription (e.g., Btg2, Fos, Nr4a2), synaptic plasticity (e.g., Arc, Homer2), and neuron apoptosis (Grik2, Nmnat1). Treatment with methylphenidate and/or atomoxetine increased choice of the large, delayed reward in SHR/NCrl and Wistar rats and changed, in varying degrees, mRNA levels of Nr4a2, Btg2, and Homer2, genes with previously described roles in neuropsychiatric disorders characterized by impulsivity. While further studies are required, we dissected potential genetic factors that may influence impulsivity by identifying genetic overlaps in the PFC of "impulsive" SHR/NCrl and Wistar rats. Notably, these are also drug-responsive transcripts which may be studied further as biomarkers to predict response to ADHD drugs, and as potential targets for the development of treatments to improve impulsivity.

Gene flow does not prevent personality and morphological differentiation between two blue tit populations.

PubMed

Dubuc-Messier, Gabrielle; Caro, Samuel P; Perrier, Charles; van Oers, Kees; Réale, Denis; Charmantier, Anne

2018-05-23

Understanding the causes and consequences of population phenotypic divergence is a central goal in ecology and evolution. Phenotypic divergence among populations can result from genetic divergence, phenotypic plasticity or a combination of the two. However, few studies have deciphered these mechanisms for populations geographically close and connected by gene flow, especially in the case of personality traits. In this study, we used a common garden experiment to explore the genetic basis of the phenotypic divergence observed between two blue tit (Cyanistes caeruleus) populations inhabiting contrasting habitats separated by 25 km, for two personality traits (exploration speed and handling aggression), one physiological trait (heart rate during restraint) and two morphological traits (tarsus length and body mass). Blue tit nestlings were removed from their population and raised in a common garden for up to five years. We then compared adult phenotypes between the two populations, as well as trait-specific Q st and F st . Our results revealed differences between populations similar to those found in the wild, suggesting a genetic divergence for all traits. Q st - F st comparisons revealed that the traits divergences likely result from dissimilar selection patterns rather than from genetic drift. Our study is one of the first to report a Q st - F st comparison for personality traits and adds to the growing body of evidence that population genetic divergence is possible at a small scale for a variety of traits including behavioural traits. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

[Genetic diversity of modern Russian durum wheat cultivars at the gliadin-coding loci].

PubMed

Kudriavtsev, A M; Dedova, L V; Mel'nik, V A; Shishkina, A A; Upelniek, V P; Novosel'skaia-Dragovich, A Iu

2014-05-01

The allelic diversity at four gliadin-coding loci was examined in modern cultivars of the spring and winter durum wheat Triticum durum Desf. Comparative analysis of the allelic diversity showed that the gene pools of these two types of durum wheat, having different life styles, were considerably different. For the modern spring durum wheat cultivars, a certain reduction of the genetic diversity was observed compared to the cultivars bred in the 20th century.

New insights into mitogenomic phylogeny and copy number in eight indigenous sheep populations based on the ATP synthase and cytochrome c oxidase genes.

PubMed

Xiao, P; Niu, L L; Zhao, Q J; Chen, X Y; Wang, L J; Li, L; Zhang, H P; Guo, J Z; Xu, H Y; Zhong, T

2017-11-16

The origins and phylogeny of different sheep breeds has been widely studied using polymorphisms within the mitochondrial hypervariable region. However, little is known about the mitochondrial DNA (mtDNA) content and phylogeny based on mtDNA protein-coding genes. In this study, we assessed the phylogeny and copy number of the mtDNA in eight indigenous (population size, n=184) and three introduced (n=66) sheep breeds in China based on five mitochondrial coding genes (COX1, COX2, ATP8, ATP6 and COX3). The mean haplotype and nucleotide diversities were 0.944 and 0.00322, respectively. We identified a correlation between the lineages distribution and the genetic distance, whereby Valley-type Tibetan sheep had a closer genetic relationship with introduced breeds (Dorper, Poll Dorset and Suffolk) than with other indigenous breeds. Similarly, the Median-joining profile of haplotypes revealed the distribution of clusters according to genetic differences. Moreover, copy number analysis based on the five mitochondrial coding genes was affected by the genetic distance combining with genetic phylogeny; we also identified obvious non-synonymous mutations in ATP6 between the different levels of copy number expressions. These results imply that differences in mitogenomic compositions resulting from geographical separation lead to differences in mitochondrial function.

Deciphering the kinetic structure of multi-ion plasma shocks

DOE PAGES

Keenan, Brett D.; Simakov, Andrei N.; Chacón, Luis; ...

2017-11-15

Here, strong collisional shocks in multi-ion plasmas are featured in many high-energy-density environments, including inertial confinement fusion implosions. However, their basic structure and its dependence on key parameters (e.g., the Mach number and the plasma ion composition) are poorly understood, and inconsistencies in that regard remain in the literature. In particular, the shock width's dependence on the Mach number has been hotly debated for decades. Using a high-fidelity Vlasov-Fokker-Planck code, iFP, and direct comparisons to multi-ion hydrodynamic simulations and semianalytic predictions, we resolve the structure of steady-state planar shocks in D- 3He plasmas. Additionally, we derive and confirm with kineticmore » simulations a quantitative description of the dependence of the shock width on the Mach number and initial ion concentration.« less

Deciphering the kinetic structure of multi-ion plasma shocks

DOE Office of Scientific and Technical Information (OSTI.GOV)

Keenan, Brett D.; Simakov, Andrei N.; Chacón, Luis

Here, strong collisional shocks in multi-ion plasmas are featured in many high-energy-density environments, including inertial confinement fusion implosions. However, their basic structure and its dependence on key parameters (e.g., the Mach number and the plasma ion composition) are poorly understood, and inconsistencies in that regard remain in the literature. In particular, the shock width's dependence on the Mach number has been hotly debated for decades. Using a high-fidelity Vlasov-Fokker-Planck code, iFP, and direct comparisons to multi-ion hydrodynamic simulations and semianalytic predictions, we resolve the structure of steady-state planar shocks in D- 3He plasmas. Additionally, we derive and confirm with kineticmore » simulations a quantitative description of the dependence of the shock width on the Mach number and initial ion concentration.« less

Deciphering mRNA Sequence Determinants of Protein Production Rate

NASA Astrophysics Data System (ADS)

Szavits-Nossan, Juraj; Ciandrini, Luca; Romano, M. Carmen

2018-03-01

One of the greatest challenges in biophysical models of translation is to identify coding sequence features that affect the rate of translation and therefore the overall protein production in the cell. We propose an analytic method to solve a translation model based on the inhomogeneous totally asymmetric simple exclusion process, which allows us to unveil simple design principles of nucleotide sequences determining protein production rates. Our solution shows an excellent agreement when compared to numerical genome-wide simulations of S. cerevisiae transcript sequences and predicts that the first 10 codons, which is the ribosome footprint length on the mRNA, together with the value of the initiation rate, are the main determinants of protein production rate under physiological conditions. Finally, we interpret the obtained analytic results based on the evolutionary role of the codons' choice for regulating translation rates and ribosome densities.

An investigation of messy genetic algorithms

NASA Technical Reports Server (NTRS)

Goldberg, David E.; Deb, Kalyanmoy; Korb, Bradley

1990-01-01

Genetic algorithms (GAs) are search procedures based on the mechanics of natural selection and natural genetics. They combine the use of string codings or artificial chromosomes and populations with the selective and juxtapositional power of reproduction and recombination to motivate a surprisingly powerful search heuristic in many problems. Despite their empirical success, there has been a long standing objection to the use of GAs in arbitrarily difficult problems. A new approach was launched. Results to a 30-bit, order-three-deception problem were obtained using a new type of genetic algorithm called a messy genetic algorithm (mGAs). Messy genetic algorithms combine the use of variable-length strings, a two-phase selection scheme, and messy genetic operators to effect a solution to the fixed-coding problem of standard simple GAs. The results of the study of mGAs in problems with nonuniform subfunction scale and size are presented. The mGA approach is summarized, both its operation and the theory of its use. Experiments on problems of varying scale, varying building-block size, and combined varying scale and size are presented.

Intact coding region of the serotonin transporter gene in obsessive-compulsive disorder

DOE Office of Scientific and Technical Information (OSTI.GOV)

Altemus, M.; Murphy, D.L.; Greenberg, B.

1996-07-26

Epidemiologic studies indicate that obsessive-compulsive disorder is genetically transmitted in some families, although no genetic abnormalities have been identified in individuals with this disorder. The selective response of obsessive-compulsive disorder to treatment with agents which block serotonin reuptake suggests the gene coding for the serotonin transporter as a candidate gene. The primary structure of the serotonin-transporter coding region was sequenced in 22 patients with obsessive-compulsive disorder, using direct PCR sequencing of cDNA synthesized from platelet serotonin-transporter mRNA. No variations in amino acid sequence were found among the obsessive-compulsive disorder patients or healthy controls. These results do not support a rolemore » for alteration in the primary structure of the coding region of the serotonin-transporter gene in the pathogenesis of obsessive-compulsive disorder. 27 refs.« less

Identification of common, unique and polymorphic microsatellites among 73 cyanobacterial genomes.

PubMed

Kabra, Ritika; Kapil, Aditi; Attarwala, Kherunnisa; Rai, Piyush Kant; Shanker, Asheesh

2016-04-01

Microsatellites also known as Simple Sequence Repeats are short tandem repeats of 1-6 nucleotides. These repeats are found in coding as well as non-coding regions of both prokaryotic and eukaryotic genomes and play a significant role in the study of gene regulation, genetic mapping, DNA fingerprinting and evolutionary studies. The availability of 73 complete genome sequences of cyanobacteria enabled us to mine and statistically analyze microsatellites in these genomes. The cyanobacterial microsatellites identified through bioinformatics analysis were stored in a user-friendly database named CyanoSat, which is an efficient data representation and query system designed using ASP.net. The information in CyanoSat comprises of perfect, imperfect and compound microsatellites found in coding, non-coding and coding-non-coding regions. Moreover, it contains PCR primers with 200 nucleotides long flanking region. The mined cyanobacterial microsatellites can be freely accessed at www.compubio.in/CyanoSat/home.aspx. In addition to this 82 polymorphic, 13,866 unique and 2390 common microsatellites were also detected. These microsatellites will be useful in strain identification and genetic diversity studies of cyanobacteria.

Genetic dissection of main and epistatic effects of QTL based on augmented triple test cross design

PubMed Central

Zhang, Zheng; Dai, Zhijun; Chen, Yuan; Yuan, Xiong; Yuan, Zheming; Tang, Wenbang; Li, Lanzhi; Hu, Zhongli

2017-01-01

The use of heterosis has considerably increased the productivity of many crops; however, the biological mechanism underpinning the technique remains elusive. The North Carolina design III (NCIII) and the triple test cross (TTC) are powerful and popular genetic mating design that can be used to decipher the genetic basis of heterosis. However, when using the NCIII design with the present quantitative trait locus (QTL) mapping method, if epistasis exists, the estimated additive or dominant effects are confounded with epistatic effects. Here, we propose a two-step approach to dissect all genetic effects of QTL and digenic interactions on a whole genome without sacrificing statistical power based on an augmented TTC (aTTC) design. Because the aTTC design has more transformation combinations than do the NCIII and TTC designs, it greatly enriches the QTL mapping for studying heterosis. When the basic population comprises recombinant inbred lines (RIL), we can use the same materials in the NCIII design for aTTC-design QTL mapping with transformation combination Z1, Z2, and Z4 to obtain genetic effect of QTL and digenic interactions. Compared with RIL-based TTC design, RIL-based aTTC design saves time, money, and labor for basic population crossed with F1. Several Monte Carlo simulation studies were carried out to confirm the proposed approach; the present genetic parameters could be identified with high statistical power, precision, and calculation speed, even at small sample size or low heritability. Additionally, two elite rice hybrid datasets for nine agronomic traits were estimated for real data analysis. We dissected the genetic effects and calculated the dominance degree of each QTL and digenic interaction. Real mapping results suggested that the dominance degree in Z2 that mainly characterize heterosis showed overdominance and dominance for QTL and digenic interactions. Dominance and overdominance were the major genetic foundations of heterosis in rice. PMID:29240818

Using forensic microsatellites to decipher the genetic structure of linguistic and geographic isolates: A survey in the eastern Italian Alps.

PubMed

Montinaro, Francesco; Boschi, Ilaria; Trombetta, Federica; Merigioli, Sara; Anagnostou, Paolo; Battaggia, Cinzia; Capocasa, Marco; Crivellaro, Federica; Destro Bisol, Giovanni; Coia, Valentina

2012-12-01

The study of geographically and/or linguistically isolated populations could represent a potential area of interaction between population and forensic genetics. These investigations may be useful to evaluate the suitability of loci which have been selected using forensic criteria for bio-anthropological studies. At the same time, they give us an opportunity to evaluate the efficiency of forensic tools for parentage testing in groups with peculiar allele frequency profiles. Within the frame of a long-term project concerning Italian linguistic isolates, we studied 15 microsatellite loci (Identifiler kit) comprising the CODIS panel in 11 populations from the north-eastern Italian Alps (Veneto, Trentino and Friuli Venezia Giulia regions). All our analyses of inter-population differentiation highlight the genetic distinctiveness of most Alpine populations comparing them either to each other or with large and non-isolated Italian populations. Interestingly, we brought to light some aspects of population genetic structure which cannot be detected using unilinear polymorphisms. In fact, the analysis of genotypic disequilibrium between loci detected signals of population substructure when all the individuals of Alpine populations are pooled in a single group. Furthermore, despite the relatively low number of loci analyzed, genetic differentiation among Alpine populations was detected at individual level using a Bayesian method to cluster multilocus genotypes. Among the various populations studied, the four linguistic minorities (Fassa Valley, Luserna, Sappada and Sauris) showed the most pronounced diversity and signatures of a peculiar genetic ancestry. Finally, we show that database replacement may affect estimates of probability of paternity even when the local database is replaced by another based on populations which share a common genetic background but which differ in their demographic history. These findings point to the importance of considering the demographic and cultural profile of populations in forensic applications, even in a context of substantial genetic homogeneity such as that of European populations. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Single cell transcriptomics to explore the immune system in health and disease†

PubMed Central

Regev, Aviv; Teichmann, Sarah A.

2017-01-01

The immune system varies in cell types, states, and locations. The complex networks, interactions and responses of immune cells produce diverse cellular ecosystems composed of multiple cell types, accompanied by genetic diversity in antigen receptors. Within this ecosystem, innate and adaptive immune cells maintain and protect tissue function, integrity and homeostasis upon changes in functional demands and diverse insults. Characterizing this inherent complexity requires studies at single-cell resolution. Recent advances such as, massively-parallel single cell RNA-Seq and sophisticated computational methods are catalysing a revolution in our understanding of immunology. Here, we provide an overview of the state of single cell genomics methods and an outlook on the use of single-cell techniques to decipher the adaptive and innate components of immunity. PMID:28983043

Sequencing the head and neck cancer genome: implications for therapy

PubMed Central

Sun, Wenyue; Califano, Joseph A.

2015-01-01

Head and neck squamous cell carcinoma (HNSCC) is a disease with significant morbidity and mortality. The advancement of next-generation sequencing technologies now enables the landscape of genetic alterations in HNSCCs to be deciphered. In this review, we describe the mutation spectrum discovered in HNSCCs, especially human papilloma virus (HPV)- and/or tobacco smoke exposure–associated HNSCCs. We also describe related research from two independent investigators and from the Cancer Genome Atlas (TCGA). Emphasis is placed on the therapeutic implications of genes frequently altered in HNSCCs (i.e., TP53, PIK3CA, and NOTCH1) and their corresponding pathways, with a particular focus on recent findings of NOTCH pathway activation in HNSCC. We also discuss the application of integrated genomic pathway–based analysis for precision cancer therapy in HNSCC. PMID:25440877

Functional genomics approaches in parasitic helminths.

PubMed

Hagen, J; Lee, E F; Fairlie, W D; Kalinna, B H

2012-01-01

As research on parasitic helminths is moving into the post-genomic era, an enormous effort is directed towards deciphering gene function and to achieve gene annotation. The sequences that are available in public databases undoubtedly hold information that can be utilized for new interventions and control but the exploitation of these resources has until recently remained difficult. Only now, with the emergence of methods to genetically manipulate and transform parasitic worms will it be possible to gain a comprehensive understanding of the molecular mechanisms involved in nutrition, metabolism, developmental switches/maturation and interaction with the host immune system. This review focuses on functional genomics approaches in parasitic helminths that are currently used, to highlight potential applications of these technologies in the areas of cell biology, systems biology and immunobiology of parasitic helminths. © 2011 Blackwell Publishing Ltd.

Identification of ATM Protein Kinase Phosphorylation Sites by Mass Spectrometry.

PubMed

Graham, Mark E; Lavin, Martin F; Kozlov, Sergei V

2017-01-01

ATM (ataxia-telangiectasia mutated) protein kinase is a key regulator of cellular responses to DNA damage and oxidative stress. DNA damage triggers complex cascade of signaling events leading to numerous posttranslational modification on multitude of proteins. Understanding the regulation of ATM kinase is therefore critical not only for understanding the human genetic disorder ataxia-telangiectasia and potential treatment strategies, but essential for deciphering physiological responses of cells to stress. These responses play an important role in carcinogenesis, neurodegeneration, and aging. We focus here on the identification of DNA damage inducible ATM phosphorylation sites to understand the importance of autophosphorylation in the mechanism of ATM kinase activation. We demonstrate the utility of using immunoprecipitated ATM in quantitative LC-MS/MS workflow with stable isotope dimethyl labeling of ATM peptides for identification of phosphorylation sites.

Genomic diversity and introgression in O. sativa reveal the impact of domestication and breeding on the rice genome.

PubMed

Zhao, Keyan; Wright, Mark; Kimball, Jennifer; Eizenga, Georgia; McClung, Anna; Kovach, Michael; Tyagi, Wricha; Ali, Md Liakat; Tung, Chih-Wei; Reynolds, Andy; Bustamante, Carlos D; McCouch, Susan R

2010-05-24

The domestication of Asian rice (Oryza sativa) was a complex process punctuated by episodes of introgressive hybridization among and between subpopulations. Deep genetic divergence between the two main varietal groups (Indica and Japonica) suggests domestication from at least two distinct wild populations. However, genetic uniformity surrounding key domestication genes across divergent subpopulations suggests cultural exchange of genetic material among ancient farmers. In this study, we utilize a novel 1,536 SNP panel genotyped across 395 diverse accessions of O. sativa to study genome-wide patterns of polymorphism, to characterize population structure, and to infer the introgression history of domesticated Asian rice. Our population structure analyses support the existence of five major subpopulations (indica, aus, tropical japonica, temperate japonica and GroupV) consistent with previous analyses. Our introgression analysis shows that most accessions exhibit some degree of admixture, with many individuals within a population sharing the same introgressed segment due to artificial selection. Admixture mapping and association analysis of amylose content and grain length illustrate the potential for dissecting the genetic basis of complex traits in domesticated plant populations. Genes in these regions control a myriad of traits including plant stature, blast resistance, and amylose content. These analyses highlight the power of population genomics in agricultural systems to identify functionally important regions of the genome and to decipher the role of human-directed breeding in refashioning the genomes of a domesticated species.

The genetics of age-related macular degeneration (AMD)--Novel targets for designing treatment options?

PubMed

Grassmann, Felix; Fauser, Sascha; Weber, Bernhard H F

2015-09-01

Age-related macular degeneration (AMD) is a progressive disease of the central retina and the main cause of legal blindness in industrialized countries. Risk to develop the disease is conferred by both individual as well as genetic factors with the latter being increasingly deciphered over the last decade. Therapeutically, striking advances have been made for the treatment of the neovascular form of late stage AMD while for the late stage atrophic form of the disease, which accounts for almost half of the visually impaired, there is currently no effective therapy on the market. This review highlights our current knowledge on the genetic architecture of early and late stage AMD and explores its potential for the discovery of novel, target-guided treatment options. We reflect on current clinical and experimental therapies for all forms of AMD and specifically note a persisting lack of efficacy for treatment in atrophic AMD. We further explore the current insight in AMD-associated genes and pathways and critically question whether this knowledge is suited to design novel treatment options. Specifically, we point out that known genetic factors associated with AMD govern the risk to develop disease and thus may not play a role in its severity or progression. Treatments based on such knowledge appear appropriate rather for prevention than treatment of manifest disease. As a consequence, future research in AMD needs to be greatly focused on approaches relevant to the patients and their medical needs. Copyright © 2015 Elsevier B.V. All rights reserved.

Potential for adaptive evolution at species range margins: contrasting interactions between red coral populations and their environment in a changing ocean.

PubMed

Ledoux, Jean-Baptiste; Aurelle, Didier; Bensoussan, Nathaniel; Marschal, Christian; Féral, Jean-Pierre; Garrabou, Joaquim

2015-03-01

Studying population-by-environment interactions (PEIs) at species range margins offers the opportunity to characterize the responses of populations facing an extreme regime of selection, as expected due to global change. Nevertheless, the importance of these marginal populations as putative reservoirs of adaptive genetic variation has scarcely been considered in conservation biology. This is particularly true in marine ecosystems for which the deep refugia hypothesis proposes that disturbed shallow and marginal populations of a given species can be replenished by mesophotic ones. This hypothesis therefore assumes that identical PEIs exist between populations, neglecting the potential for adaptation at species range margins. Here, we combine reciprocal transplant and common garden experiments with population genetics analyses to decipher the PEIs in the red coral, Corallium rubrum. Our analyses reveal partially contrasting PEIs between shallow and mesophotic populations separated by approximately one hundred meters, suggesting that red coral populations may potentially be locally adapted to their environment. Based on the effective population size and connectivity analyses, we posit that genetic drift may be more important than gene flow in the adaptation of the red coral. We further investigate how adaptive divergence could impact population viability in the context of warming and demonstrate differential phenotypic buffering capacities against thermal stress. Our study questions the relevance of the deep refugia hypothesis and highlights the conservation value of marginal populations as a putative reservoir of adaptive genetic polymorphism.

Additional molecular findings in 11p15-associated imprinting disorders: an urgent need for multi-locus testing.

PubMed

Eggermann, Thomas; Heilsberg, Ann-Kathrin; Bens, Susanne; Siebert, Reiner; Beygo, Jasmin; Buiting, Karin; Begemann, Matthias; Soellner, Lukas

2014-07-01

The chromosomal region 11p15 contains two imprinting control regions (ICRs) and is a key player in molecular processes regulated by genomic imprinting. Genomic as well as epigenetic changes affecting 11p15 are associated either with Silver-Russell syndrome (SRS) or Beckwith-Wiedemann syndrome (BWS). In the last years, a growing number of patients affected by imprinting disorders (IDs) have reported carrying the disease-specific 11p15 hypomethylation patterns as well as methylation changes at imprinted loci at other chromosomal sites (multi-locus methylation defects, MLMD). Furthermore, in several patients, molecular alterations (e.g., uniparental disomies, UPDs) additional to the primary epimutations have been reported. To determine the frequency and distribution of mutations and epimutations in patients referred as SRS or BWS for genetic testing, we retrospectively ascertained our routine patient cohort consisting of 711 patients (SRS, n = 571; BWS, n = 140). As this cohort represents the typical cohort in a routine diagnostic lab without clinical preselection, the detection rates were much lower than those reported from clinically characterized cohorts in the literature (SRS, 19.9%; BWS, 28.6%). Among the molecular subgroups known to be predisposed to MLMD, the frequencies corresponded to that in the literature (SRS, 7.1% in ICR1 hypomethylation carriers; BWS, 20.8% in ICR2 hypomethylation patients). In several patients, more than one epigenetic or genetic disturbance could be identified. Our study illustrates that the complex molecular alterations as well as the overlapping and sometimes unusual clinical findings in patients with imprinting disorders (IDs) often make the decision for a specific imprinting disorder test difficult. We therefore suggest to implement molecular assays in routine ID diagnostics which allow the detection of a broad range of (epi)mutation types (epimutations, UPDs, chromosomal imbalances) and cover the clinically most relevant known ID loci because of the following: (a) Multi-locus tests increase the detection rates as they cover numerous loci. (b) Patients with unexpected molecular alterations are detected. (c) The testing of rare imprinting disorders becomes more efficient and quality of molecular diagnosis increases. (d) The tests identify MLMDs. In the future, the detailed characterization of clinical and molecular findings in ID patients will help us to decipher the complex regulation of imprinting and thereby providing the basis for more directed genetic counseling and therapeutic managements in IDs. Molecular disturbances in patients with imprinting disorders are often not restricted to the disease-specific locus but also affect other chromosomal regions. These additional disturbances include methylation defects, uniparental disomies as well as chromosomal imbalances. The identification of these additional alterations is mandatory for a well-directed genetic counseling. Furthermore, these findings help to decipher the complex regulation of imprinting.

Assessing the readiness of precision medicine interoperabilty: An exploratory study of the National Institutes of Health genetic testing registry.

PubMed

Ronquillo, Jay G; Weng, Chunhua; Lester, William T

2017-11-17

  Precision medicine involves three major innovations currently taking place in healthcare:  electronic health records, genomics, and big data.  A major challenge for healthcare providers, however, is understanding the readiness for practical application of initiatives like precision medicine.   To better understand the current state and challenges of precision medicine interoperability using a national genetic testing registry as a starting point, placed in the context of established interoperability formats.   We performed an exploratory analysis of the National Institutes of Health Genetic Testing Registry.  Relevant standards included Health Level Seven International Version 3 Implementation Guide for Family History, the Human Genome Organization Gene Nomenclature Committee (HGNC) database, and Systematized Nomenclature of Medicine - Clinical Terms (SNOMED CT).  We analyzed the distribution of genetic testing laboratories, genetic test characteristics, and standardized genome/clinical code mappings, stratified by laboratory setting. There were a total of 25472 genetic tests from 240 laboratories testing for approximately 3632 distinct genes.  Most tests focused on diagnosis, mutation confirmation, and/or risk assessment of germline mutations that could be passed to offspring.  Genes were successfully mapped to all HGNC identifiers, but less than half of tests mapped to SNOMED CT codes, highlighting significant gaps when linking genetic tests to standardized clinical codes that explain the medical motivations behind test ordering.  Conclusion:  While precision medicine could potentially transform healthcare, successful practical and clinical application will first require the comprehensive and responsible adoption of interoperable standards, terminologies, and formats across all aspects of the precision medicine pipeline.

Systematic screening for mutations in the promoter and the coding region of the 5-HT{sub 1A} gene

DOE Office of Scientific and Technical Information (OSTI.GOV)

Erdmann, J.; Shimron-Abarbanell, D.; Cichon, S.

1995-10-09

In the present study we sought to identify genetic variation in the 5-HT{sub 1A} receptor gene which through alteration of protein function or level of expression might contribute to the genetic predisposition to neuropsychiatric diseases. Genomic DNA samples from 159 unrelated subjects (including 45 schizophrenic, 46 bipolar affective, and 43 patients with Tourette`s syndrome, as well as 25 healthy controls) were investigated by single-strand conformation analysis. Overlapping PCR (polymerase chain reaction) fragments covered the whole coding sequence as well as the 5{prime} untranslated region of the 5-HT{sub 1A} gene. The region upstream to the coding sequence we investigated contains amore » functional promoter. We found two rare nucleotide sequence variants. Both mutations are located in the coding region of the gene: a coding mutation (A{yields}G) in nucleotide position 82 which leads to an amino acid exchange (Ile{yields}Val) in position 28 of the receptor protein and a silent mutation (C{yields}T) in nucleotide position 549. The occurrence of the Ile-28-Val substitution was studied in an extended sample of patients (n = 352) and controls (n = 210) but was found in similar frequencies in all groups. Thus, this mutation is unlikely to play a significant role in the genetic predisposition to the diseases investigated. In conclusion, our study does not provide evidence that the 5-HT{sub 1A} gene plays either a major or a minor role in the genetic predisposition to schizophrenia, bipolar affective disorder, or Tourette`s syndrome. 29 refs., 4 figs., 1 tab.« less

Deciphering indented impressions on plastic.

PubMed

Brown, Sharon; Klein, Asne; Chaikovsky, Alan

2003-07-01

The questioned document laboratory is often called upon to decipher writing that has been erased, obliterated, or that has faded. In cases like these, the original writing is no longer legible to the naked eye, but may be enhanced using various light sources. Certain remnants of the ink's components absorb into the substrate's fibers and can be visualized, usually as luminescence or absorbance. A case is described here that involved the theft of a credit card. An empty plastic credit card holder was found in the possession of a suspect, and as submitted for examination. Indented impressions could be discerned on its clear plastic window and presumably originated from the credit card that had been held in the envelope. These indented impressions were deciphered in the hope that they would reveal enough details from the credit card to establish a connection between the plastic envelope and the stolen credit card. With methods generally utilized in the toolmarks and materials laboratory and the photography laboratory of the Israel Police, most of the indented impressions on the plastic were deciphered and a connection between the plastic envelope and the stolen credit card was demonstrated.

Piecemeal Buildup of the Genetic Code, Ribosomes, and Genomes from Primordial tRNA Building Blocks

PubMed Central

Caetano-Anollés, Derek; Caetano-Anollés, Gustavo

2016-01-01

The origin of biomolecular machinery likely centered around an ancient and central molecule capable of interacting with emergent macromolecular complexity. tRNA is the oldest and most central nucleic acid molecule of the cell. Its co-evolutionary interactions with aminoacyl-tRNA synthetase protein enzymes define the specificities of the genetic code and those with the ribosome their accurate biosynthetic interpretation. Phylogenetic approaches that focus on molecular structure allow reconstruction of evolutionary timelines that describe the history of RNA and protein structural domains. Here we review phylogenomic analyses that reconstruct the early history of the synthetase enzymes and the ribosome, their interactions with RNA, and the inception of amino acid charging and codon specificities in tRNA that are responsible for the genetic code. We also trace the age of domains and tRNA onto ancient tRNA homologies that were recently identified in rRNA. Our findings reveal a timeline of recruitment of tRNA building blocks for the formation of a functional ribosome, which holds both the biocatalytic functions of protein biosynthesis and the ability to store genetic memory in primordial RNA genomic templates. PMID:27918435

Biosamples, genomics, and human rights: context and content of Iceland's Biobanks Act.

PubMed

Winickoff, D E

2001-01-01

In recent years, human DNA sampling and collection has accelerated without the development of enforceable rules protecting the human rights of donors. The need for regulation of biobanking is especially acute in Iceland, whose parliament has granted a for-profit corporation, deCODE Genetics, an exclusive license to create a centralized database of health records for studies on human genetic variation. Until recently, how deCODE Genetics would get genetic material for its genotypic-phenotypic database remained unclear. However, in May 2000, the Icelandic Parliament passed the Icelandic Biobanks Act, the world's earliest attempt to construct binding rules for the use of biobanks in scientific research. Unfortunately, Iceland has lost an opportunity for bringing clear and ethically sound standards to the use of human biological samples in deCODE's database and in other projects: the Biobanks Act has extended a notion of "presumed consent" from the use of medical records to the use of patients' biological samples; worse, the act has made it possible--perhaps likely--that a donor's wish to withdraw his/her sample will be ignored. Inadequacies in the Act's legislative process help account for these deficiencies in the protection of donor autonomy.

Piecemeal Buildup of the Genetic Code, Ribosomes, and Genomes from Primordial tRNA Building Blocks.

PubMed

Caetano-Anollés, Derek; Caetano-Anollés, Gustavo

2016-12-02

The origin of biomolecular machinery likely centered around an ancient and central molecule capable of interacting with emergent macromolecular complexity. tRNA is the oldest and most central nucleic acid molecule of the cell. Its co-evolutionary interactions with aminoacyl-tRNA synthetase protein enzymes define the specificities of the genetic code and those with the ribosome their accurate biosynthetic interpretation. Phylogenetic approaches that focus on molecular structure allow reconstruction of evolutionary timelines that describe the history of RNA and protein structural domains. Here we review phylogenomic analyses that reconstruct the early history of the synthetase enzymes and the ribosome, their interactions with RNA, and the inception of amino acid charging and codon specificities in tRNA that are responsible for the genetic code. We also trace the age of domains and tRNA onto ancient tRNA homologies that were recently identified in rRNA. Our findings reveal a timeline of recruitment of tRNA building blocks for the formation of a functional ribosome, which holds both the biocatalytic functions of protein biosynthesis and the ability to store genetic memory in primordial RNA genomic templates.

Exome sequencing in an admixed isolated population indicates NFXL1 variants confer a risk for specific language impairment.

PubMed

Villanueva, Pía; Nudel, Ron; Hoischen, Alexander; Fernández, María Angélica; Simpson, Nuala H; Gilissen, Christian; Reader, Rose H; Jara, Lillian; Echeverry, María Magdalena; Echeverry, Maria Magdalena; Francks, Clyde; Baird, Gillian; Conti-Ramsden, Gina; O'Hare, Anne; Bolton, Patrick F; Hennessy, Elizabeth R; Palomino, Hernán; Carvajal-Carmona, Luis; Veltman, Joris A; Cazier, Jean-Baptiste; De Barbieri, Zulema; Fisher, Simon E; Newbury, Dianne F

2015-03-01

Children affected by Specific Language Impairment (SLI) fail to acquire age appropriate language skills despite adequate intelligence and opportunity. SLI is highly heritable, but the understanding of underlying genetic mechanisms has proved challenging. In this study, we use molecular genetic techniques to investigate an admixed isolated founder population from the Robinson Crusoe Island (Chile), who are affected by a high incidence of SLI, increasing the power to discover contributory genetic factors. We utilize exome sequencing in selected individuals from this population to identify eight coding variants that are of putative significance. We then apply association analyses across the wider population to highlight a single rare coding variant (rs144169475, Minor Allele Frequency of 4.1% in admixed South American populations) in the NFXL1 gene that confers a nonsynonymous change (N150K) and is significantly associated with language impairment in the Robinson Crusoe population (p = 2.04 × 10-4, 8 variants tested). Subsequent sequencing of NFXL1 in 117 UK SLI cases identified four individuals with heterozygous variants predicted to be of functional consequence. We conclude that coding variants within NFXL1 confer an increased risk of SLI within a complex genetic model.

Analysis of protein-coding genetic variation in 60,706 humans.

PubMed

Lek, Monkol; Karczewski, Konrad J; Minikel, Eric V; Samocha, Kaitlin E; Banks, Eric; Fennell, Timothy; O'Donnell-Luria, Anne H; Ware, James S; Hill, Andrew J; Cummings, Beryl B; Tukiainen, Taru; Birnbaum, Daniel P; Kosmicki, Jack A; Duncan, Laramie E; Estrada, Karol; Zhao, Fengmei; Zou, James; Pierce-Hoffman, Emma; Berghout, Joanne; Cooper, David N; Deflaux, Nicole; DePristo, Mark; Do, Ron; Flannick, Jason; Fromer, Menachem; Gauthier, Laura; Goldstein, Jackie; Gupta, Namrata; Howrigan, Daniel; Kiezun, Adam; Kurki, Mitja I; Moonshine, Ami Levy; Natarajan, Pradeep; Orozco, Lorena; Peloso, Gina M; Poplin, Ryan; Rivas, Manuel A; Ruano-Rubio, Valentin; Rose, Samuel A; Ruderfer, Douglas M; Shakir, Khalid; Stenson, Peter D; Stevens, Christine; Thomas, Brett P; Tiao, Grace; Tusie-Luna, Maria T; Weisburd, Ben; Won, Hong-Hee; Yu, Dongmei; Altshuler, David M; Ardissino, Diego; Boehnke, Michael; Danesh, John; Donnelly, Stacey; Elosua, Roberto; Florez, Jose C; Gabriel, Stacey B; Getz, Gad; Glatt, Stephen J; Hultman, Christina M; Kathiresan, Sekar; Laakso, Markku; McCarroll, Steven; McCarthy, Mark I; McGovern, Dermot; McPherson, Ruth; Neale, Benjamin M; Palotie, Aarno; Purcell, Shaun M; Saleheen, Danish; Scharf, Jeremiah M; Sklar, Pamela; Sullivan, Patrick F; Tuomilehto, Jaakko; Tsuang, Ming T; Watkins, Hugh C; Wilson, James G; Daly, Mark J; MacArthur, Daniel G

2016-08-18

Large-scale reference data sets of human genetic variation are critical for the medical and functional interpretation of DNA sequence changes. Here we describe the aggregation and analysis of high-quality exome (protein-coding region) DNA sequence data for 60,706 individuals of diverse ancestries generated as part of the Exome Aggregation Consortium (ExAC). This catalogue of human genetic diversity contains an average of one variant every eight bases of the exome, and provides direct evidence for the presence of widespread mutational recurrence. We have used this catalogue to calculate objective metrics of pathogenicity for sequence variants, and to identify genes subject to strong selection against various classes of mutation; identifying 3,230 genes with near-complete depletion of predicted protein-truncating variants, with 72% of these genes having no currently established human disease phenotype. Finally, we demonstrate that these data can be used for the efficient filtering of candidate disease-causing variants, and for the discovery of human 'knockout' variants in protein-coding genes.

Design optimization of cold-formed steel portal frames taking into account the effect of building topology

NASA Astrophysics Data System (ADS)

Phan, Duoc T.; Lim, James B. P.; Sha, Wei; Siew, Calvin Y. M.; Tanyimboh, Tiku T.; Issa, Honar K.; Mohammad, Fouad A.

2013-04-01

Cold-formed steel portal frames are a popular form of construction for low-rise commercial, light industrial and agricultural buildings with spans of up to 20 m. In this article, a real-coded genetic algorithm is described that is used to minimize the cost of the main frame of such buildings. The key decision variables considered in this proposed algorithm consist of both the spacing and pitch of the frame as continuous variables, as well as the discrete section sizes. A routine taking the structural analysis and frame design for cold-formed steel sections is embedded into a genetic algorithm. The results show that the real-coded genetic algorithm handles effectively the mixture of design variables, with high robustness and consistency in achieving the optimum solution. All wind load combinations according to Australian code are considered in this research. Results for frames with knee braces are also included, for which the optimization achieved even larger savings in cost.

Non-coding RNAs' partitioning in the evolution of photosynthetic organisms via energy transduction and redox signaling.

PubMed

Kotakis, Christos

2015-01-01

Ars longa, vita brevis -Hippocrates Chloroplasts and mitochondria are genetically semi-autonomous organelles inside the plant cell. These constructions formed after endosymbiosis and keep evolving throughout the history of life. Experimental evidence is provided for active non-coding RNAs (ncRNAs) in these prokaryote-like structures, and a possible functional imprinting on cellular electrophysiology by those RNA entities is described. Furthermore, updated knowledge on RNA metabolism of organellar genomes uncovers novel inter-communication bridges with the nucleus. This class of RNA molecules is considered as a unique ontogeny which transforms their biological role as a genetic rheostat into a synchronous biochemical one that can affect the energetic charge and redox homeostasis inside cells. A hypothesis is proposed where such modulation by non-coding RNAs is integrated with genetic signals regulating gene transfer. The implications of this working hypothesis are discussed, with particular reference to ncRNAs involvement in the organellar and nuclear genomes evolution since their integrity is functionally coupled with redox signals in photosynthetic organisms.

Optimal sensor placement for spatial lattice structure based on genetic algorithms

NASA Astrophysics Data System (ADS)

Liu, Wei; Gao, Wei-cheng; Sun, Yi; Xu, Min-jian

2008-10-01

Optimal sensor placement technique plays a key role in structural health monitoring of spatial lattice structures. This paper considers the problem of locating sensors on a spatial lattice structure with the aim of maximizing the data information so that structural dynamic behavior can be fully characterized. Based on the criterion of optimal sensor placement for modal test, an improved genetic algorithm is introduced to find the optimal placement of sensors. The modal strain energy (MSE) and the modal assurance criterion (MAC) have been taken as the fitness function, respectively, so that three placement designs were produced. The decimal two-dimension array coding method instead of binary coding method is proposed to code the solution. Forced mutation operator is introduced when the identical genes appear via the crossover procedure. A computational simulation of a 12-bay plain truss model has been implemented to demonstrate the feasibility of the three optimal algorithms above. The obtained optimal sensor placements using the improved genetic algorithm are compared with those gained by exiting genetic algorithm using the binary coding method. Further the comparison criterion based on the mean square error between the finite element method (FEM) mode shapes and the Guyan expansion mode shapes identified by data-driven stochastic subspace identification (SSI-DATA) method are employed to demonstrate the advantage of the different fitness function. The results showed that some innovations in genetic algorithm proposed in this paper can enlarge the genes storage and improve the convergence of the algorithm. More importantly, the three optimal sensor placement methods can all provide the reliable results and identify the vibration characteristics of the 12-bay plain truss model accurately.

ANT: Software for Generating and Evaluating Degenerate Codons for Natural and Expanded Genetic Codes.

PubMed

Engqvist, Martin K M; Nielsen, Jens

2015-08-21

The Ambiguous Nucleotide Tool (ANT) is a desktop application that generates and evaluates degenerate codons. Degenerate codons are used to represent DNA positions that have multiple possible nucleotide alternatives. This is useful for protein engineering and directed evolution, where primers specified with degenerate codons are used as a basis for generating libraries of protein sequences. ANT is intuitive and can be used in a graphical user interface or by interacting with the code through a defined application programming interface. ANT comes with full support for nonstandard, user-defined, or expanded genetic codes (translation tables), which is important because synthetic biology is being applied to an ever widening range of natural and engineered organisms. The Python source code for ANT is freely distributed so that it may be used without restriction, modified, and incorporated in other software or custom data pipelines.

Physical Model for the Evolution of the Genetic Code

NASA Astrophysics Data System (ADS)

Yamashita, Tatsuro; Narikiyo, Osamu

2011-12-01

Using the shape space of codons and tRNAs we give a physical description of the genetic code evolution on the basis of the codon capture and ambiguous intermediate scenarios in a consistent manner. In the lowest dimensional version of our description, a physical quantity, codon level is introduced. In terms of the codon levels two scenarios are typically classified into two different routes of the evolutional process. In the case of the ambiguous intermediate scenario we perform an evolutional simulation implemented cost selection of amino acids and confirm a rapid transition of the code change. Such rapidness reduces uncomfortableness of the non-unique translation of the code at intermediate state that is the weakness of the scenario. In the case of the codon capture scenario the survival against mutations under the mutational pressure minimizing GC content in genomes is simulated and it is demonstrated that cells which experience only neutral mutations survive.

Color-coding cancer and stromal cells with genetic reporters in a patient-derived orthotopic xenograft (PDOX) model of pancreatic cancer enhances fluorescence-guided surgery

PubMed Central

Yano, Shuya; Hiroshima, Yukihiko; Maawy, Ali; Kishimoto, Hiroyuki; Suetsugu, Atsushi; Miwa, Shinji; Toneri, Makoto; Yamamoto, Mako; Katz, Matthew H.G.; Fleming, Jason B.; Urata, Yasuo; Tazawa, Hiroshi; Kagawa, Shunsuke; Bouvet, Michael; Fujiwara, Toshiyoshi; Hoffman, Robert M.

2015-01-01

Precise fluorescence-guided surgery (FGS) for pancreatic cancer has the potential to greatly improve the outcome in this recalcitrant disease. In order to achieve this goal, we have used genetic reporters to color code cancer and stroma cells in a patient-derived orthotopic xenograft (PDOX) model. The telomerase-dependent green fluorescent protein (GFP) containing adenovirus OBP401 was used to label the cancer cells of the pancreatic cancer PDOX. The PDOX was previously grown in a red fluorescent protein (RFP) transgenic mouse that stably labeled the PDOX stroma cells bright red. The color-coded PDOX model enabled FGS to completely resect the pancreatic tumors including stroma. Dual-colored FGS significantly prevented local recurrence, which bright-light surgery (BLS) or single color could not. FGS, with color-coded cancer and stroma cells has important potential for improving the outcome of recalcitrant cancer. PMID:26088297

Prenatal Genetic Testing Chart

MedlinePlus

... www.acog.org/Patients/FAQs/Prenatal-Genetic-Diagnostic-Tests › › Resources & Publications Committee Opinions Practice Bulletins Patient Education Green Journal Clinical Updates Practice Management Coding Health Info Technology Professional Liability Managing Your Practice Patient Safety & Quality ...

Molecular & Genetic Investigation of Tau in Chronic Traumatic Encephalopathy

DTIC Science & Technology

2015-10-01

available, work will commence. Tau, genetics , susceptibility, MAPT, chronic traumatic encephalopathy, Alzheimer disease U U U U 1 USAMRMC Table of...AWARD NUMBER: W81XWH-14-1-0399 TITLE: Molecular & Genetic Investigation of Tau in Chronic Traumatic Encephalopathy PRINCIPAL INVESTIGATOR: John F...Include area code) October 2015 Annual Report 30 Sep 2014 - 29 Sep 2015 Molecular & Genetic Investigation of Tau in Chronic Traumatic Encephalopathy John

An integrated, structure- and energy-based view of the genetic code.

PubMed

Grosjean, Henri; Westhof, Eric

2016-09-30

The principles of mRNA decoding are conserved among all extant life forms. We present an integrative view of all the interaction networks between mRNA, tRNA and rRNA: the intrinsic stability of codon-anticodon duplex, the conformation of the anticodon hairpin, the presence of modified nucleotides, the occurrence of non-Watson-Crick pairs in the codon-anticodon helix and the interactions with bases of rRNA at the A-site decoding site. We derive a more information-rich, alternative representation of the genetic code, that is circular with an unsymmetrical distribution of codons leading to a clear segregation between GC-rich 4-codon boxes and AU-rich 2:2-codon and 3:1-codon boxes. All tRNA sequence variations can be visualized, within an internal structural and energy framework, for each organism, and each anticodon of the sense codons. The multiplicity and complexity of nucleotide modifications at positions 34 and 37 of the anticodon loop segregate meaningfully, and correlate well with the necessity to stabilize AU-rich codon-anticodon pairs and to avoid miscoding in split codon boxes. The evolution and expansion of the genetic code is viewed as being originally based on GC content with progressive introduction of A/U together with tRNA modifications. The representation we present should help the engineering of the genetic code to include non-natural amino acids. © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

Structure finding in cosmological simulations: the state of affairs

NASA Astrophysics Data System (ADS)

Knebe, Alexander; Pearce, Frazer R.; Lux, Hanni; Ascasibar, Yago; Behroozi, Peter; Casado, Javier; Moran, Christine Corbett; Diemand, Juerg; Dolag, Klaus; Dominguez-Tenreiro, Rosa; Elahi, Pascal; Falck, Bridget; Gottlöber, Stefan; Han, Jiaxin; Klypin, Anatoly; Lukić, Zarija; Maciejewski, Michal; McBride, Cameron K.; Merchán, Manuel E.; Muldrew, Stuart I.; Neyrinck, Mark; Onions, Julian; Planelles, Susana; Potter, Doug; Quilis, Vicent; Rasera, Yann; Ricker, Paul M.; Roy, Fabrice; Ruiz, Andrés N.; Sgró, Mario A.; Springel, Volker; Stadel, Joachim; Sutter, P. M.; Tweed, Dylan; Zemp, Marcel

2013-10-01

The ever increasing size and complexity of data coming from simulations of cosmic structure formation demand equally sophisticated tools for their analysis. During the past decade, the art of object finding in these simulations has hence developed into an important discipline itself. A multitude of codes based upon a huge variety of methods and techniques have been spawned yet the question remained as to whether or not they will provide the same (physical) information about the structures of interest. Here we summarize and extent previous work of the `halo finder comparison project': we investigate in detail the (possible) origin of any deviations across finders. To this extent, we decipher and discuss differences in halo-finding methods, clearly separating them from the disparity in definitions of halo properties. We observe that different codes not only find different numbers of objects leading to a scatter of up to 20 per cent in the halo mass and Vmax function, but also that the particulars of those objects that are identified by all finders differ. The strength of the variation, however, depends on the property studied, e.g. the scatter in position, bulk velocity, mass and the peak value of the rotation curve is practically below a few per cent, whereas derived quantities such as spin and shape show larger deviations. Our study indicates that the prime contribution to differences in halo properties across codes stems from the distinct particle collection methods and - to a minor extent - the particular aspects of how the procedure for removing unbound particles is implemented. We close with a discussion of the relevance and implications of the scatter across different codes for other fields such as semi-analytical galaxy formation models, gravitational lensing and observables in general.

Rewiring protein synthesis: From natural to synthetic amino acids.

PubMed

Fan, Yongqiang; Evans, Christopher R; Ling, Jiqiang

2017-11-01

The protein synthesis machinery uses 22 natural amino acids as building blocks that faithfully decode the genetic information. Such fidelity is controlled at multiple steps and can be compromised in nature and in the laboratory to rewire protein synthesis with natural and synthetic amino acids. This review summarizes the major quality control mechanisms during protein synthesis, including aminoacyl-tRNA synthetases, elongation factors, and the ribosome. We will discuss evolution and engineering of such components that allow incorporation of natural and synthetic amino acids at positions that deviate from the standard genetic code. The protein synthesis machinery is highly selective, yet not fixed, for the correct amino acids that match the mRNA codons. Ambiguous translation of a codon with multiple amino acids or complete reassignment of a codon with a synthetic amino acid diversifies the proteome. Expanding the genetic code with synthetic amino acids through rewiring protein synthesis has broad applications in synthetic biology and chemical biology. Biochemical, structural, and genetic studies of the translational quality control mechanisms are not only crucial to understand the physiological role of translational fidelity and evolution of the genetic code, but also enable us to better design biological parts to expand the proteomes of synthetic organisms. This article is part of a Special Issue entitled "Biochemistry of Synthetic Biology - Recent Developments" Guest Editor: Dr. Ilka Heinemann and Dr. Patrick O'Donoghue. Copyright © 2017 Elsevier B.V. All rights reserved.

[Assisted reproduction and artificial insemination and genetic manipulation in the Criminal Code of the Federal District, Mexico].

PubMed

Brena Sesma, Ingrid

2004-01-01

The article that one presents has for purpose outline and comment on the recent modifications to the Penal Code for the Federal District of México which establish, for the first time, crimes related to the artificial procreation and to the genetic manipulation. Also one refers to the interaction of the new legal texts with the sanitary legislation of the country. Since it will be stated in some cases they present confrontations between the penal and the sanitary reglamentation and some points related to the legality or unlawfulness of a conduct that stayed without the enough development. These lacks will complicate the application of the new rules of the Penal Code of the Federal District.

Mind the gut: genomic insights to population divergence and gut microbial composition of two marine keystone species.

PubMed

Fietz, Katharina; Rye Hintze, Christian Olaf; Skovrind, Mikkel; Kjærgaard Nielsen, Tue; Limborg, Morten T; Krag, Marcus A; Palsbøll, Per J; Hestbjerg Hansen, Lars; Rask Møller, Peter; Gilbert, M Thomas P

2018-05-02

Deciphering the mechanisms governing population genetic divergence and local adaptation across heterogeneous environments is a central theme in marine ecology and conservation. While population divergence and ecological adaptive potential are classically viewed at the genetic level, it has recently been argued that their microbiomes may also contribute to population genetic divergence. We explored whether this might be plausible along the well-described environmental gradient of the Baltic Sea in two species of sand lance (Ammodytes tobianus and Hyperoplus lanceolatus). Specifically, we assessed both their population genetic and gut microbial composition variation and investigated not only which environmental parameters correlate with the observed variation, but whether host genome also correlates with microbiome variation. We found a clear genetic structure separating the high-salinity North Sea from the low-salinity Baltic Sea sand lances. The observed genetic divergence was not simply a function of isolation by distance, but correlated with environmental parameters, such as salinity, sea surface temperature, and, in the case of A. tobianus, possibly water microbiota. Furthermore, we detected two distinct genetic groups in Baltic A. tobianus that might represent sympatric spawning types. Investigation of possible drivers of gut microbiome composition variation revealed that host species identity was significantly correlated with the microbial community composition of the gut. A potential influence of host genetic factors on gut microbiome composition was further confirmed by the results of a constrained analysis of principal coordinates. The host genetic component was among the parameters that best explain observed variation in gut microbiome composition. Our findings have relevance for the population structure of two commercial species but also provide insights into potentially relevant genomic and microbial factors with regards to sand lance adaptation across the North Sea-Baltic Sea environmental gradient. Furthermore, our findings support the hypothesis that host genetics may play a role in regulating the gut microbiome at both the interspecific and intraspecific levels. As sequencing costs continue to drop, we anticipate that future studies that include full genome and microbiome sequencing will be able to explore the full relationship and its potential adaptive implications for these species.

Cone-Deciphered Modes of Problem Solving Action (MPSA Cone): Alternative Perspectives on Diversified Professions.

ERIC Educational Resources Information Center

Lai, Su-Huei

A conceptual framework of the modes of problem-solving action has been developed on the basis of a simple relationship cone to assist individuals in diversified professions in inquiry and implementation of theory and practice in their professional development. The conceptual framework is referred to as the Cone-Deciphered Modes of Problem Solving…

A genetic code Boolean structure. II. The genetic information system as a Boolean information system.

PubMed

Sanchez, Robersy; Grau, Ricardo

2005-09-01

A Boolean structure of the genetic code where Boolean deductions have biological and physicochemical meanings was discussed in a previous paper. Now, from these Boolean deductions we propose to define the value of amino acid information in order to consider the genetic information system as a communication system and to introduce the semantic content of information ignored by the conventional information theory. In this proposal, the value of amino acid information is proportional to the molecular weight of amino acids with a proportional constant of about 1.96 x 10(25) bits per kg. In addition to this, for the experimental estimations of the minimum energy dissipation in genetic logic operations, we present two postulates: (1) the energy Ei (i=1,2,...,20) of amino acids in the messages conveyed by proteins is proportional to the value of information, and (2) amino acids are distributed according to their energy Ei so the amino acid population in proteins follows a Boltzmann distribution. Specifically, in the genetic message carried by the DNA from the genomes of living organisms, we found that the minimum energy dissipation in genetic logic operations was close to kTLn(2) joules per bit.

Decoding the non-coding genome: elucidating genetic risk outside the coding genome.

PubMed

Barr, C L; Misener, V L

2016-01-01

Current evidence emerging from genome-wide association studies indicates that the genetic underpinnings of complex traits are likely attributable to genetic variation that changes gene expression, rather than (or in combination with) variation that changes protein-coding sequences. This is particularly compelling with respect to psychiatric disorders, as genetic changes in regulatory regions may result in differential transcriptional responses to developmental cues and environmental/psychosocial stressors. Until recently, however, the link between transcriptional regulation and psychiatric genetic risk has been understudied. Multiple obstacles have contributed to the paucity of research in this area, including challenges in identifying the positions of remote (distal from the promoter) regulatory elements (e.g. enhancers) and their target genes and the underrepresentation of neural cell types and brain tissues in epigenome projects - the availability of high-quality brain tissues for epigenetic and transcriptome profiling, particularly for the adolescent and developing brain, has been limited. Further challenges have arisen in the prediction and testing of the functional impact of DNA variation with respect to multiple aspects of transcriptional control, including regulatory-element interaction (e.g. between enhancers and promoters), transcription factor binding and DNA methylation. Further, the brain has uncommon DNA-methylation marks with unique genomic distributions not found in other tissues - current evidence suggests the involvement of non-CG methylation and 5-hydroxymethylation in neurodevelopmental processes but much remains unknown. We review here knowledge gaps as well as both technological and resource obstacles that will need to be overcome in order to elucidate the involvement of brain-relevant gene-regulatory variants in genetic risk for psychiatric disorders. © 2015 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

Genetics and culture: the geneticization thesis.

PubMed

ten Have, H A

2001-01-01

The concept of 'geneticization' has been introduced in the scholarly literature to describe the various interlocking and imperceptible mechanisms of interaction between medicine, genetics, society and culture. It is argued that Western culture currently is deeply involved in a process of geneticization. This process implies a redefinition of individuals in terms of DNA codes, a new language to describe and interpret human life and behavior in a genomic vocabulary of codes, blueprints, traits, dispositions, genetic mapping, and a gentechnological approach to disease, health and the body. This article analyses the thesis of 'geneticization'. Explaining the implications of the thesis, and discussing the critical refutations, it is argued that 'geneticization' primarily is a heuristic tool that can help to re-focus the moral debate on the implications of new genetic knowledge towards interpersonal relations, the power of medicine, the cultural context and social constraints, rather than emphasizing issues as personal autonomy and individual rights.

Proof of concept of microbiome-metabolome analysis and delayed gluten exposure on celiac disease autoimmunity in genetically at-risk infants.

PubMed

Sellitto, Maria; Bai, Guoyun; Serena, Gloria; Fricke, W Florian; Sturgeon, Craig; Gajer, Pawel; White, James R; Koenig, Sara S K; Sakamoto, Joyce; Boothe, Dustin; Gicquelais, Rachel; Kryszak, Deborah; Puppa, Elaine; Catassi, Carlo; Ravel, Jacques; Fasano, Alessio

2012-01-01

Celiac disease (CD) is a unique autoimmune disorder in which the genetic factors (DQ2/DQ8) and the environmental trigger (gluten) are known and necessary but not sufficient for its development. Other environmental components contributing to CD are poorly understood. Studies suggest that aspects of gluten intake might influence the risk of CD occurrence and timing of its onset, i.e., the amount and quality of ingested gluten, together with the pattern of infant feeding and the age at which gluten is introduced in the diet. In this study, we hypothesize that the intestinal microbiota as a whole rather than specific infections dictates the switch from tolerance to immune response in genetically susceptible individuals. Using a sample of infants genetically at risk of CD, we characterized the longitudinal changes in the microbial communities that colonize infants from birth to 24 months and the impact of two patterns of gluten introduction (early vs. late) on the gut microbiota and metabolome, and the switch from gluten tolerance to immune response, including onset of CD autoimmunity. We show that infants genetically susceptible to CD who are exposed to gluten early mount an immune response against gluten and develop CD autoimmunity more frequently than at-risk infants in which gluten exposure is delayed until 12 months of age. The data, while derived from a relatively small number of subjects, suggest differences between the developing microbiota of infants with genetic predisposition for CD and the microbiota from infants with a non-selected genetic background, with an overall lack of bacteria of the phylum Bacteriodetes along with a high abundance of Firmicutes and microbiota that do not resemble that of adults even at 2 years of age. Furthermore, metabolomics analysis reveals potential biomarkers for the prediction of CD. This study constitutes a definite proof-of-principle that these combined genomic and metabolomic approaches will be key to deciphering the role of the gut microbiota on CD onset.

Genetic influences in caries and periodontal diseases.

PubMed

Hassell, T M; Harris, E L

1995-01-01

Deciphering the relative roles of heredity and environmental factors ("nature vs. nurture") in the pathogenesis of dental caries and diseases of the periodontium has occupied clinical and basic researchers for decades. Success in the endeavor has come more easily in the case of caries; the complex interactions that occur between host-response mechanisms and putative microbiologic pathogens in periodontal disease have made elucidation of genetic factors in disease susceptibility more difficult. In addition, during the 30-year period between 1958 and 1987, only meager resources were targeted toward the "nature" side of the nature/nurture dipole in periodontology. In this article, we present a brief history of the development of genetic epistemology, then describe the three main research mechanisms by which questions about the hereditary component of diseases in humans can be addressed. A critical discussion of the evidence for a hereditary component in caries susceptibility is next presented, also from a historical perspective. The evolution of knowledge concerning possible genetic ("endogenous", "idiotypic") factors in the pathogenesis of inflammatory periodontal disease is initiated with an analysis of some foreign-language (primarily German) literature that is likely to be unfamiliar to the reader. We identify a turning point at about 1960, when the periodontal research community turned away from genetics in favor of microbiology research. During the past five years, investigators have re-initiated the search for the hereditary component in susceptibility to common adult periodontal disease; this small but growing body of literature is reviewed. Recent applications of in vitro methods for genetic analyses in periodontal research are presented, with an eye toward a future in which persons who are at risk--genetically predisposed--to periodontal disease may be identified and targeted for interventive strategies. Critical is the realization that genes and environment do not act independently of each other; the appearance or magnitude of heritability may differ with various environments.

The science of neural interface systems.

PubMed

Hatsopoulos, Nicholas G; Donoghue, John P

2009-01-01

The ultimate goal of neural interface research is to create links between the nervous system and the outside world either by stimulating or by recording from neural tissue to treat or assist people with sensory, motor, or other disabilities of neural function. Although electrical stimulation systems have already reached widespread clinical application, neural interfaces that record neural signals to decipher movement intentions are only now beginning to develop into clinically viable systems to help paralyzed people. We begin by reviewing state-of-the-art research and early-stage clinical recording systems and focus on systems that record single-unit action potentials. We then address the potential for neural interface research to enhance basic scientific understanding of brain function by offering unique insights in neural coding and representation, plasticity, brain-behavior relations, and the neurobiology of disease. Finally, we discuss technical and scientific challenges faced by these systems before they are widely adopted by severely motor-disabled patients.

Deciphering the consumer behaviour facets of functional foods: A literature review.

PubMed

Kaur, Navdeep; Singh, Devinder Pal

2017-05-01

This paper presents a systematic literature review of studies investigating various facets of consumer behaviour towards functional foods. It focuses on published international research on functional food attitude and behaviour from across the world. Research papers (n = 112) that were identified were coded in terms of study type, variables studied, product type, participant profile, research methodology and analysis details, as well as results and implications for future research. Results provide a systematic overview of the context in which behaviour towards functional foods have been examined in the past and provide a synthesis of findings in four categories of determinants, namely (1) Personal Factors, (2) Psychological Factors, (3) Cultural & Social Factors, and (4) Factors relating to the functional food product. A reference model for the relationships between these factors and behaviour of consumers is derived. Copyright © 2017 Elsevier Ltd. All rights reserved.

Integration, warehousing, and analysis strategies of Omics data.

PubMed

Gedela, Srinubabu

2011-01-01

"-Omics" is a current suffix for numerous types of large-scale biological data generation procedures, which naturally demand the development of novel algorithms for data storage and analysis. With next generation genome sequencing burgeoning, it is pivotal to decipher a coding site on the genome, a gene's function, and information on transcripts next to the pure availability of sequence information. To explore a genome and downstream molecular processes, we need umpteen results at the various levels of cellular organization by utilizing different experimental designs, data analysis strategies and methodologies. Here comes the need for controlled vocabularies and data integration to annotate, store, and update the flow of experimental data. This chapter explores key methodologies to merge Omics data by semantic data carriers, discusses controlled vocabularies as eXtensible Markup Languages (XML), and provides practical guidance, databases, and software links supporting the integration of Omics data.

Genetically improved BarraCUDA.

PubMed

Langdon, W B; Lam, Brian Yee Hong

2017-01-01

BarraCUDA is an open source C program which uses the BWA algorithm in parallel with nVidia CUDA to align short next generation DNA sequences against a reference genome. Recently its source code was optimised using "Genetic Improvement". The genetically improved (GI) code is up to three times faster on short paired end reads from The 1000 Genomes Project and 60% more accurate on a short BioPlanet.com GCAT alignment benchmark. GPGPU BarraCUDA running on a single K80 Tesla GPU can align short paired end nextGen sequences up to ten times faster than bwa on a 12 core server. The speed up was such that the GI version was adopted and has been regularly downloaded from SourceForge for more than 12 months.

MARRVEL: Integration of Human and Model Organism Genetic Resources to Facilitate Functional Annotation of the Human Genome.

PubMed

Wang, Julia; Al-Ouran, Rami; Hu, Yanhui; Kim, Seon-Young; Wan, Ying-Wooi; Wangler, Michael F; Yamamoto, Shinya; Chao, Hsiao-Tuan; Comjean, Aram; Mohr, Stephanie E; Perrimon, Norbert; Liu, Zhandong; Bellen, Hugo J

2017-06-01

One major challenge encountered with interpreting human genetic variants is the limited understanding of the functional impact of genetic alterations on biological processes. Furthermore, there remains an unmet demand for an efficient survey of the wealth of information on human homologs in model organisms across numerous databases. To efficiently assess the large volume of publically available information, it is important to provide a concise summary of the most relevant information in a rapid user-friendly format. To this end, we created MARRVEL (model organism aggregated resources for rare variant exploration). MARRVEL is a publicly available website that integrates information from six human genetic databases and seven model organism databases. For any given variant or gene, MARRVEL displays information from OMIM, ExAC, ClinVar, Geno2MP, DGV, and DECIPHER. Importantly, it curates model organism-specific databases to concurrently display a concise summary regarding the human gene homologs in budding and fission yeast, worm, fly, fish, mouse, and rat on a single webpage. Experiment-based information on tissue expression, protein subcellular localization, biological process, and molecular function for the human gene and homologs in the seven model organisms are arranged into a concise output. Hence, rather than visiting multiple separate databases for variant and gene analysis, users can obtain important information by searching once through MARRVEL. Altogether, MARRVEL dramatically improves efficiency and accessibility to data collection and facilitates analysis of human genes and variants by cross-disciplinary integration of 18 million records available in public databases to facilitate clinical diagnosis and basic research. Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

tRNA acceptor-stem and anticodon bases embed separate features of amino acid chemistry

PubMed Central

Carter, Charles W.; Wolfenden, Richard

2016-01-01

abstract The universal genetic code is a translation table by which nucleic acid sequences can be interpreted as polypeptides with a wide range of biological functions. That information is used by aminoacyl-tRNA synthetases to translate the code. Moreover, amino acid properties dictate protein folding. We recently reported that digital correlation techniques could identify patterns in tRNA identity elements that govern recognition by synthetases. Our analysis, and the functionality of truncated synthetases that cannot recognize the tRNA anticodon, support the conclusion that the tRNA acceptor stem houses an independent code for the same 20 amino acids that likely functioned earlier in the emergence of genetics. The acceptor-stem code, related to amino acid size, is distinct from a code in the anticodon that is related to amino acid polarity. Details of the acceptor-stem code suggest that it was useful in preserving key properties of stereochemically-encoded peptides that had developed the capacity to interact catalytically with RNA. The quantitative embedding of the chemical properties of amino acids into tRNA bases has implications for the origins of molecular biology. PMID:26595350

Tapping into yeast diversity.

PubMed

Fay, Justin C

2012-11-01

Domesticated organisms demonstrate our capacity to influence wild species but also provide us with the opportunity to understand rapid evolution in the context of substantially altered environments and novel selective pressures. Recent advances in genetics and genomics have brought unprecedented insights into the domestication of many organisms and have opened new avenues for further improvements to be made. Yet, our ability to engineer biological systems is not without limits; genetic manipulation is often quite difficult. The budding yeast, Saccharomyces cerevisiae, is not only one of the most powerful model organisms, but is also the premier producer of fermented foods and beverages around the globe. As a model system, it entertains a hefty workforce dedicated to deciphering its genome and the function it encodes at a rich mechanistic level. As a producer, it is used to make leavened bread, and dozens of different alcoholic beverages, such as beer and wine. Yet, applying the awesome power of yeast genetics to understanding its origins and evolution requires some knowledge of its wild ancestors and the environments from which they were derived. A number of surprisingly diverse lineages of S. cerevisiae from both primeval and secondary forests in China have been discovered by Wang and his colleagues. These lineages substantially expand our knowledge of wild yeast diversity and will be a boon to elucidating the ecology, evolution and domestication of this academic and industrial workhorse.

The Coding of Biological Information: From Nucleotide Sequence to Protein Recognition

NASA Astrophysics Data System (ADS)

Štambuk, Nikola

The paper reviews the classic results of Swanson, Dayhoff, Grantham, Blalock and Root-Bernstein, which link genetic code nucleotide patterns to the protein structure, evolution and molecular recognition. Symbolic representation of the binary addresses defining particular nucleotide and amino acid properties is discussed, with consideration of: structure and metric of the code, direct correspondence between amino acid and nucleotide information, and molecular recognition of the interacting protein motifs coded by the complementary DNA and RNA strands.

Analysis of Molecular Genetics Content in Spanish Secondary School Textbooks

ERIC Educational Resources Information Center

Martinez-Gracia, M. V.; Gil-Quilez, M. J.; Osada, J.

2006-01-01

The treatment of molecular biology in thirty-four Spanish high school biology textbooks has been analysed using a check-list made up of twenty-three items. The study showed a tendency to confuse the genetic code with genetic information. The treatment of DNA transcription, regulation of gene expression and translation were presented as masses of…

A field release of genetically engineered gypsy moth (Lymantria dispar L.) Nuclear Polyhedrosis Virus (LdNPV)

Treesearch

Vincent D' Amico; Joseph S. Elkinton; John D. Podgwaite; James M. Slavicek; Michael L. McManus; John P. Burand

1999-01-01

The gypsy moth (Lymantria dispar L.) nuclear polyhedrosis virus was genetically engineered for nonpersistence by removal of the gene coding for polyhedrin production and stabilized using a coocclusion process. A β-galactosidase marker gene was inserted into the genetically engineered virus (LdGEV) so that infected larvae could be tested for...

Length and nucleotide sequence polymorphism at the trnL and trnF non-coding regions of chloroplast genomes among Saccharum and Erianthus species

USDA-ARS?s Scientific Manuscript database

The aneupolyploidy genome of sugarcane (Saccharum hybrids spp.) and lack of a classical genetic linkage map make genetics research most difficult for sugarcane. Whole genome sequencing and genetic characterization of sugarcane and related taxa are far behind other crops. In this study, universal PCR...

Shannon information entropy in the canonical genetic code.

PubMed

Nemzer, Louis R

2017-02-21

The Shannon entropy measures the expected information value of messages. As with thermodynamic entropy, the Shannon entropy is only defined within a system that identifies at the outset the collections of possible messages, analogous to microstates, that will be considered indistinguishable macrostates. This fundamental insight is applied here for the first time to amino acid alphabets, which group the twenty common amino acids into families based on chemical and physical similarities. To evaluate these schemas objectively, a novel quantitative method is introduced based the inherent redundancy in the canonical genetic code. Each alphabet is taken as a separate system that partitions the 64 possible RNA codons, the microstates, into families, the macrostates. By calculating the normalized mutual information, which measures the reduction in Shannon entropy, conveyed by single nucleotide messages, groupings that best leverage this aspect of fault tolerance in the code are identified. The relative importance of properties related to protein folding - like hydropathy and size - and function, including side-chain acidity, can also be estimated. This approach allows the quantification of the average information value of nucleotide positions, which can shed light on the coevolution of the canonical genetic code with the tRNA-protein translation mechanism. Copyright © 2016 Elsevier Ltd. All rights reserved.

FitSKIRT: genetic algorithms to automatically fit dusty galaxies with a Monte Carlo radiative transfer code

NASA Astrophysics Data System (ADS)

De Geyter, G.; Baes, M.; Fritz, J.; Camps, P.

2013-02-01

We present FitSKIRT, a method to efficiently fit radiative transfer models to UV/optical images of dusty galaxies. These images have the advantage that they have better spatial resolution compared to FIR/submm data. FitSKIRT uses the GAlib genetic algorithm library to optimize the output of the SKIRT Monte Carlo radiative transfer code. Genetic algorithms prove to be a valuable tool in handling the multi- dimensional search space as well as the noise induced by the random nature of the Monte Carlo radiative transfer code. FitSKIRT is tested on artificial images of a simulated edge-on spiral galaxy, where we gradually increase the number of fitted parameters. We find that we can recover all model parameters, even if all 11 model parameters are left unconstrained. Finally, we apply the FitSKIRT code to a V-band image of the edge-on spiral galaxy NGC 4013. This galaxy has been modeled previously by other authors using different combinations of radiative transfer codes and optimization methods. Given the different models and techniques and the complexity and degeneracies in the parameter space, we find reasonable agreement between the different models. We conclude that the FitSKIRT method allows comparison between different models and geometries in a quantitative manner and minimizes the need of human intervention and biasing. The high level of automation makes it an ideal tool to use on larger sets of observed data.

Tooth Eruption without Roots

PubMed Central

2013-01-01

Root development and tooth eruption are very important topics in dentistry. However, they remain among the less-studied and -understood subjects. Root development accompanies rapid tooth eruption, but roots are required for the movement of teeth into the oral cavity. It has been shown that the dental follicle and bone remodeling are essential for tooth eruption. So far, only limited genes have been associated with root formation and tooth eruption. This may be due to the difficulties in studying late stages of tooth development and tooth movement and the lack of good model systems. Transgenic mice with eruption problems and short or no roots can be used as a powerful model for further deciphering of the cellular, molecular, and genetic mechanisms underlying root formation and tooth eruption. Better understanding of these processes can provide hints on delivering more efficient dental therapies in the future. PMID:23345536

Adult stem cell lineage tracing and deep tissue imaging

PubMed Central

Fink, Juergen; Andersson-Rolf, Amanda; Koo, Bon-Kyoung

2015-01-01

Lineage tracing is a widely used method for understanding cellular dynamics in multicellular organisms during processes such as development, adult tissue maintenance, injury repair and tumorigenesis. Advances in tracing or tracking methods, from light microscopy-based live cell tracking to fluorescent label-tracing with two-photon microscopy, together with emerging tissue clearing strategies and intravital imaging approaches have enabled scientists to decipher adult stem and progenitor cell properties in various tissues and in a wide variety of biological processes. Although technical advances have enabled time-controlled genetic labeling and simultaneous live imaging, a number of obstacles still need to be overcome. In this review, we aim to provide an in-depth description of the traditional use of lineage tracing as well as current strategies and upcoming new methods of labeling and imaging. [BMB Reports 2015; 48(12): 655-667] PMID:26634741

Reconstructing each cell's genome within complex microbial communities-dream or reality?

PubMed

Clingenpeel, Scott; Clum, Alicia; Schwientek, Patrick; Rinke, Christian; Woyke, Tanja

2014-01-01

As the vast majority of microorganisms have yet to be cultivated in a laboratory setting, access to their genetic makeup has largely been limited to cultivation-independent methods. These methods, namely metagenomics and more recently single-cell genomics, have become cornerstones for microbial ecology and environmental microbiology. One ultimate goal is the recovery of genome sequences from each cell within an environment to move toward a better understanding of community metabolic potential and to provide substrate for experimental work. As single-cell sequencing has the ability to decipher all sequence information contained in an individual cell, this method holds great promise in tackling such challenge. Methodological limitations and inherent biases however do exist, which will be discussed here based on environmental and benchmark data, to assess how far we are from reaching this goal.

The Molecular Revolution in Cutaneous Biology: Era of Next-Generation Sequencing.

PubMed

Sarig, Ofer; Sprecher, Eli

2017-05-01

Like any true conceptual revolution, next-generation sequencing (NGS) has not only radically changed research and clinical practice, it has also modified scientific culture. With the possibility to investigate DNA contents of any organism and in any context, including in somatic disorders or in tissues carrying complex microbial populations, it initially seemed as if the genetic underpinning of any biological phenomenon could now be deciphered in an almost streamlined fashion. However, over the past recent years, we have once again come to understand that there is no such a thing as great opportunities without great challenges. The steadily expanding use of NGS and related applications is now facing biologists and physicians with novel technological obstacles, analytical hurdles and increasingly pressing ethical questions. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

The advancement of chemical cross-linking and mass spectrometry for structural proteomics: from single proteins to protein interaction networks.

PubMed

Sinz, Andrea

2014-12-01

During the last 15 years, chemical cross-linking combined with mass spectrometry (MS) and computational modeling has advanced from investigating 3D-structures of isolated proteins to deciphering protein interaction networks. In this article, the author discusses the advent, the development and the current status of the chemical cross-linking/MS strategy in the context of recent technological developments. A direct way to probe in vivo protein-protein interactions is by site-specific incorporation of genetically encoded photo-reactive amino acids or by non-directed incorporation of photo-reactive amino acids. As the chemical cross-linking/MS approach allows the capture of transient and weak interactions, it has the potential to become a routine technique for unraveling protein interaction networks in their natural cellular environment.

The generation of meaningful information in molecular systems.

PubMed

Wills, Peter R

2016-03-13

The physico-chemical processes occurring inside cells are under the computational control of genetic (DNA) and epigenetic (internal structural) programming. The origin and evolution of genetic information (nucleic acid sequences) is reasonably well understood, but scant attention has been paid to the origin and evolution of the molecular biological interpreters that give phenotypic meaning to the sequence information that is quite faithfully replicated during cellular reproduction. The near universality and age of the mapping from nucleotide triplets to amino acids embedded in the functionality of the protein synthetic machinery speaks to the early development of a system of coding which is still extant in every living organism. We take the origin of genetic coding as a paradigm of the emergence of computation in natural systems, focusing on the requirement that the molecular components of an interpreter be synthesized autocatalytically. Within this context, it is seen that interpreters of increasing complexity are generated by series of transitions through stepped dynamic instabilities (non-equilibrium phase transitions). The early phylogeny of the amino acyl-tRNA synthetase enzymes is discussed in such terms, leading to the conclusion that the observed optimality of the genetic code is a natural outcome of the processes of self-organization that produced it. © 2016 The Author(s).

Exome Sequencing in an Admixed Isolated Population Indicates NFXL1 Variants Confer a Risk for Specific Language Impairment

PubMed Central

Villanueva, Pía; Nudel, Ron; Hoischen, Alexander; Fernández, María Angélica; Simpson, Nuala H.; Gilissen, Christian; Reader, Rose H.; Jara, Lillian; Echeverry, Maria Magdalena; Francks, Clyde; Baird, Gillian; Conti-Ramsden, Gina; O’Hare, Anne; Bolton, Patrick F.; Hennessy, Elizabeth R.; Palomino, Hernán; Carvajal-Carmona, Luis; Veltman, Joris A.; Cazier, Jean-Baptiste; De Barbieri, Zulema

2015-01-01

Children affected by Specific Language Impairment (SLI) fail to acquire age appropriate language skills despite adequate intelligence and opportunity. SLI is highly heritable, but the understanding of underlying genetic mechanisms has proved challenging. In this study, we use molecular genetic techniques to investigate an admixed isolated founder population from the Robinson Crusoe Island (Chile), who are affected by a high incidence of SLI, increasing the power to discover contributory genetic factors. We utilize exome sequencing in selected individuals from this population to identify eight coding variants that are of putative significance. We then apply association analyses across the wider population to highlight a single rare coding variant (rs144169475, Minor Allele Frequency of 4.1% in admixed South American populations) in the NFXL1 gene that confers a nonsynonymous change (N150K) and is significantly associated with language impairment in the Robinson Crusoe population (p = 2.04 × 10–4, 8 variants tested). Subsequent sequencing of NFXL1 in 117 UK SLI cases identified four individuals with heterozygous variants predicted to be of functional consequence. We conclude that coding variants within NFXL1 confer an increased risk of SLI within a complex genetic model. PMID:25781923

BiRen: predicting enhancers with a deep-learning-based model using the DNA sequence alone.

PubMed

Yang, Bite; Liu, Feng; Ren, Chao; Ouyang, Zhangyi; Xie, Ziwei; Bo, Xiaochen; Shu, Wenjie

2017-07-01

Enhancer elements are noncoding stretches of DNA that play key roles in controlling gene expression programmes. Despite major efforts to develop accurate enhancer prediction methods, identifying enhancer sequences continues to be a challenge in the annotation of mammalian genomes. One of the major issues is the lack of large, sufficiently comprehensive and experimentally validated enhancers for humans or other species. Thus, the development of computational methods based on limited experimentally validated enhancers and deciphering the transcriptional regulatory code encoded in the enhancer sequences is urgent. We present a deep-learning-based hybrid architecture, BiRen, which predicts enhancers using the DNA sequence alone. Our results demonstrate that BiRen can learn common enhancer patterns directly from the DNA sequence and exhibits superior accuracy, robustness and generalizability in enhancer prediction relative to other state-of-the-art enhancer predictors based on sequence characteristics. Our BiRen will enable researchers to acquire a deeper understanding of the regulatory code of enhancer sequences. Our BiRen method can be freely accessed at https://github.com/wenjiegroup/BiRen . shuwj@bmi.ac.cn or boxc@bmi.ac.cn. Supplementary data are available at Bioinformatics online. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com

Decoding the complex genetic causes of heart diseases using systems biology.

PubMed

Djordjevic, Djordje; Deshpande, Vinita; Szczesnik, Tomasz; Yang, Andrian; Humphreys, David T; Giannoulatou, Eleni; Ho, Joshua W K

2015-03-01

The pace of disease gene discovery is still much slower than expected, even with the use of cost-effective DNA sequencing and genotyping technologies. It is increasingly clear that many inherited heart diseases have a more complex polygenic aetiology than previously thought. Understanding the role of gene-gene interactions, epigenetics, and non-coding regulatory regions is becoming increasingly critical in predicting the functional consequences of genetic mutations identified by genome-wide association studies and whole-genome or exome sequencing. A systems biology approach is now being widely employed to systematically discover genes that are involved in heart diseases in humans or relevant animal models through bioinformatics. The overarching premise is that the integration of high-quality causal gene regulatory networks (GRNs), genomics, epigenomics, transcriptomics and other genome-wide data will greatly accelerate the discovery of the complex genetic causes of congenital and complex heart diseases. This review summarises state-of-the-art genomic and bioinformatics techniques that are used in accelerating the pace of disease gene discovery in heart diseases. Accompanying this review, we provide an interactive web-resource for systems biology analysis of mammalian heart development and diseases, CardiacCode ( http://CardiacCode.victorchang.edu.au/ ). CardiacCode features a dataset of over 700 pieces of manually curated genetic or molecular perturbation data, which enables the inference of a cardiac-specific GRN of 280 regulatory relationships between 33 regulator genes and 129 target genes. We believe this growing resource will fill an urgent unmet need to fully realise the true potential of predictive and personalised genomic medicine in tackling human heart disease.

Phenotype-loci associations in networks of patients with rare disorders: application to assist in the diagnosis of novel clinical cases.

PubMed

Bueno, Anibal; Rodríguez-López, Rocío; Reyes-Palomares, Armando; Rojano, Elena; Corpas, Manuel; Nevado, Julián; Lapunzina, Pablo; Sánchez-Jiménez, Francisca; Ranea, Juan A G

2018-06-26

Copy number variations (CNVs) are genomic structural variations (deletions, duplications, or translocations) that represent the 4.8-9.5% of human genome variation in healthy individuals. In some cases, CNVs can also lead to disease, being the etiology of many known rare genetic/genomic disorders. Despite the last advances in genomic sequencing and diagnosis, the pathological effects of many rare genetic variations remain unresolved, largely due to the low number of patients available for these cases, making it difficult to identify consistent patterns of genotype-phenotype relationships. We aimed to improve the identification of statistically consistent genotype-phenotype relationships by integrating all the genetic and clinical data of thousands of patients with rare genomic disorders (obtained from the DECIPHER database) into a phenotype-patient-genotype tripartite network. Then we assessed how our network approach could help in the characterization and diagnosis of novel cases in clinical genetics. The systematic approach implemented in this work is able to better define the relationships between phenotypes and specific loci, by exploiting large-scale association networks of phenotypes and genotypes in thousands of rare disease patients. The application of the described methodology facilitated the diagnosis of novel clinical cases, ranking phenotypes by locus specificity and reporting putative new clinical features that may suggest additional clinical follow-ups. In this work, the proof of concept developed over a set of novel clinical cases demonstrates that this network-based methodology might help improve the precision of patient clinical records and the characterization of rare syndromes.

Caenorhabditis elegans as a powerful alternative model organism to promote research in genetic toxicology and biomedicine.

PubMed

Honnen, Sebastian

2017-05-01

In view of increased life expectancy the risk for disturbed integrity of genetic information increases. This inevitably holds the implication for higher incidence of age-related diseases leading to considerable cost increase in health care systems. To develop preventive strategies it is crucial to evaluate external and internal noxae as possible threats to our DNA. Especially the interplay of DNA damage response (DDR) and DNA repair (DR) mechanisms needs further deciphering. Moreover, there is a distinct need for alternative in vivo test systems for basic research and also risk assessment in toxicology. Especially the evaluation of combinational toxicity of environmentally present genotoxins and adverse effects of clinically used DNA damaging anticancer drugs is a major challenge for modern toxicology. This review focuses on the applicability of Caenorhabditis elegans as a model organism to unravel and tackle scientific questions related to the biological consequences of genotoxin exposure and highlights methods for studying DDR and DR. In this regard large-scale in vivo screens of mixtures of chemicals and extensive parallel sequencing are highlighted as unique advantages of C. elegans. In addition, concise information regarding evolutionary conserved molecular mechanisms of the DDR and DR as well as currently available data obtained from the use of prototypical genotoxins and preferential read-outs of genotoxin testing are discussed. The use of established protocols, which are already available in the community, is encouraged to facilitate and further improve the implementation of C. elegans as a powerful genetic model system in genetic toxicology and biomedicine.

Broad AOX expression in a genetically tractable mouse model does not disturb normal physiology

PubMed Central

Szibor, Marten; Dhandapani, Praveen K.; Dufour, Eric; Holmström, Kira M.; Zhuang, Yuan; Salwig, Isabelle; Wittig, Ilka; Heidler, Juliana; Gizatullina, Zemfira; Fuchs, Helmut; Gailus-Durner, Valérie; de Angelis, Martin Hrabě; Nandania, Jatin; Velagapudi, Vidya; Wietelmann, Astrid; Rustin, Pierre; Gellerich, Frank N.; Braun, Thomas

2017-01-01

ABSTRACT Plants and many lower organisms, but not mammals, express alternative oxidases (AOXs) that branch the mitochondrial respiratory chain, transferring electrons directly from ubiquinol to oxygen without proton pumping. Thus, they maintain electron flow under conditions when the classical respiratory chain is impaired, limiting excess production of oxygen radicals and supporting redox and metabolic homeostasis. AOX from Ciona intestinalis has been used to study and mitigate mitochondrial impairments in mammalian cell lines, Drosophila disease models and, most recently, in the mouse, where multiple lentivector-AOX transgenes conferred substantial expression in specific tissues. Here, we describe a genetically tractable mouse model in which Ciona AOX has been targeted to the Rosa26 locus for ubiquitous expression. The AOXRosa26 mouse exhibited only subtle phenotypic effects on respiratory complex formation, oxygen consumption or the global metabolome, and showed an essentially normal physiology. AOX conferred robust resistance to inhibitors of the respiratory chain in organello; moreover, animals exposed to a systemically applied LD50 dose of cyanide did not succumb. The AOXRosa26 mouse is a useful tool to investigate respiratory control mechanisms and to decipher mitochondrial disease aetiology in vivo. PMID:28067626

Putting mechanisms into crop production models.

PubMed

Boote, Kenneth J; Jones, James W; White, Jeffrey W; Asseng, Senthold; Lizaso, Jon I

2013-09-01

Crop growth models dynamically simulate processes of C, N and water balance on daily or hourly time-steps to predict crop growth and development and at season-end, final yield. Their ability to integrate effects of genetics, environment and crop management have led to applications ranging from understanding gene function to predicting potential impacts of climate change. The history of crop models is reviewed briefly, and their level of mechanistic detail for assimilation and respiration, ranging from hourly leaf-to-canopy assimilation to daily radiation-use efficiency is discussed. Crop models have improved steadily over the past 30-40 years, but much work remains. Improvements are needed for the prediction of transpiration response to elevated CO₂ and high temperature effects on phenology and reproductive fertility, and simulation of root growth and nutrient uptake under stressful edaphic conditions. Mechanistic improvements are needed to better connect crop growth to genetics and to soil fertility, soil waterlogging and pest damage. Because crop models integrate multiple processes and consider impacts of environment and management, they have excellent potential for linking research from genomics and allied disciplines to crop responses at the field scale, thus providing a valuable tool for deciphering genotype by environment by management effects. © 2013 John Wiley & Sons Ltd.

Review of functional markers for improving cooking, eating, and the nutritional qualities of rice

PubMed Central

Lau, Wendy C. P.; Rafii, Mohd Y.; Ismail, Mohd R.; Puteh, Adam; Latif, Mohammad A.; Ramli, Asfaliza

2015-01-01

After yield, quality is one of the most important aspects of rice breeding. Preference for rice quality varies among cultures and regions; therefore, rice breeders have to tailor the quality according to the preferences of local consumers. Rice quality assessment requires routine chemical analysis procedures. The advancement of molecular marker technology has revolutionized the strategy in breeding programs. The availability of rice genome sequences and the use of forward and reverse genetics approaches facilitate gene discovery and the deciphering of gene functions. A well-characterized gene is the basis for the development of functional markers, which play an important role in plant genotyping and, in particular, marker-assisted breeding. In addition, functional markers offer advantages that counteract the limitations of random DNA markers. Some functional markers have been applied in marker-assisted breeding programs and have successfully improved rice quality to meet local consumers’ preferences. Although functional markers offer a plethora of advantages over random genetic markers, the development and application of functional markers should be conducted with care. The decreasing cost of sequencing will enable more functional markers for rice quality improvement to be developed, and application of these markers in rice quality breeding programs is highly anticipated. PMID:26528304

The role of protein structural analysis in the next generation sequencing era.

PubMed

Yue, Wyatt W; Froese, D Sean; Brennan, Paul E

2014-01-01

Proteins are macromolecules that serve a cell's myriad processes and functions in all living organisms via dynamic interactions with other proteins, small molecules and cellular components. Genetic variations in the protein-encoding regions of the human genome account for >85% of all known Mendelian diseases, and play an influential role in shaping complex polygenic diseases. Proteins also serve as the predominant target class for the design of small molecule drugs to modulate their activity. Knowledge of the shape and form of proteins, by means of their three-dimensional structures, is therefore instrumental to understanding their roles in disease and their potentials for drug development. In this chapter we outline, with the wide readership of non-structural biologists in mind, the various experimental and computational methods available for protein structure determination. We summarize how the wealth of structure information, contributed to a large extent by the technological advances in structure determination to date, serves as a useful tool to decipher the molecular basis of genetic variations for disease characterization and diagnosis, particularly in the emerging era of genomic medicine, and becomes an integral component in the modern day approach towards rational drug development.

Genomics and Biochemistry of Saccharomyces cerevisiae Wine Yeast Strains.

PubMed

Eldarov, M A; Kishkovskaia, S A; Tanaschuk, T N; Mardanov, A V

2016-12-01

Saccharomyces yeasts have been used for millennia for the production of beer, wine, bread, and other fermented products. Long-term "unconscious" selection and domestication led to the selection of hundreds of strains with desired production traits having significant phenotypic and genetic differences from their wild ancestors. This review summarizes the results of recent research in deciphering the genomes of wine Saccharomyces strains, the use of comparative genomics methods to study the mechanisms of yeast genome evolution under conditions of artificial selection, and the use of genomic and postgenomic approaches to identify the molecular nature of the important characteristics of commercial wine strains of Saccharomyces. Succinctly, data concerning metagenomics of microbial communities of grapes and wine and the dynamics of yeast and bacterial flora in the course of winemaking is provided. A separate section is devoted to an overview of the physiological, genetic, and biochemical features of sherry yeast strains used to produce biologically aged wines. The goal of the review is to convince the reader of the efficacy of new genomic and postgenomic technologies as tools for developing strategies for targeted selection and creation of new strains using "classical" and modern techniques for improving winemaking technology.

Versatile synthesis and rational design of caged morpholinos.

PubMed

Ouyang, Xiaohu; Shestopalov, Ilya A; Sinha, Surajit; Zheng, Genhua; Pitt, Cameron L W; Li, Wen-Hong; Olson, Andrew J; Chen, James K

2009-09-23

Embryogenesis is regulated by genetic programs that are dynamically executed in a stereotypic manner, and deciphering these molecular mechanisms requires the ability to control embryonic gene function with similar spatial and temporal precision. Chemical technologies can enable such genetic manipulations, as exemplified by the use of caged morpholino (cMO) oligonucleotides to inactivate genes in zebrafish and other optically transparent organisms with spatiotemporal control. Here we report optimized methods for the design and synthesis of hairpin cMOs incorporating a dimethoxynitrobenzyl (DMNB)-based bifunctional linker that permits cMO assembly in only three steps from commercially available reagents. Using this simplified procedure, we have systematically prepared cMOs with differing structural configurations and investigated how the in vitro thermodynamic properties of these reagents correlate with their in vivo activities. Through these studies, we have established general principles for cMO design and successfully applied them to several developmental genes. Our optimized synthetic and design methodologies have also enabled us to prepare a next-generation cMO that contains a bromohydroxyquinoline (BHQ)-based linker for two-photon uncaging. Collectively, these advances establish the generality of cMO technologies and will facilitate the application of these chemical probes in vivo for functional genomic studies.

Versatile Synthesis and Rational Design of Caged Morpholinos

PubMed Central

2009-01-01

Embryogenesis is regulated by genetic programs that are dynamically executed in a stereotypic manner, and deciphering these molecular mechanisms requires the ability to control embryonic gene function with similar spatial and temporal precision. Chemical technologies can enable such genetic manipulations, as exemplified by the use of caged morpholino (cMO) oligonucleotides to inactivate genes in zebrafish and other optically transparent organisms with spatiotemporal control. Here we report optimized methods for the design and synthesis of hairpin cMOs incorporating a dimethoxynitrobenzyl (DMNB)-based bifunctional linker that permits cMO assembly in only three steps from commercially available reagents. Using this simplified procedure, we have systematically prepared cMOs with differing structural configurations and investigated how the in vitro thermodynamic properties of these reagents correlate with their in vivo activities. Through these studies, we have established general principles for cMO design and successfully applied them to several developmental genes. Our optimized synthetic and design methodologies have also enabled us to prepare a next-generation cMO that contains a bromohydroxyquinoline (BHQ)-based linker for two-photon uncaging. Collectively, these advances establish the generality of cMO technologies and will facilitate the application of these chemical probes in vivo for functional genomic studies. PMID:19708646

Sordaria macrospora, a model organism to study fungal cellular development.

PubMed

Engh, Ines; Nowrousian, Minou; Kück, Ulrich

2010-12-01

During the development of multicellular eukaryotes, the processes of cellular growth and organogenesis are tightly coordinated. Since the 1940s, filamentous fungi have served as genetic model organisms to decipher basic mechanisms underlying eukaryotic cell differentiation. Here, we focus on Sordaria macrospora, a homothallic ascomycete and important model organism for developmental biology. During its sexual life cycle, S. macrospora forms three-dimensional fruiting bodies, a complex process involving the formation of different cell types. S. macrospora can be used for genetic, biochemical and cellular experimental approaches since diverse tools, including fluorescence microscopy, a marker recycling system and gene libraries, are available. Moreover, the genome of S. macrospora has been sequenced and allows functional genomics analyses. Over the past years, our group has generated and analysed a number of developmental mutants which has greatly enhanced our fundamental understanding about fungal morphogenesis. In addition, our recent research activities have established a link between developmental proteins and conserved signalling cascades, ultimately leading to a regulatory network controlling differentiation processes in a eukaryotic model organism. This review summarizes the results of our recent findings, thus advancing current knowledge of the general principles and paradigms underpinning eukaryotic cell differentiation and development. Copyright © 2010 Elsevier GmbH. All rights reserved.

Deciphering the genomes of 16 Acanthamoeba species does not provide evidence of integration of known giant virus-associated mobile genetic elements.

PubMed

Chelkha, Nisrine; Colson, Philippe; Levasseur, Anthony; La Scola, Bernard

2018-06-02

Giant viruses infect protozoa, especially amoebae of the genus Acanthamoeba. These viruses possess genetic elements named Mobilome. So far, this mobilome comprises provirophages which are integrated into the genome of their hosts, transpovirons, and Maverick/Polintons. Virophages replicate inside virus factories within Acanthamoeba and can decrease the infectivity of giant viruses. The virophage infecting CroV was found to be integrated in the host of CroV, Cafeteria roenbergensis, thus protecting C. roenbergensis by reduction of CroV multiplication. Because of this unique property, assessment of the mechanisms of replication of virophages and their relationship with giant viruses is a key element of this investigation. This work aimed at evaluating the presence and the dynamic of these mobile elements in sixteen Acanthamoeba genomes. No significant traces of the integration of genomes or sequences from known virophages were identified in all the available Acanthamoeba genomes. These results brought us to hypothesize that the interactions between mimiviruses and their virophages might occur through different mechanisms, or at low frequency. An additional explanation could be that our knowledge of the diversity of virophages is still very limited. Copyright © 2018 Elsevier B.V. All rights reserved.

Harnessing epigenome modifications for better crops

USDA-ARS?s Scientific Manuscript database

Chemical DNA modifications such as methylation influence translation of the DNA code to specific genetic outcomes. While such modifications can be heritable, others are transient, and their overall contribution to plant genetic diversity remains intriguing but uncertain. The focus of this article is...

Informational structure of genetic sequences and nature of gene splicing

NASA Astrophysics Data System (ADS)

Trifonov, E. N.

1991-10-01

Only about 1/20 of DNA of higher organisms codes for proteins, by means of classical triplet code. The rest of DNA sequences is largely silent, with unclear functions, if any. The triplet code is not the only code (message) carried by the sequences. There are three levels of molecular communication, where the same sequence ``talks'' to various bimolecules, while having, respectively, three different appearances: DNA, RNA and protein. Since the molecular structures and, hence, sequence specific preferences of these are substantially different, the original DNA sequence has to carry simultaneously three types of sequence patterns (codes, messages), thus, being a composite structure in which one had the same letter (nucleotide) is frequently involved in several overlapping codes of different nature. This multiplicity and overlapping of the codes is a unique feature of the Gnomic, language of genetic sequences. The coexisting codes have to be degenerate in various degrees to allow an optimal and concerted performance of all the encoded functions. There is an obvious conflict between the best possible performance of a given function and necessity to compromise the quality of a given sequence pattern in favor of other patterns. It appears that the major role of various changes in the sequences on their ``ontogenetic'' way from DNA to RNA to protein, like RNA editing and splicing, or protein post-translational modifications is to resolve such conflicts. New data are presented strongly indicating that the gene splicing is such a device to resolve the conflict between the code of DNA folding in chromatin and the triplet code for protein synthesis.

The genetic structure of Arabidopsis thaliana in the south-western Mediterranean range reveals a shared history between North Africa and southern Europe

PubMed Central

2014-01-01

Background Deciphering the genetic structure of Arabidopsis thaliana diversity across its geographic range provides the bases for elucidating the demographic history of this model plant. Despite the unique A. thaliana genomic resources currently available, its history in North Africa, the extreme southern limit in the biodiversity hotspot of the Mediterranean Basin, remains virtually unknown. Results To approach A. thaliana evolutionary history in North Africa, we have analysed the genetic diversity and structure of 151 individuals collected from 20 populations distributed across Morocco. Genotyping of 249 genome-wide SNPs indicated that Morocco contains substantially lower diversity than most analyzed world regions. However, IBD, STRUCTURE and PCA clustering analyses showed that genetic variation is strongly geographically structured. We also determined the genetic relationships between Morocco and the closest European region, the Iberian Peninsula, by analyses of 201 populations from both regions genotyped with the same SNPs. These analyses detected four genetic groups, but all Moroccan accessions belonged to a common Iberian/Moroccan cluster that appeared highly differentiated from the remaining groups. Thus, we identified a genetic lineage with an isolated demographic history in the south-western Mediterranean region. The existence of this lineage was further supported by the study of several flowering genes and traits, which also found Moroccan accessions similar to the same Iberian group. Nevertheless, genetic diversity for neutral SNPs and flowering genes was higher in Moroccan than in Iberian populations of this lineage. Furthermore, we analyzed the genetic relationships between Morocco and other world regions by joint analyses of a worldwide collection of 337 accessions, which detected an additional weak relationship between North Africa and Asia. Conclusions The patterns of genetic diversity and structure of A. thaliana in Morocco show that North Africa is part of the species native range and support the occurrence of a glacial refugium in the Atlas Mountains. In addition, the identification of a genetic lineage specific of Morocco and the Iberian Peninsula indicates that the Strait of Gibraltar has been an A. thaliana migration route between Europe and Africa. Finally, the genetic relationship between Morocco and Asia suggests another migration route connecting north-western Africa and Asia. PMID:24411008

Influence of language and ancestry on genetic structure of contiguous populations: A microsatellite based study on populations of Orissa

PubMed Central

Sahoo, Sanghamitra; Kashyap, VK

2005-01-01

Background We have examined genetic diversity at fifteen autosomal microsatellite loci in seven predominant populations of Orissa to decipher whether populations inhabiting the same geographic region can be differentiated on the basis of language or ancestry. The studied populations have diverse historical accounts of their origin, belong to two major ethnic groups and different linguistic families. Caucasoid caste populations are speakers of Indo-European language and comprise Brahmins, Khandayat, Karan and Gope, while the three Australoid tribal populations include two Austric speakers: Juang and Saora and a Dravidian speaking population, Paroja. These divergent groups provide a varied substratum for understanding variation of genetic patterns in a geographical area resulting from differential admixture between migrants groups and aboriginals, and the influence of this admixture on population stratification. Results The allele distribution pattern showed uniformity in the studied groups with approximately 81% genetic variability within populations. The coefficient of gene differentiation was found to be significantly higher in tribes (0.014) than caste groups (0.004). Genetic variance between the groups was 0.34% in both ethnic and linguistic clusters and statistically significant only in the ethnic apportionment. Although the populations were genetically close (FST = 0.010), the contemporary caste and tribal groups formed distinct clusters in both Principal-Component plot and Neighbor-Joining tree. In the phylogenetic tree, the Orissa Brahmins showed close affinity to populations of North India, while Khandayat and Gope clustered with the tribal groups, suggesting a possibility of their origin from indigenous people. Conclusions The extent of genetic differentiation in the contemporary caste and tribal groups of Orissa is highly significant and constitutes two distinct genetic clusters. Based on our observations, we suggest that since genetic distances and coefficient of gene differentiation were fairly small, the studied populations are indeed genetically similar and that the genetic structure of populations in a geographical region is primarily influenced by their ancestry and not by socio-cultural hierarchy or language. The scenario of genetic structure, however, might be different for other regions of the subcontinent where populations have more similar ethnic and linguistic backgrounds and there might be variations in the patterns of genomic and socio-cultural affinities in different geographical regions. PMID:15694006

Beyond terrestrial biology: charting the chemical universe of α-amino acid structures.

PubMed

Meringer, Markus; Cleaves, H James; Freeland, Stephen J

2013-11-25

α-Amino acids are fundamental to biochemistry as the monomeric building blocks with which cells construct proteins according to genetic instructions. However, the 20 amino acids of the standard genetic code represent a tiny fraction of the number of α-amino acid chemical structures that could plausibly play such a role, both from the perspective of natural processes by which life emerged and evolved, and from the perspective of human-engineered genetically coded proteins. Until now, efforts to describe the structures comprising this broader set, or even estimate their number, have been hampered by the complex combinatorial properties of organic molecules. Here, we use computer software based on graph theory and constructive combinatorics in order to conduct an efficient and exhaustive search of the chemical structures implied by two careful and precise definitions of the α-amino acids relevant to coded biological proteins. Our results include two virtual libraries of α-amino acid structures corresponding to these different approaches, comprising 121 044 and 3 846 structures, respectively, and suggest a simple approach to exploring much larger, as yet uncomputed, libraries of interest.

Generation of a variety of stable Influenza A reporter viruses by genetic engineering of the NS gene segment

PubMed Central

Reuther, Peter; Göpfert, Kristina; Dudek, Alexandra H.; Heiner, Monika; Herold, Susanne; Schwemmle, Martin

2015-01-01

Influenza A viruses (IAV) pose a constant threat to the human population and therefore a better understanding of their fundamental biology and identification of novel therapeutics is of upmost importance. Various reporter-encoding IAV were generated to achieve these goals, however, one recurring difficulty was the genetic instability especially of larger reporter genes. We employed the viral NS segment coding for the non-structural protein 1 (NS1) and nuclear export protein (NEP) for stable expression of diverse reporter proteins. This was achieved by converting the NS segment into a single open reading frame (ORF) coding for NS1, the respective reporter and NEP. To allow expression of individual proteins, the reporter genes were flanked by two porcine Teschovirus-1 2A peptide (PTV-1 2A)-coding sequences. The resulting viruses encoding luciferases, fluorescent proteins or a Cre recombinase are characterized by a high genetic stability in vitro and in mice and can be readily employed for antiviral compound screenings, visualization of infected cells or cells that survived acute infection. PMID:26068081

Long noncoding RNAs and tumorigenesis: genetic associations, molecular mechanisms, and therapeutic strategies.

PubMed

Zhang, Fan; Zhang, Liang; Zhang, Caiguo

2016-01-01

The human genome contains a large number of nonprotein-coding sequences. Recently, new discoveries in the functions of nonprotein-coding sequences have demonstrated that the "Dark Genome" significantly contributes to human diseases, especially with regard to cancer. Of particular interest in this review are long noncoding RNAs (lncRNAs), which comprise a class of nonprotein-coding transcripts that are longer than 200 nucleotides. Accumulating evidence indicates that a large number of lncRNAs exhibit genetic associations with tumorigenesis, tumor progression, and metastasis. Our current understanding of the molecular bases of these lncRNAs that are associated with cancer indicate that they play critical roles in gene transcription, translation, and chromatin modification. Therapeutic strategies based on the targeting of lncRNAs to disrupt their expression or their functions are being developed. In this review, we briefly summarize and discuss the genetic associations and the aberrant expression of lncRNAs in cancer, with a particular focus on studies that have revealed the molecular mechanisms of lncRNAs in tumorigenesis. In addition, we also discuss different therapeutic strategies that involve the targeting of lncRNAs.

Conservation genetics and geographic patterns of genetic variation of the endangered officinal herb Fritillaria pallidiflora

Treesearch

Zhihao Su; Borong Pan; Stewart C. Sanderson; Xiaolong Jiang; Mingli Zhang

2015-01-01

Fritillaria pallidiflora is an endangered officinal herb distributed in the Tianshan Mountains of northwestern China. We examined its phylogeography to study evolutionary processes and suggest implications for conservation. Six haplotypes were detected based on three chloroplast non-coding spacers (psbA-trnH, rps16, and trnS-trnG); genetic variation mainly occurred...

The Future of Genetics in Psychology and Psychiatry: Microarrays, Genome-Wide Association, and Non-Coding RNA

ERIC Educational Resources Information Center

Plomin, Robert; Davis, Oliver S. P.

2009-01-01

Background: Much of what we thought we knew about genetics needs to be modified in light of recent discoveries. What are the implications of these advances for identifying genes responsible for the high heritability of many behavioural disorders and dimensions in childhood? Methods: Although quantitative genetics such as twin studies will continue…

Exome chip meta-analysis identifies novel loci and East Asian-specific coding variants that contribute to lipid levels and coronary artery disease.

PubMed

Lu, Xiangfeng; Peloso, Gina M; Liu, Dajiang J; Wu, Ying; Zhang, He; Zhou, Wei; Li, Jun; Tang, Clara Sze-Man; Dorajoo, Rajkumar; Li, Huaixing; Long, Jirong; Guo, Xiuqing; Xu, Ming; Spracklen, Cassandra N; Chen, Yang; Liu, Xuezhen; Zhang, Yan; Khor, Chiea Chuen; Liu, Jianjun; Sun, Liang; Wang, Laiyuan; Gao, Yu-Tang; Hu, Yao; Yu, Kuai; Wang, Yiqin; Cheung, Chloe Yu Yan; Wang, Feijie; Huang, Jianfeng; Fan, Qiao; Cai, Qiuyin; Chen, Shufeng; Shi, Jinxiu; Yang, Xueli; Zhao, Wanting; Sheu, Wayne H-H; Cherny, Stacey Shawn; He, Meian; Feranil, Alan B; Adair, Linda S; Gordon-Larsen, Penny; Du, Shufa; Varma, Rohit; Chen, Yii-Der Ida; Shu, Xiao-Ou; Lam, Karen Siu Ling; Wong, Tien Yin; Ganesh, Santhi K; Mo, Zengnan; Hveem, Kristian; Fritsche, Lars G; Nielsen, Jonas Bille; Tse, Hung-Fat; Huo, Yong; Cheng, Ching-Yu; Chen, Y Eugene; Zheng, Wei; Tai, E Shyong; Gao, Wei; Lin, Xu; Huang, Wei; Abecasis, Goncalo; Kathiresan, Sekar; Mohlke, Karen L; Wu, Tangchun; Sham, Pak Chung; Gu, Dongfeng; Willer, Cristen J

2017-12-01

Most genome-wide association studies have been of European individuals, even though most genetic variation in humans is seen only in non-European samples. To search for novel loci associated with blood lipid levels and clarify the mechanism of action at previously identified lipid loci, we used an exome array to examine protein-coding genetic variants in 47,532 East Asian individuals. We identified 255 variants at 41 loci that reached chip-wide significance, including 3 novel loci and 14 East Asian-specific coding variant associations. After a meta-analysis including >300,000 European samples, we identified an additional nine novel loci. Sixteen genes were identified by protein-altering variants in both East Asians and Europeans, and thus are likely to be functional genes. Our data demonstrate that most of the low-frequency or rare coding variants associated with lipids are population specific, and that examining genomic data across diverse ancestries may facilitate the identification of functional genes at associated loci.

Exome chip meta-analysis identifies novel loci and East Asian-specific coding variants contributing to lipid levels and coronary artery disease

PubMed Central

Lu, Xiangfeng; Peloso, Gina M; Liu, Dajiang J.; Wu, Ying; Zhang, He; Zhou, Wei; Li, Jun; Tang, Clara Sze-man; Dorajoo, Rajkumar; Li, Huaixing; Long, Jirong; Guo, Xiuqing; Xu, Ming; Spracklen, Cassandra N.; Chen, Yang; Liu, Xuezhen; Zhang, Yan; Khor, Chiea Chuen; Liu, Jianjun; Sun, Liang; Wang, Laiyuan; Gao, Yu-Tang; Hu, Yao; Yu, Kuai; Wang, Yiqin; Cheung, Chloe Yu Yan; Wang, Feijie; Huang, Jianfeng; Fan, Qiao; Cai, Qiuyin; Chen, Shufeng; Shi, Jinxiu; Yang, Xueli; Zhao, Wanting; Sheu, Wayne H.-H.; Cherny, Stacey Shawn; He, Meian; Feranil, Alan B.; Adair, Linda S.; Gordon-Larsen, Penny; Du, Shufa; Varma, Rohit; da Chen, Yii-Der I; Shu, XiaoOu; Lam, Karen Siu Ling; Wong, Tien Yin; Ganesh, Santhi K.; Mo, Zengnan; Hveem, Kristian; Fritsche, Lars; Nielsen, Jonas Bille; Tse, Hung-fat; Huo, Yong; Cheng, Ching-Yu; Chen, Y. Eugene; Zheng, Wei; Tai, E Shyong; Gao, Wei; Lin, Xu; Huang, Wei; Abecasis, Goncalo; Consortium, GLGC; Kathiresan, Sekar; Mohlke, Karen L.; Wu, Tangchun; Sham, Pak Chung; Gu, Dongfeng; Willer, Cristen J

2017-01-01

Most genome-wide association studies have been conducted in European individuals, even though most genetic variation in humans is seen only in non-European samples. To search for novel loci associated with blood lipid levels and clarify the mechanism of action at previously identified lipid loci, we examined protein-coding genetic variants in 47,532 East Asian individuals using an exome array. We identified 255 variants at 41 loci reaching chip-wide significance, including 3 novel loci and 14 East Asian-specific coding variant associations. After meta-analysis with > 300,000 European samples, we identified an additional 9 novel loci. The same 16 genes were identified by the protein-altering variants in both East Asians and Europeans, likely pointing to the functional genes. Our data demonstrate that most of the low-frequency or rare coding variants associated with lipids are population-specific, and that examining genomic data across diverse ancestries may facilitate the identification of functional genes at associated loci. PMID:29083407

Shannon Entropy of the Canonical Genetic Code

NASA Astrophysics Data System (ADS)

Nemzer, Louis

The probability that a non-synonymous point mutation in DNA will adversely affect the functionality of the resultant protein is greatly reduced if the substitution is conservative. In that case, the amino acid coded by the mutated codon has similar physico-chemical properties to the original. Many simplified alphabets, which group the 20 common amino acids into families, have been proposed. To evaluate these schema objectively, we introduce a novel, quantitative method based on the inherent redundancy in the canonical genetic code. By calculating the Shannon information entropy carried by 1- or 2-bit messages, groupings that best leverage the robustness of the code are identified. The relative importance of properties related to protein folding - like hydropathy and size - and function, including side-chain acidity, can also be estimated. In addition, this approach allows us to quantify the average information value of nucleotide codon positions, and explore the physiological basis for distinguishing between transition and transversion mutations. Supported by NSU PFRDG Grant #335347.

Metabolic Signaling and Therapy of Lung Cancer

DTIC Science & Technology

2013-09-01

this grant is to decipher molecular mechanisms by which glycolytic enzyme phosphoglycerate mutase 1 (PGAM1) promotes lung cancer cell metabolism and...PGAM1 in regulation of lung cancer metabolism; molecular mechanisms underlying PGAM1 activation in lung cancer; PGAM1 inhibitor as novel therapy to...leukemia cells from human patients with minimal toxicity. Therefore, the current funded proposal focuses to decipher molecular mechanisms by which

Exosomes and microvesicles: extracellular vesicles for genetic information transfer and gene therapy.

PubMed

Lee, Yi; El Andaloussi, Samir; Wood, Matthew J A

2012-10-15

Exosomes and microvesicles are extracellular nanovesicles released by most but not all cells. They are specifically equipped to mediate intercellular communication via the transfer of genetic information, including the transfer of both coding and non-coding RNAs, to recipient cells. As a result, both exosomes and microvesicles play a fundamental biological role in the regulation of normal physiological as well as aberrant pathological processes, via altered gene regulatory networks and/or via epigenetic programming. For example, microvesicle-mediated genetic transfer can regulate the maintenance of stem cell plasticity and induce beneficial cell phenotype modulation. Alternatively, such vesicles play a role in tumor pathogenesis and the spread of neurodegenerative diseases via the transfer of specific microRNAs and pathogenic proteins. Given this natural property for genetic information transfer, the possibility of exploiting these vesicles for therapeutic purposes is now being investigated. Stem cell-derived microvesicles appear to be naturally equipped to mediate tissue regeneration under certain conditions, while recent evidence suggests that exosomes might be harnessed for the targeted delivery of human genetic therapies via the introduction of exogenous genetic cargoes such as siRNA. Thus, extracellular vesicles are emerging as potent genetic information transfer agents underpinning a range of biological processes and with therapeutic potential.

Improved genetic algorithm for the protein folding problem by use of a Cartesian combination operator.

PubMed Central

Rabow, A. A.; Scheraga, H. A.

1996-01-01

We have devised a Cartesian combination operator and coding scheme for improving the performance of genetic algorithms applied to the protein folding problem. The genetic coding consists of the C alpha Cartesian coordinates of the protein chain. The recombination of the genes of the parents is accomplished by: (1) a rigid superposition of one parent chain on the other, to make the relation of Cartesian coordinates meaningful, then, (2) the chains of the children are formed through a linear combination of the coordinates of their parents. The children produced with this Cartesian combination operator scheme have similar topology and retain the long-range contacts of their parents. The new scheme is significantly more efficient than the standard genetic algorithm methods for locating low-energy conformations of proteins. The considerable superiority of genetic algorithms over Monte Carlo optimization methods is also demonstrated. We have also devised a new dynamic programming lattice fitting procedure for use with the Cartesian combination operator method. The procedure finds excellent fits of real-space chains to the lattice while satisfying bond-length, bond-angle, and overlap constraints. PMID:8880904

The importance of immune gene variability (MHC) in evolutionary ecology and conservation

PubMed Central

Sommer, Simone

2005-01-01

Genetic studies have typically inferred the effects of human impact by documenting patterns of genetic differentiation and levels of genetic diversity among potentially isolated populations using selective neutral markers such as mitochondrial control region sequences, microsatellites or single nucleotide polymorphism (SNPs). However, evolutionary relevant and adaptive processes within and between populations can only be reflected by coding genes. In vertebrates, growing evidence suggests that genetic diversity is particularly important at the level of the major histocompatibility complex (MHC). MHC variants influence many important biological traits, including immune recognition, susceptibility to infectious and autoimmune diseases, individual odours, mating preferences, kin recognition, cooperation and pregnancy outcome. These diverse functions and characteristics place genes of the MHC among the best candidates for studies of mechanisms and significance of molecular adaptation in vertebrates. MHC variability is believed to be maintained by pathogen-driven selection, mediated either through heterozygote advantage or frequency-dependent selection. Up to now, most of our knowledge has derived from studies in humans or from model organisms under experimental, laboratory conditions. Empirical support for selective mechanisms in free-ranging animal populations in their natural environment is rare. In this review, I first introduce general information about the structure and function of MHC genes, as well as current hypotheses and concepts concerning the role of selection in the maintenance of MHC polymorphism. The evolutionary forces acting on the genetic diversity in coding and non-coding markers are compared. Then, I summarise empirical support for the functional importance of MHC variability in parasite resistance with emphasis on the evidence derived from free-ranging animal populations investigated in their natural habitat. Finally, I discuss the importance of adaptive genetic variability with respect to human impact and conservation, and implications for future studies. PMID:16242022

JavaGenes and Condor: Cycle-Scavenging Genetic Algorithms

NASA Technical Reports Server (NTRS)

Globus, Al; Langhirt, Eric; Livny, Miron; Ramamurthy, Ravishankar; Soloman, Marvin; Traugott, Steve

2000-01-01

A genetic algorithm code, JavaGenes, was written in Java and used to evolve pharmaceutical drug molecules and digital circuits. JavaGenes was run under the Condor cycle-scavenging batch system managing 100-170 desktop SGI workstations. Genetic algorithms mimic biological evolution by evolving solutions to problems using crossover and mutation. While most genetic algorithms evolve strings or trees, JavaGenes evolves graphs representing (currently) molecules and circuits. Java was chosen as the implementation language because the genetic algorithm requires random splitting and recombining of graphs, a complex data structure manipulation with ample opportunities for memory leaks, loose pointers, out-of-bound indices, and other hard to find bugs. Java garbage-collection memory management, lack of pointer arithmetic, and array-bounds index checking prevents these bugs from occurring, substantially reducing development time. While a run-time performance penalty must be paid, the only unacceptable performance we encountered was using standard Java serialization to checkpoint and restart the code. This was fixed by a two-day implementation of custom checkpointing. JavaGenes is minimally integrated with Condor; in other words, JavaGenes must do its own checkpointing and I/O redirection. A prototype Java-aware version of Condor was developed using standard Java serialization for checkpointing. For the prototype to be useful, standard Java serialization must be significantly optimized. JavaGenes is approximately 8700 lines of code and a few thousand JavaGenes jobs have been run. Most jobs ran for a few days. Results include proof that genetic algorithms can evolve directed and undirected graphs, development of a novel crossover operator for graphs, a paper in the journal Nanotechnology, and another paper in preparation.

Characterization and phylogenetic analysis of the swine leukocyte antigen 3 gene from Korean native pigs.

PubMed

Chung, H Y; Choi, Y C; Park, H N

2015-05-18

We investigated the phylogenetic relationships between pig breeds, compared the genetic similarity between humans and pigs, and provided basic genetic information on Korean native pigs (KNPs), using genetic variants of the swine leukocyte antigen 3 (SLA-3) gene. Primers were based on sequences from GenBank (accession Nos. AF464010 and AF464009). Polymerase chain reaction analysis amplified approximately 1727 bp of segments, which contained 1086 bp of coding regions and 641 bp of the 3'- and 5'-untranslated regions. Bacterial artificial chromosome clones of miniature pigs were used for sequencing the SLA-3 genomic region, which was 3114 bp in total length, including the coding (1086 bp) and non-coding (2028 bp) regions. Sequence analysis detected 53 single nucleotide polymorphisms (SNPs), based on a minor allele frequency greater than 0.01, which is low compared with other pig breeds, and the results suggest that there is low genetic variability in KNPs. Comparative analysis revealed that humans possess approximately three times more genetic variation than do pigs. Approximately 71% of SNPs in exons 2 and 3 were detected in KNPs, and exon 5 in humans is a highly polymorphic region. Newly identified sequences of SLA-3 using KNPs were submitted to GenBank (accession No. DQ992512-18). Cluster analysis revealed that KNPs were grouped according to three major alleles: SLA-3*0502 (DQ992518), SLA-3*0302 (DQ992513 and DQ992516), and SLA-3*0303 (DQ992512, DQ992514, DQ992515, and DQ992517). Alignments revealed that humans have a relatively close genetic relationship with pigs and chimpanzees. The information provided by this study may be useful in KNP management.

Utilization of genetic tests: analysis of gene-specific billing in Medicare claims data.

PubMed

Lynch, Julie A; Berse, Brygida; Dotson, W David; Khoury, Muin J; Coomer, Nicole; Kautter, John

2017-08-01

We examined the utilization of precision medicine tests among Medicare beneficiaries through analysis of gene-specific tier 1 and 2 billing codes developed by the American Medical Association in 2012. We conducted a retrospective cross-sectional study. The primary source of data was 2013 Medicare 100% fee-for-service claims. We identified claims billed for each laboratory test, the number of patients tested, expenditures, and the diagnostic codes indicated for testing. We analyzed variations in testing by patient demographics and region of the country. Pharmacogenetic tests were billed most frequently, accounting for 48% of the expenditures for new codes. The most common indications for testing were breast cancer, long-term use of medications, and disorders of lipid metabolism. There was underutilization of guideline-recommended tumor mutation tests (e.g., epidermal growth factor receptor) and substantial overutilization of a test discouraged by guidelines (methylenetetrahydrofolate reductase). Methodology-based tier 2 codes represented 15% of all claims billed with the new codes. The highest rate of testing per beneficiary was in Mississippi and the lowest rate was in Alaska. Gene-specific billing codes significantly improved our ability to conduct population-level research of precision medicine. Analysis of these data in conjunction with clinical records should be conducted to validate findings.Genet Med advance online publication 26 January 2017.

The DNA Methylome of Human Peripheral Blood Mononuclear Cells

PubMed Central

Ye, Mingzhi; Zheng, Hancheng; Yu, Jian; Wu, Honglong; Sun, Jihua; Zhang, Hongyu; Chen, Quan; Luo, Ruibang; Chen, Minfeng; He, Yinghua; Jin, Xin; Zhang, Qinghui; Yu, Chang; Zhou, Guangyu; Sun, Jinfeng; Huang, Yebo; Zheng, Huisong; Cao, Hongzhi; Zhou, Xiaoyu; Guo, Shicheng; Hu, Xueda; Li, Xin; Kristiansen, Karsten; Bolund, Lars; Xu, Jiujin; Wang, Wen; Yang, Huanming; Wang, Jian; Li, Ruiqiang; Beck, Stephan; Wang, Jun; Zhang, Xiuqing

2010-01-01

DNA methylation plays an important role in biological processes in human health and disease. Recent technological advances allow unbiased whole-genome DNA methylation (methylome) analysis to be carried out on human cells. Using whole-genome bisulfite sequencing at 24.7-fold coverage (12.3-fold per strand), we report a comprehensive (92.62%) methylome and analysis of the unique sequences in human peripheral blood mononuclear cells (PBMC) from the same Asian individual whose genome was deciphered in the YH project. PBMC constitute an important source for clinical blood tests world-wide. We found that 68.4% of CpG sites and <0.2% of non-CpG sites were methylated, demonstrating that non-CpG cytosine methylation is minor in human PBMC. Analysis of the PBMC methylome revealed a rich epigenomic landscape for 20 distinct genomic features, including regulatory, protein-coding, non-coding, RNA-coding, and repeat sequences. Integration of our methylome data with the YH genome sequence enabled a first comprehensive assessment of allele-specific methylation (ASM) between the two haploid methylomes of any individual and allowed the identification of 599 haploid differentially methylated regions (hDMRs) covering 287 genes. Of these, 76 genes had hDMRs within 2 kb of their transcriptional start sites of which >80% displayed allele-specific expression (ASE). These data demonstrate that ASM is a recurrent phenomenon and is highly correlated with ASE in human PBMCs. Together with recently reported similar studies, our study provides a comprehensive resource for future epigenomic research and confirms new sequencing technology as a paradigm for large-scale epigenomics studies. PMID:21085693

MicroRNAs in genetic disease: rethinking the dosage.

PubMed

Henrion-Caude, Alexandra; Girard, Muriel; Amiel, Jeanne

2012-08-01

To date, the general assumption was that most mutations interested protein-coding genes only. Thus, only few illustrations have mentioned here that mutations may occur in non-protein coding genes such as microRNAs (miRNAs). We thus report progress in delineating their contribution as phenotypic modulators, genetic switches and fine-tuners of gene expression. We reasoned that browsing their contribution to genetic disease may provide a framework for understanding the proper requirements to devise miRNA-based therapy strategies, in particular the relief of an appropriate dosage. Gain and loss of function of miRNA enforce the need to respectively antagonize or supply the miRNAs. We further categorized human disease according to the different ways in which the miRNA was altered arising either de novo, or inherited whether as a mendelian or as an epistatic trait, uncovering its role in epigenetics. We discuss how improving our knowledge on the contribution of miRNAs to genetic disease may be beneficial to devise appropriate gene therapy strategies.

Hypothalamic transcriptomes of 99 mouse strains reveal trans eQTL hotspots, splicing QTLs and novel non-coding genes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hasin-Brumshtein, Yehudit; Khan, Arshad H.; Hormozdiari, Farhad

2016-09-13

Previous studies had shown that the integration of genome wide expression profiles, in metabolic tissues, with genetic and phenotypic variance, provided valuable insight into the underlying molecular mechanisms. We used RNA-Seq to characterize hypothalamic transcriptome in 99 inbred strains of mice from the Hybrid Mouse Diversity Panel (HMDP), a reference resource population for cardiovascular and metabolic traits. We report numerous novel transcripts supported by proteomic analyses, as well as novel non coding RNAs. High resolution genetic mapping of transcript levels in HMDP, reveals bothlocalandtransexpression Quantitative Trait Loci (eQTLs) demonstrating 2transeQTL 'hotspots' associated with expression of hundreds of genes. We alsomore » report thousands of alternative splicing events regulated by genetic variants. Finally, comparison with about 150 metabolic and cardiovascular traits revealed many highly significant associations. Our data provide a rich resource for understanding the many physiologic functions mediated by the hypothalamus and their genetic regulation.« less

The conservation of forest genetic resources: case histories from Canada, Mexico, and the United States

Treesearch

F. Thomas Ledig; J. Jesús Vargas-Hernández; Kurt H. Johnsen

1998-01-01

The genetic codes of living organisms are natural resources no less than soil, air, and water. Genetic resources-from nucleotide sequences in DNA to selected genotypes, populations, and species-are the raw material in forestry: for breeders, for the forest manager who produces an economic crop, for society that reaps the environmental benefits provided by forests, and...

Prevalence of virulence genes in Escherichia coli strains isolated from Romanian adult urinary tract infection cases.

PubMed

Usein, C R; Damian, M; Tatu-Chitoiu, D; Capusa, C; Fagaras, R; Tudorache, D; Nica, M; Le Bouguénec, C

2001-01-01

A total of 78 E. coli strains isolated from adults with different types of urinary tract infections were screened by polymerase chain reaction for prevalence of genetic regions coding for virulence factors. The targeted genetic determinants were those coding for type 1 fimbriae (fimH), pili associated with pyelonephritis (pap), S and F1C fimbriae (sfa and foc), afimbrial adhesins (afa), hemolysin (hly), cytotoxic necrotizing factor (cnf), aerobactin (aer). Among the studied strains, the prevalence of genes coding for fimbrial adhesive systems was 86%, 36%, and 23% for fimH, pap, and sfa/foc,respectively. The operons coding for Afa afimbrial adhesins were identified in 14% of strains. The hly and cnf genes coding for toxins were amplified in 23% and 13% of strains, respectively. A prevalence of 54% was found for the aer gene. The various combinations of detected genes were designated as virulence patterns. The strains isolated from the hospitalized patients displayed a greater number of virulence genes and a diversity of gene associations compared to the strains isolated from the ambulatory subjects. A rapid assessment of the bacterial pathogenicity characteristics may contribute to a better medical approach of the patients with urinary tract infections.

Learning about the Benetic Code via Programming: Representing the Process of Translation.

ERIC Educational Resources Information Center

Ploger, Don

1991-01-01

This study examined the representations that a 16-year-old student made using the flexible computer system, "Boxer," in learning the genetic code. Results indicated that programing made it easier to build and explore flexible and useful representations and encouraged interdisciplinary collaboration between mathematics and biology…

Theory of epigenetic coding.

PubMed

Elder, D

1984-06-07

The logic of genetic control of development may be based on a binary epigenetic code. This paper revises the author's previous scheme dealing with the numerology of annelid metamerism in these terms. Certain features of the code had been deduced to be combinatorial, others not. This paradoxical contrast is resolved here by the interpretation that these features relate to different operations of the code; the combinatiorial to coding identity of units, the non-combinatorial to coding production of units. Consideration of a second paradox in the theory of epigenetic coding leads to a new solution which further provides a basis for epimorphic regeneration, and may in particular throw light on the "regeneration-duplication" phenomenon. A possible test of the model is also put forward.

Heuristic rules embedded genetic algorithm for in-core fuel management optimization

NASA Astrophysics Data System (ADS)

Alim, Fatih

The objective of this study was to develop a unique methodology and a practical tool for designing loading pattern (LP) and burnable poison (BP) pattern for a given Pressurized Water Reactor (PWR) core. Because of the large number of possible combinations for the fuel assembly (FA) loading in the core, the design of the core configuration is a complex optimization problem. It requires finding an optimal FA arrangement and BP placement in order to achieve maximum cycle length while satisfying the safety constraints. Genetic Algorithms (GA) have been already used to solve this problem for LP optimization for both PWR and Boiling Water Reactor (BWR). The GA, which is a stochastic method works with a group of solutions and uses random variables to make decisions. Based on the theories of evaluation, the GA involves natural selection and reproduction of the individuals in the population for the next generation. The GA works by creating an initial population, evaluating it, and then improving the population by using the evaluation operators. To solve this optimization problem, a LP optimization package, GARCO (Genetic Algorithm Reactor Code Optimization) code is developed in the framework of this thesis. This code is applicable for all types of PWR cores having different geometries and structures with an unlimited number of FA types in the inventory. To reach this goal, an innovative GA is developed by modifying the classical representation of the genotype. To obtain the best result in a shorter time, not only the representation is changed but also the algorithm is changed to use in-core fuel management heuristics rules. The improved GA code was tested to demonstrate and verify the advantages of the new enhancements. The developed methodology is explained in this thesis and preliminary results are shown for the VVER-1000 reactor hexagonal geometry core and the TMI-1 PWR. The improved GA code was tested to verify the advantages of new enhancements. The core physics code used for VVER in this research is Moby-Dick, which was developed to analyze the VVER by SKODA Inc. The SIMULATE-3 code, which is an advanced two-group nodal code, is used to analyze the TMI-1.

Privacy rules for DNA databanks. Protecting coded 'future diaries'.

PubMed

Annas, G J

1993-11-17

In privacy terms, genetic information is like medical information. But the information contained in the DNA molecule itself is more sensitive because it contains an individual's probabilistic "future diary," is written in a code that has only partially been broken, and contains information about an individual's parents, siblings, and children. Current rules for protecting the privacy of medical information cannot protect either genetic information or identifiable DNA samples stored in DNA databanks. A review of the legal and public policy rationales for protecting genetic privacy suggests that specific enforceable privacy rules for DNA databanks are needed. Four preliminary rules are proposed to govern the creation of DNA databanks, the collection of DNA samples for storage, limits on the use of information derived from the samples, and continuing obligations to those whose DNA samples are in the databanks.

SEQassembly: A Practical Tools Program for Coding Sequences Splicing

NASA Astrophysics Data System (ADS)

Lee, Hongbin; Yang, Hang; Fu, Lei; Qin, Long; Li, Huili; He, Feng; Wang, Bo; Wu, Xiaoming

CDS (Coding Sequences) is a portion of mRNA sequences, which are composed by a number of exon sequence segments. The construction of CDS sequence is important for profound genetic analysis such as genotyping. A program in MATLAB environment is presented, which can process batch of samples sequences into code segments under the guide of reference exon models, and splice these code segments of same sample source into CDS according to the exon order in queue file. This program is useful in transcriptional polymorphism detection and gene function study.

Teaching Molecular Biology with Microcomputers.

ERIC Educational Resources Information Center

Reiss, Rebecca; Jameson, David

1984-01-01

Describes a series of computer programs that use simulation and gaming techniques to present the basic principles of the central dogma of molecular genetics, mutation, and the genetic code. A history of discoveries in molecular biology is presented and the evolution of these computer assisted instructional programs is described. (MBR)

Lactate racemase is a nickel-dependent enzyme activated by a widespread maturation system

PubMed Central

Desguin, Benoît; Goffin, Philippe; Viaene, Eric; Kleerebezem, Michiel; Martin-Diaconescu, Vlad; Maroney, Michael J; Declercq, Jean-Paul; Soumillion, Patrice; Hols, Pascal

2014-01-01

Racemases catalyze the inversion of stereochemistry in biological molecules, giving the organism the ability to use both isomers. Among them, lactate racemase remains unexplored due to its intrinsic instability and lack of molecular characterization. Here we determine the genetic basis of lactate racemization in Lactobacillus plantarum. We show that, unexpectedly, the racemase is a nickel-dependent enzyme with a novel α/β fold. In addition, we decipher the process leading to an active enzyme, which involves the activation of the apo-enzyme by a single nickel-containing maturation protein that requires preactivation by two other accessory proteins. Genomic investigations reveal the wide distribution of the lactate racemase system among prokaryotes, showing the high significance of both lactate enantiomers in carbon metabolism. The even broader distribution of the nickel-based maturation system suggests a function beyond activation of the lactate racemase and possibly linked with other undiscovered nickel-dependent enzymes. PMID:24710389

Germline Transgenic Methods for Tracking Cells and Testing Gene Function during Regeneration in the Axolotl

PubMed Central

Khattak, Shahryar; Schuez, Maritta; Richter, Tobias; Knapp, Dunja; Haigo, Saori L.; Sandoval-Guzmán, Tatiana; Hradlikova, Kristyna; Duemmler, Annett; Kerney, Ryan; Tanaka, Elly M.

2013-01-01

The salamander is the only tetrapod that regenerates complex body structures throughout life. Deciphering the underlying molecular processes of regeneration is fundamental for regenerative medicine and developmental biology, but the model organism had limited tools for molecular analysis. We describe a comprehensive set of germline transgenic strains in the laboratory-bred salamander Ambystoma mexicanum (axolotl) that open up the cellular and molecular genetic dissection of regeneration. We demonstrate tissue-dependent control of gene expression in nerve, Schwann cells, oligodendrocytes, muscle, epidermis, and cartilage. Furthermore, we demonstrate the use of tamoxifen-induced Cre/loxP-mediated recombination to indelibly mark different cell types. Finally, we inducibly overexpress the cell-cycle inhibitor p16INK4a, which negatively regulates spinal cord regeneration. These tissue-specific germline axolotl lines and tightly inducible Cre drivers and LoxP reporter lines render this classical regeneration model molecularly accessible. PMID:24052945

PPL2ab neurons restore sexual responses in aged Drosophila males through dopamine.

PubMed

Kuo, Shu-Yun; Wu, Chia-Lin; Hsieh, Min-Yen; Lin, Chen-Ta; Wen, Rong-Kun; Chen, Lien-Cheng; Chen, Yu-Hui; Yu, Yhu-Wei; Wang, Horng-Dar; Su, Yi-Ju; Lin, Chun-Ju; Yang, Cian-Yi; Guan, Hsien-Yu; Wang, Pei-Yu; Lan, Tsuo-Hung; Fu, Tsai-Feng

2015-06-30

Male sexual desire typically declines with ageing. However, our understanding of the neurobiological basis for this phenomenon is limited by our knowledge of the brain circuitry and neuronal pathways controlling male sexual desire. A number of studies across species suggest that dopamine (DA) affects sexual desire. Here we use genetic tools and behavioural assays to identify a novel subset of DA neurons that regulate age-associated male courtship activity in Drosophila. We find that increasing DA levels in a subset of cells in the PPL2ab neuronal cluster is necessary and sufficient for increased sustained courtship in both young and aged male flies. Our results indicate that preventing the age-related decline in DA levels in PPL2ab neurons alleviates diminished courtship behaviours in male Drosophila. These results may provide the foundation for deciphering the circuitry involved in sexual motivation in the male Drosophila brain.

Activation of IRF1 in Human Adipocytes Leads to Phenotypes Associated with Metabolic Disease.

PubMed

Friesen, Max; Camahort, Raymond; Lee, Youn-Kyoung; Xia, Fang; Gerszten, Robert E; Rhee, Eugene P; Deo, Rahul C; Cowan, Chad A

2017-05-09

The striking rise of obesity-related metabolic disorders has focused attention on adipocytes as critical mediators of disease phenotypes. To better understand the role played by excess adipose in metabolic dysfunction it is crucial to decipher the transcriptional underpinnings of the low-grade adipose inflammation characteristic of diseases such as type 2 diabetes. Through employing a comparative transcriptomics approach, we identified IRF1 as differentially regulated between primary and in vitro-derived genetically matched adipocytes. This suggests a role as a mediator of adipocyte inflammatory phenotypes, similar to its function in other tissues. Utilizing adipose-derived mesenchymal progenitors we subsequently demonstrated that expression of IRF1 in adipocytes indeed contributes to upregulation of inflammatory processes, both in vitro and in vivo. This highlights IRF1's relevance to obesity-related inflammation and the resultant metabolic dysregulation. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

NKX2-5 regulates human cardiomyogenesis via a HEY2 dependent transcriptional network.

PubMed

Anderson, David J; Kaplan, David I; Bell, Katrina M; Koutsis, Katerina; Haynes, John M; Mills, Richard J; Phelan, Dean G; Qian, Elizabeth L; Leitoguinho, Ana Rita; Arasaratnam, Deevina; Labonne, Tanya; Ng, Elizabeth S; Davis, Richard P; Casini, Simona; Passier, Robert; Hudson, James E; Porrello, Enzo R; Costa, Mauro W; Rafii, Arash; Curl, Clare L; Delbridge, Lea M; Harvey, Richard P; Oshlack, Alicia; Cheung, Michael M; Mummery, Christine L; Petrou, Stephen; Elefanty, Andrew G; Stanley, Edouard G; Elliott, David A

2018-04-10

Congenital heart defects can be caused by mutations in genes that guide cardiac lineage formation. Here, we show deletion of NKX2-5, a critical component of the cardiac gene regulatory network, in human embryonic stem cells (hESCs), results in impaired cardiomyogenesis, failure to activate VCAM1 and to downregulate the progenitor marker PDGFRα. Furthermore, NKX2-5 null cardiomyocytes have abnormal physiology, with asynchronous contractions and altered action potentials. Molecular profiling and genetic rescue experiments demonstrate that the bHLH protein HEY2 is a key mediator of NKX2-5 function during human cardiomyogenesis. These findings identify HEY2 as a novel component of the NKX2-5 cardiac transcriptional network, providing tangible evidence that hESC models can decipher the complex pathways that regulate early stage human heart development. These data provide a human context for the evaluation of pathogenic mutations in congenital heart disease.

Epigenetic regulation of female puberty.

PubMed

Lomniczi, Alejandro; Wright, Hollis; Ojeda, Sergio R

2015-01-01

Substantial progress has been made in recent years toward deciphering the molecular and genetic underpinnings of the pubertal process. The availability of powerful new methods to interrogate the human genome has led to the identification of genes that are essential for puberty to occur. Evidence has also emerged suggesting that the initiation of puberty requires the coordinated activity of gene sets organized into functional networks. At a cellular level, it is currently thought that loss of transsynaptic inhibition, accompanied by an increase in excitatory inputs, results in the pubertal activation of GnRH release. This concept notwithstanding, a mechanism of epigenetic repression targeting genes required for the pubertal activation of GnRH neurons was recently identified as a core component of the molecular machinery underlying the central restraint of puberty. In this chapter we will discuss the potential contribution of various mechanisms of epigenetic regulation to the hypothalamic control of female puberty. Copyright © 2014 Elsevier Inc. All rights reserved.

[Epigenetics in atherosclerosis].

PubMed

Guardiola, Montse; Vallvé, Joan C; Zaina, Silvio; Ribalta, Josep

2016-01-01

The association studies based on candidate genes carried on for decades have helped in visualizing the influence of the genetic component in complex diseases such as atherosclerosis, also showing the interaction between different genes and environmental factors. Even with all the knowledge accumulated, there is still some way to go to decipher the individual predisposition to disease, and if we consider the great influence that environmental factors play in the development and progression of atherosclerosis, epigenetics is presented as a key element in trying to expand our knowledge on individual predisposition to atherosclerosis and cardiovascular disease. Epigenetics can be described as the discipline that studies the mechanisms of transcriptional regulation, independent of changes in the sequence of DNA, and mostly induced by environmental factors. This review aims to describe what epigenetics is and how epigenetic mechanisms are involved in atherosclerosis. Copyright © 2015 Sociedad Española de Arteriosclerosis. Published by Elsevier España. All rights reserved.

FRET imaging and in silico simulation: analysis of the signaling network of nerve growth factor-induced neuritogenesis.

PubMed

Nakamura, Takeshi; Aoki, Kazuhiro; Matsuda, Michiyuki

2008-08-01

Genetically encoded probes based on Förster resonance energy transfer (FRET) enable us to decipher spatiotemporal information encoded in complex tissues such as the brain. Firstly, this review focuses on FRET probes wherein both the donor and acceptor are fluorescence proteins and are incorporated into a single molecule, i.e. unimolecular probes. Advantages of these probes lie in their easy loading into cells, the simple acquisition of FRET images, and the clear evaluation of data. Next, we introduce our recent study which encompasses FRET imaging and in silico simulation. In nerve growth factor-induced neurite outgrowth in PC12 cells, we found positive and negative signaling feedback loops. We propose that these feedback loops determine neurite-budding sites. We would like to emphasize that it is now time to accelerate crossover research in neuroscience, optics, and computational biology.

Mapping Sub-Second Structure in Mouse Behavior

PubMed Central

Wiltschko, Alexander B.; Johnson, Matthew J.; Iurilli, Giuliano; Peterson, Ralph E.; Katon, Jesse M.; Pashkovski, Stan L.; Abraira, Victoria E.; Adams, Ryan P.; Datta, Sandeep Robert

2015-01-01

Summary Complex animal behaviors are likely built from simpler modules, but their systematic identification in mammals remains a significant challenge. Here we use depth imaging to show that three-dimensional (3D) mouse pose dynamics are structured at the sub-second timescale. Computational modeling of these fast dynamics effectively describes mouse behavior as a series of reused and stereotyped modules with defined transition probabilities. We demonstrate this combined 3D imaging and machine learning method can be used to unmask potential strategies employed by the brain to adapt to the environment, to capture both predicted and previously-hidden phenotypes caused by genetic or neural manipulations, and to systematically expose the global structure of behavior within an experiment. This work reveals that mouse body language is built from identifiable components and is organized in a predictable fashion; deciphering this language establishes an objective framework for characterizing the influence of environmental cues, genes and neural activity on behavior. PMID:26687221

Chemical tools to investigate mechanisms associated with HSP90 and HSP70 in disease

PubMed Central

Shrestha, Liza; Patel, Hardik J.; Chiosis, Gabriela

2016-01-01

The chaperome is a large and diverse protein machinery composed of chaperone proteins and a variety of helpers, such as the co-chaperones, folding enzymes and scaffolding and adapter proteins. Heat shock protein 90s and 70s (HSP90s and HSP70s), the most abundant chaperome members in human cells, are also the most complex. As we have learned to appreciate, their functions are context dependent and manifested through a variety of conformations that each recruit a subset of co-chaperone, scaffolding and folding proteins and which are further diversified by the post-translational modifications each carry, making their study through classic genetic and biochemical techniques quite a challenge. Chemical biology tools and techniques have been developed over the years to help decipher the complexities of the HSPs and this review will provide an overview of such efforts with focus on HSP90 and HSP70. PMID:26933742

Scientific rationality, uncertainty and the governance of human genetics: an interview study with researchers at deCODE genetics.

PubMed

Hjörleifsson, Stefán; Schei, Edvin

2006-07-01

Technology development in human genetics is fraught with uncertainty, controversy and unresolved moral issues, and industry scientists are sometimes accused of neglecting the implications of their work. The present study was carried out to elicit industry scientists' reflections on the relationship between commercial, scientific and ethical dimensions of present day genetics and the resources needed for robust governance of new technologies. Interviewing scientists of the company deCODE genetics in Iceland, we found that in spite of optimism, the informants revealed ambiguity and uncertainty concerning the use of human genetic technologies for the prevention of common diseases. They concurred that uncritical marketing of scientific success might cause exaggerated public expectations of health benefits from genetics, with the risk of backfiring and causing resistance to genetics in the population. On the other hand, the scientists did not address dilemmas arising from the commercial nature of their own employer. Although the scientists tended to describe public fear as irrational, they identified issues where scepticism might be well founded and explored examples where they, despite expert knowledge, held ambiguous or tentative personal views on the use of predictive genetic technologies. The rationality of science was not seen as sufficient to ensure beneficial governance of new technologies. The reflexivity and suspension of judgement demonstrated in the interviews exemplify productive features of moral deliberation in complex situations. Scientists should take part in dialogues concerning the governance of genetic technologies, acknowledge any vested interests, and use their expertise to highlight, not conceal the technical and moral complexity involved.

A novel neutron energy spectrum unfolding code using particle swarm optimization

NASA Astrophysics Data System (ADS)

Shahabinejad, H.; Sohrabpour, M.

2017-07-01

A novel neutron Spectrum Deconvolution using Particle Swarm Optimization (SDPSO) code has been developed to unfold the neutron spectrum from a pulse height distribution and a response matrix. The Particle Swarm Optimization (PSO) imitates the bird flocks social behavior to solve complex optimization problems. The results of the SDPSO code have been compared with those of the standard spectra and recently published Two-steps Genetic Algorithm Spectrum Unfolding (TGASU) code. The TGASU code have been previously compared with the other codes such as MAXED, GRAVEL, FERDOR and GAMCD and shown to be more accurate than the previous codes. The results of the SDPSO code have been demonstrated to match well with those of the TGASU code for both under determined and over-determined problems. In addition the SDPSO has been shown to be nearly two times faster than the TGASU code.

Deciphering Genome Content and Evolutionary Relationships of Isolates from the Fungus Magnaporthe oryzae Attacking Different Host Plants

PubMed Central

Chiapello, Hélène; Mallet, Ludovic; Guérin, Cyprien; Aguileta, Gabriela; Amselem, Joëlle; Kroj, Thomas; Ortega-Abboud, Enrique; Lebrun, Marc-Henri; Henrissat, Bernard; Gendrault, Annie; Rodolphe, François; Tharreau, Didier; Fournier, Elisabeth

2015-01-01

Deciphering the genetic bases of pathogen adaptation to its host is a key question in ecology and evolution. To understand how the fungus Magnaporthe oryzae adapts to different plants, we sequenced eight M. oryzae isolates differing in host specificity (rice, foxtail millet, wheat, and goosegrass), and one Magnaporthe grisea isolate specific of crabgrass. Analysis of Magnaporthe genomes revealed small variation in genome sizes (39–43 Mb) and gene content (12,283–14,781 genes) between isolates. The whole set of Magnaporthe genes comprised 14,966 shared families, 63% of which included genes present in all the nine M. oryzae genomes. The evolutionary relationships among Magnaporthe isolates were inferred using 6,878 single-copy orthologs. The resulting genealogy was mostly bifurcating among the different host-specific lineages, but was reticulate inside the rice lineage. We detected traces of introgression from a nonrice genome in the rice reference 70-15 genome. Among M. oryzae isolates and host-specific lineages, the genome composition in terms of frequencies of genes putatively involved in pathogenicity (effectors, secondary metabolism, cazome) was conserved. However, 529 shared families were found only in nonrice lineages, whereas the rice lineage possessed 86 specific families absent from the nonrice genomes. Our results confirmed that the host specificity of M. oryzae isolates was associated with a divergence between lineages without major gene flow and that, despite the strong conservation of gene families between lineages, adaptation to different hosts, especially to rice, was associated with the presence of a small number of specific gene families. All information was gathered in a public database (http://genome.jouy.inra.fr/gemo). PMID:26454013

The Use of Animal Models to Decipher Physiological and Neurobiological Alterations of Anorexia Nervosa Patients

PubMed Central

Méquinion, Mathieu; Chauveau, Christophe; Viltart, Odile

2015-01-01

Extensive studies were performed to decipher the mechanisms regulating feeding due to the worldwide obesity pandemy and its complications. The data obtained might be adapted to another disorder related to alteration of food intake, the restrictive anorexia nervosa. This multifactorial disease with a complex and unknown etiology is considered as an awful eating disorder since the chronic refusal to eat leads to severe, and sometimes, irreversible complications for the whole organism, until death. There is an urgent need to better understand the different aspects of the disease to develop novel approaches complementary to the usual psychological therapies. For this purpose, the use of pertinent animal models becomes a necessity. We present here the various rodent models described in the literature that might be used to dissect central and peripheral mechanisms involved in the adaptation to deficient energy supplies and/or the maintenance of physiological alterations on the long term. Data obtained from the spontaneous or engineered genetic models permit to better apprehend the implication of one signaling system (hormone, neuropeptide, neurotransmitter) in the development of several symptoms observed in anorexia nervosa. As example, mutations in the ghrelin, serotonin, dopamine pathways lead to alterations that mimic the phenotype, but compensatory mechanisms often occur rendering necessary the use of more selective gene strategies. Until now, environmental animal models based on one or several inducing factors like diet restriction, stress, or physical activity mimicked more extensively central and peripheral alterations decribed in anorexia nervosa. They bring significant data on feeding behavior, energy expenditure, and central circuit alterations. Animal models are described and criticized on the basis of the criteria of validity for anorexia nervosa. PMID:26042085

Deciphering the Routes of invasion of Drosophila suzukii by Means of ABC Random Forest.

PubMed

Fraimout, Antoine; Debat, Vincent; Fellous, Simon; Hufbauer, Ruth A; Foucaud, Julien; Pudlo, Pierre; Marin, Jean-Michel; Price, Donald K; Cattel, Julien; Chen, Xiao; Deprá, Marindia; François Duyck, Pierre; Guedot, Christelle; Kenis, Marc; Kimura, Masahito T; Loeb, Gregory; Loiseau, Anne; Martinez-Sañudo, Isabel; Pascual, Marta; Polihronakis Richmond, Maxi; Shearer, Peter; Singh, Nadia; Tamura, Koichiro; Xuéreb, Anne; Zhang, Jinping; Estoup, Arnaud

2017-04-01

Deciphering invasion routes from molecular data is crucial to understanding biological invasions, including identifying bottlenecks in population size and admixture among distinct populations. Here, we unravel the invasion routes of the invasive pest Drosophila suzukii using a multi-locus microsatellite dataset (25 loci on 23 worldwide sampling locations). To do this, we use approximate Bayesian computation (ABC), which has improved the reconstruction of invasion routes, but can be computationally expensive. We use our study to illustrate the use of a new, more efficient, ABC method, ABC random forest (ABC-RF) and compare it to a standard ABC method (ABC-LDA). We find that Japan emerges as the most probable source of the earliest recorded invasion into Hawaii. Southeast China and Hawaii together are the most probable sources of populations in western North America, which then in turn served as sources for those in eastern North America. European populations are genetically more homogeneous than North American populations, and their most probable source is northeast China, with evidence of limited gene flow from the eastern US as well. All introduced populations passed through bottlenecks, and analyses reveal five distinct admixture events. These findings can inform hypotheses concerning how this species evolved between different and independent source and invasive populations. Methodological comparisons indicate that ABC-RF and ABC-LDA show concordant results if ABC-LDA is based on a large number of simulated datasets but that ABC-RF out-performs ABC-LDA when using a comparable and more manageable number of simulated datasets, especially when analyzing complex introduction scenarios. © The Author 2017. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

Efficient targeted mutagenesis in the monarch butterfly using zinc-finger nucleases

PubMed Central

Merlin, Christine; Beaver, Lauren E.; Taylor, Orley R.; Wolfe, Scot A.; Reppert, Steven M.

2013-01-01

The development of reverse-genetic tools in “nonmodel” insect species with distinct biology is critical to establish them as viable model systems. The eastern North American monarch butterfly (Danaus plexippus), whose genome is sequenced, has emerged as a model to study animal clocks, navigational mechanisms, and the genetic basis of long-distance migration. Here, we developed a highly efficient gene-targeting approach in the monarch using zinc-finger nucleases (ZFNs), engineered nucleases that generate mutations at targeted genomic sequences. We focused our ZFN approach on targeting the type 2 vertebrate-like cryptochrome gene of the monarch (designated cry2), which encodes a putative transcriptional repressor of the monarch circadian clockwork. Co-injections of mRNAs encoding ZFNs targeting the second exon of monarch cry2 into “one nucleus” stage embryos led to high-frequency nonhomologous end-joining-mediated, mutagenic lesions in the germline (up to 50%). Heritable ZFN-induced lesions in two independent lines produced truncated, nonfunctional CRY2 proteins, resulting in the in vivo disruption of circadian behavior and the molecular clock mechanism. Our work genetically defines CRY2 as an essential transcriptional repressor of the monarch circadian clock and provides a proof of concept for the use of ZFNs for manipulating genes in the monarch butterfly genome. Importantly, this approach could be used in other lepidopterans and “nonmodel” insects, thus opening new avenues to decipher the molecular underpinnings of a variety of biological processes. PMID:23009861

Applications of a formal approach to decipher discrete genetic networks.

PubMed

Corblin, Fabien; Fanchon, Eric; Trilling, Laurent

2010-07-20

A growing demand for tools to assist the building and analysis of biological networks exists in systems biology. We argue that the use of a formal approach is relevant and applicable to address questions raised by biologists about such networks. The behaviour of these systems being complex, it is essential to exploit efficiently every bit of experimental information. In our approach, both the evolution rules and the partial knowledge about the structure and the behaviour of the network are formalized using a common constraint-based language. In this article our formal and declarative approach is applied to three biological applications. The software environment that we developed allows to specifically address each application through a new class of biologically relevant queries. We show that we can describe easily and in a formal manner the partial knowledge about a genetic network. Moreover we show that this environment, based on a constraint algorithmic approach, offers a wide variety of functionalities, going beyond simple simulations, such as proof of consistency, model revision, prediction of properties, search for minimal models relatively to specified criteria. The formal approach proposed here deeply changes the way to proceed in the exploration of genetic and biochemical networks, first by avoiding the usual trial-and-error procedure, and second by placing the emphasis on sets of solutions, rather than a single solution arbitrarily chosen among many others. Last, the constraint approach promotes an integration of model and experimental data in a single framework.

Differentially expressed genes during the imbibition of dormant and after-ripened seeds - a reverse genetics approach.

PubMed

Yazdanpanah, Farzaneh; Hanson, Johannes; Hilhorst, Henk W M; Bentsink, Leónie

2017-09-11

Seed dormancy, defined as the incapability of a viable seed to germinate under favourable conditions, is an important trait in nature and agriculture. Despite extensive research on dormancy and germination, many questions about the molecular mechanisms controlling these traits remain unanswered, likely due to its genetic complexity and the large environmental effects which are characteristic of these quantitative traits. To boost research towards revealing mechanisms in the control of seed dormancy and germination we depend on the identification of genes controlling those traits. We used transcriptome analysis combined with a reverse genetics approach to identify genes that are prominent for dormancy maintenance and germination in imbibed seeds of Arabidopsis thaliana. Comparative transcriptomics analysis was employed on freshly harvested (dormant) and after-ripened (AR; non-dormant) 24-h imbibed seeds of four different DELAY OF GERMINATION near isogenic lines (DOGNILs) and the Landsberg erecta (Ler) wild type with varying levels of primary dormancy. T-DNA knock-out lines of the identified genes were phenotypically investigated for their effect on dormancy and AR. We identified conserved sets of 46 and 25 genes which displayed higher expression in seeds of all dormant and all after-ripened DOGNILs and Ler, respectively. Knock-out mutants in these genes showed dormancy and germination related phenotypes. Most of the identified genes had not been implicated in seed dormancy or germination. This research will be useful to further decipher the molecular mechanisms by which these important ecological and commercial traits are regulated.

Detecting QTLs and putative candidate genes involved in budbreak and flowering time in an apple multiparental population

PubMed Central

Allard, Alix; Bink, Marco C.A.M.; Martinez, Sébastien; Kelner, Jean-Jacques; Legave, Jean-Michel; di Guardo, Mario; Di Pierro, Erica A.; Laurens, François; van de Weg, Eric W.; Costes, Evelyne

2016-01-01

In temperate trees, growth resumption in spring time results from chilling and heat requirements, and is an adaptive trait under global warming. Here, the genetic determinism of budbreak and flowering time was deciphered using five related full-sib apple families. Both traits were observed over 3 years and two sites and expressed in calendar and degree-days. Best linear unbiased predictors of genotypic effect or interaction with climatic year were extracted from mixed linear models and used for quantitative trait locus (QTL) mapping, performed with an integrated genetic map containing 6849 single nucleotide polymorphisms (SNPs), grouped into haplotypes, and with a Bayesian pedigree-based analysis. Four major regions, on linkage group (LG) 7, LG10, LG12, and LG9, the latter being the most stable across families, sites, and years, explained 5.6–21.3% of trait variance. Co-localizations for traits in calendar days or growing degree hours (GDH) suggested common genetic determinism for chilling and heating requirements. Homologs of two major flowering genes, AGL24 and FT, were predicted close to LG9 and LG12 QTLs, respectively, whereas Dormancy Associated MADs-box (DAM) genes were near additional QTLs on LG8 and LG15. This suggests that chilling perception mechanisms could be common among perennial and annual plants. Progenitors with favorable alleles depending on trait and LG were identified and could benefit new breeding strategies for apple adaptation to temperature increase. PMID:27034326

Evaluating Air Force Civil Engineer’s Current Automated Information Systems

DTIC Science & Technology

2002-03-26

started with identifying specific processes that needed to be accomplished. These processes were flowcharted and relationships were developed (31:1...Roofs) - Critical 1. Process not defined well enough per Ron Stoner to rework a. WPAFB to flowchart and decipher ACES process for SSG/AFCESA b...Ron Stoner to rework a. WPAFB to flowchart and decipher ACES process for SSG/AFCESA b. Investigate usage of ACES as is and define Needs 2. EEIC

Synthetic Genome Recoding: New genetic codes for new features

PubMed Central

Kuo, James; Stirling, Finn; Lau, Yu Heng; Shulgina, Yekaterina; Way, Jeffrey C.; Silver, Pamela A.

2018-01-01

Full genome recoding, or rewriting codon meaning, through chemical synthesis of entire bacterial chromosomes has become feasible in the past several years. Recoding an organism can impart new properties including non-natural amino acid incorporation, virus resistance, and biocontainment. The estimated cost of construction that includes DNA synthesis, assembly by recombination, and troubleshooting, is now comparable to costs of early stage development of drugs or other high-tech products. Here we discuss several recently published assembly methods and provide some thoughts on the future, including how synthetic efforts might benefit from analysis of natural recoding processes and organisms that use alternative genetic codes. PMID:28983660

Grain Propellant Optimization Using Real Code Genetic Algorithm (RCGA)

NASA Astrophysics Data System (ADS)

Farizi, Muhammad Farraz Al; Oktovianus Bura, Romie; Fajar Junjunan, Soleh; Jihad, Bagus H.

2018-04-01

Grain propellant design is important in rocket motor design. The total impulse and ISP of the rocket motor is influenced by the grain propellant design. One way to get a grain propellant shape that generates the maximum total impulse value is to use the Real Code Genetic Algorithm (RCGA) method. In this paper RCGA is applied to star grain Rx-450. To find burn area of propellant used analytical method. While the combustion chamber pressures are sought with zero-dimensional equations. The optimization result can reach the desired target and increase the total impulse value by 3.3% from the initial design of Rx-450.

Metabolic basis for the self-referential genetic code.

PubMed

Guimarães, Romeu Cardoso

2011-08-01

An investigation of the biosynthesis pathways producing glycine and serine was necessary to clarify an apparent inconsistency between the self-referential model (SRM) for the formation of the genetic code and the model of coevolution of encodings and of amino acid biosynthesis routes. According to the SRM proposal, glycine was the first amino acid encoded, followed by serine. The coevolution model does not state precisely which the first encodings were, only presenting a list of about ten early assignments including the derivation of glycine from serine-this being derived from the glycolysis intermediate glycerate, which reverses the order proposed by the self-referential model. Our search identified the glycine-serine pathway of syntheses based on one-carbon sources, involving activities of the glycine decarboxylase complex and its associated serine hydroxymethyltransferase, which is consistent with the order proposed by the self-referential model and supports its rationale for the origin of the genetic code: protein synthesis was developed inside an early metabolic system, serving the function of a sink of amino acids; the first peptides were glycine-rich and fit for the function of building the early ribonucleoproteins; glycine consumption in proteins drove the fixation of the glycine-serine pathway.

Supporting Students' Knowledge Transfer in Modeling Activities

ERIC Educational Resources Information Center

Piksööt, Jaanika; Sarapuu, Tago

2014-01-01

This study investigates ways to enhance secondary school students' knowledge transfer in complex science domains by implementing question prompts. Two samples of students applied two web-based models to study molecular genetics--the model of genetic code (n = 258) and translation (n = 245). For each model, the samples were randomly divided into…

Using Economics and Genetics To Produce Leaner Pork.

ERIC Educational Resources Information Center

Welch, Mary A., Ed.

1994-01-01

The booklet describes the STAGES (Swine Testing and Genetic Evaluation System) program developed at Purdue University (Indiana), along with the USDA, National Pork Producers Council and swine breed associations. By selecting breeding stock from a coded catalogue developed by STAGES, producers are able to select the best breeding stock for more…

An Inquiry Activity for Genetics Using Chromosome Mapping.

ERIC Educational Resources Information Center

Leonard, William H.; Snodgrass, George

1982-01-01

Concepts to be developed, objectives, and student instructions are provided for an activity useful as an introduction to or review of Mendelian genetics and sex determination. Universal codes (read by optical scanners at supermarket checkout stands) from soup can labels are used as chromosome maps during the activity. (JN)

Recent evidence for evolution of the genetic code

NASA Technical Reports Server (NTRS)

Osawa, S.; Jukes, T. H.; Watanabe, K.; Muto, A.

1992-01-01

The genetic code, formerly thought to be frozen, is now known to be in a state of evolution. This was first shown in 1979 by Barrell et al. (G. Barrell, A. T. Bankier, and J. Drouin, Nature [London] 282:189-194, 1979), who found that the universal codons AUA (isoleucine) and UGA (stop) coded for methionine and tryptophan, respectively, in human mitochondria. Subsequent studies have shown that UGA codes for tryptophan in Mycoplasma spp. and in all nonplant mitochondria that have been examined. Universal stop codons UAA and UAG code for glutamine in ciliated protozoa (except Euplotes octacarinatus) and in a green alga, Acetabularia. E. octacarinatus uses UAA for stop and UGA for cysteine. Candida species, which are yeasts, use CUG (leucine) for serine. Other departures from the universal code, all in nonplant mitochondria, are CUN (leucine) for threonine (in yeasts), AAA (lysine) for asparagine (in platyhelminths and echinoderms), UAA (stop) for tyrosine (in planaria), and AGR (arginine) for serine (in several animal orders) and for stop (in vertebrates). We propose that the changes are typically preceded by loss of a codon from all coding sequences in an organism or organelle, often as a result of directional mutation pressure, accompanied by loss of the tRNA that translates the codon. The codon reappears later by conversion of another codon and emergence of a tRNA that translates the reappeared codon with a different assignment. Changes in release factors also contribute to these revised assignments. We also discuss the use of UGA (stop) as a selenocysteine codon and the early history of the code.

Population genetic evidence for speciation pattern and gene flow between Picea wilsonii, P. morrisonicola and P. neoveitchii

PubMed Central

Zou, Jiabin; Sun, Yongshuai; Li, Long; Wang, Gaini; Yue, Wei; Lu, Zhiqiang; Wang, Qian; Liu, Jianquan

2013-01-01

Background and Aims Genetic drift due to geographical isolation, gene flow and mutation rates together make it difficult to determine the evolutionary relationships of present-day species. In this study, population genetic data were used to model and decipher interspecific relationships, speciation patterns and gene flow between three species of spruce with similar morphology, Picea wilsonii, P. neoveitchii and P. morrisonicola. Picea wilsonii and P. neoveitchii occur from central to north-west China, where they have overlapping distributions. Picea morrisonicola, however, is restricted solely to the island of Taiwan and is isolated from the other two species by a long distance. Methods Sequence variations were examined in 18 DNA fragments for 22 populations, including three fragments from the chloroplast (cp) genome, two from the mitochondrial (mt) genome and 13 from the nuclear genome. Key Results In both the cpDNA and the mtDNA, P. morrisonicola accumulated more species-specific mutations than the other two species. However, most nuclear haplotypes of P. morrisonicola were shared by P. wilsonii, or derived from the dominant haplotypes found in that species. Modelling of population genetic data supported the hypothesis that P. morrisonicola derived from P. wilsonii within the more recent past, most probably indicating progenitor–derivative speciation with a distinct bottleneck, although further gene flow from the progenitor to the derivative continued. In addition, the occurrence was detected of an obvious mtDNA introgression from P. neoveitchii to P. wilsonii despite their early divergence. Conclusions The extent of mutation, introgression and lineage sorting taking place during interspecific divergence and demographic changes in the three species had varied greatly between the three genomes. The findings highlight the complex evolutionary histories of these three Asian spruce species. PMID:24220103

Genetics of human epilepsies: Continuing progress.

PubMed

Szepetowski, Pierre

2018-03-01

Numerous epilepsy genes have been identified in the last years, mostly in the (rare) monogenic forms and thanks to the increased availability and the decreased cost of next-generation sequencing approaches. Besides the somehow expected group of epilepsy genes encoding various ion channel subunits (e.g. sodium or potassium channel subunits, or GABA receptors, or glutamate-gated NMDA receptors), more diversity has emerged recently, with novel epilepsy genes encoding proteins playing a wide range of physiological roles at the cellular and molecular levels, such as synaptic proteins, members of the mTOR pathway, or proteins involved in chromatin remodeling. The overall picture is somehow complicated: one given epilepsy gene can be associated with more than one epileptic phenotype, and with variable degrees of severity, from the benign to the severe forms (e.g. epileptic encephalopathies), and with various comorbid conditions such as migraine or autism spectrum of disorders. Conversely, one given epileptic syndrome may be associated with different genes, some of which have obvious links with each other (e.g. encoding different subunits of the same receptor) while other ones have no clear relationships. Also genomic copy number variations have been detected, some of which, albeit rare, may confer high risk to epilepsy. Whereas translation from gene identification to targeted medicine still remains challenging, progress in epilepsy genetics is currently revolutionizing genetic-based diagnosis and genetic counseling. Epilepsy gene identification also represents a key entry point to start in deciphering the underlying pathophysiological mechanisms via the design and the study of the most pertinent cellular and animal models - which may in turn provide proofs-of-principle for future applications in human epilepsies. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Revealing the selection history of adaptive loci using genome-wide scans for selection: an example from domestic sheep.

PubMed

Rochus, Christina Marie; Tortereau, Flavie; Plisson-Petit, Florence; Restoux, Gwendal; Moreno-Romieux, Carole; Tosser-Klopp, Gwenola; Servin, Bertrand

2018-01-23

One of the approaches to detect genetics variants affecting fitness traits is to identify their surrounding genomic signatures of past selection. With established methods for detecting selection signatures and the current and future availability of large datasets, such studies should have the power to not only detect these signatures but also to infer their selective histories. Domesticated animals offer a powerful model for these approaches as they adapted rapidly to environmental and human-mediated constraints in a relatively short time. We investigated this question by studying a large dataset of 542 individuals from 27 domestic sheep populations raised in France, genotyped for more than 500,000 SNPs. Population structure analysis revealed that this set of populations harbour a large part of European sheep diversity in a small geographical area, offering a powerful model for the study of adaptation. Identification of extreme SNP and haplotype frequency differences between populations listed 126 genomic regions likely affected by selection. These signatures revealed selection at loci commonly identified as selection targets in many species ("selection hotspots") including ABCG2, LCORL/NCAPG, MSTN, and coat colour genes such as ASIP, MC1R, MITF, and TYRP1. For one of these regions (ABCG2, LCORL/NCAPG), we could propose a historical scenario leading to the introgression of an adaptive allele into a new genetic background. Among selection signatures, we found clear evidence for parallel selection events in different genetic backgrounds, most likely for different mutations. We confirmed this allelic heterogeneity in one case by resequencing the MC1R gene in three black-faced breeds. Our study illustrates how dense genetic data in multiple populations allows the deciphering of evolutionary history of populations and of their adaptive mutations.

Common Genetic Variants Associated with Resting Oxygenation in Chronic Obstructive Pulmonary Disease

PubMed Central

Cho, Michael H.; Sørheim, Inga-Cecilie; Lutz, Sharon M.; Castaldi, Peter J.; Lomas, David A.; Coxson, Harvey O.; Edwards, Lisa D.; MacNee, William; Vestbo, Jørgen; Yates, Julie C.; Agusti, Alvar; Calverley, Peter M. A.; Celli, Bartolome; Crim, Courtney; Rennard, Stephen I.; Wouters, Emiel F. M.; Bakke, Per; Tal-Singer, Ruth; Miller, Bruce E.; Gulsvik, Amund; Casaburi, Richard; Wells, J. Michael; Regan, Elizabeth A.; Make, Barry J.; Hokanson, John E.; Lange, Christoph; Crapo, James D.; Beaty, Terri H.; Silverman, Edwin K.; Hersh, Craig P.

2014-01-01

Hypoxemia is a major complication of chronic obstructive pulmonary disease (COPD) that correlates with disease prognosis. Identifying genetic variants associated with oxygenation may provide clues for deciphering the heterogeneity in prognosis among patients with COPD. However, previous genetic studies have been restricted to investigating COPD candidate genes for association with hypoxemia. To report results from the first genome-wide association study (GWAS) of resting oxygen saturation (as measured by pulse oximetry [Spo2]) in subjects with COPD, we performed a GWAS of Spo2 in two large, well characterized COPD populations: COPDGene, including both the non-Hispanic white (NHW) and African American (AA) groups, and Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE). We identified several suggestive loci (P < 1 × 10−5) associated with Spo2 in COPDGene in the NHW (n = 2810) and ECLIPSE (n = 1758) groups, and two loci on chromosomes 14 and 15 in the AA group (n = 820) from COPDGene achieving a level of genome-wide significance (P < 5 × 10−8). The chromosome 14 single-nucleotide polymorphism, rs6576132, located in an intergenic region, was nominally replicated (P < 0.05) in the NHW group from COPDGene. The chromosome 15 single-nucleotide polymorphisms were rare in subjects of European ancestry, so the results could not be replicated. The chromosome 15 region contains several genes, including TICRR and KIF7, and is proximal to RHCG (Rh family C glyocoprotein gene). We have identified two loci associated with resting oxygen saturation in AA subjects with COPD, and several suggestive regions in subjects of European descent with COPD. Our study highlights the importance of investigating the genetics of complex traits in different racial groups. PMID:24825563

Common genetic variants associated with resting oxygenation in chronic obstructive pulmonary disease.

PubMed

McDonald, Merry-Lynn N; Cho, Michael H; Sørheim, Inga-Cecilie; Lutz, Sharon M; Castaldi, Peter J; Lomas, David A; Coxson, Harvey O; Edwards, Lisa D; MacNee, William; Vestbo, Jørgen; Yates, Julie C; Agusti, Alvar; Calverley, Peter M A; Celli, Bartolome; Crim, Courtney; Rennard, Stephen I; Wouters, Emiel F M; Bakke, Per; Tal-Singer, Ruth; Miller, Bruce E; Gulsvik, Amund; Casaburi, Richard; Wells, J Michael; Regan, Elizabeth A; Make, Barry J; Hokanson, John E; Lange, Christoph; Crapo, James D; Beaty, Terri H; Silverman, Edwin K; Hersh, Craig P

2014-11-01

Hypoxemia is a major complication of chronic obstructive pulmonary disease (COPD) that correlates with disease prognosis. Identifying genetic variants associated with oxygenation may provide clues for deciphering the heterogeneity in prognosis among patients with COPD. However, previous genetic studies have been restricted to investigating COPD candidate genes for association with hypoxemia. To report results from the first genome-wide association study (GWAS) of resting oxygen saturation (as measured by pulse oximetry [Spo2]) in subjects with COPD, we performed a GWAS of Spo2 in two large, well characterized COPD populations: COPDGene, including both the non-Hispanic white (NHW) and African American (AA) groups, and Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE). We identified several suggestive loci (P < 1 × 10(-5)) associated with Spo2 in COPDGene in the NHW (n = 2810) and ECLIPSE (n = 1758) groups, and two loci on chromosomes 14 and 15 in the AA group (n = 820) from COPDGene achieving a level of genome-wide significance (P < 5 × 10(-8)). The chromosome 14 single-nucleotide polymorphism, rs6576132, located in an intergenic region, was nominally replicated (P < 0.05) in the NHW group from COPDGene. The chromosome 15 single-nucleotide polymorphisms were rare in subjects of European ancestry, so the results could not be replicated. The chromosome 15 region contains several genes, including TICRR and KIF7, and is proximal to RHCG (Rh family C glyocoprotein gene). We have identified two loci associated with resting oxygen saturation in AA subjects with COPD, and several suggestive regions in subjects of European descent with COPD. Our study highlights the importance of investigating the genetics of complex traits in different racial groups.

The developmental genetics of biological robustness

PubMed Central

Mestek Boukhibar, Lamia; Barkoulas, Michalis

2016-01-01

Background Living organisms are continuously confronted with perturbations, such as environmental changes that include fluctuations in temperature and nutrient availability, or genetic changes such as mutations. While some developmental systems are affected by such challenges and display variation in phenotypic traits, others continue consistently to produce invariable phenotypes despite perturbation. This ability of a living system to maintain an invariable phenotype in the face of perturbations is termed developmental robustness. Biological robustness is a phenomenon observed across phyla, and studying its mechanisms is central to deciphering the genotype–phenotype relationship. Recent work in yeast, animals and plants has shown that robustness is genetically controlled and has started to reveal the underlying mechinisms behind it. Scope and Conclusions Studying biological robustness involves focusing on an important property of developmental traits, which is the phenotypic distribution within a population. This is often neglected because the vast majority of developmental biology studies instead focus on population aggregates, such as trait averages. By drawing on findings in animals and yeast, this Viewpoint considers how studies on plant developmental robustness may benefit from strict definitions of what is the developmental system of choice and what is the relevant perturbation, and also from clear distinctions between gene effects on the trait mean and the trait variance. Recent advances in quantitative developmental biology and high-throughput phenotyping now allow the design of targeted genetic screens to identify genes that amplify or restrict developmental trait variance and to study how variation propagates across different phenotypic levels in biological systems. The molecular characterization of more quantitative trait loci affecting trait variance will provide further insights into the evolution of genes modulating developmental robustness. The study of robustness mechanisms in closely related species will address whether mechanisms of robustness are evolutionarily conserved. PMID:26292993

A Recurrent De Novo PACS2 Heterozygous Missense Variant Causes Neonatal-Onset Developmental Epileptic Encephalopathy, Facial Dysmorphism, and Cerebellar Dysgenesis.

PubMed

Olson, Heather E; Jean-Marçais, Nolwenn; Yang, Edward; Heron, Delphine; Tatton-Brown, Katrina; van der Zwaag, Paul A; Bijlsma, Emilia K; Krock, Bryan L; Backer, E; Kamsteeg, Erik-Jan; Sinnema, Margje; Reijnders, Margot R F; Bearden, David; Begtrup, Amber; Telegrafi, Aida; Lunsing, Roelineke J; Burglen, Lydie; Lesca, Gaetan; Cho, Megan T; Smith, Lacey A; Sheidley, Beth R; Moufawad El Achkar, Christelle; Pearl, Phillip L; Poduri, Annapurna; Skraban, Cara M; Tarpinian, Jennifer; Nesbitt, Addie I; Fransen van de Putte, Dietje E; Ruivenkamp, Claudia A L; Rump, Patrick; Chatron, Nicolas; Sabatier, Isabelle; De Bellescize, Julitta; Guibaud, Laurent; Sweetser, David A; Waxler, Jessica L; Wierenga, Klaas J; Donadieu, Jean; Narayanan, Vinodh; Ramsey, Keri M; Nava, Caroline; Rivière, Jean-Baptiste; Vitobello, Antonio; Tran Mau-Them, Frédéric; Philippe, Christophe; Bruel, Ange-Line; Duffourd, Yannis; Thomas, Laurel; Lelieveld, Stefan H; Schuurs-Hoeijmakers, Janneke; Brunner, Han G; Keren, Boris; Thevenon, Julien; Faivre, Laurence; Thomas, Gary; Thauvin-Robinet, Christel

2018-05-03

Developmental and epileptic encephalopathies (DEEs) represent a large clinical and genetic heterogeneous group of neurodevelopmental diseases. The identification of pathogenic genetic variants in DEEs remains crucial for deciphering this complex group and for accurately caring for affected individuals (clinical diagnosis, genetic counseling, impacting medical, precision therapy, clinical trials, etc.). Whole-exome sequencing and intensive data sharing identified a recurrent de novo PACS2 heterozygous missense variant in 14 unrelated individuals. Their phenotype was characterized by epilepsy, global developmental delay with or without autism, common cerebellar dysgenesis, and facial dysmorphism. Mixed focal and generalized epilepsy occurred in the neonatal period, controlled with difficulty in the first year, but many improved in early childhood. PACS2 is an important PACS1 paralog and encodes a multifunctional sorting protein involved in nuclear gene expression and pathway traffic regulation. Both proteins harbor cargo(furin)-binding regions (FBRs) that bind cargo proteins, sorting adaptors, and cellular kinase. Compared to the defined PACS1 recurrent variant series, individuals with PACS2 variant have more consistently neonatal/early-infantile-onset epilepsy that can be challenging to control. Cerebellar abnormalities may be similar but PACS2 individuals exhibit a pattern of clear dysgenesis ranging from mild to severe. Functional studies demonstrated that the PACS2 recurrent variant reduces the ability of the predicted autoregulatory domain to modulate the interaction between the PACS2 FBR and client proteins, which may disturb cellular function. These findings support the causality of this recurrent de novo PACS2 heterozygous missense in DEEs with facial dysmorphim and cerebellar dysgenesis. Copyright © 2018 American Society of Human Genetics. All rights reserved.