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

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.

Numeral series hidden in the distribution of atomic mass of amino acids to codon domains in the genetic code.

PubMed

Wohlin, Åsa

2015-03-21

The distribution of codons in the nearly universal genetic code is a long discussed issue. At the atomic level, the numeral series 2x(2) (x=5-0) lies behind electron shells and orbitals. Numeral series appear in formulas for spectral lines of hydrogen. The question here was if some similar scheme could be found in the genetic code. A table of 24 codons was constructed (synonyms counted as one) for 20 amino acids, four of which have two different codons. An atomic mass analysis was performed, built on common isotopes. It was found that a numeral series 5 to 0 with exponent 2/3 times 10(2) revealed detailed congruency with codon-grouped amino acid side-chains, simultaneously with the division on atom kinds, further with main 3rd base groups, backbone chains and with codon-grouped amino acids in relation to their origin from glycolysis or the citrate cycle. Hence, it is proposed that this series in a dynamic way may have guided the selection of amino acids into codon domains. Series with simpler exponents also showed noteworthy correlations with the atomic mass distribution on main codon domains; especially the 2x(2)-series times a factor 16 appeared as a conceivable underlying level, both for the atomic mass and charge distribution. Furthermore, it was found that atomic mass transformations between numeral systems, possibly interpretable as dimension degree steps, connected the atomic mass of codon bases with codon-grouped amino acids and with the exponent 2/3-series in several astonishing ways. Thus, it is suggested that they may be part of a deeper reference system. Copyright © 2015 The Author. Published by Elsevier Ltd.. All rights reserved.

A role for the Fas/FasL system in modulating genetic susceptibility to T-cell lymphoblastic lymphomas.

PubMed

Villa-Morales, María; Santos, Javier; Pérez-Gómez, Eduardo; Quintanilla, Miguel; Fernández-Piqueras, José

2007-06-01

The Fas/FasL system mediates induced apoptosis of immature thymocytes and peripheral T lymphocytes, but little is known about its implication in genetic susceptibility to T-cell malignancies. In this article, we report that the expression of FasL increases early in all mice after gamma-radiation treatments, maintaining such high levels for a long time in mice that resisted tumor induction. However, its expression is practically absent in T-cell lymphoblastic lymphomas. Interestingly, there exist significant differences in the level of expression between two mice strains exhibiting extremely distinct susceptibilities that can be attributed to promoter functional polymorphisms. In addition, several functional nucleotide changes in the coding sequences of both Fas and FasL genes significantly affect their biological activity. These results lead us to propose that germ-line functional polymorphisms affecting either the levels of expression or the biological activity of both Fas and FasL genes could be contributing to the genetic risk to develop T-cell lymphoblastic lymphomas and support the use of radiotherapy as an adequate procedure to choose in the treatment of T-cell malignancies.

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.

Computational power and generative capacity of genetic systems.

PubMed

Igamberdiev, Abir U; Shklovskiy-Kordi, Nikita E

2016-01-01

Semiotic characteristics of genetic sequences are based on the general principles of linguistics formulated by Ferdinand de Saussure, such as the arbitrariness of sign and the linear nature of the signifier. Besides these semiotic features that are attributable to the basic structure of the genetic code, the principle of generativity of genetic language is important for understanding biological transformations. The problem of generativity in genetic systems arises to a possibility of different interpretations of genetic texts, and corresponds to what Alexander von Humboldt called "the infinite use of finite means". These interpretations appear in the individual development as the spatiotemporal sequences of realizations of different textual meanings, as well as the emergence of hyper-textual statements about the text itself, which underlies the process of biological evolution. These interpretations are accomplished at the level of the readout of genetic texts by the structures defined by Efim Liberman as "the molecular computer of cell", which includes DNA, RNA and the corresponding enzymes operating with molecular addresses. The molecular computer performs physically manifested mathematical operations and possesses both reading and writing capacities. Generativity paradoxically resides in the biological computational system as a possibility to incorporate meta-statements about the system, and thus establishes the internal capacity for its evolution. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

A Simple Test of Class-Level Genetic Association Can Reveal Novel Cardiometabolic Trait Loci.

PubMed

Qian, Jing; Nunez, Sara; Reed, Eric; Reilly, Muredach P; Foulkes, Andrea S

2016-01-01

Characterizing the genetic determinants of complex diseases can be further augmented by incorporating knowledge of underlying structure or classifications of the genome, such as newly developed mappings of protein-coding genes, epigenetic marks, enhancer elements and non-coding RNAs. We apply a simple class-level testing framework, termed Genetic Class Association Testing (GenCAT), to identify protein-coding gene association with 14 cardiometabolic (CMD) related traits across 6 publicly available genome wide association (GWA) meta-analysis data resources. GenCAT uses SNP-level meta-analysis test statistics across all SNPs within a class of elements, as well as the size of the class and its unique correlation structure, to determine if the class is statistically meaningful. The novelty of findings is evaluated through investigation of regional signals. A subset of findings are validated using recently updated, larger meta-analysis resources. A simulation study is presented to characterize overall performance with respect to power, control of family-wise error and computational efficiency. All analysis is performed using the GenCAT package, R version 3.2.1. We demonstrate that class-level testing complements the common first stage minP approach that involves individual SNP-level testing followed by post-hoc ascribing of statistically significant SNPs to genes and loci. GenCAT suggests 54 protein-coding genes at 41 distinct loci for the 13 CMD traits investigated in the discovery analysis, that are beyond the discoveries of minP alone. An additional application to biological pathways demonstrates flexibility in defining genetic classes. We conclude that it would be prudent to include class-level testing as standard practice in GWA analysis. GenCAT, for example, can be used as a simple, complementary and efficient strategy for class-level testing that leverages existing data resources, requires only summary level data in the form of test statistics, and adds significant value with respect to its potential for identifying multiple novel and clinically relevant trait associations.

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.

DNA as information: at the crossroads between biology, mathematics, physics and chemistry.

PubMed

Cartwright, Julyan H E; Giannerini, Simone; González, Diego L

2016-03-13

On the one hand, biology, chemistry and also physics tell us how the process of translating the genetic information into life could possibly work, but we are still very far from a complete understanding of this process. On the other hand, mathematics and statistics give us methods to describe such natural systems-or parts of them-within a theoretical framework. Also, they provide us with hints and predictions that can be tested at the experimental level. Furthermore, there are peculiar aspects of the management of genetic information that are intimately related to information theory and communication theory. This theme issue is aimed at fostering the discussion on the problem of genetic coding and information through the presentation of different innovative points of view. The aim of the editors is to stimulate discussions and scientific exchange that will lead to new research on why and how life can exist from the point of view of the coding and decoding of genetic information. The present introduction represents the point of view of the editors on the main aspects that could be the subject of future scientific debate. © 2016 The Author(s).

Single-nucleotide polymorphisms and haplotypes of non-coding area in the CP gene are correlated with Parkinson's disease.

PubMed

Zhao, Na; Xiao, Jianqiu; Zheng, Zhiyong; Fei, Guoqiang; Zhang, Feng; Jin, Lirong; Zhong, Chunjiu

2015-04-01

Our previous studies have demonstrated that ceruloplasmin (CP) dysmetabolism is correlated with Parkinson's disease (PD). However, the causes of decreased serum CP levels in PD patients remain to be clarified. This study aimed to explore the potential association between genetic variants of the CP gene and PD. Clinical features, serum CP levels, and the CP gene (both promoter and coding regions) were analyzed in 60 PD patients and 50 controls. A luciferase reporter system was used to investigate the function of promoter single-nucleotide polymorphisms (SNPs). High-density comparative genomic hybridization microarrays were also used to detect large-scale copy-number variations in CP and an additional 47 genes involved in PD and/or copper/iron metabolism. The frequencies of eight SNPs (one intronic SNP and seven promoter SNPs of the CP gene) and their haplotypes were significantly different between PD patients, especially those with lowered serum CP levels, and controls. However, the luciferase reporter system revealed no significant effect of the risk haplotype on promoter activity of the CP gene. Neither these SNPs nor their haplotypes were correlated with the Hoehn and Yahr staging of PD. The results of this study suggest that common genetic variants of CP are associated with PD and further investigation is needed to explore their functions in PD.

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.

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.

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.

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

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.

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.

Genome-Wide Association Analysis of Blood Biomarkers in Chronic Obstructive Pulmonary Disease

PubMed Central

Kim, Deog Kyeom; Cho, Michael H.; Hersh, Craig P.; Lomas, David A.; Miller, Bruce E.; Kong, Xiangyang; Bakke, Per; Gulsvik, Amund; Agustí, Alvar; Wouters, Emiel; Celli, Bartolome; Coxson, Harvey; Vestbo, Jørgen; MacNee, William; Yates, Julie C.; Rennard, Stephen; Litonjua, Augusto; Qiu, Weiliang; Beaty, Terri H.; Crapo, James D.; Riley, John H.; Tal-Singer, Ruth

2012-01-01

Rationale: A genome-wide association study (GWAS) for circulating chronic obstructive pulmonary disease (COPD) biomarkers could identify genetic determinants of biomarker levels and COPD susceptibility. Objectives: To identify genetic variants of circulating protein biomarkers and novel genetic determinants of COPD. Methods: GWAS was performed for two pneumoproteins, Clara cell secretory protein (CC16) and surfactant protein D (SP-D), and five systemic inflammatory markers (C-reactive protein, fibrinogen, IL-6, IL-8, and tumor necrosis factor-α) in 1,951 subjects with COPD. For genome-wide significant single nucleotide polymorphisms (SNPs) (P < 1 × 10−8), association with COPD susceptibility was tested in 2,939 cases with COPD and 1,380 smoking control subjects. The association of candidate SNPs with mRNA expression in induced sputum was also elucidated. Measurements and Main Results: Genome-wide significant susceptibility loci affecting biomarker levels were found only for the two pneumoproteins. Two discrete loci affecting CC16, one region near the CC16 coding gene (SCGB1A1) on chromosome 11 and another locus approximately 25 Mb away from SCGB1A1, were identified, whereas multiple SNPs on chromosomes 6 and 16, in addition to SNPs near SFTPD, had genome-wide significant associations with SP-D levels. Several SNPs affecting circulating CC16 levels were significantly associated with sputum mRNA expression of SCGB1A1 (P = 0.009–0.03). Several SNPs highly associated with CC16 or SP-D levels were nominally associated with COPD in a collaborative GWAS (P = 0.001–0.049), although these COPD associations were not replicated in two additional cohorts. Conclusions: Distant genetic loci and biomarker-coding genes affect circulating levels of COPD-related pneumoproteins. A subset of these protein quantitative trait loci may influence their gene expression in the lung and/or COPD susceptibility. Clinical trial registered with www.clinicaltrials.gov (NCT 00292552). PMID:23144326

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.

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.

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.

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.

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

High-throughput screens in mammalian cells using the CRISPR-Cas9 system.

PubMed

Peng, Jingyu; Zhou, Yuexin; Zhu, Shiyou; Wei, Wensheng

2015-06-01

As a powerful genome-editing tool, the clustered regularly interspaced short palindromic repeats (CRISPR)-clustered regularly interspaced short palindromic repeats-associated protein 9 (Cas9) system has been quickly developed into a large-scale function-based screening strategy in mammalian cells. This new type of genetic library is constructed through the lentiviral delivery of single-guide RNA collections that direct Cas9 or inactive dead Cas9 fused with effectors to interrogate gene function or regulate gene transcription in targeted cells. Compared with RNA interference screening, the CRISPR-Cas9 system demonstrates much higher levels of effectiveness and reliability with respect to both loss-of-function and gain-of-function screening. Unlike the RNA interference strategy, a CRISPR-Cas9 library can target both protein-coding sequences and regulatory elements, including promoters, enhancers and elements transcribing microRNAs and long noncoding RNAs. This powerful genetic tool will undoubtedly accelerate the mechanistic discovery of various biological processes. In this mini review, we summarize the general procedure of CRISPR-Cas9 library mediated functional screening, system optimization strategies and applications of this new genetic toolkit. © 2015 FEBS.

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.

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 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).

Electrochemical sensor for multiplex screening of genetically modified DNA: identification of biotech crops by logic-based biomolecular analysis.

PubMed

Liao, Wei-Ching; Chuang, Min-Chieh; Ho, Ja-An Annie

2013-12-15

Genetically modified (GM) technique, one of the modern biomolecular engineering technologies, has been deemed as profitable strategy to fight against global starvation. Yet rapid and reliable analytical method is deficient to evaluate the quality and potential risk of such resulting GM products. We herein present a biomolecular analytical system constructed with distinct biochemical activities to expedite the computational detection of genetically modified organisms (GMOs). The computational mechanism provides an alternative to the complex procedures commonly involved in the screening of GMOs. Given that the bioanalytical system is capable of processing promoter, coding and species genes, affirmative interpretations succeed to identify specified GM event in terms of both electrochemical and optical fashions. The biomolecular computational assay exhibits detection capability of genetically modified DNA below sub-nanomolar level and is found interference-free by abundant coexistence of non-GM DNA. This bioanalytical system, furthermore, sophisticates in array fashion operating multiplex screening against variable GM events. Such a biomolecular computational assay and biosensor holds great promise for rapid, cost-effective, and high-fidelity screening of GMO. Copyright © 2013 Elsevier B.V. All rights reserved.

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.

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.

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.

Allele-Selective Transcriptome Recruitment to Polysomes Primed for Translation: Protein-Coding and Noncoding RNAs, and RNA Isoforms.

PubMed

Mascarenhas, Roshan; Pietrzak, Maciej; Smith, Ryan M; Webb, Amy; Wang, Danxin; Papp, Audrey C; Pinsonneault, Julia K; Seweryn, Michal; Rempala, Grzegorz; Sadee, Wolfgang

2015-01-01

mRNA translation into proteins is highly regulated, but the role of mRNA isoforms, noncoding RNAs (ncRNAs), and genetic variants remains poorly understood. mRNA levels on polysomes have been shown to correlate well with expressed protein levels, pointing to polysomal loading as a critical factor. To study regulation and genetic factors of protein translation we measured levels and allelic ratios of mRNAs and ncRNAs (including microRNAs) in lymphoblast cell lines (LCL) and in polysomal fractions. We first used targeted assays to measure polysomal loading of mRNA alleles, confirming reported genetic effects on translation of OPRM1 and NAT1, and detecting no effect of rs1045642 (3435C>T) in ABCB1 (MDR1) on polysomal loading while supporting previous results showing increased mRNA turnover of the 3435T allele. Use of high-throughput sequencing of complete transcript profiles (RNA-Seq) in three LCLs revealed significant differences in polysomal loading of individual RNA classes and isoforms. Correlated polysomal distribution between protein-coding and non-coding RNAs suggests interactions between them. Allele-selective polysome recruitment revealed strong genetic influence for multiple RNAs, attributable either to differential expression of RNA isoforms or to differential loading onto polysomes, the latter defining a direct genetic effect on translation. Genes identified by different allelic RNA ratios between cytosol and polysomes were enriched with published expression quantitative trait loci (eQTLs) affecting RNA functions, and associations with clinical phenotypes. Polysomal RNA-Seq combined with allelic ratio analysis provides a powerful approach to study polysomal RNA recruitment and regulatory variants affecting protein translation.

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.

High intralocus variability and interlocus recombination promote immunological diversity in a minimal major histocompatibility system.

PubMed

Wilson, Anthony B; Whittington, Camilla M; Bahr, Angela

2014-12-20

The genes of the major histocompatibility complex (MHC/MH) have attracted considerable scientific interest due to their exceptional levels of variability and important function as part of the adaptive immune system. Despite a large number of studies on MH class II diversity of both model and non-model organisms, most research has focused on patterns of genetic variability at individual loci, failing to capture the functional diversity of the biologically active dimeric molecule. Here, we take a systematic approach to the study of MH variation, analyzing patterns of genetic variation at MH class IIα and IIβ loci of the seahorse, which together form the immunologically active peptide binding cleft of the MH class II molecule. The seahorse carries a minimal class II system, consisting of single copies of both MH class IIα and IIβ, which are physically linked and inherited in a Mendelian fashion. Both genes are ubiquitously expressed and detectible in the brood pouch of male seahorses throughout pregnancy. Genetic variability of the two genes is high, dominated by non-synonymous variation concentrated in their peptide-binding regions. Coding variation outside these regions is negligible, a pattern thought to be driven by intra- and interlocus recombination. Despite the tight physical linkage of MH IIα and IIβ loci, recombination has produced novel composite alleles, increasing functional diversity at sites responsible for antigen recognition. Antigen recognition by the adaptive immune system of the seahorse is enhanced by high variability at both MH class IIα and IIβ loci. Strong positive selection on sites involved in pathogen recognition, coupled with high levels of intra- and interlocus recombination, produce a patchwork pattern of genetic variation driven by genetic hitchhiking. Studies focusing on variation at individual MH loci may unintentionally overlook an important component of ecologically relevant variation.

Maintenance and expression of the S. cerevisiae mitochondrial genome--from genetics to evolution and systems biology.

PubMed

Lipinski, Kamil A; Kaniak-Golik, Aneta; Golik, Pawel

2010-01-01

As a legacy of their endosymbiotic eubacterial origin, mitochondria possess a residual genome, encoding only a few proteins and dependent on a variety of factors encoded by the nuclear genome for its maintenance and expression. As a facultative anaerobe with well understood genetics and molecular biology, Saccharomyces cerevisiae is the model system of choice for studying nucleo-mitochondrial genetic interactions. Maintenance of the mitochondrial genome is controlled by a set of nuclear-coded factors forming intricately interconnected circuits responsible for replication, recombination, repair and transmission to buds. Expression of the yeast mitochondrial genome is regulated mostly at the post-transcriptional level, and involves many general and gene-specific factors regulating splicing, RNA processing and stability and translation. A very interesting aspect of the yeast mitochondrial system is the relationship between genome maintenance and gene expression. Deletions of genes involved in many different aspects of mitochondrial gene expression, notably translation, result in an irreversible loss of functional mtDNA. The mitochondrial genetic system viewed from the systems biology perspective is therefore very fragile and lacks robustness compared to the remaining systems of the cell. This lack of robustness could be a legacy of the reductive evolution of the mitochondrial genome, but explanations involving selective advantages of increased evolvability have also been postulated. Copyright © 2009 Elsevier B.V. All rights reserved.

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.

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.

Indoor high precision three-dimensional positioning system based on visible light communication using modified genetic algorithm

NASA Astrophysics Data System (ADS)

Chen, Hao; Guan, Weipeng; Li, Simin; Wu, Yuxiang

2018-04-01

To improve the precision of indoor positioning and actualize three-dimensional positioning, a reversed indoor positioning system based on visible light communication (VLC) using genetic algorithm (GA) is proposed. In order to solve the problem of interference between signal sources, CDMA modulation is used. Each light-emitting diode (LED) in the system broadcasts a unique identity (ID) code using CDMA modulation. Receiver receives mixed signal from every LED reference point, by the orthogonality of spreading code in CDMA modulation, ID information and intensity attenuation information from every LED can be obtained. According to positioning principle of received signal strength (RSS), the coordinate of the receiver can be determined. Due to system noise and imperfection of device utilized in the system, distance between receiver and transmitters will deviate from the real value resulting in positioning error. By introducing error correction factors to global parallel search of genetic algorithm, coordinates of the receiver in three-dimensional space can be determined precisely. Both simulation results and experimental results show that in practical application scenarios, the proposed positioning system can realize high precision positioning service.

A System to Automatically Classify and Name Any Individual Genome-Sequenced Organism Independently of Current Biological Classification and Nomenclature

PubMed Central

Song, Yuhyun; Leman, Scotland; Monteil, Caroline L.; Heath, Lenwood S.; Vinatzer, Boris A.

2014-01-01

A broadly accepted and stable biological classification system is a prerequisite for biological sciences. It provides the means to describe and communicate about life without ambiguity. Current biological classification and nomenclature use the species as the basic unit and require lengthy and laborious species descriptions before newly discovered organisms can be assigned to a species and be named. The current system is thus inadequate to classify and name the immense genetic diversity within species that is now being revealed by genome sequencing on a daily basis. To address this lack of a general intra-species classification and naming system adequate for today’s speed of discovery of new diversity, we propose a classification and naming system that is exclusively based on genome similarity and that is suitable for automatic assignment of codes to any genome-sequenced organism without requiring any phenotypic or phylogenetic analysis. We provide examples demonstrating that genome similarity-based codes largely align with current taxonomic groups at many different levels in bacteria, animals, humans, plants, and viruses. Importantly, the proposed approach is only slightly affected by the order of code assignment and can thus provide codes that reflect similarity between organisms and that do not need to be revised upon discovery of new diversity. We envision genome similarity-based codes to complement current biological nomenclature and to provide a universal means to communicate unambiguously about any genome-sequenced organism in fields as diverse as biodiversity research, infectious disease control, human and microbial forensics, animal breed and plant cultivar certification, and human ancestry research. PMID:24586551

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.

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

The minimal autopoietic unit.

PubMed

Luisi, Pier Luigi

2014-12-01

It is argued that closed, cell-like compartments, may have existed in prebiotic time, showing a simplified metabolism which was bringing about a primitive form of stationary state- a kind of homeostasis. The autopoietic primitive cell can be taken as an example and there are preliminary experimental data supporting the possible existence of this primitive form of cell activity. The genetic code permits, among other things, the continuous self-reproduction of proteins; enzymic proteins permit the synthesis of nucleic acids, and in this way there is a perfect recycling between the two most important classes of biopolymers in our life. On the other hand, the genetic code is a complex machinery, which cannot be posed at the very early time of the origin of life. And the question then arises, whether some form of alternative beginning, prior to the genetic code, would have been possible: and this is the core of the question asked. Is something with the flavor of early life conceivable, prior to the genetic code? My answer is positive, although I am too well aware that the term "conceivable" does not mean that this something is easily to be performed experimentally. To illustrate my answer, I would first go back to the operational description of cellular life as given by the theory of autopoiesis. Accordingly, a living cell is an open system capable of self-maintenance, due to a process of internal self-regeneration of the components, all within a boundary which is itself product from within. This is a universal code, valid not only for a cell, but for any living macroscopic entity, as no living system exists on Earth which does not obey this principle. In this definition (or better operational description) there is no mention of DNA or genetic code. I added in that definition the term "open system"-which is not present in the primary literature (Varela, et al., 1974) to make clear that every living system is indeed an open system-without this addition, it may seem that with autopoiesis we are dealing with a perpetuum mobile, against the second principle of thermodynamics. Now consider the following figure (Fig. 1). It represents in a very schematic form a cell, as an open system, with a semipermeable membrane constituted by the chemical S, which permits the entrance of the nutrient A and the elimination of the decay product P. A is transformed inside the cell into S by a chemical reaction characterized by kgen, and S can be transformed into P by the reaction kdec. The two reactions actually may represent two entire families of reaction, in the sense that one can envisage several A and several S and several P.

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.

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.

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

In vivo Proton NMR spectroscopy of genetic mouse models BALB/cJ and C57BL/6By: variation in hippocampal glutamate level and the metabotropic glutamate receptor, subtype 7 (Grm7) gene.

PubMed

Guilfoyle, David N; Gerum, Scott; Vadasz, Csaba

2014-05-01

Glutamatergic neurotransmission in the brain is modulated by metabotropic glutamate receptors (mGluR). In recent studies, we identified a cis-regulated variant of a gene (Grm7) which codes for mGluR subtype 7 (mGluR7), a presynaptic inhibitory receptor. The genetic variant derived from the BALB/cJ mouse strain (Grm7 (BALB/cJ)) codes for higher abundance of mGluR7 mRNA in the hippocampus than the C57BL/6By strain-derived variant (Grm7 (C57BL/6By)). Here, we used localized in vivo (1)H NMR spectroscopy to test the hypothesis that Grm7 (BALB/cJ) is also associated with lower glutamate concentration in the same brain region. All data were obtained on a 7.0 T Agilent (Santa Clara, CA, USA) 40-cm bore system using experimentally naive adult male inbred C57BL/6By, BALB/cJ, and congenic mice (B6By.C.6.132.54) constructed in our laboratory carrying Grm7 (BALB/cJ) on C57BL/6By genetic background. The voxel of interest size was 6 μL (1 × 2 × 3 mm(3)) placed in the hippocampal CA1 region. The results showed that the hippocampal level of glutamate in the congenic mouse strain was significantly lower than that in the background C57BL/6By strain which carried the Grm7 (C57BL/6By) allele. Because the two inbred strains are genetically highly similar except at the region of the Grm7 gene, the results raise the possibility that allelic variation at the Grm7 locus contributes to the strain differences in both hippocampal mRNA abundance and glutamate level which may modulate complex behavioral traits, such as learning and memory, addiction, epilepsy, and mood disorders.

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…

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

Universal evolutionary selection for high dimensional silent patterns of information hidden in the redundancy of viral genetic code.

PubMed

Goz, Eli; Zafrir, Zohar; Tuller, Tamir

2018-04-30

Understanding how viruses co-evolve with their hosts and adapt various genomic level strategies in order to ensure their fitness may have essential implications in unveiling the secrets of viral evolution, and in developing new vaccines and therapeutic approaches. Here, based on a novel genomic analysis of 2,625 different viruses and 439 corresponding host organisms, we provide evidence of universal evolutionary selection for high dimensional 'silent' patterns of information hidden in the redundancy of viral genetic code. Our model suggests that long substrings of nucleotides in the coding regions of viruses from all classes, often also repeat in the corresponding viral hosts from all domains of life. Selection for these substrings cannot be explained only by such phenomena as codon usage bias, horizontal gene transfer, and the encoded proteins. Genes encoding structural proteins responsible for building the core of the viral particles were found to include more host-repeating substrings, and these substrings tend to appear in the middle parts of the viral coding regions. In addition, in human viruses these substrings tend to be enriched with motives related to transcription factors and RNA binding proteins. The host-repeating substrings are possibly related to the evolutionary pressure on the viruses to effectively interact with host's intracellular factors and to efficiently escape from the host's immune system. tamirtul@post.tau.ac.il (TT). Supplementary data are available at Bioinformatics online.

Partitioning of genetic variation between regulatory and coding gene segments: the predominance of software variation in genes encoding introvert proteins.

PubMed

Mitchison, A

1997-01-01

In considering genetic variation in eukaryotes, a fundamental distinction can be made between variation in regulatory (software) and coding (hardware) gene segments. For quantitative traits the bulk of variation, particularly that near the population mean, appears to reside in regulatory segments. The main exceptions to this rule concern proteins which handle extrinsic substances, here termed extrovert proteins. The immune system includes an unusually large proportion of this exceptional category, but even so its chief source of variation may well be polymorphism in regulatory gene segments. The main evidence for this view emerges from genome scanning for quantitative trait loci (QTL), which in the case of the immune system points to a major contribution of pro-inflammatory cytokine genes. Further support comes from sequencing of major histocompatibility complex (Mhc) class II promoters, where a high level of polymorphism has been detected. These Mhc promoters appear to act, in part at least, by gating the back-signal from T cells into antigen-presenting cells. Both these forms of polymorphism are likely to be sustained by the need for flexibility in the immune response. Future work on promoter polymorphism is likely to benefit from the input from genome informatics.

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.

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.

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…

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/

Genetic Algorithm Optimization of a Cost Competitive Hybrid Rocket Booster

NASA Technical Reports Server (NTRS)

Story, George

2015-01-01

Performance, reliability and cost have always been drivers in the rocket business. Hybrid rockets have been late entries into the launch business due to substantial early development work on liquid rockets and solid rockets. Slowly the technology readiness level of hybrids has been increasing due to various large scale testing and flight tests of hybrid rockets. One remaining issue is the cost of hybrids versus the existing launch propulsion systems. This paper will review the known state-of-the-art hybrid development work to date and incorporate it into a genetic algorithm to optimize the configuration based on various parameters. A cost module will be incorporated to the code based on the weights of the components. The design will be optimized on meeting the performance requirements at the lowest cost.

Genetic Algorithm Optimization of a Cost Competitive Hybrid Rocket Booster

NASA Technical Reports Server (NTRS)

Story, George

2014-01-01

Performance, reliability and cost have always been drivers in the rocket business. Hybrid rockets have been late entries into the launch business due to substantial early development work on liquid rockets and later on solid rockets. Slowly the technology readiness level of hybrids has been increasing due to various large scale testing and flight tests of hybrid rockets. A remaining issue is the cost of hybrids vs the existing launch propulsion systems. This paper will review the known state of the art hybrid development work to date and incorporate it into a genetic algorithm to optimize the configuration based on various parameters. A cost module will be incorporated to the code based on the weights of the components. The design will be optimized on meeting the performance requirements at the lowest cost.

Quantum microbiology.

PubMed

Trevors, J T; Masson, L

2011-01-01

During his famous 1943 lecture series at Trinity College Dublin, the reknown physicist Erwin Schrodinger discussed the failure and challenges of interpreting life by classical physics alone and that a new approach, rooted in Quantum principles, must be involved. Quantum events are simply a level of organization below the molecular level. This includes the atomic and subatomic makeup of matter in microbial metabolism and structures, as well as the organic, genetic information code of DNA and RNA. Quantum events at this time do not elucidate, for example, how specific genetic instructions were first encoded in an organic genetic code in microbial cells capable of growth and division, and its subsequent evolution over 3.6 to 4 billion years. However, due to recent technological advances, biologists and physicists are starting to demonstrate linkages between various quantum principles like quantum tunneling, entanglement and coherence in biological processes illustrating that nature has exerted some level quantum control to optimize various processes in living organisms. In this article we explore the role of quantum events in microbial processes and endeavor to show that after nearly 67 years, Schrödinger was prophetic and visionary in his view of quantum theory and its connection with some of the fundamental mechanisms of life.

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.

Avatar DNA Nanohybrid System in Chip-on-a-Phone

NASA Astrophysics Data System (ADS)

Park, Dae-Hwan; Han, Chang Jo; Shul, Yong-Gun; Choy, Jin-Ho

2014-05-01

Long admired for informational role and recognition function in multidisciplinary science, DNA nanohybrids have been emerging as ideal materials for molecular nanotechnology and genetic information code. Here, we designed an optical machine-readable DNA icon on microarray, Avatar DNA, for automatic identification and data capture such as Quick Response and ColorZip codes. Avatar icon is made of telepathic DNA-DNA hybrids inscribed on chips, which can be identified by camera of smartphone with application software. Information encoded in base-sequences can be accessed by connecting an off-line icon to an on-line web-server network to provide message, index, or URL from database library. Avatar DNA is then converged with nano-bio-info-cogno science: each building block stands for inorganic nanosheets, nucleotides, digits, and pixels. This convergence could address item-level identification that strengthens supply-chain security for drug counterfeits. It can, therefore, provide molecular-level vision through mobile network to coordinate and integrate data management channels for visual detection and recording.

Avatar DNA Nanohybrid System in Chip-on-a-Phone

PubMed Central

Park, Dae-Hwan; Han, Chang Jo; Shul, Yong-Gun; Choy, Jin-Ho

2014-01-01

Long admired for informational role and recognition function in multidisciplinary science, DNA nanohybrids have been emerging as ideal materials for molecular nanotechnology and genetic information code. Here, we designed an optical machine-readable DNA icon on microarray, Avatar DNA, for automatic identification and data capture such as Quick Response and ColorZip codes. Avatar icon is made of telepathic DNA-DNA hybrids inscribed on chips, which can be identified by camera of smartphone with application software. Information encoded in base-sequences can be accessed by connecting an off-line icon to an on-line web-server network to provide message, index, or URL from database library. Avatar DNA is then converged with nano-bio-info-cogno science: each building block stands for inorganic nanosheets, nucleotides, digits, and pixels. This convergence could address item-level identification that strengthens supply-chain security for drug counterfeits. It can, therefore, provide molecular-level vision through mobile network to coordinate and integrate data management channels for visual detection and recording. PMID:24824876

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.

Competence in Streptococcus pneumoniae is regulated by the rate of ribosomal decoding errors.

PubMed

Stevens, Kathleen E; Chang, Diana; Zwack, Erin E; Sebert, Michael E

2011-01-01

Competence for genetic transformation in Streptococcus pneumoniae develops in response to accumulation of a secreted peptide pheromone and was one of the initial examples of bacterial quorum sensing. Activation of this signaling system induces not only expression of the proteins required for transformation but also the production of cellular chaperones and proteases. We have shown here that activity of this pathway is sensitively responsive to changes in the accuracy of protein synthesis that are triggered by either mutations in ribosomal proteins or exposure to antibiotics. Increasing the error rate during ribosomal decoding promoted competence, while reducing the error rate below the baseline level repressed the development of both spontaneous and antibiotic-induced competence. This pattern of regulation was promoted by the bacterial HtrA serine protease. Analysis of strains with the htrA (S234A) catalytic site mutation showed that the proteolytic activity of HtrA selectively repressed competence when translational fidelity was high but not when accuracy was low. These findings redefine the pneumococcal competence pathway as a response to errors during protein synthesis. This response has the capacity to address the immediate challenge of misfolded proteins through production of chaperones and proteases and may also be able to address, through genetic exchange, upstream coding errors that cause intrinsic protein folding defects. The competence pathway may thereby represent a strategy for dealing with lesions that impair proper protein coding and for maintaining the coding integrity of the genome. The signaling pathway that governs competence in the human respiratory tract pathogen Streptococcus pneumoniae regulates both genetic transformation and the production of cellular chaperones and proteases. The current study shows that this pathway is sensitively controlled in response to changes in the accuracy of protein synthesis. Increasing the error rate during ribosomal decoding induced competence, while decreasing the error rate repressed competence. This pattern of regulation was promoted by the HtrA protease, which selectively repressed competence when translational fidelity was high but not when accuracy was low. Our findings demonstrate that this organism is able to monitor the accuracy of information used for protein biosynthesis and suggest that errors trigger a response addressing both the immediate challenge of misfolded proteins and, through genetic exchange, upstream coding errors that may underlie protein folding defects. This pathway may represent an evolutionary strategy for maintaining the coding integrity of the genome.

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.

Stochastic many-body problems in ecology, evolution, neuroscience, and systems biology

NASA Astrophysics Data System (ADS)

Butler, Thomas C.

Using the tools of many-body theory, I analyze problems in four different areas of biology dominated by strong fluctuations: The evolutionary history of the genetic code, spatiotemporal pattern formation in ecology, spatiotemporal pattern formation in neuroscience and the robustness of a model circadian rhythm circuit in systems biology. In the first two research chapters, I demonstrate that the genetic code is extremely optimal (in the sense that it manages the effects of point mutations or mistranslations efficiently), more than an order of magnitude beyond what was previously thought. I further show that the structure of the genetic code implies that early proteins were probably only loosely defined. Both the nature of early proteins and the extreme optimality of the genetic code are interpreted in light of recent theory [1] as evidence that the evolution of the genetic code was driven by evolutionary dynamics that were dominated by horizontal gene transfer. I then explore the optimality of a proposed precursor to the genetic code. The results show that the precursor code has only limited optimality, which is interpreted as evidence that the precursor emerged prior to translation, or else never existed. In the next part of the dissertation, I introduce a many-body formalism for reaction-diffusion systems described at the mesoscopic scale with master equations. I first apply this formalism to spatially-extended predator-prey ecosystems, resulting in the prediction that many-body correlations and fluctuations drive population cycles in time, called quasicycles. Most of these results were previously known, but were derived using the system size expansion [2, 3]. I next apply the analytical techniques developed in the study of quasi-cycles to a simple model of Turing patterns in a predator-prey ecosystem. This analysis shows that fluctuations drive the formation of a new kind of spatiotemporal pattern formation that I name "quasi-patterns." These quasi-patterns exist over a much larger range of physically accessible parameters than the patterns predicted in mean field theory and therefore account for the apparent observations in ecology of patterns in regimes where Turing patterns do not occur. I further show that quasi-patterns have statistical properties that allow them to be distinguished empirically from mean field Turing patterns. I next analyze a model of visual cortex in the brain that has striking similarities to the activator-inhibitor model of ecosystem quasi-pattern formation. Through analysis of the resulting phase diagram, I show that the architecture of the neural network in the visual cortex is configured to make the visual cortex robust to unwanted internally generated spatial structure that interferes with normal visual function. I also predict that some geometric visual hallucinations are quasi-patterns and that the visual cortex supports a new phase of spatially scale invariant behavior present far from criticality. In the final chapter, I explore the effects of fluctuations on cycles in systems biology, specifically the pervasive phenomenon of circadian rhythms. By exploring the behavior of a generic stochastic model of circadian rhythms, I show that the circadian rhythm circuit exploits leaky mRNA production to safeguard the cycle from failure. I also show that this safeguard mechanism is highly robust to changes in the rate of leaky mRNA production. Finally, I explore the failure of the deterministic model in two different contexts, one where the deterministic model predicts cycles where they do not exist, and another context in which cycles are not predicted by the deterministic model.

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

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

Oncogenomic disruptions in arsenic-induced carcinogenesis

PubMed Central

Ng, Kevin W.; Stewart, Greg L.; Dummer, Trevor J.B.; Lam, Wan L.; Martinez, Victor D

2017-01-01

Chronic exposure to arsenic affects more than 200 million people worldwide, and has been associated with many adverse health effects, including cancer in several organs. There is accumulating evidence that arsenic biotransformation, a step in the elimination of arsenic from the human body, can induce changes at a genetic and epigenetic level, leading to carcinogenesis. At the genetic level, arsenic interferes with key cellular processes such as DNA damage-repair and chromosomal structure, leading to genomic instability. At the epigenetic level, arsenic places a high demand on the cellular methyl pool, leading to global hypomethylation and hypermethylation of specific gene promoters. These arsenic-associated DNA alterations result in the deregulation of both oncogenic and tumour-suppressive genes. Furthermore, recent reports have implicated aberrant expression of non-coding RNAs and the consequential disruption of signaling pathways in the context of arsenic-induced carcinogenesis. This article provides an overview of the oncogenomic anomalies associated with arsenic exposure and conveys the importance of non-coding RNAs in the arsenic-induced carcinogenic process. PMID:28179585

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.

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

Genetic associations with micronutrient levels identified in immune and gastrointestinal networks.

PubMed

Morine, Melissa J; Monteiro, Jacqueline Pontes; Wise, Carolyn; Teitel, Candee; Pence, Lisa; Williams, Anna; Ning, Baitang; McCabe-Sellers, Beverly; Champagne, Catherine; Turner, Jerome; Shelby, Beatrice; Bogle, Margaret; Beger, Richard D; Priami, Corrado; Kaput, Jim

2014-07-01

The discovery of vitamins and clarification of their role in preventing frank essential nutrient deficiencies occurred in the early 1900s. Much vitamin research has understandably focused on public health and the effects of single nutrients to alleviate acute conditions. The physiological processes for maintaining health, however, are complex systems that depend upon interactions between multiple nutrients, environmental factors, and genetic makeup. To analyze the relationship between these factors and nutritional health, data were obtained from an observational, community-based participatory research program of children and teens (age 6-14) enrolled in a summer day camp in the Delta region of Arkansas. Assessments of erythrocyte S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH), plasma homocysteine (Hcy) and 6 organic micronutrients (retinol, 25-hydroxy vitamin D3, pyridoxal, thiamin, riboflavin, and vitamin E), and 1,129 plasma proteins were performed at 3 time points in each of 2 years. Genetic makeup was analyzed with 1 M SNP genotyping arrays, and nutrient status was assessed with 24-h dietary intake questionnaires. A pattern of metabolites (met_PC1) that included the ratio of erythrocyte SAM/SAH, Hcy, and 5 vitamins were identified by principal component analysis. Met_PC1 levels were significantly associated with (1) single-nucleotide polymorphisms, (2) levels of plasma proteins, and (3) multilocus genotypes coding for gastrointestinal and immune functions, as identified in a global network of metabolic/protein-protein interactions. Subsequent mining of data from curated pathway, network, and genome-wide association studies identified genetic and functional relationships that may be explained by gene-nutrient interactions. The systems nutrition strategy described here has thus associated a multivariate metabolite pattern in blood with genes involved in immune and gastrointestinal functions.

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.

The coding region of the UFGT gene is a source of diagnostic SNP markers that allow single-locus DNA genotyping for the assessment of cultivar identity and ancestry in grapevine (Vitis vinifera L.)

PubMed Central

2013-01-01

Background Vitis vinifera L. is one of society’s most important agricultural crops with a broad genetic variability. The difficulty in recognizing grapevine genotypes based on ampelographic traits and secondary metabolites prompted the development of molecular markers suitable for achieving variety genetic identification. Findings Here, we propose a comparison between a multi-locus barcoding approach based on six chloroplast markers and a single-copy nuclear gene sequencing method using five coding regions combined with a character-based system with the aim of reconstructing cultivar-specific haplotypes and genotypes to be exploited for the molecular characterization of 157 V. vinifera accessions. The analysis of the chloroplast target regions proved the inadequacy of the DNA barcoding approach at the subspecies level, and hence further DNA genotyping analyses were targeted on the sequences of five nuclear single-copy genes amplified across all of the accessions. The sequencing of the coding region of the UFGT nuclear gene (UDP-glucose: flavonoid 3-0-glucosyltransferase, the key enzyme for the accumulation of anthocyanins in berry skins) enabled the discovery of discriminant SNPs (1/34 bp) and the reconstruction of 130 V. vinifera distinct genotypes. Most of the genotypes proved to be cultivar-specific, and only few genotypes were shared by more, although strictly related, cultivars. Conclusion On the whole, this technique was successful for inferring SNP-based genotypes of grapevine accessions suitable for assessing the genetic identity and ancestry of international cultivars and also useful for corroborating some hypotheses regarding the origin of local varieties, suggesting several issues of misidentification (synonymy/homonymy). PMID:24298902

The Genetics of Pulmonary Arterial Hypertension

PubMed Central

Austin, Eric D.; Loyd, James E.

2014-01-01

Pulmonary arterial hypertension (PAH) is a progressive and fatal disease for which there is an ever-expanding body of genetic and related pathophysiological information on disease pathogenesis. A number of germline gene mutations have now been described, including mutations in the gene coding bone morphogenic protein receptor type 2 (BMPR2) and related genes. Recent advanced gene sequencing methods have facilitated the discovery of additional genes with mutations among those with and without familial forms of PAH (CAV1, KCNK3, EIF2AK4). The reduced penetrance, variable expressivity, and female predominance of PAH suggest that genetic, genomic and other factors modify disease expression. These multi-faceted variations are an active area of investigation in the field, including but not limited to common genetic variants and epigenetic processes, and may provide novel opportunities for pharmacologic intervention in the near future. They also highlight the need for a systems-oriented multi-level approach to incorporate the multitude of biologic variations now associated with PAH. Ultimately, improved understanding provides the opportunity for improved patient and family counseling about this devastating disease, but do require in depth understanding of the genetic factors relevant to PAH. PMID:24951767

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

An Ontology-Based, Mobile-Optimized System for Pharmacogenomic Decision Support at the Point-of-Care

PubMed Central

Miñarro-Giménez, Jose Antonio; Blagec, Kathrin; Boyce, Richard D.; Adlassnig, Klaus-Peter; Samwald, Matthias

2014-01-01

Background The development of genotyping and genetic sequencing techniques and their evolution towards low costs and quick turnaround have encouraged a wide range of applications. One of the most promising applications is pharmacogenomics, where genetic profiles are used to predict the most suitable drugs and drug dosages for the individual patient. This approach aims to ensure appropriate medical treatment and avoid, or properly manage, undesired side effects. Results We developed the Medicine Safety Code (MSC) service, a novel pharmacogenomics decision support system, to provide physicians and patients with the ability to represent pharmacogenomic data in computable form and to provide pharmacogenomic guidance at the point-of-care. Pharmacogenomic data of individual patients are encoded as Quick Response (QR) codes and can be decoded and interpreted with common mobile devices without requiring a centralized repository for storing genetic patient data. In this paper, we present the first fully functional release of this system and describe its architecture, which utilizes Web Ontology Language 2 (OWL 2) ontologies to formalize pharmacogenomic knowledge and to provide clinical decision support functionalities. Conclusions The MSC system provides a novel approach for enabling the implementation of personalized medicine in clinical routine. PMID:24787444

An ontology-based, mobile-optimized system for pharmacogenomic decision support at the point-of-care.

PubMed

Miñarro-Giménez, Jose Antonio; Blagec, Kathrin; Boyce, Richard D; Adlassnig, Klaus-Peter; Samwald, Matthias

2014-01-01

The development of genotyping and genetic sequencing techniques and their evolution towards low costs and quick turnaround have encouraged a wide range of applications. One of the most promising applications is pharmacogenomics, where genetic profiles are used to predict the most suitable drugs and drug dosages for the individual patient. This approach aims to ensure appropriate medical treatment and avoid, or properly manage, undesired side effects. We developed the Medicine Safety Code (MSC) service, a novel pharmacogenomics decision support system, to provide physicians and patients with the ability to represent pharmacogenomic data in computable form and to provide pharmacogenomic guidance at the point-of-care. Pharmacogenomic data of individual patients are encoded as Quick Response (QR) codes and can be decoded and interpreted with common mobile devices without requiring a centralized repository for storing genetic patient data. In this paper, we present the first fully functional release of this system and describe its architecture, which utilizes Web Ontology Language 2 (OWL 2) ontologies to formalize pharmacogenomic knowledge and to provide clinical decision support functionalities. The MSC system provides a novel approach for enabling the implementation of personalized medicine in clinical routine.

The Genetic Counseling Video Project (GCVP): Models of Practice

PubMed Central

Roter, D.; Ellington, L.; Erby, L. Hamby; Larson, S.; W, Dudley

2009-01-01

Genetic counseling is conceptualized as having both “teaching” and “counseling” functions; however, little is known about how these functions are articulated in routine practice. This study addresses the question by documenting, on videotape, the practices of a national sample of prenatal and cancer genetic counselors (GCs) providing routine pretest counseling to simulated clients (SCs). 177 GCs recruited at two annual conferences of the National Society of Genetic Counselors (NSGC) were randomly assigned to counsel one of six female SCs of varying ethnicity, with or without a spouse, in their specialty. 152 videotapes were coded with the Roter Interaction Analysis System (RIAS) and both GCs and SCs completed evaluative questionnaires. Two teaching and two counseling patterns of practice emerged from cluster analysis. The teaching patterns included: (1) Clinical teaching (31%) characterized by low psychosocial, emotional and facilitative talk, high levels of clinical exchange, and high verbal dominance; and (2) Psycho-educational teaching (27%) characterized by high levels of both clinical and psychosocial exchange, low levels of emotional and facilitative talk, and higher verbal dominance. The counseling patterns included: (1) Supportive counseling (33%) characterized by low psychosocial and clinical exchange, high levels of emotional and facilitative talk, and low verbal dominance; and (2) Psychosocial counseling (9%) with high emotional and facilitative talk, low clinical and high psychosocial exchange, and the lowest verbal dominance. SCs ratings of satisfaction with communication, the counselor’s affective demeanor, and the counselor’s use of nonverbal skills were highest for the counseling model sessions. Both the teaching and counseling models seem to be represented in routine practice and predict variation in client satisfaction. PMID:16941666

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.

The emergence of DNA in the RNA world: an in silico simulation study of genetic takeover.

PubMed

Ma, Wentao; Yu, Chunwu; Zhang, Wentao; Wu, Sanmao; Feng, Yu

2015-12-07

It is now popularly accepted that there was an "RNA world" in early evolution of life. This idea has a direct consequence that later on there should have been a takeover of genetic material - RNA by DNA. However, since genetic material carries genetic information, the "source code" of all living activities, it is actually reasonable to question the plausibility of such a "revolutionary" transition. Due to our inability to model relevant "primitive living systems" in reality, it is as yet impossible to explore the plausibility and mechanisms of the "genetic takeover" by experiments. Here we investigated this issue by computer simulation using a Monte-Carlo method. It shows that an RNA-by-DNA genetic takeover may be triggered by the emergence of a nucleotide reductase ribozyme with a moderate activity in a pure RNA system. The transition is unstable and limited in scale (i.e., cannot spread in the population), but can get strengthened and globalized if certain parameters are changed against RNA (i.e., in favor of DNA). In relation to the subsequent evolution, an advanced system with a larger genome, which uses DNA as genetic material and RNA as functional material, is modeled - the system cannot sustain if the nucleotide reductase ribozyme is "turned off" (thus, DNA cannot be synthesized). Moreover, the advanced system cannot sustain if only DNA's stability, template suitability or replication fidelity (any of the three) is turned down to the level of RNA's. Genetic takeover should be plausible. In the RNA world, such a takeover may have been triggered by the emergence of some ribozyme favoring the formation of deoxynucleotides. The transition may initially have been "weak", but could have been reinforced by environmental changes unfavorable to RNA (such as temperature or pH rise), and would have ultimately become irreversible accompanying the genome's enlargement. Several virtues of DNA (versus RNA) - higher stability against hydrolysis, greater suitability as template and higher fidelity in replication, should have, each in its own way, all been significant for the genetic takeover in evolution. This study enhances our understandings of the relationship between information and material in the living world.

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.

Genetic diversity of the HLA-G coding region in Amerindian populations from the Brazilian Amazon: a possible role of natural selection.

PubMed

Mendes-Junior, C T; Castelli, E C; Meyer, D; Simões, A L; Donadi, E A

2013-12-01

HLA-G has an important role in the modulation of the maternal immune system during pregnancy, and evidence that balancing selection acts in the promoter and 3'UTR regions has been previously reported. To determine whether selection acts on the HLA-G coding region in the Amazon Rainforest, exons 2, 3 and 4 were analyzed in a sample of 142 Amerindians from nine villages of five isolated tribes that inhabit the Central Amazon. Six previously described single-nucleotide polymorphisms (SNPs) were identified and the Expectation-Maximization (EM) and PHASE algorithms were used to computationally reconstruct SNP haplotypes (HLA-G alleles). A new HLA-G allele, which originated in Amerindian populations by a crossing-over event between two widespread HLA-G alleles, was identified in 18 individuals. Neutrality tests evidenced that natural selection has a complex part in the HLA-G coding region. Although balancing selection is the type of selection that shapes variability at a local level (Native American populations), we have also shown that purifying selection may occur on a worldwide scale. Moreover, the balancing selection does not seem to act on the coding region as strongly as it acts on the flanking regulatory regions, and such coding signature may actually reflect a hitchhiking effect.

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.

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.

DNA codes for nanoscience.

PubMed

Samorì, Bruno; Zuccheri, Giampaolo

2005-02-11

The nanometer scale is a special place where all sciences meet and develop a particularly strong interdisciplinarity. While biology is a source of inspiration for nanoscientists, chemistry has a central role in turning inspirations and methods from biological systems to nanotechnological use. DNA is the biological molecule by which nanoscience and nanotechnology is mostly fascinated. Nature uses DNA not only as a repository of the genetic information, but also as a controller of the expression of the genes it contains. Thus, there are codes embedded in the DNA sequence that serve to control recognition processes on the atomic scale, such as the base pairing, and others that control processes taking place on the nanoscale. From the chemical point of view, DNA is the supramolecular building block with the highest informational content. Nanoscience has therefore the opportunity of using DNA molecules to increase the level of complexity and efficiency in self-assembling and self-directing processes.

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

The physics of symbols: bridging the epistemic cut.

PubMed

Pattee, H H

2001-01-01

Evolution requires the genotype-phenotype distinction, a primeval epistemic cut that separates energy-degenerate, rate-independent genetic symbols from the rate-dependent dynamics of construction that they control. This symbol-matter or subject-object distinction occurs at all higher levels where symbols are related to a referent by an arbitrary code. The converse of control is measurement in which a rate-dependent dynamical state is coded into quiescent symbols. Non-integrable constraints are one necessary condition for bridging the epistemic cut by measurement, control, and coding. Additional properties of heteropolymer constraints are necessary for biological evolution.

Couplings of character and of chirality in the origin of the genetic system

NASA Technical Reports Server (NTRS)

Lacey, J. C. Jr; Wickramasinghe, N. S.; Cook, G. W.; Anderson, G.; Lacey JC, J. r. (Principal Investigator)

1993-01-01

Data from the literature and new data presented here suggest that the genetic system (coding and protein synthesis) is based on relationships of character and structure between amino acids and nucleic acids. Character relationships seem to be anticodonic and structurally the greatest preferences are seen between the heteropair, L-amino acids and D-ribose nucleic acids. However, living systems using the other heteropair must have been equally likely. Homopairing (L-L and D-D) in living systems seems unlikely. Awareness of the heterocoupling of steric forms narrows somewhat the problem of understanding the origin of chirality.

Optimization of wavefront coding imaging system using heuristic algorithms

NASA Astrophysics Data System (ADS)

González-Amador, E.; Padilla-Vivanco, A.; Toxqui-Quitl, C.; Zermeño-Loreto, O.

2017-08-01

Wavefront Coding (WFC) systems make use of an aspheric Phase-Mask (PM) and digital image processing to extend the Depth of Field (EDoF) of computational imaging systems. For years, several kinds of PM have been designed to produce a point spread function (PSF) near defocus-invariant. In this paper, the optimization of the phase deviation parameter is done by means of genetic algorithms (GAs). In this, the merit function minimizes the mean square error (MSE) between the diffraction limited Modulated Transfer Function (MTF) and the MTF of the system that is wavefront coded with different misfocus. WFC systems were simulated using the cubic, trefoil, and 4 Zernike polynomials phase-masks. Numerical results show defocus invariance aberration in all cases. Nevertheless, the best results are obtained by using the trefoil phase-mask, because the decoded image is almost free of artifacts.

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.

Decoding Mechanisms by which Silent Codon Changes Influence Protein Biogenesis and Function

PubMed Central

Bali, Vedrana; Bebok, Zsuzsanna

2015-01-01

Scope Synonymous codon usage has been a focus of investigation since the discovery of the genetic code and its redundancy. The occurrences of synonymous codons vary between species and within genes of the same genome, known as codon usage bias. Today, bioinformatics and experimental data allow us to compose a global view of the mechanisms by which the redundancy of the genetic code contributes to the complexity of biological systems from affecting survival in prokaryotes, to fine tuning the structure and function of proteins in higher eukaryotes. Studies analyzing the consequences of synonymous codon changes in different organisms have revealed that they impact nucleic acid stability, protein levels, structure and function without altering amino acid sequence. As such, synonymous mutations inevitably contribute to the pathogenesis of complex human diseases. Yet, fundamental questions remain unresolved regarding the impact of silent mutations in human disorders. In the present review we describe developments in this area concentrating on mechanisms by which synonymous mutations may affect protein function and human health. Purpose This synopsis illustrates the significance of synonymous mutations in disease pathogenesis. We review the different steps of gene expression affected by silent mutations, and assess the benefits and possible harmful effects of codon optimization applied in the development of therapeutic biologics. Physiological and medical relevance Understanding mechanisms by which synonymous mutations contribute to complex diseases such as cancer, neurodegeneration and genetic disorders, including the limitations of codon-optimized biologics, provides insight concerning interpretation of silent variants and future molecular therapies. PMID:25817479

DNA as information: at the crossroads between biology, mathematics, physics and chemistry

PubMed Central

2016-01-01

On the one hand, biology, chemistry and also physics tell us how the process of translating the genetic information into life could possibly work, but we are still very far from a complete understanding of this process. On the other hand, mathematics and statistics give us methods to describe such natural systems—or parts of them—within a theoretical framework. Also, they provide us with hints and predictions that can be tested at the experimental level. Furthermore, there are peculiar aspects of the management of genetic information that are intimately related to information theory and communication theory. This theme issue is aimed at fostering the discussion on the problem of genetic coding and information through the presentation of different innovative points of view. The aim of the editors is to stimulate discussions and scientific exchange that will lead to new research on why and how life can exist from the point of view of the coding and decoding of genetic information. The present introduction represents the point of view of the editors on the main aspects that could be the subject of future scientific debate. PMID:26857674

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

Molecular Genetics Information System (MOLGENIS): alternatives in developing local experimental genomics databases.

PubMed

Swertz, Morris A; De Brock, E O; Van Hijum, Sacha A F T; De Jong, Anne; Buist, Girbe; Baerends, Richard J S; Kok, Jan; Kuipers, Oscar P; Jansen, Ritsert C

2004-09-01

Genomic research laboratories need adequate infrastructure to support management of their data production and research workflow. But what makes infrastructure adequate? A lack of appropriate criteria makes any decision on buying or developing a system difficult. Here, we report on the decision process for the case of a molecular genetics group establishing a microarray laboratory. Five typical requirements for experimental genomics database systems were identified: (i) evolution ability to keep up with the fast developing genomics field; (ii) a suitable data model to deal with local diversity; (iii) suitable storage of data files in the system; (iv) easy exchange with other software; and (v) low maintenance costs. The computer scientists and the researchers of the local microarray laboratory considered alternative solutions for these five requirements and chose the following options: (i) use of automatic code generation; (ii) a customized data model based on standards; (iii) storage of datasets as black boxes instead of decomposing them in database tables; (iv) loosely linking to other programs for improved flexibility; and (v) a low-maintenance web-based user interface. Our team evaluated existing microarray databases and then decided to build a new system, Molecular Genetics Information System (MOLGENIS), implemented using code generation in a period of three months. This case can provide valuable insights and lessons to both software developers and a user community embarking on large-scale genomic projects. http://www.molgenis.nl

Nonlinear inversion of potential-field data using a hybrid-encoding genetic algorithm

USGS Publications Warehouse

Chen, C.; Xia, J.; Liu, J.; Feng, G.

2006-01-01

Using a genetic algorithm to solve an inverse problem of complex nonlinear geophysical equations is advantageous because it does not require computer gradients of models or "good" initial models. The multi-point search of a genetic algorithm makes it easier to find the globally optimal solution while avoiding falling into a local extremum. As is the case in other optimization approaches, the search efficiency for a genetic algorithm is vital in finding desired solutions successfully in a multi-dimensional model space. A binary-encoding genetic algorithm is hardly ever used to resolve an optimization problem such as a simple geophysical inversion with only three unknowns. The encoding mechanism, genetic operators, and population size of the genetic algorithm greatly affect search processes in the evolution. It is clear that improved operators and proper population size promote the convergence. Nevertheless, not all genetic operations perform perfectly while searching under either a uniform binary or a decimal encoding system. With the binary encoding mechanism, the crossover scheme may produce more new individuals than with the decimal encoding. On the other hand, the mutation scheme in a decimal encoding system will create new genes larger in scope than those in the binary encoding. This paper discusses approaches of exploiting the search potential of genetic operations in the two encoding systems and presents an approach with a hybrid-encoding mechanism, multi-point crossover, and dynamic population size for geophysical inversion. We present a method that is based on the routine in which the mutation operation is conducted in the decimal code and multi-point crossover operation in the binary code. The mix-encoding algorithm is called the hybrid-encoding genetic algorithm (HEGA). HEGA provides better genes with a higher probability by a mutation operator and improves genetic algorithms in resolving complicated geophysical inverse problems. Another significant result is that final solution is determined by the average model derived from multiple trials instead of one computation due to the randomness in a genetic algorithm procedure. These advantages were demonstrated by synthetic and real-world examples of inversion of potential-field data. ?? 2005 Elsevier Ltd. All rights reserved.

Pyrrolysyl-tRNA Synthetase, an Aminoacyl-tRNA Synthetase for Genetic Code Expansion

DOE PAGES

Crnkovic, Ana; Suzuki, Tateki; Soll, Dieter; ...

2016-06-14

Genetic code expansion (GCE) has become a central topic of synthetic biology. GCE relies on engineered aminoacyl-tRNA synthetases (aaRSs) and a cognate tRNA species to allow codon reassignment by co-translational insertion of non-canonical amino acids (ncAAs) into proteins. Introduction of such amino acids increases the chemical diversity of recombinant proteins endowing them with novel properties. Such proteins serve in sophisticated biochemical and biophysical studies both in vitro and in vivo, they may become unique biomaterials or therapeutic agents, and they afford metabolic dependence of genetically modified organisms for biocontainment purposes. In the Methanosarcinaceae the incorporation of the 22nd genetically encodedmore » amino acid, pyrrolysine (Pyl), is facilitated by pyrrolysyl-tRNA synthetase (PylRS) and the cognate UAG-recognizing tRNAPyl. This unique aaRS•tRNA pair functions as an orthogonal translation system (OTS) in most model organisms. The facile directed evolution of the large PylRS active site to accommodate many ncAAs, and the enzyme’s anticodon-blind specific recognition of the cognate tRNAPyl make this system highly amenable for GCE purposes. The remarkable polyspecificity of PylRS has been exploited to incorporate >100 different ncAAs into proteins. Here we review the Pyl-OT system and selected GCE applications to examine the properties of an effective OTS.« less

Engineering blood meal-activated systemic immunity in the yellow fever mosquito, Aedes aegypti.

PubMed

Kokoza, V; Ahmed, A; Cho, W L; Jasinskiene, N; James, A A; Raikhel, A

2000-08-01

Progress in molecular genetics makes possible the development of alternative disease control strategies that target the competence of mosquitoes to transmit pathogens. We tested the regulatory region of the vitellogenin (Vg) gene of Aedes aegypti for its ability to express potential antipathogen factors in transgenic mosquitoes. Hermes-mediated transformation was used to integrate a 2.1-kb Vg-promoter fragment driving the expression of the Defensin A (DefA) coding region, one of the major insect immune factors. PCR amplification of genomic DNA and Southern blot analyses, carried out through the ninth generation, showed that the Vg-DefA transgene insertion was stable. The Vg-DefA transgene was strongly activated in the fat body by a blood meal. The mRNA levels reached a maximum at 24-h postblood meal, corresponding to the peak expression time of the endogenous Vg gene. High levels of transgenic defensin were accumulated in the hemolymph of bloodfed female mosquitoes, persisting for 20-22 days after a single blood feeding. Purified transgenic defensin showed antibacterial activity comparable to that of defensin isolated from bacterially challenged control mosquitoes. Thus, we have been able to engineer the genetically stable transgenic mosquito with an element of systemic immunity, which is activated through the blood meal-triggered cascade rather than by infection. This work represents a significant step toward the development of molecular genetic approaches to the control of vector competence in pathogen transmission.

Evaluation of LOINC for Representing Constitutional Cytogenetic Test Result Reports

PubMed Central

Heras, Yan Z.; Mitchell, Joyce A.; Williams, Marc S.; Brothman, Arthur R.; Huff, Stanley M.

2009-01-01

Genetic testing is becoming increasingly important to medical practice. Integrating genetics and genomics data into electronic medical records is crucial in translating genetic discoveries into improved patient care. Information technology, especially Clinical Decision Support Systems, holds great potential to help clinical professionals take full advantage of genomic advances in their daily medical practice. However, issues relating to standard terminology and information models for exchanging genetic testing results remain relatively unexplored. This study evaluates whether the current LOINC standard is adequate to represent constitutional cytogenetic test result reports using sample result reports from ARUP Laboratories. The results demonstrate that current standard terminology is insufficient to support the needs of coding cytogenetic test results. The terminology infrastructure must be developed before clinical information systems will be able to handle the high volumes of genetic data expected in the near future. PMID:20351857

Evaluation of LOINC for representing constitutional cytogenetic test result reports.

PubMed

Heras, Yan Z; Mitchell, Joyce A; Williams, Marc S; Brothman, Arthur R; Huff, Stanley M

2009-11-14

Genetic testing is becoming increasingly important to medical practice. Integrating genetics and genomics data into electronic medical records is crucial in translating genetic discoveries into improved patient care. Information technology, especially Clinical Decision Support Systems, holds great potential to help clinical professionals take full advantage of genomic advances in their daily medical practice. However, issues relating to standard terminology and information models for exchanging genetic testing results remain relatively unexplored. This study evaluates whether the current LOINC standard is adequate to represent constitutional cytogenetic test result reports using sample result reports from ARUP Laboratories. The results demonstrate that current standard terminology is insufficient to support the needs of coding cytogenetic test results. The terminology infrastructure must be developed before clinical information systems will be able to handle the high volumes of genetic data expected in the near future.

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.

The Genetic Counseling Video Project (GCVP): models of practice.

PubMed

Roter, D; Ellington, L; Erby, L Hamby; Larson, S; Dudley, W

2006-11-15

Genetic counseling is conceptualized as having both "teaching" and "counseling" functions; however, little is known about how these functions are articulated in routine practice. This study addresses the question by documenting, on videotape, the practices of a national sample of prenatal and cancer genetic counselors (GCs) providing routine pre-test counseling to simulated clients (SCs). One hundred and seventy-seven GCs recruited at two annual conferences of the National Society of Genetic Counselors (NSGC) were randomly assigned to counsel one of six female SCs of varying ethnicity, with or without a spouse, in their specialty. One hundred and fifty-two videotapes were coded with the Roter Interaction Analysis System (RIAS) and both GCs and SCs completed evaluative questionnaires. Two teaching and two counseling patterns of practice emerged from cluster analysis. The teaching patterns included: (1) clinical teaching (31%) characterized by low psychosocial, emotional and facilitative talk, high levels of clinical exchange, and high verbal dominance; and (2) psycho-educational teaching (27%) characterized by high levels of both clinical and psychosocial exchange, low levels of emotional and facilitative talk, and higher verbal dominance. The counseling patterns included: (1) supportive counseling (33%) characterized by low psychosocial and clinical exchange, high levels of emotional and facilitative talk, and low verbal dominance; and (2) psychosocial counseling (9%) with high emotional and facilitative talk, low clinical and high psychosocial exchange, and the lowest verbal dominance. SCs ratings of satisfaction with communication, the counselor's affective demeanor, and the counselor's use of non-verbal skills were highest for the counseling model sessions. Both the teaching and counseling models seem to be represented in routine practice and predict variation in client satisfaction, affective demeanor, and nonverbal effectiveness. (c) 2006 Wiley-Liss, Inc.

Aquaculture genomics, genetics and breeding in the United States: current status, challenges, and priorities for future research.

PubMed

Abdelrahman, Hisham; ElHady, Mohamed; Alcivar-Warren, Acacia; Allen, Standish; Al-Tobasei, Rafet; Bao, Lisui; Beck, Ben; Blackburn, Harvey; Bosworth, Brian; Buchanan, John; Chappell, Jesse; Daniels, William; Dong, Sheng; Dunham, Rex; Durland, Evan; Elaswad, Ahmed; Gomez-Chiarri, Marta; Gosh, Kamal; Guo, Ximing; Hackett, Perry; Hanson, Terry; Hedgecock, Dennis; Howard, Tiffany; Holland, Leigh; Jackson, Molly; Jin, Yulin; Khalil, Karim; Kocher, Thomas; Leeds, Tim; Li, Ning; Lindsey, Lauren; Liu, Shikai; Liu, Zhanjiang; Martin, Kyle; Novriadi, Romi; Odin, Ramjie; Palti, Yniv; Peatman, Eric; Proestou, Dina; Qin, Guyu; Reading, Benjamin; Rexroad, Caird; Roberts, Steven; Salem, Mohamed; Severin, Andrew; Shi, Huitong; Shoemaker, Craig; Stiles, Sheila; Tan, Suxu; Tang, Kathy F J; Thongda, Wilawan; Tiersch, Terrence; Tomasso, Joseph; Prabowo, Wendy Tri; Vallejo, Roger; van der Steen, Hein; Vo, Khoi; Waldbieser, Geoff; Wang, Hanping; Wang, Xiaozhu; Xiang, Jianhai; Yang, Yujia; Yant, Roger; Yuan, Zihao; Zeng, Qifan; Zhou, Tao

2017-02-20

Advancing the production efficiency and profitability of aquaculture is dependent upon the ability to utilize a diverse array of genetic resources. The ultimate goals of aquaculture genomics, genetics and breeding research are to enhance aquaculture production efficiency, sustainability, product quality, and profitability in support of the commercial sector and for the benefit of consumers. In order to achieve these goals, it is important to understand the genomic structure and organization of aquaculture species, and their genomic and phenomic variations, as well as the genetic basis of traits and their interrelationships. In addition, it is also important to understand the mechanisms of regulation and evolutionary conservation at the levels of genome, transcriptome, proteome, epigenome, and systems biology. With genomic information and information between the genomes and phenomes, technologies for marker/causal mutation-assisted selection, genome selection, and genome editing can be developed for applications in aquaculture. A set of genomic tools and resources must be made available including reference genome sequences and their annotations (including coding and non-coding regulatory elements), genome-wide polymorphic markers, efficient genotyping platforms, high-density and high-resolution linkage maps, and transcriptome resources including non-coding transcripts. Genomic and genetic control of important performance and production traits, such as disease resistance, feed conversion efficiency, growth rate, processing yield, behaviour, reproductive characteristics, and tolerance to environmental stressors like low dissolved oxygen, high or low water temperature and salinity, must be understood. QTL need to be identified, validated across strains, lines and populations, and their mechanisms of control understood. Causal gene(s) need to be identified. Genetic and epigenetic regulation of important aquaculture traits need to be determined, and technologies for marker-assisted selection, causal gene/mutation-assisted selection, genome selection, and genome editing using CRISPR and other technologies must be developed, demonstrated with applicability, and application to aquaculture industries.Major progress has been made in aquaculture genomics for dozens of fish and shellfish species including the development of genetic linkage maps, physical maps, microarrays, single nucleotide polymorphism (SNP) arrays, transcriptome databases and various stages of genome reference sequences. This paper provides a general review of the current status, challenges and future research needs of aquaculture genomics, genetics, and breeding, with a focus on major aquaculture species in the United States: catfish, rainbow trout, Atlantic salmon, tilapia, striped bass, oysters, and shrimp. While the overall research priorities and the practical goals are similar across various aquaculture species, the current status in each species should dictate the next priority areas within the species. This paper is an output of the USDA Workshop for Aquaculture Genomics, Genetics, and Breeding held in late March 2016 in Auburn, Alabama, with participants from all parts of the United States.

The Comprehensive AOCMF Classification: Skull Base and Cranial Vault Fractures – Level 2 and 3 Tutorial

PubMed Central

Ieva, Antonio Di; Audigé, Laurent; Kellman, Robert M.; Shumrick, Kevin A.; Ringl, Helmut; Prein, Joachim; Matula, Christian

2014-01-01

The AOCMF Classification Group developed a hierarchical three-level craniomaxillofacial classification system with increasing level of complexity and details. The highest level 1 system distinguish four major anatomical units, including the mandible (code 91), midface (code 92), skull base (code 93), and cranial vault (code 94). This tutorial presents the level 2 and more detailed level 3 systems for the skull base and cranial vault units. The level 2 system describes fracture location outlining the topographic boundaries of the anatomic regions, considering in particular the endocranial and exocranial skull base surfaces. The endocranial skull base is divided into nine regions; a central skull base adjoining a left and right side are divided into the anterior, middle, and posterior skull base. The exocranial skull base surface and cranial vault are divided in regions defined by the names of the bones involved: frontal, parietal, temporal, sphenoid, and occipital bones. The level 3 system allows assessing fracture morphology described by the presence of fracture fragmentation, displacement, and bone loss. A documentation of associated intracranial diagnostic features is proposed. This tutorial is organized in a sequence of sections dealing with the description of the classification system with illustrations of the topographical skull base and cranial vault regions along with rules for fracture location and coding, a series of case examples with clinical imaging and a general discussion on the design of this classification. PMID:25489394

Refactored M13 Bacteriophage as a Platform for Tumor Cell Imaging and Drug Delivery

PubMed Central

MOSER, FELIX; ENDY, DREW; BELCHER, ANGELA M.

2014-01-01

M13 bacteriophage is a well-characterized platform for peptide display. The utility of the M13 display platform is derived from the ability to encode phage protein fusions with display peptides at the genomic level. However, the genome of the phage is complicated by overlaps of key genetic elements. These overlaps directly couple the coding sequence of one gene to the coding or regulatory sequence of another, making it difficult to alter one gene without disrupting the other. Specifically, overlap of the end of gene VII and the beginning of gene IX has prevented the functional genomic modification of the N-terminus of p9. By redesigning the M13 genome to physically separate these overlapping genetic elements, a process known as “refactoring,” we enabled independent manipulation of gene VII and gene IX and the construction of the first N-terminal genomic modification of p9 for peptide display. We demonstrate the utility of this refactored genome by developing an M13 bacteriophage-based platform for targeted imaging of and drug delivery to prostate cancer cells in vitro. This successful use of refactoring principles to reengineer a natural biological system strengthens the suggestion that natural genomes can be rationally designed for a number of applications. PMID:23656279

Refactored M13 bacteriophage as a platform for tumor cell imaging and drug delivery.

PubMed

Ghosh, Debadyuti; Kohli, Aditya G; Moser, Felix; Endy, Drew; Belcher, Angela M

2012-12-21

M13 bacteriophage is a well-characterized platform for peptide display. The utility of the M13 display platform is derived from the ability to encode phage protein fusions with display peptides at the genomic level. However, the genome of the phage is complicated by overlaps of key genetic elements. These overlaps directly couple the coding sequence of one gene to the coding or regulatory sequence of another, making it difficult to alter one gene without disrupting the other. Specifically, overlap of the end of gene VII and the beginning of gene IX has prevented the functional genomic modification of the N-terminus of p9. By redesigning the M13 genome to physically separate these overlapping genetic elements, a process known as "refactoring," we enabled independent manipulation of gene VII and gene IX and the construction of the first N-terminal genomic modification of p9 for peptide display. We demonstrate the utility of this refactored genome by developing an M13 bacteriophage-based platform for targeted imaging of and drug delivery to prostate cancer cells in vitro. This successful use of refactoring principles to re-engineer a natural biological system strengthens the suggestion that natural genomes can be rationally designed for a number of applications.

Accurate clinical genetic testing for autoinflammatory diseases using the next-generation sequencing platform MiSeq.

PubMed

Nakayama, Manabu; Oda, Hirotsugu; Nakagawa, Kenji; Yasumi, Takahiro; Kawai, Tomoki; Izawa, Kazushi; Nishikomori, Ryuta; Heike, Toshio; Ohara, Osamu

2017-03-01

Autoinflammatory diseases occupy one of a group of primary immunodeficiency diseases that are generally thought to be caused by mutation of genes responsible for innate immunity, rather than by acquired immunity. Mutations related to autoinflammatory diseases occur in 12 genes. For example, low-level somatic mosaic NLRP3 mutations underlie chronic infantile neurologic, cutaneous, articular syndrome (CINCA), also known as neonatal-onset multisystem inflammatory disease (NOMID). In current clinical practice, clinical genetic testing plays an important role in providing patients with quick, definite diagnoses. To increase the availability of such testing, low-cost high-throughput gene-analysis systems are required, ones that not only have the sensitivity to detect even low-level somatic mosaic mutations, but also can operate simply in a clinical setting. To this end, we developed a simple method that employs two-step tailed PCR and an NGS system, MiSeq platform, to detect mutations in all coding exons of the 12 genes responsible for autoinflammatory diseases. Using this amplicon sequencing system, we amplified a total of 234 amplicons derived from the 12 genes with multiplex PCR. This was done simultaneously and in one test tube. Each sample was distinguished by an index sequence of second PCR primers following PCR amplification. With our procedure and tips for reducing PCR amplification bias, we were able to analyze 12 genes from 25 clinical samples in one MiSeq run. Moreover, with the certified primers designed by our short program-which detects and avoids common SNPs in gene-specific PCR primers-we used this system for routine genetic testing. Our optimized procedure uses a simple protocol, which can easily be followed by virtually any office medical staff. Because of the small PCR amplification bias, we can analyze simultaneously several clinical DNA samples with low cost and can obtain sufficient read numbers to detect a low level of somatic mosaic mutations.

How much of reinforcement learning is working memory, not reinforcement learning? A behavioral, computational, and neurogenetic analysis

PubMed Central

Collins, Anne G. E.; Frank, Michael J.

2012-01-01

Instrumental learning involves corticostriatal circuitry and the dopaminergic system. This system is typically modeled in the reinforcement learning (RL) framework by incrementally accumulating reward values of states and actions. However, human learning also implicates prefrontal cortical mechanisms involved in higher level cognitive functions. The interaction of these systems remains poorly understood, and models of human behavior often ignore working memory (WM) and therefore incorrectly assign behavioral variance to the RL system. Here we designed a task that highlights the profound entanglement of these two processes, even in simple learning problems. By systematically varying the size of the learning problem and delay between stimulus repetitions, we separately extracted WM-specific effects of load and delay on learning. We propose a new computational model that accounts for the dynamic integration of RL and WM processes observed in subjects' behavior. Incorporating capacity-limited WM into the model allowed us to capture behavioral variance that could not be captured in a pure RL framework even if we (implausibly) allowed separate RL systems for each set size. The WM component also allowed for a more reasonable estimation of a single RL process. Finally, we report effects of two genetic polymorphisms having relative specificity for prefrontal and basal ganglia functions. Whereas the COMT gene coding for catechol-O-methyl transferase selectively influenced model estimates of WM capacity, the GPR6 gene coding for G-protein-coupled receptor 6 influenced the RL learning rate. Thus, this study allowed us to specify distinct influences of the high-level and low-level cognitive functions on instrumental learning, beyond the possibilities offered by simple RL models. PMID:22487033

WONOEP appraisal: new genetic approaches to study epilepsy

PubMed Central

Rossignol, Elsa; Kobow, Katja; Simonato, Michele; Loeb, Jeffrey A.; Grisar, Thierry; Gilby, Krista L.; Vinet, Jonathan; Kadam, Shilpa D.; Becker, Albert J.

2014-01-01

Objective New genetic investigation techniques, including next-generation sequencing, epigenetic profiling, cell lineage mapping, targeted genetic manipulation of specific neuronal cell types, stem cell reprogramming and optogenetic manipulations within epileptic networks are progressively unravelling the mysteries of epileptogenesis and ictogenesis. These techniques have opened new avenues to discover the molecular basis of epileptogenesis and to study the physiological impacts of mutations in epilepsy-associated genes on a multilayer level, from cells to circuits. Methods This manuscript reviews recently published applications of these new genetic technologies in the study of epilepsy, as well as work presented by the authors at the genetic session of the XII Workshop on the Neurobiology of Epilepsy in Quebec, Canada. Results Next-generation sequencing is providing investigators with an unbiased means to assess the molecular causes of sporadic forms of epilepsy and have revealed the complexity and genetic heterogeneity of sporadic epilepsy disorders. To assess the functional impact of mutations in these newly identified genes on specific neuronal cell-types during brain development, new modeling strategies in animals, including conditional genetics in mice and in utero knockdown approaches, are enabling functional validation with exquisite cell-type and temporal specificity. In addition, optogenetics, using cell-type specific Cre recombinase driver lines, is enabling investigators to dissect networks involved in epilepsy. Genetically-encoded cell-type labeling is also providing new means to assess the role of the non-neuronal components of epileptic networks such as glial cells. Furthermore, beyond its role in revealing coding variants involved in epileptogenesis, next-generation sequencing can be used to assess the epigenetic modifications that lead to sustained network hyperexcitability in epilepsy, including methylation changes in gene promoters and non-coding RNAs involved in modifying gene expression following seizures. In addition, genetically-based bioluminescent reporters are providing new opportunities to assess neuronal activity and neurotransmitter levels both in vitro and in vivo in the context of epilepsy. Finally, genetically rederived neurons generated from patient iPS cells and genetically-modified zebrafish have become high-throughput means to investigate disease mechanisms and potential new therapies. Significance Genetics has considerably changed the field of epilepsy research and is paving the way for better diagnosis and therapies for patients with epilepsy. PMID:24965021

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.

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

Genetic learning in rule-based and neural systems

NASA Technical Reports Server (NTRS)

Smith, Robert E.

1993-01-01

The design of neural networks and fuzzy systems can involve complex, nonlinear, and ill-conditioned optimization problems. Often, traditional optimization schemes are inadequate or inapplicable for such tasks. Genetic Algorithms (GA's) are a class of optimization procedures whose mechanics are based on those of natural genetics. Mathematical arguments show how GAs bring substantial computational leverage to search problems, without requiring the mathematical characteristics often necessary for traditional optimization schemes (e.g., modality, continuity, availability of derivative information, etc.). GA's have proven effective in a variety of search tasks that arise in neural networks and fuzzy systems. This presentation begins by introducing the mechanism and theoretical underpinnings of GA's. GA's are then related to a class of rule-based machine learning systems called learning classifier systems (LCS's). An LCS implements a low-level production-system that uses a GA as its primary rule discovery mechanism. This presentation illustrates how, despite its rule-based framework, an LCS can be thought of as a competitive neural network. Neural network simulator code for an LCS is presented. In this context, the GA is doing more than optimizing and objective function. It is searching for an ecology of hidden nodes with limited connectivity. The GA attempts to evolve this ecology such that effective neural network performance results. The GA is particularly well adapted to this task, given its naturally-inspired basis. The LCS/neural network analogy extends itself to other, more traditional neural networks. Conclusions to the presentation discuss the implications of using GA's in ecological search problems that arise in neural and fuzzy systems.

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.

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

Assessment of genetic and epigenetic changes in virus-free garlic (Allium sativum L.) plants obtained by meristem culture followed by in vitro propagation.

PubMed

Gimenez, Magalí Diana; Yañez-Santos, Anahí Mara; Paz, Rosalía Cristina; Quiroga, Mariana Paola; Marfil, Carlos Federico; Conci, Vilma Cecilia; García-Lampasona, Sandra Claudia

2016-01-01

This is the first report assessing epigenetic variation in garlic. High genetic and epigenetic polymorphism during in vitro culture was detected.Sequencing of MSAP fragments revealed homology with ESTs. Garlic (Allium sativum) is a worldwide crop of economic importance susceptible to viral infections that can cause significant yield losses. Meristem tissue culture is the most employed method to sanitize elite cultivars.Often the virus-free garlic plants obtained are multiplied in vitro (micro propagation). However, it was reported that micro-propagation frequently produces somaclonal variation at the phenotypic level, which is an undesirable trait when breeders are seeking to maintain varietal stability. We employed amplification fragment length polymorphism and methylation sensitive amplified polymorphism (MSAP) methodologies to assess genetic and epigenetic modifications in two culture systems: virus-free plants obtained by meristem culture followed by in vitro multiplication and field culture. Our results suggest that garlic exhibits genetic and epigenetic polymorphism under field growing conditions. However, during in vitro culture system both kinds of polymorphisms intensify indicating that this system induces somaclonal variation. Furthermore, while genetic changes accumulated along the time of in vitro culture, epigenetic polymorphism reached the major variation at 6 months and then stabilize, being demethylation and CG methylation the principal conversions.Cloning and sequencing differentially methylated MSAP fragments allowed us to identify coding and unknown sequences of A. sativum, including sequences belonging to LTR Gypsy retrotransposons. Together, our results highlight that main changes occur in the initial 6 months of micro propagation. For the best of our knowledge, this is the first report on epigenetic assessment in garlic.

Decoding the disease-associated proteins encoded in the human chromosome 4.

PubMed

Chen, Lien-Chin; Liu, Mei-Ying; Hsiao, Yung-Chin; Choong, Wai-Kok; Wu, Hsin-Yi; Hsu, Wen-Lian; Liao, Pao-Chi; Sung, Ting-Yi; Tsai, Shih-Feng; Yu, Jau-Song; Chen, Yu-Ju

2013-01-04

Chromosome 4 is the fourth largest chromosome, containing approximately 191 megabases (~6.4% of the human genome) with 757 protein-coding genes. A number of marker genes for many diseases have been found in this chromosome, including genetic diseases (e.g., hepatocellular carcinoma) and biomedical research (cardiac system, aging, metabolic disorders, immune system, cancer and stem cell) related genes (e.g., oncogenes, growth factors). As a pilot study for the chromosome 4-centric human proteome project (Chr 4-HPP), we present here a systematic analysis of the disease association, protein isoforms, coding single nucleotide polymorphisms of these 757 protein-coding genes and their experimental evidence at the protein level. We also describe how the findings from the chromosome 4 project might be used to drive the biomarker discovery and validation study in disease-oriented projects, using the examples of secretomic and membrane proteomic approaches in cancer research. By integrating with cancer cell secretomes and several other existing databases in the public domain, we identified 141 chromosome 4-encoded proteins as cancer cell-secretable/shedable proteins. Additionally, we also identified 54 chromosome 4-encoded proteins that have been classified as cancer-associated proteins with successful selected or multiple reaction monitoring (SRM/MRM) assays developed. From literature annotation and topology analysis, 271 proteins were recognized as membrane proteins while 27.9% of the 757 proteins do not have any experimental evidence at the protein-level. In summary, the analysis revealed that the chromosome 4 is a rich resource for cancer-associated proteins for biomarker verification projects and for drug target discovery projects.

Functional Effects of Genetic Polymorphisms in the N-acetyltransferase 1 Coding and 3′ Untranslated Regions

PubMed Central

Zhu, Yuanqi; States, J. Christopher; Wang, Yang; Hein, David W.

2011-01-01

BACKGROUND The functional effects of N-acetyltransferase 1 (NAT1) polymorphisms and haplotypes are poorly understood, compromising the validity of associations reported with diseases including birth defects and numerous cancers. METHODS We investigated the effects of genetic polymorphisms within the NAT1 coding region and the 3′-untranslated region (3′-UTR) and their associated haplotypes on N- and O-acetyltransferase catalytic activities, and NAT1 mRNA and protein levels following recombinant expression in COS-1 cells. RESULTS 1088T>A (rs1057126; 3′-UTR) and 1095C>A (rs15561; 3′-UTR) each slightly reduced NAT1 catalytic activity and NAT1 mRNA and protein levels. A 9-base pair (TAATAATAA) deletion between nucleotides 1065-1090 (3′-UTR) reduced NAT1 catalytic activity and NAT1 mRNA and protein levels. In contrast, a 445G>A (rs4987076; V149I), 459G>A (rs4986990; T153T), 640T>G (rs4986783; S214A) coding region haplotype present in NAT1*11 increased NAT1 catalytic activity and NAT1 protein, but not NAT1 mRNA levels. A combination of the 9-base pair (TAATAATAA) deletion and the 445G>A, 459G>A, 640T>G coding region haplotypes, both present in NAT1*11, appeared to neutralize the opposing effects on NAT1 protein and catalytic activity, resulting in levels of NAT1 protein and catalytic activity that did not differ significantly from the NAT1*4 reference. CONCLUSIONS Since 1095C>A (3′-UTR) is the sole polymorphism present in NAT1*3, our data suggests that NAT1*3 is not functionally equivalent to the NAT1*4 reference. Furthermore, our findings provide biological support for reported associations of 1088T>A and 1095C>A polymorphisms with birth defects. PMID:21290563

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.

Introgression from Domestic Goat Generated Variation at the Major Histocompatibility Complex of Alpine Ibex

PubMed Central

Grossen, Christine; Keller, Lukas; Biebach, Iris; Croll, Daniel

2014-01-01

The major histocompatibility complex (MHC) is a crucial component of the vertebrate immune system and shows extremely high levels of genetic polymorphism. The extraordinary genetic variation is thought to be ancient polymorphisms maintained by balancing selection. However, introgression from related species was recently proposed as an additional mechanism. Here we provide evidence for introgression at the MHC in Alpine ibex (Capra ibex ibex). At a usually very polymorphic MHC exon involved in pathogen recognition (DRB exon 2), Alpine ibex carried only two alleles. We found that one of these DRB alleles is identical to a DRB allele of domestic goats (Capra aegagrus hircus). We sequenced 2489 bp of the coding and non-coding regions of the DRB gene and found that Alpine ibex homozygous for the goat-type DRB exon 2 allele showed nearly identical sequences (99.8%) to a breed of domestic goats. Using Sanger and RAD sequencing, microsatellite and SNP chip data, we show that the chromosomal region containing the goat-type DRB allele has a signature of recent introgression in Alpine ibex. A region of approximately 750 kb including the DRB locus showed high rates of heterozygosity in individuals carrying one copy of the goat-type DRB allele. These individuals shared SNP alleles both with domestic goats and other Alpine ibex. In a survey of four Alpine ibex populations, we found that the region surrounding the DRB allele shows strong linkage disequilibria, strong sequence clustering and low diversity among haplotypes carrying the goat-type allele. Introgression at the MHC is likely adaptive and introgression critically increased MHC DRB diversity in the genetically impoverished Alpine ibex. Our finding contradicts the long-standing view that genetic variability at the MHC is solely a consequence of ancient trans-species polymorphism. Introgression is likely an underappreciated source of genetic diversity at the MHC and other loci under balancing selection. PMID:24945814

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.

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

Phylogenetic distribution and expression of a penicillin-binding protein homologue, Ear and its significance in virulence of Staphylococcus aureus.

PubMed

Singh, Vineet K; Ring, Robert P; Aswani, Vijay; Stemper, Mary E; Kislow, Jennifer; Ye, Zhan; Shukla, Sanjay K

2017-12-01

Staphylococcus aureus is an opportunistic human pathogen that can cause serious infections in humans. A plethora of known and putative virulence factors are produced by staphylococci that collectively orchestrate pathogenesis. Ear protein (Escherichia coli ampicillin resistance) in S. aureus is an exoprotein in COL strain, predicted to be a superantigen, and speculated to play roles in antibiotic resistance and virulence. The goal of this study was to determine if expression of ear is modulated by single nucleotide polymorphisms in its promoter and coding sequences and whether this gene plays roles in antibiotic resistance and virulence. Promoter, coding sequences and expression of the ear gene in clinical and carriage S. aureus strains with distinct genetic backgrounds were analysed. The JE2 strain and its isogenic ear mutant were used in a systemic infection mouse model to determine the competiveness of the ear mutant.Results/Key findings. The ear gene showed a variable expression, with USA300FPR3757 showing a high-level expression compared to many of the other strains tested including some showing negligible expression. Higher expression was associated with agr type 1 but not correlated with phylogenetic relatedness of the ear gene based upon single nucleotide polymorphisms in the promoter or coding regions suggesting a complex regulation. An isogenic JE2 (USA300 background) ear mutant showed no significant difference in its growth, antibiotic susceptibility or virulence in a mouse model. Our data suggests that despite being highly expressed in a USA300 genetic background, Ear is not a significant contributor to virulence in that strain.

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.

Candidate innate immune system gene expression in the ecological model Daphnia

PubMed Central

Decaestecker, Ellen; Labbé, Pierrick; Ellegaard, Kirsten; Allen, Judith E.; Little, Tom J.

2011-01-01

The last ten years have witnessed increasing interest in host–pathogen interactions involving invertebrate hosts. The invertebrate innate immune system is now relatively well characterised, but in a limited range of genetic model organisms and under a limited number of conditions. Immune systems have been little studied under real-world scenarios of environmental variation and parasitism. Thus, we have investigated expression of candidate innate immune system genes in the water flea Daphnia, a model organism for ecological genetics, and whose capacity for clonal reproduction facilitates an exceptionally rigorous control of exposure dose or the study of responses at many time points. A unique characteristic of the particular Daphnia clones and pathogen strain combinations used presently is that they have been shown to be involved in specific host–pathogen coevolutionary interactions in the wild. We choose five genes, which are strong candidates to be involved in Daphnia–pathogen interactions, given that they have been shown to code for immune effectors in related organisms. Differential expression of these genes was quantified by qRT-PCR following exposure to the bacterial pathogen Pasteuria ramosa. Constitutive expression levels differed between host genotypes, and some genes appeared to show correlated expression. However, none of the genes appeared to show a major modification of expression level in response to Pasteuria exposure. By applying knowledge from related genetic model organisms (e.g. Drosophila) to models for the study of evolutionary ecology and coevolution (i.e. Daphnia), the candidate gene approach is temptingly efficient. However, our results show that detection of only weak patterns is likely if one chooses target genes for study based on previously identified genome sequences by comparison to homologues from other related organisms. Future work on the Daphnia–Pasteuria system will need to balance a candidate gene approach with more comprehensive approaches to de novo identify immune system genes specific to the Daphnia–Pasteuria interaction. PMID:21550363

Candidate innate immune system gene expression in the ecological model Daphnia.

PubMed

Decaestecker, Ellen; Labbé, Pierrick; Ellegaard, Kirsten; Allen, Judith E; Little, Tom J

2011-10-01

The last ten years have witnessed increasing interest in host-pathogen interactions involving invertebrate hosts. The invertebrate innate immune system is now relatively well characterised, but in a limited range of genetic model organisms and under a limited number of conditions. Immune systems have been little studied under real-world scenarios of environmental variation and parasitism. Thus, we have investigated expression of candidate innate immune system genes in the water flea Daphnia, a model organism for ecological genetics, and whose capacity for clonal reproduction facilitates an exceptionally rigorous control of exposure dose or the study of responses at many time points. A unique characteristic of the particular Daphnia clones and pathogen strain combinations used presently is that they have been shown to be involved in specific host-pathogen coevolutionary interactions in the wild. We choose five genes, which are strong candidates to be involved in Daphnia-pathogen interactions, given that they have been shown to code for immune effectors in related organisms. Differential expression of these genes was quantified by qRT-PCR following exposure to the bacterial pathogen Pasteuria ramosa. Constitutive expression levels differed between host genotypes, and some genes appeared to show correlated expression. However, none of the genes appeared to show a major modification of expression level in response to Pasteuria exposure. By applying knowledge from related genetic model organisms (e.g. Drosophila) to models for the study of evolutionary ecology and coevolution (i.e. Daphnia), the candidate gene approach is temptingly efficient. However, our results show that detection of only weak patterns is likely if one chooses target genes for study based on previously identified genome sequences by comparison to homologues from other related organisms. Future work on the Daphnia-Pasteuria system will need to balance a candidate gene approach with more comprehensive approaches to de novo identify immune system genes specific to the Daphnia-Pasteuria interaction. Copyright © 2011 Elsevier Ltd. All rights reserved.

Comparison of procedure coding systems for level 1 and 2 hospitals in South Africa.

PubMed

Montewa, Lebogang; Hanmer, Lyn; Reagon, Gavin

2013-01-01

The ability of three procedure coding systems to reflect the procedure concepts extracted from patient records from six hospitals was compared, in order to inform decision making about a procedure coding standard for South Africa. A convenience sample of 126 procedure concepts was extracted from patient records at three level 1 hospitals and three level 2 hospitals. Each procedure concept was coded using ICPC-2, ICD-9-CM, and CCSA-2001. The extent to which each code assigned actually reflected the procedure concept was evaluated (between 'no match' and 'complete match'). For the study sample, CCSA-2001 was found to reflect the procedure concepts most completely, followed by ICD-9-CM and then ICPC-2. In practice, decision making about procedure coding standards would depend on multiple factors in addition to coding accuracy.

Translation efficiency of heterologous proteins is significantly affected by the genetic context of RBS sequences in engineered cyanobacterium Synechocystis sp. PCC 6803.

PubMed

Thiel, Kati; Mulaku, Edita; Dandapani, Hariharan; Nagy, Csaba; Aro, Eva-Mari; Kallio, Pauli

2018-03-02

Photosynthetic cyanobacteria have been studied as potential host organisms for direct solar-driven production of different carbon-based chemicals from CO 2 and water, as part of the development of sustainable future biotechnological applications. The engineering approaches, however, are still limited by the lack of comprehensive information on most optimal expression strategies and validated species-specific genetic elements which are essential for increasing the intricacy, predictability and efficiency of the systems. This study focused on the systematic evaluation of the key translational control elements, ribosome binding sites (RBS), in the cyanobacterial host Synechocystis sp. PCC 6803, with the objective of expanding the palette of tools for more rigorous engineering approaches. An expression system was established for the comparison of 13 selected RBS sequences in Synechocystis, using several alternative reporter proteins (sYFP2, codon-optimized GFPmut3 and ethylene forming enzyme) as quantitative indicators of the relative translation efficiencies. The set-up was shown to yield highly reproducible expression patterns in independent analytical series with low variation between biological replicates, thus allowing statistical comparison of the activities of the different RBSs in vivo. While the RBSs covered a relatively broad overall expression level range, the downstream gene sequence was demonstrated in a rigorous manner to have a clear impact on the resulting translational profiles. This was expected to reflect interfering sequence-specific mRNA-level interaction between the RBS and the coding region, yet correlation between potential secondary structure formation and observed translation levels could not be resolved with existing in silico prediction tools. The study expands our current understanding on the potential and limitations associated with the regulation of protein expression at translational level in engineered cyanobacteria. The acquired information can be used for selecting appropriate RBSs for optimizing over-expression constructs or multicistronic pathways in Synechocystis, while underlining the complications in predicting the activity due to gene-specific interactions which may reduce the translational efficiency for a given RBS-gene combination. Ultimately, the findings emphasize the need for additional characterized insulator sequence elements to decouple the interaction between the RBS and the coding region for future engineering approaches.

The system-resonance approach in modeling genetic structures.

PubMed

Petoukhov, Sergey V

2016-01-01

The founder of the theory of resonance in structural chemistry Linus Pauling established the importance of resonance patterns in organization of living systems. Any living organism is a great chorus of coordinated oscillatory processes. From the formal point of view, biological organism is an oscillatory system with a great number of degrees of freedom. Such systems are studied in the theory of oscillations using matrix mathematics of their resonance characteristics. This study is devoted to a new approach for modeling genetically inherited structures and processes in living organisms using mathematical tools of the theory of resonances. This approach reveals hidden relationships in a number of genetic phenomena and gives rise to a new class of bio-mathematical models, which contribute to a convergence of biology with physics and informatics. In addition some relationships of molecular-genetic ensembles with mathematics of noise-immunity coding of information in modern communications technology are shown. Perspectives of applications of the phenomena of vibrational mechanics for modeling in biology are discussed. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

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.…

Enhanced 2/3 four-ary modulation code using soft-decision Viterbi decoding for four-level holographic data storage systems

NASA Astrophysics Data System (ADS)

Kong, Gyuyeol; Choi, Sooyong

2017-09-01

An enhanced 2/3 four-ary modulation code using soft-decision Viterbi decoding is proposed for four-level holographic data storage systems. While the previous four-ary modulation codes focus on preventing maximum two-dimensional intersymbol interference patterns, the proposed four-ary modulation code aims at maximizing the coding gains for better bit error rate performances. For achieving significant coding gains from the four-ary modulation codes, we design a new 2/3 four-ary modulation code in order to enlarge the free distance on the trellis through extensive simulation. The free distance of the proposed four-ary modulation code is extended from 1.21 to 2.04 compared with that of the conventional four-ary modulation code. The simulation result shows that the proposed four-ary modulation code has more than 1 dB gains compared with the conventional four-ary modulation code.

The neurovirulence and neuroinvasiveness of chimeric tick-borne encephalitis/dengue virus can be attenuated by introducing defined mutations into the envelope and NS5 protein genes and the 3' non-coding region of the genome

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

Engel, Amber R., E-mail: engelam@mail.nih.go; Rumyantsev, Alexander A., E-mail: alexander.rumyantsev@sanofipasteur.co; Maximova, Olga A., E-mail: maximovao@mail.nih.go

Tick-borne encephalitis (TBE) is a severe disease affecting thousands of people throughout Eurasia. Despite the use of formalin-inactivated vaccines in endemic areas, an increasing incidence of TBE emphasizes the need for an alternative vaccine that will induce a more durable immunity against TBE virus (TBEV). The chimeric attenuated virus vaccine candidate containing the structural protein genes of TBEV on a dengue virus genetic background (TBEV/DEN4) retains a high level of neurovirulence in both mice and monkeys. Therefore, attenuating mutations were introduced into the envelope (E{sub 315}) and NS5 (NS5{sub 654,655}) proteins, and into the 3' non-coding region ({Delta}30) of TBEV/DEN4.more » The variant that contained all three mutations (v{Delta}30/E{sub 315}/NS5{sub 654,655}) was significantly attenuated for neuroinvasiveness and neurovirulence and displayed a reduced level of replication and virus-induced histopathology in the brains of mice. The high level of safety in the central nervous system indicates that v{Delta}30/E{sub 315}/NS5{sub 654,655} should be further evaluated as a TBEV vaccine.« less

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.

JavaGenes Molecular Evolution

NASA Technical Reports Server (NTRS)

Lohn, Jason; Smith, David; Frank, Jeremy; Globus, Al; Crawford, James

2007-01-01

JavaGenes is a general-purpose, evolutionary software system written in Java. It implements several versions of a genetic algorithm, simulated annealing, stochastic hill climbing, and other search techniques. This software has been used to evolve molecules, atomic force field parameters, digital circuits, Earth Observing Satellite schedules, and antennas. This version differs from version 0.7.28 in that it includes the molecule evolution code and other improvements. Except for the antenna code, JaveGenes is available for NASA Open Source distribution.

Copy Number Variants and Congenital Anomalies Surveillance: A Suggested Coding Strategy Using the Royal College of Paediatrics and Child Health Version of ICD-10.

PubMed

Bedard, Tanya; Lowry, R Brian; Sibbald, Barbara; Thomas, Mary Ann; Innes, A Micheil

2016-01-01

The use of array-based comparative genomic hybridization to assess DNA copy number is increasing in many jurisdictions. Such technology identifies more genetic causes of congenital anomalies; however, the clinical significance of some results may be challenging to interpret. A coding strategy to address cases with copy number variants has recently been implemented by the Alberta Congenital Anomalies Surveillance System and is described.

BioCichlid: central dogma-based 3D visualization system of time-course microarray data on a hierarchical biological network.

PubMed

Ishiwata, Ryosuke R; Morioka, Masaki S; Ogishima, Soichi; Tanaka, Hiroshi

2009-02-15

BioCichlid is a 3D visualization system of time-course microarray data on molecular networks, aiming at interpretation of gene expression data by transcriptional relationships based on the central dogma with physical and genetic interactions. BioCichlid visualizes both physical (protein) and genetic (regulatory) network layers, and provides animation of time-course gene expression data on the genetic network layer. Transcriptional regulations are represented to bridge the physical network (transcription factors) and genetic network (regulated genes) layers, thus integrating promoter analysis into the pathway mapping. BioCichlid enhances the interpretation of microarray data and allows for revealing the underlying mechanisms causing differential gene expressions. BioCichlid is freely available and can be accessed at http://newton.tmd.ac.jp/. Source codes for both biocichlid server and client are also available.

Deadlock-free genetic scheduling algorithm for automated manufacturing systems based on deadlock control policy.

PubMed

Xing, KeYi; Han, LiBin; Zhou, MengChu; Wang, Feng

2012-06-01

Deadlock-free control and scheduling are vital for optimizing the performance of automated manufacturing systems (AMSs) with shared resources and route flexibility. Based on the Petri net models of AMSs, this paper embeds the optimal deadlock avoidance policy into the genetic algorithm and develops a novel deadlock-free genetic scheduling algorithm for AMSs. A possible solution of the scheduling problem is coded as a chromosome representation that is a permutation with repetition of parts. By using the one-step look-ahead method in the optimal deadlock control policy, the feasibility of a chromosome is checked, and infeasible chromosomes are amended into feasible ones, which can be easily decoded into a feasible deadlock-free schedule. The chromosome representation and polynomial complexity of checking and amending procedures together support the cooperative aspect of genetic search for scheduling problems strongly.

Is my study system good enough? A case study for identifying maternal effects.

PubMed

Holand, Anna Marie; Steinsland, Ingelin

2016-06-01

In this paper, we demonstrate how simulation studies can be used to answer questions about identifiability and consequences of omitting effects from a model. The methodology is presented through a case study where identifiability of genetic and/or individual (environmental) maternal effects is explored. Our study system is a wild house sparrow ( Passer domesticus ) population with known pedigree. We fit pedigree-based (generalized) linear mixed models (animal models), with and without additive genetic and individual maternal effects, and use deviance information criterion (DIC) for choosing between these models. Pedigree and R-code for simulations are available. For this study system, the simulation studies show that only large maternal effects can be identified. The genetic maternal effect (and similar for individual maternal effect) has to be at least half of the total genetic variance to be identified. The consequences of omitting a maternal effect when it is present are explored. Our results indicate that the total (genetic and individual) variance are accounted for. When an individual (environmental) maternal effect is omitted from the model, this only influences the estimated (direct) individual (environmental) variance. When a genetic maternal effect is omitted from the model, both (direct) genetic and (direct) individual variance estimates are overestimated.

Neuronal cell fate specification by the molecular convergence of different spatio-temporal cues on a common initiator terminal selector gene

PubMed Central

Stratmann, Johannes

2017-01-01

The extensive genetic regulatory flows underlying specification of different neuronal subtypes are not well understood at the molecular level. The Nplp1 neuropeptide neurons in the developing Drosophila nerve cord belong to two sub-classes; Tv1 and dAp neurons, generated by two distinct progenitors. Nplp1 neurons are specified by spatial cues; the Hox homeotic network and GATA factor grn, and temporal cues; the hb -> Kr -> Pdm -> cas -> grh temporal cascade. These spatio-temporal cues combine into two distinct codes; one for Tv1 and one for dAp neurons that activate a common terminal selector feedforward cascade of col -> ap/eya -> dimm -> Nplp1. Here, we molecularly decode the specification of Nplp1 neurons, and find that the cis-regulatory organization of col functions as an integratory node for the different spatio-temporal combinatorial codes. These findings may provide a logical framework for addressing spatio-temporal control of neuronal sub-type specification in other systems. PMID:28414802

Enhanced fault-tolerant quantum computing in d-level systems.

PubMed

Campbell, Earl T

2014-12-05

Error-correcting codes protect quantum information and form the basis of fault-tolerant quantum computing. Leading proposals for fault-tolerant quantum computation require codes with an exceedingly rare property, a transversal non-Clifford gate. Codes with the desired property are presented for d-level qudit systems with prime d. The codes use n=d-1 qudits and can detect up to ∼d/3 errors. We quantify the performance of these codes for one approach to quantum computation known as magic-state distillation. Unlike prior work, we find performance is always enhanced by increasing d.

Error-correction coding for digital communications

NASA Astrophysics Data System (ADS)

Clark, G. C., Jr.; Cain, J. B.

This book is written for the design engineer who must build the coding and decoding equipment and for the communication system engineer who must incorporate this equipment into a system. It is also suitable as a senior-level or first-year graduate text for an introductory one-semester course in coding theory. Fundamental concepts of coding are discussed along with group codes, taking into account basic principles, practical constraints, performance computations, coding bounds, generalized parity check codes, polynomial codes, and important classes of group codes. Other topics explored are related to simple nonalgebraic decoding techniques for group codes, soft decision decoding of block codes, algebraic techniques for multiple error correction, the convolutional code structure and Viterbi decoding, syndrome decoding techniques, and sequential decoding techniques. System applications are also considered, giving attention to concatenated codes, coding for the white Gaussian noise channel, interleaver structures for coded systems, and coding for burst noise channels.

Efficient transformation of an auditory population code in a small sensory system.

PubMed

Clemens, Jan; Kutzki, Olaf; Ronacher, Bernhard; Schreiber, Susanne; Wohlgemuth, Sandra

2011-08-16

Optimal coding principles are implemented in many large sensory systems. They include the systematic transformation of external stimuli into a sparse and decorrelated neuronal representation, enabling a flexible readout of stimulus properties. Are these principles also applicable to size-constrained systems, which have to rely on a limited number of neurons and may only have to fulfill specific and restricted tasks? We studied this question in an insect system--the early auditory pathway of grasshoppers. Grasshoppers use genetically fixed songs to recognize mates. The first steps of neural processing of songs take place in a small three-layer feed-forward network comprising only a few dozen neurons. We analyzed the transformation of the neural code within this network. Indeed, grasshoppers create a decorrelated and sparse representation, in accordance with optimal coding theory. Whereas the neuronal input layer is best read out as a summed population, a labeled-line population code for temporal features of the song is established after only two processing steps. At this stage, information about song identity is maximal for a population decoder that preserves neuronal identity. We conclude that optimal coding principles do apply to the early auditory system of the grasshopper, despite its size constraints. The inputs, however, are not encoded in a systematic, map-like fashion as in many larger sensory systems. Already at its periphery, part of the grasshopper auditory system seems to focus on behaviorally relevant features, and is in this property more reminiscent of higher sensory areas in vertebrates.

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

Genetic therapy for the nervous system.

PubMed

Bowers, William J; Breakefield, Xandra O; Sena-Esteves, Miguel

2011-04-15

Genetic therapy is undergoing a renaissance with expansion of viral and synthetic vectors, use of oligonucleotides (RNA and DNA) and sequence-targeted regulatory molecules, as well as genetically modified cells, including induced pluripotent stem cells from the patients themselves. Several clinical trials for neurologic syndromes appear quite promising. This review covers genetic strategies to ameliorate neurologic syndromes of different etiologies, including lysosomal storage diseases, Alzheimer's disease and other amyloidopathies, Parkinson's disease, spinal muscular atrophy, amyotrophic lateral sclerosis and brain tumors. This field has been propelled by genetic technologies, including identifying disease genes and disruptive mutations, design of genomic interacting elements to regulate transcription and splicing of specific precursor mRNAs and use of novel non-coding regulatory RNAs. These versatile new tools for manipulation of genetic elements provide the ability to tailor the mode of genetic intervention to specific aspects of a disease state.

Studying the genetic basis of speciation in high gene flow marine invertebrates

PubMed Central

2016-01-01

A growing number of genes responsible for reproductive incompatibilities between species (barrier loci) exhibit the signals of positive selection. However, the possibility that genes experiencing positive selection diverge early in speciation and commonly cause reproductive incompatibilities has not been systematically investigated on a genome-wide scale. Here, I outline a research program for studying the genetic basis of speciation in broadcast spawning marine invertebrates that uses a priori genome-wide information on a large, unbiased sample of genes tested for positive selection. A targeted sequence capture approach is proposed that scores single-nucleotide polymorphisms (SNPs) in widely separated species populations at an early stage of allopatric divergence. The targeted capture of both coding and non-coding sequences enables SNPs to be characterized at known locations across the genome and at genes with known selective or neutral histories. The neutral coding and non-coding SNPs provide robust background distributions for identifying FST-outliers within genes that can, in principle, identify specific mutations experiencing diversifying selection. If natural hybridization occurs between species, the neutral coding and non-coding SNPs can provide a neutral admixture model for genomic clines analyses aimed at finding genes exhibiting strong blocks to introgression. Strongylocentrotid sea urchins are used as a model system to outline the approach but it can be used for any group that has a complete reference genome available. PMID:29491951

Towards defining the role of glycans as hardware in information storage and transfer: basic principles, experimental approaches and recent progress.

PubMed

Solís, D; Jiménez-Barbero, J; Kaltner, H; Romero, A; Siebert, H C; von der Lieth, C W; Gabius, H J

2001-01-01

The term 'code' in biological information transfer appears to be tightly and hitherto exclusively connected with the genetic code based on nucleotides and translated into functional activities via proteins. However, the recent appreciation of the enormous coding capacity of oligosaccharide chains of natural glycoconjugates has spurred to give heed to a new concept: versatile glycan assembly by the genetically encoded glycosyltransferases endows cells with a probably not yet fully catalogued array of meaningful messages. Enciphered by sugar receptors such as endogenous lectins the information of code words established by a series of covalently linked monosaccharides as letters for example guides correct intra- and intercellular routing of glycoproteins, modulates cell proliferation or migration and mediates cell adhesion. Evidently, the elucidation of the structural frameworks and the recognition strategies within the operation of the sugar code poses a fascinating conundrum. The far-reaching impact of this recognition mode on the level of cells, tissues and organs has fueled vigorous investigations to probe the subtleties of protein-carbohydrate interactions. This review presents information on the necessarily concerted approach using X-ray crystallography, molecular modeling, nuclear magnetic resonance spectroscopy, thermodynamic analysis and engineered ligands and receptors. This part of the treatise is flanked by exemplarily chosen insights made possible by these techniques. Copyright 2001 S. Karger AG, Basel

[Genetic diversity of common wheat varieties at the gliadin-coding loci].

PubMed

Novoselskaya-Dragovich, A Yu; Bespalova, L A; Shishkina, A A; Melnik, V A; Upelniek, V P; Fisenko, A V; Dedova, L V; Kudryavtsev, A M

2015-03-01

One hundred and fifty Russian and foreign winter common wheat varieties were examined by the PAGE method. A total of 70 alleles were identified at seven gliadin-coding loci. It was demonstrated that 42% of varieties were heterogeneous, i.e., were represented by a number of genotypes, while 52% of varieties were homogeneous. A unique combination of gliadin alleles was typical of 91.3% of examined varieties, while 8.7% of varieties had identical alleles of all gliadin-coding loci and were indistinguishable. Frequent and rare alleles were identified, with the former accounting for 18.6% of all alleles. It was demonstrated that allelic diversity at the Gli-2 loci (47 alleles) was almost twice that at the Gli-1 loci (23 loci) and was determined by the number of rare alleles. New alleles for the winter common wheat, including three alleles of the GliA2 locus and two alleles of the Gli-B2 locus, were determined. A tendency toward a reduction of the genetic diversity level in modern varieties, which was due to the use of identical parental varieties in breeding programs, was identified.

Variation in Seed Fatty Acid Composition, and Sequence Divergence in the FAD2 Gene Coding Region between Wild and Cultivated Sesame

USDA-ARS?s Scientific Manuscript database

Sesame germplasm harbors genetic diversity which can be useful for sesame improvement in breeding programs. Seven accessions with different levels of oleic acid were selected from the entire USDA sesame germplasm collection (1232 accessions) and planted for morphological observation and re-examinati...

Systematic reconstruction of autism biology from massive genetic mutation profiles

PubMed Central

Zhang, Chaolin; Jiang, Yong-hui

2018-01-01

Autism spectrum disorder (ASD) affects 1% of world population and has become a pressing medical and social problem worldwide. As a paradigmatic complex genetic disease, ASD has been intensively studied and thousands of gene mutations have been reported. Because these mutations rarely recur, it is difficult to (i) pinpoint the fewer disease-causing versus majority random events and (ii) replicate or verify independent studies. A coherent and systematic understanding of autism biology has not been achieved. We analyzed 3392 and 4792 autism-related mutations from two large-scale whole-exome studies across multiple resolution levels, that is, variants (single-nucleotide), genes (protein-coding unit), and pathways (molecular module). These mutations do not recur or replicate at the variant level, but significantly and increasingly do so at gene and pathway levels. Genetic association reveals a novel gene + pathway dual-hit model, where the mutation burden becomes less relevant. In multiple independent analyses, hundreds of variants or genes repeatedly converge to several canonical pathways, either novel or literature-supported. These pathways define recurrent and systematic ASD biology, distinct from previously reported gene groups or networks. They also present a catalog of novel ASD risk factors including 118 variants and 72 genes. At a subpathway level, most variants disrupt the pathway-related gene functions, and in the same gene, they tend to hit residues extremely close to each other and in the same domain. Multiple interacting variants spotlight key modules, including the cAMP (adenosine 3′,5′-monophosphate) second-messenger system and mGluR (metabotropic glutamate receptor) signaling regulation by GRKs (G protein–coupled receptor kinases). At a superpathway level, distinct pathways further interconnect and converge to three biology themes: synaptic function, morphology, and plasticity. PMID:29651456

Systematic reconstruction of autism biology from massive genetic mutation profiles.

PubMed

Luo, Weijun; Zhang, Chaolin; Jiang, Yong-Hui; Brouwer, Cory R

2018-04-01

Autism spectrum disorder (ASD) affects 1% of world population and has become a pressing medical and social problem worldwide. As a paradigmatic complex genetic disease, ASD has been intensively studied and thousands of gene mutations have been reported. Because these mutations rarely recur, it is difficult to (i) pinpoint the fewer disease-causing versus majority random events and (ii) replicate or verify independent studies. A coherent and systematic understanding of autism biology has not been achieved. We analyzed 3392 and 4792 autism-related mutations from two large-scale whole-exome studies across multiple resolution levels, that is, variants (single-nucleotide), genes (protein-coding unit), and pathways (molecular module). These mutations do not recur or replicate at the variant level, but significantly and increasingly do so at gene and pathway levels. Genetic association reveals a novel gene + pathway dual-hit model, where the mutation burden becomes less relevant. In multiple independent analyses, hundreds of variants or genes repeatedly converge to several canonical pathways, either novel or literature-supported. These pathways define recurrent and systematic ASD biology, distinct from previously reported gene groups or networks. They also present a catalog of novel ASD risk factors including 118 variants and 72 genes. At a subpathway level, most variants disrupt the pathway-related gene functions, and in the same gene, they tend to hit residues extremely close to each other and in the same domain. Multiple interacting variants spotlight key modules, including the cAMP (adenosine 3',5'-monophosphate) second-messenger system and mGluR (metabotropic glutamate receptor) signaling regulation by GRKs (G protein-coupled receptor kinases). At a superpathway level, distinct pathways further interconnect and converge to three biology themes: synaptic function, morphology, and plasticity.

Characterization of an Equine α-S2-Casein Variant Due to a 1.3 kb Deletion Spanning Two Coding Exons

PubMed Central

Brinkmann, Julia; Koudelka, Tomas; Keppler, Julia K.; Tholey, Andreas; Schwarz, Karin; Thaller, Georg; Tetens, Jens

2015-01-01

The production and consumption of mare’s milk in Europe has gained importance, mainly based on positive health effects and a lower allergenic potential as compared to cows’ milk. The allergenicity of milk is to a certain extent affected by different genetic variants. In classical dairy species, much research has been conducted into the genetic variability of milk proteins, but the knowledge in horses is scarce. Here, we characterize two major forms of equine αS2-casein arising from genomic 1.3 kb in-frame deletion involving two coding exons, one of which represents an equid specific duplication. Findings at the DNA-level have been verified by cDNA sequencing from horse milk of mares with different genotypes. At the protein-level, we were able to show by SDS-page and in-gel digestion with subsequent LC-MS analysis that both proteins are actually expressed. The comparison with published sequences of other equids revealed that the deletion has probably occurred before the ancestor of present-day asses and zebras diverged from the horse lineage. PMID:26444874

System Design for FEC in Aeronautical Telemetry

DTIC Science & Technology

2012-03-12

rate punctured convolutional codes for soft decision Viterbi...below follows that given in [8]. The final coding rate of exactly 2/3 is achieved by puncturing the rate -1/2 code as follows. We begin with the buffer c1...concatenated convolutional code (SCCC). The contributions of this paper are on the system-design level. One major contribution is to design a SCCC code

How anonymous is ‘anonymous’? Some suggestions towards a coherent universal coding system for genetic samples

PubMed Central

Schmidt, Harald; Callier, Shawneequa

2012-01-01

So-called ‘anonymous’ tissue samples are widely used in research. Because they lack externally identifying information, they are viewed as useful in reconciling conflicts between the control, privacy and confidentiality interests of those from whom the samples originated and the public (or commercial) interest in carrying out research, as reflected in ‘consent or anonymise’ policies. High level guidance documents suggest that withdrawal of consent and samples and the provision of feedback are impossible in the case of anonymous samples. In view of recent developments in science and consumer-driven genomics the authors argue that such statements are misleading and only muddle complex ethical questions about possible entitlements to control over samples. The authors therefore propose that terms such as ‘anonymised’, ‘anonymous’ or ‘non-identifiable’ be removed entirely from documents describing research samples, especially from those aimed at the public. This is necessary as a matter of conceptual clarity and because failure to do so may jeopardise public trust in the governance of large scale databases. As there is wide variation in the taxonomy for tissue samples and no uniform national or international standards, the authors propose that a numeral-based universal coding system be implemented that focuses on specifying incremental levels of identifiability, rather than use terms that imply that the reidentification of research samples and associated actions are categorically impossible. PMID:22345546

How anonymous is 'anonymous'? Some suggestions towards a coherent universal coding system for genetic samples.

PubMed

Schmidt, Harald; Callier, Shawneequa

2012-05-01

So-called 'anonymous' tissue samples are widely used in research. Because they lack externally identifying information, they are viewed as useful in reconciling conflicts between the control, privacy and confidentiality interests of those from whom the samples originated and the public (or commercial) interest in carrying out research, as reflected in 'consent or anonymise' policies. High level guidance documents suggest that withdrawal of consent and samples and the provision of feedback are impossible in the case of anonymous samples. In view of recent developments in science and consumer-driven genomics the authors argue that such statements are misleading and only muddle complex ethical questions about possible entitlements to control over samples. The authors therefore propose that terms such as 'anonymised', 'anonymous' or 'non-identifiable' be removed entirely from documents describing research samples, especially from those aimed at the public. This is necessary as a matter of conceptual clarity and because failure to do so may jeopardise public trust in the governance of large scale databases. As there is wide variation in the taxonomy for tissue samples and no uniform national or international standards, the authors propose that a numeral-based universal coding system be implemented that focuses on specifying incremental levels of identifiability, rather than use terms that imply that the reidentification of research samples and associated actions are categorically impossible.

Intramolecular interactions in aminoacyl nucleotides: Implications regarding the origin of genetic coding and protein synthesis

NASA Technical Reports Server (NTRS)

Lacey, J. C., Jr.; Mullins, D. W., Jr.; Watkins, C. L.; Hall, L. M.

1986-01-01

Cellular organisms store information as sequences of nucleotides in double stranded DNA. This information is useless unless it can be converted into the active molecular species, protein. This is done in contemporary creatures first by transcription of one strand to give a complementary strand of mRNA. The sequence of nucleotides is then translated into a specific sequence of amino acids in a protein. Translation is made possible by a genetic coding system in which a sequence of three nucleotides codes for a specific amino acid. The origin and evolution of any chemical system can be understood through elucidation of the properties of the chemical entities which make up the system. There is an underlying logic to the coding system revealed by a correlation of the hydrophobicities of amino acids and their anticodonic nucleotides (i.e., the complement of the codon). Its importance lies in the fact that every amino acid going into protein synthesis must first be activated. This is universally accomplished with ATP. Past studies have concentrated on the chemistry of the adenylates, but more recently we have found, through the use of NMR, that we can observe intramolecular interactions even at low concentrations, between amino acid side chains and nucleotide base rings in these adenylates. The use of this type of compound thus affords a novel way of elucidating the manner in which amino acids and nucleotides interact with each other. In aqueous solution, when a hydrophobic amino acid is attached to the most hydrophobic nucleotide, AMP, a hydrophobic interaction takes place between the amino acid side chain and the adenine ring. The studies to be reported concern these hydrophobic interactions.

Perceptron Genetic to Recognize Openning Strategy Ruy Lopez

NASA Astrophysics Data System (ADS)

Azmi, Zulfian; Mawengkang, Herman

2018-01-01

The application of Perceptron method is not effective for coding on hardware based systems because it is not real time learning. With Genetic algorithm approach in calculating and searching the best weight (fitness value) system will do learning only one iteration. And the results of this analysis were tested in the case of the introduction of the opening pattern of chess Ruy Lopez. The Analysis with Perceptron Model with Algorithm Approach Genetics from group Artificial Neural Network for open Ruy Lopez. The data is processed with base open chess, with step eight a position white Pion from end open chess. Using perceptron method have many input and one output process many weight and refraction until output equal goal. Data trained and test with software Matlab and system can recognize the chess opening Ruy Lopez or Not open Ruy Lopez with Real time.

An expanded genetic code in mammalian cells with a functional quadruplet codon.

PubMed

Niu, Wei; Schultz, Peter G; Guo, Jiantao

2013-07-19

We have utilized in vitro evolution to identify tRNA variants with significantly enhanced activity for the incorporation of unnatural amino acids into proteins in response to a quadruplet codon in both bacterial and mammalian cells. This approach will facilitate the creation of an optimized and standardized system for the genetic incorporation of unnatural amino acids using quadruplet codons, which will allow the biosynthesis of biopolymers that contain multiple unnatural building blocks.

The Social Interactive Coding System (SICS): An On-Line, Clinically Relevant Descriptive Tool.

ERIC Educational Resources Information Center

Rice, Mabel L.; And Others

1990-01-01

The Social Interactive Coding System (SICS) assesses the continuous verbal interactions of preschool children as a function of play areas, addressees, script codes, and play levels. This paper describes the 26 subjects and the setting involved in SICS development, coding definitions and procedures, training procedures, reliability, sample…

Recombination within the nonstructural genes of the parvovirus minute virus of mice (MVM) generates functional levels of wild-type NS1, which can be detected in the absence of selective pressure following transfection of nonreplicating plasmids.

PubMed

Pearson, J L; Pintel, D J

2000-03-30

Recombination within the coding region of the nonstructural genes of minute virus of mice (MVM), which generates functional levels of wild-type NS1, was observed in the absence of selective pressure following cotransfection of nonreplicating plasmids. P38 activity was used as a measure of recombinant NS1 production, which, together with direct detection of recombinant-generated products by RT-PCR, allowed an estimation of recombination efficiency. In addition, we show that very low levels of wild-type NS1 were able to significantly transactivate P38. Given that recombination following cotransfection can generate NS1 at these levels, our observations have implications for the study of parvoviral genetics, the construction of recombinant parvoviral vectors for gene therapy applications, and perhaps other systems using cotransfection of plasmids that share homologous sequences. Copyright 2000 Academic Press.

Industry and Occupation in the Electronic Health Record: An Investigation of the National Institute for Occupational Safety and Health Industry and Occupation Computerized Coding System.

PubMed

Schmitz, Matthew; Forst, Linda

2016-02-15

Inclusion of information about a patient's work, industry, and occupation, in the electronic health record (EHR) could facilitate occupational health surveillance, better health outcomes, prevention activities, and identification of workers' compensation cases. The US National Institute for Occupational Safety and Health (NIOSH) has developed an autocoding system for "industry" and "occupation" based on 1990 Bureau of Census codes; its effectiveness requires evaluation in conjunction with promoting the mandatory addition of these variables to the EHR. The objective of the study was to evaluate the intercoder reliability of NIOSH's Industry and Occupation Computerized Coding System (NIOCCS) when applied to data collected in a community survey conducted under the Affordable Care Act; to determine the proportion of records that are autocoded using NIOCCS. Standard Occupational Classification (SOC) codes are used by several federal agencies in databases that capture demographic, employment, and health information to harmonize variables related to work activities among these data sources. There are 359 industry and occupation responses that were hand coded by 2 investigators, who came to a consensus on every code. The same variables were autocoded using NIOCCS at the high and moderate criteria level. Kappa was .84 for agreement between hand coders and between the hand coder consensus code versus NIOCCS high confidence level codes for the first 2 digits of the SOC code. For 4 digits, NIOCCS coding versus investigator coding ranged from kappa=.56 to .70. In this study, NIOCCS was able to achieve production rates (ie, to autocode) 31%-36% of entered variables at the "high confidence" level and 49%-58% at the "medium confidence" level. Autocoding (production) rates are somewhat lower than those reported by NIOSH. Agreement between manually coded and autocoded data are "substantial" at the 2-digit level, but only "fair" to "good" at the 4-digit level. This work serves as a baseline for performance of NIOCCS by investigators in the field. Further field testing will clarify NIOCCS effectiveness in terms of ability to assign codes and coding accuracy and will clarify its value as inclusion of these occupational variables in the EHR is promoted.

A bicistronic transgene system for genetic modification of Parthenium argentatum

USDA-ARS?s Scientific Manuscript database

Parthenium argentatum (guayule) was transformed with a bicistronic transgene containing a viral 2A cleavage sequence. The transgene includes the coding sequences of two key enzymes of the mevalonate pathway, 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) and farnesyl pyrophosphate synthase (FPPS), ...

Progress toward a reduced phage genetic code.

PubMed

Yao, Anzhi; Reed, Sean A; Koh, Minseob; Yu, Chenguang; Luo, Xiaozhou; Mehta, Angad P; Schultz, Peter G

2018-03-26

All known living organisms use at least 20 amino acids as the basic building blocks of life. Efforts to reduce the number of building blocks in a replicating system to below the 20 canonical amino acids have not been successful to date. In this work, we use filamentous phage as a model system to investigate the feasibility of removing methionine (Met) from the proteome. We show that all 24 elongation Met sites in the M13 phage genome can be replaced by other canonical amino acids. Most of these changes involve substitution of methionine by leucine (Leu), but in some cases additional compensatory mutations are required. Combining Met substituted sites in the proteome generally led to lower viability/infectivity of the mutant phages, which remains the major challenge in eliminating all methionines from the phage proteome. To date a total of 15 (out of all 24) elongation Mets have been simultaneously deleted from the M13 proteome, providing a useful foundation for future efforts to minimize the genetic code. Copyright © 2018. Published by Elsevier Ltd.

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.

Sounds of silence: synonymous nucleotides as a key to biological regulation and complexity

PubMed Central

Shabalina, Svetlana A.; Spiridonov, Nikolay A.; Kashina, Anna

2013-01-01

Messenger RNA is a key component of an intricate regulatory network of its own. It accommodates numerous nucleotide signals that overlap protein coding sequences and are responsible for multiple levels of regulation and generation of biological complexity. A wealth of structural and regulatory information, which mRNA carries in addition to the encoded amino acid sequence, raises the question of how these signals and overlapping codes are delineated along non-synonymous and synonymous positions in protein coding regions, especially in eukaryotes. Silent or synonymous codon positions, which do not determine amino acid sequences of the encoded proteins, define mRNA secondary structure and stability and affect the rate of translation, folding and post-translational modifications of nascent polypeptides. The RNA level selection is acting on synonymous sites in both prokaryotes and eukaryotes and is more common than previously thought. Selection pressure on the coding gene regions follows three-nucleotide periodic pattern of nucleotide base-pairing in mRNA, which is imposed by the genetic code. Synonymous positions of the coding regions have a higher level of hybridization potential relative to non-synonymous positions, and are multifunctional in their regulatory and structural roles. Recent experimental evidence and analysis of mRNA structure and interspecies conservation suggest that there is an evolutionary tradeoff between selective pressure acting at the RNA and protein levels. Here we provide a comprehensive overview of the studies that define the role of silent positions in regulating RNA structure and processing that exert downstream effects on proteins and their functions. PMID:23293005

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.

Molecular Genetic Characterization of Mutagenesis Using a Highly Sensitive Single-Stranded DNA Reporter System in Budding Yeast.

PubMed

Chan, Kin

2018-01-01

Mutations are permanent alterations to the coding content of DNA. They are starting material for the Darwinian evolution of species by natural selection, which has yielded an amazing diversity of life on Earth. Mutations can also be the fundamental basis of serious human maladies, most notably cancers. In this chapter, I describe a highly sensitive reporter system for the molecular genetic analysis of mutagenesis, featuring controlled generation of long stretches of single-stranded DNA in budding yeast cells. This system is ~100- to ~1000-fold more susceptible to mutation than conventional double-stranded DNA reporters, and is well suited for generating large mutational datasets to investigate the properties of mutagens.

SOURCELESS STARTUP. A MACHINE CODE FOR COMPUTING LOW-SOURCE REACTOR STARTUPS

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

MacMillan, D.B.

1960-06-01

>A revision to the sourceless start-up code is presented. The code solves a system of differential equations encountered in computing the probability distribution of activity at an observed power level during reactor start-up from a very low source level. (J.R.D.)

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.

Genetic therapy for the nervous system

PubMed Central

Bowers, William J.; Breakefield, Xandra O.; Sena-Esteves, Miguel

2011-01-01

Genetic therapy is undergoing a renaissance with expansion of viral and synthetic vectors, use of oligonucleotides (RNA and DNA) and sequence-targeted regulatory molecules, as well as genetically modified cells, including induced pluripotent stem cells from the patients themselves. Several clinical trials for neurologic syndromes appear quite promising. This review covers genetic strategies to ameliorate neurologic syndromes of different etiologies, including lysosomal storage diseases, Alzheimer's disease and other amyloidopathies, Parkinson's disease, spinal muscular atrophy, amyotrophic lateral sclerosis and brain tumors. This field has been propelled by genetic technologies, including identifying disease genes and disruptive mutations, design of genomic interacting elements to regulate transcription and splicing of specific precursor mRNAs and use of novel non-coding regulatory RNAs. These versatile new tools for manipulation of genetic elements provide the ability to tailor the mode of genetic intervention to specific aspects of a disease state. PMID:21429918

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.

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

An RNA Phage Lab: MS2 in Walter Fiers' laboratory of molecular biology in Ghent, from genetic code to gene and genome, 1963-1976.

PubMed

Pierrel, Jérôme

2012-01-01

The importance of viruses as model organisms is well-established in molecular biology and Max Delbrück's phage group set standards in the DNA phage field. In this paper, I argue that RNA phages, discovered in the 1960s, were also instrumental in the making of molecular biology. As part of experimental systems, RNA phages stood for messenger RNA (mRNA), genes and genome. RNA was thought to mediate information transfers between DNA and proteins. Furthermore, RNA was more manageable at the bench than DNA due to the availability of specific RNases, enzymes used as chemical tools to analyse RNA. Finally, RNA phages provided scientists with a pure source of mRNA to investigate the genetic code, genes and even a genome sequence. This paper focuses on Walter Fiers' laboratory at Ghent University (Belgium) and their work on the RNA phage MS2. When setting up his Laboratory of Molecular Biology, Fiers planned a comprehensive study of the virus with a strong emphasis on the issue of structure. In his lab, RNA sequencing, now a little-known technique, evolved gradually from a means to solve the genetic code, to a tool for completing the first genome sequence. Thus, I follow the research pathway of Fiers and his 'RNA phage lab' with their evolving experimental system from 1960 to the late 1970s. This study illuminates two decisive shifts in post-war biology: the emergence of molecular biology as a discipline in the 1960s in Europe and of genomics in the 1990s.

Translating Advances in Cardiogenetics Into Effective Clinical Practice

PubMed Central

Silverstein, Louise Bordeaux; Stolerman, Marina; Hidayatallah, Nadia; McDonald, Thomas; Walsh, Christine A.; Paljevic, Esma; Cohen, Lilian L.; Marion, Robert W.; Wasserman, David; Dolan, Siobhan M.

2015-01-01

In this article we describe a qualitative research study in which we explored individuals’ subjective experiences of both genetic testing and cardiogenetic disorders. Using a grounded theory approach, we coded and analyzed interview and focus group transcripts from 50 participants. We found that just under half of the participants who received their diagnosis during the study reported difficulty understanding information about both the purpose of genetic testing and their cardiac disease. A high level of anxiety about genetic testing and cardiac symptoms exacerbated individuals’ cognitive confusion. Participants reported both positive and negative interactions with the medical community, depending on health care professionals’ knowledge of cardiogenetic disorders. Overall, participants expressed a range of attitudes—positive, negative, and ambivalent—toward genetic testing. We conclude with a discussion of the barriers to achieving effective clinical care for genetic conditions and offer suggestions for improving collaborative decision making between physicians and patients. PMID:25114027

On codes with multi-level error-correction capabilities

NASA Technical Reports Server (NTRS)

Lin, Shu

1987-01-01

In conventional coding for error control, all the information symbols of a message are regarded equally significant, and hence codes are devised to provide equal protection for each information symbol against channel errors. However, in some occasions, some information symbols in a message are more significant than the other symbols. As a result, it is desired to devise codes with multilevel error-correcting capabilities. Another situation where codes with multi-level error-correcting capabilities are desired is in broadcast communication systems. An m-user broadcast channel has one input and m outputs. The single input and each output form a component channel. The component channels may have different noise levels, and hence the messages transmitted over the component channels require different levels of protection against errors. Block codes with multi-level error-correcting capabilities are also known as unequal error protection (UEP) codes. Structural properties of these codes are derived. Based on these structural properties, two classes of UEP codes are constructed.

LORD: a phenotype-genotype semantically integrated biomedical data tool to support rare disease diagnosis coding in health information systems.

PubMed

Choquet, Remy; Maaroufi, Meriem; Fonjallaz, Yannick; de Carrara, Albane; Vandenbussche, Pierre-Yves; Dhombres, Ferdinand; Landais, Paul

Characterizing a rare disease diagnosis for a given patient is often made through expert's networks. It is a complex task that could evolve over time depending on the natural history of the disease and the evolution of the scientific knowledge. Most rare diseases have genetic causes and recent improvements of sequencing techniques contribute to the discovery of many new diseases every year. Diagnosis coding in the rare disease field requires data from multiple knowledge bases to be aggregated in order to offer the clinician a global information space from possible diagnosis to clinical signs (phenotypes) and known genetic mutations (genotype). Nowadays, the major barrier to the coding activity is the lack of consolidation of such information scattered in different thesaurus such as Orphanet, OMIM or HPO. The Linking Open data for Rare Diseases (LORD) web portal we developed stands as the first attempt to fill this gap by offering an integrated view of 8,400 rare diseases linked to more than 14,500 signs and 3,270 genes. The application provides a browsing feature to navigate through the relationships between diseases, signs and genes, and some Application Programming Interfaces to help its integration in health information systems in routine.

LORD: a phenotype-genotype semantically integrated biomedical data tool to support rare disease diagnosis coding in health information systems

PubMed Central

Choquet, Remy; Maaroufi, Meriem; Fonjallaz, Yannick; de Carrara, Albane; Vandenbussche, Pierre-Yves; Dhombres, Ferdinand; Landais, Paul

2015-01-01

Characterizing a rare disease diagnosis for a given patient is often made through expert’s networks. It is a complex task that could evolve over time depending on the natural history of the disease and the evolution of the scientific knowledge. Most rare diseases have genetic causes and recent improvements of sequencing techniques contribute to the discovery of many new diseases every year. Diagnosis coding in the rare disease field requires data from multiple knowledge bases to be aggregated in order to offer the clinician a global information space from possible diagnosis to clinical signs (phenotypes) and known genetic mutations (genotype). Nowadays, the major barrier to the coding activity is the lack of consolidation of such information scattered in different thesaurus such as Orphanet, OMIM or HPO. The Linking Open data for Rare Diseases (LORD) web portal we developed stands as the first attempt to fill this gap by offering an integrated view of 8,400 rare diseases linked to more than 14,500 signs and 3,270 genes. The application provides a browsing feature to navigate through the relationships between diseases, signs and genes, and some Application Programming Interfaces to help its integration in health information systems in routine. PMID:26958175

Network-assisted investigation of virulence and antibiotic-resistance systems in Pseudomonas aeruginosa

NASA Astrophysics Data System (ADS)

Hwang, Sohyun; Kim, Chan Yeong; Ji, Sun-Gou; Go, Junhyeok; Kim, Hanhae; Yang, Sunmo; Kim, Hye Jin; Cho, Ara; Yoon, Sang Sun; Lee, Insuk

2016-05-01

Pseudomonas aeruginosa is a Gram-negative bacterium of clinical significance. Although the genome of PAO1, a prototype strain of P. aeruginosa, has been extensively studied, approximately one-third of the functional genome remains unknown. With the emergence of antibiotic-resistant strains of P. aeruginosa, there is an urgent need to develop novel antibiotic and anti-virulence strategies, which may be facilitated by an approach that explores P. aeruginosa gene function in systems-level models. Here, we present a genome-wide functional network of P. aeruginosa genes, PseudomonasNet, which covers 98% of the coding genome, and a companion web server to generate functional hypotheses using various network-search algorithms. We demonstrate that PseudomonasNet-assisted predictions can effectively identify novel genes involved in virulence and antibiotic resistance. Moreover, an antibiotic-resistance network based on PseudomonasNet reveals that P. aeruginosa has common modular genetic organisations that confer increased or decreased resistance to diverse antibiotics, which accounts for the pervasiveness of cross-resistance across multiple drugs. The same network also suggests that P. aeruginosa has developed mechanism of trade-off in resistance across drugs by altering genetic interactions. Taken together, these results clearly demonstrate the usefulness of a genome-scale functional network to investigate pathogenic systems in P. aeruginosa.

Diet1, bile acid diarrhea, and FGF15/19: mouse model and human genetic variants.

PubMed

Lee, Jessica M; Ong, Jessica R; Vergnes, Laurent; de Aguiar Vallim, Thomas Q; Nolan, Jonathan; Cantor, Rita M; Walters, Julian R F; Reue, Karen

2018-03-01

Diet1 modulates intestinal production of the hormone, fibroblast growth factor (FGF)15, which signals in liver to regulate bile acid synthesis. C57BL/6ByJ mice with a spontaneous Diet1 -null mutation are resistant to hypercholesterolemia compared with wild-type C57BL/6J mice through enhanced cholesterol conversion to bile acids. To further characterize the role of Diet1 in metabolism, we generated Diet1 -/- mice on the C57BL/6J genetic background. C57BL/6J Diet1 -/- mice had elevated bile acid levels, reduced Fgf15 expression, and increased gastrointestinal motility and intestinal luminal water content, which are symptoms of bile acid diarrhea (BAD) in humans. Natural genetic variation in Diet1 mRNA expression levels across 76 inbred mouse strains correlated positively with Ffg15 mRNA and negatively with serum bile acid levels. This led us to investigate the role of DIET1 genetic variation in primary BAD patients. We identified a DIET1 coding variant ( rs12256835 ) that had skewed prevalence between BAD cases and controls. This variant causes an H1721Q amino acid substitution that increases the levels of FGF19 protein secreted from cultured cells. We propose that genetic variation in DIET1 may be a determinant of FGF19 secretion levels, and may affect bile acid metabolism in both physiological and pathological conditions. Copyright © 2018 by the American Society for Biochemistry and Molecular Biology, Inc.

Association between ADIPOQ SNPs with plasma adiponectin and glucose homeostasis and adiposity phenotypes in the IRAS Family Study.

PubMed

An, S Sandy; Hanley, Anthony J G; Ziegler, Julie T; Brown, W Mark; Haffner, Steven M; Norris, Jill M; Rotter, Jerome I; Guo, Xiuqing; Chen, Y-D Ida; Wagenknecht, Lynne E; Langefeld, Carl D; Bowden, Donald W; Palmer, Nicholette D

2012-12-01

Adiponectin is an adipocytokine associated with a variety of metabolic traits. These associations in human studies, in conjunction with functional studies in model systems, have implicated adiponectin in multiple metabolic processes. We hypothesize that genetic variants associated with plasma adiponectin would also be associated with glucose homeostasis and adiposity phenotypes. The Insulin Resistance Atherosclerosis Family Study was designed to identify the genetic and environmental basis of insulin resistance and adiposity in the Hispanic- (n=1,424) and African-American (n=604) population. High quality metabolic phenotypes, e.g. insulin sensitivity (S(I)), acute insulin response (AIR), disposition index (DI), fasting glucose, body mass index (BMI), visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and waist circumference, were explored. Based on association analysis of more than 40 genetic polymorphisms in the adiponectin gene (ADIPOQ), we found no consistent association of ADIPOQ variants with plasma adiponectin levels and adiposity phenotypes. However, there were two promoter variants, rs17300539 and rs822387, associated with plasma adiponectin levels (P=0.0079 and 0.021, respectively) in the Hispanic-American cohort that were also associated with S(I) (P=0.0067 and 0.013, respectively). In contrast, there was only a single promoter SNP, rs17300539, associated with plasma adiponectin levels (P=0.0018) and fasting glucose (P=0.042) in the African-American cohort. Strikingly, high impact coding variants did not show evidence of association. The lack of consistent patterns of association between variants, adiponectin levels, glucose homeostasis, and adiposity phenotypes suggests a reassessment of the influence of adiponectin in these pathways. Copyright © 2012 Elsevier Inc. All rights reserved.

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

Genetic Local Search for Optimum Multiuser Detection Problem in DS-CDMA Systems

NASA Astrophysics Data System (ADS)

Wang, Shaowei; Ji, Xiaoyong

Optimum multiuser detection (OMD) in direct-sequence code-division multiple access (DS-CDMA) systems is an NP-complete problem. In this paper, we present a genetic local search algorithm, which consists of an evolution strategy framework and a local improvement procedure. The evolution strategy searches the space of feasible, locally optimal solutions only. A fast iterated local search algorithm, which employs the proprietary characteristics of the OMD problem, produces local optima with great efficiency. Computer simulations show the bit error rate (BER) performance of the GLS outperforms other multiuser detectors in all cases discussed. The computation time is polynomial complexity in the number of users.

The Molecular Epidemiology of Breast Cancer: Risk from Environmental Exposures and Genetic Susceptibility.

DTIC Science & Technology

1996-10-01

Diet 16. PRICE CODE 17. SECURITY CLASSIFICATION 18. SECURITY CLASSIFICATION 19. SECURITY CLASSIFICATION 20. LIMITATION OF ABSTRACT OF REPORT OF THIS PAGE...approach, Frank et al. (1993) compared DDE and PCB residues in the general diet with blood levels of Ontario residents. Blood samples were obtained from...sources of PCBs and HCB in this geographical region. In a similar study, Kashyap et al. (1994) monitored DDT levels in duplicate diet samples and

Reduced levels of Cacna1c attenuate mesolimbic dopamine system function.

PubMed

Terrillion, C E; Dao, D T; Cachope, R; Lobo, M K; Puche, A C; Cheer, J F; Gould, T D

2017-06-01

Genetic variation in CACNA1C, which codes for the L-type calcium channel (LTCC) Ca v 1.2, is associated with clinical diagnoses of bipolar disorder, depression and schizophrenia. Dysregulation of the mesolimbic-dopamine (ML-DA) system is linked to these syndromes and LTCCs are required for normal DAergic neurotransmission between the ventral tegmental area (VTA) and nucleus accumbens (NAc). It is unclear, however, how variations in CACNA1C genotype, and potential subsequent changes in expression levels in these regions, modify risk. Using constitutive and conditional knockout mice, and treatment with the LTCC antagonist nimodipine, we examined the role of Cacna1c in DA-mediated behaviors elicited by psychomotor stimulants. Using fast-scan cyclic voltammetry, DA release and reuptake in the NAc were measured. We find that subsecond DA release in Cacna1c haploinsufficient mice lacks normal sensitivity to inhibition of the DA transporter (DAT). Constitutive haploinsufficiency of Cacna1c led to attenuation of hyperlocomotion following acute administration of stimulants specific to DAT, and locomotor sensitization of these mice to the DAT antagonist GBR12909 did not reach the same level as wild-type mice. The maintenance of sensitization to GBR12909 was attenuated by administration of nimodipine. Sensitization to GBR12909 was attenuated in mice with reduced Cacna1c selectively in the VTA but not in the NAc. Our findings show that Cacna1c is crucial for normal behavioral responses to DA stimulants and that its activity in the VTA is required for behavioral sensitization. Cacna1c likely exerts these effects through modifications to presynaptic ML-DA system function. © 2017 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

Immunogenetics as a tool in anthropological studies

PubMed Central

Sanchez-Mazas, Alicia; Fernandez-Viña, Marcelo; Middleton, Derek; Hollenbach, Jill A; Buhler, Stéphane; Di, Da; Rajalingam, Raja; Dugoujon, Jean-Michel; Mack, Steven J; Thorsby, Erik

2011-01-01

The genes coding for the main molecules involved in the human immune system – immunoglobulins, human leucocyte antigen (HLA) molecules and killer-cell immunoglobulin-like receptors (KIR) – exhibit a very high level of polymorphism that reveals remarkable frequency variation in human populations. ‘Genetic marker’ (GM) allotypes located in the constant domains of IgG antibodies have been studied for over 40 years through serological typing, leading to the identification of a variety of GM haplotypes whose frequencies vary sharply from one geographic region to another. An impressive diversity of HLA alleles, which results in amino acid substitutions located in the antigen-binding region of HLA molecules, also varies greatly among populations. The KIR differ between individuals according to both gene content and allelic variation, and also display considerable population diversity. Whereas the molecular evolution of these polymorphisms has most likely been subject to natural selection, principally driven by host–pathogen interactions, their patterns of genetic variation worldwide show significant signals of human geographic expansion, demographic history and cultural diversification. As current developments in population genetic analysis and computer simulation improve our ability to discriminate among different – either stochastic or deterministic – forces acting on the genetic evolution of human populations, the study of these systems shows great promise for investigating both the peopling history of modern humans in the time since their common origin and human adaptation to past environmental (e.g. pathogenic) changes. Therefore, in addition to mitochondrial DNA, Y-chromosome, microsatellites, single nucleotide polymorphisms and other markers, immunogenetic polymorphisms represent essential and complementary tools for anthropological studies. PMID:21480890

Genetic variants of adiponectin receptor 2 are associated with increased adiponectin levels and decreased triglyceride/VLDL levels in patients with metabolic syndrome.

PubMed

Broedl, Uli C; Lehrke, Michael; Fleischer-Brielmaier, Elisabeth; Tietz, Anne B; Nagel, Jutta M; Göke, Burkhard; Lohse, Peter; Parhofer, Klaus G

2006-05-15

Adiponectin acts as an antidiabetic, antiinflammatory and antiatherogenic adipokine. These effects are assumed to be mediated by the recently discovered adiponectin receptors AdipoR1 and AdipoR2. The purpose of this study was to determine whether variations in the AdipoR1 and AdipoR2 genes may contribute to insulin resistance, dyslipidemia and inflammation. We sequenced all seven coding exons of both genes in 20 unrelated German subjects with metabolic syndrome and tested genetic variants for association with glucose, lipid and inflammatory parameters. We identified three AdipoR2 variants (+795G/A, +870C/A and +963C/T) in perfect linkage disequilibrium (r2 = 1) with a minor allele frequency of 0.125. This haplotype was associated with higher plasma adiponectin levels and decreased fasting triglyceride, VLDL-triglyceride and VLDL-cholesterol levels. No association, however, was observed between the AdipoR2 SNP cluster and glucose metabolism. To our knowledge, this is the first study to identify an association between genetic variants of the adiponectin receptor genes and plasma adiponectin levels. Furthermore, our data suggest that AdipoR2 may play an important role in triglyceride/VLDL metabolism.

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

Design and Simulation of Material-Integrated Distributed Sensor Processing with a Code-Based Agent Platform and Mobile Multi-Agent Systems

PubMed Central

Bosse, Stefan

2015-01-01

Multi-agent systems (MAS) can be used for decentralized and self-organizing data processing in a distributed system, like a resource-constrained sensor network, enabling distributed information extraction, for example, based on pattern recognition and self-organization, by decomposing complex tasks in simpler cooperative agents. Reliable MAS-based data processing approaches can aid the material-integration of structural-monitoring applications, with agent processing platforms scaled to the microchip level. The agent behavior, based on a dynamic activity-transition graph (ATG) model, is implemented with program code storing the control and the data state of an agent, which is novel. The program code can be modified by the agent itself using code morphing techniques and is capable of migrating in the network between nodes. The program code is a self-contained unit (a container) and embeds the agent data, the initialization instructions and the ATG behavior implementation. The microchip agent processing platform used for the execution of the agent code is a standalone multi-core stack machine with a zero-operand instruction format, leading to a small-sized agent program code, low system complexity and high system performance. The agent processing is token-queue-based, similar to Petri-nets. The agent platform can be implemented in software, too, offering compatibility at the operational and code level, supporting agent processing in strong heterogeneous networks. In this work, the agent platform embedded in a large-scale distributed sensor network is simulated at the architectural level by using agent-based simulation techniques. PMID:25690550

Design and simulation of material-integrated distributed sensor processing with a code-based agent platform and mobile multi-agent systems.

PubMed

Bosse, Stefan

2015-02-16

Multi-agent systems (MAS) can be used for decentralized and self-organizing data processing in a distributed system, like a resource-constrained sensor network, enabling distributed information extraction, for example, based on pattern recognition and self-organization, by decomposing complex tasks in simpler cooperative agents. Reliable MAS-based data processing approaches can aid the material-integration of structural-monitoring applications, with agent processing platforms scaled to the microchip level. The agent behavior, based on a dynamic activity-transition graph (ATG) model, is implemented with program code storing the control and the data state of an agent, which is novel. The program code can be modified by the agent itself using code morphing techniques and is capable of migrating in the network between nodes. The program code is a self-contained unit (a container) and embeds the agent data, the initialization instructions and the ATG behavior implementation. The microchip agent processing platform used for the execution of the agent code is a standalone multi-core stack machine with a zero-operand instruction format, leading to a small-sized agent program code, low system complexity and high system performance. The agent processing is token-queue-based, similar to Petri-nets. The agent platform can be implemented in software, too, offering compatibility at the operational and code level, supporting agent processing in strong heterogeneous networks. In this work, the agent platform embedded in a large-scale distributed sensor network is simulated at the architectural level by using agent-based simulation techniques.

Industry and Occupation in the Electronic Health Record: An Investigation of the National Institute for Occupational Safety and Health Industry and Occupation Computerized Coding System

PubMed Central

2016-01-01

Background Inclusion of information about a patient’s work, industry, and occupation, in the electronic health record (EHR) could facilitate occupational health surveillance, better health outcomes, prevention activities, and identification of workers’ compensation cases. The US National Institute for Occupational Safety and Health (NIOSH) has developed an autocoding system for “industry” and “occupation” based on 1990 Bureau of Census codes; its effectiveness requires evaluation in conjunction with promoting the mandatory addition of these variables to the EHR. Objective The objective of the study was to evaluate the intercoder reliability of NIOSH’s Industry and Occupation Computerized Coding System (NIOCCS) when applied to data collected in a community survey conducted under the Affordable Care Act; to determine the proportion of records that are autocoded using NIOCCS. Methods Standard Occupational Classification (SOC) codes are used by several federal agencies in databases that capture demographic, employment, and health information to harmonize variables related to work activities among these data sources. There are 359 industry and occupation responses that were hand coded by 2 investigators, who came to a consensus on every code. The same variables were autocoded using NIOCCS at the high and moderate criteria level. Results Kappa was .84 for agreement between hand coders and between the hand coder consensus code versus NIOCCS high confidence level codes for the first 2 digits of the SOC code. For 4 digits, NIOCCS coding versus investigator coding ranged from kappa=.56 to .70. In this study, NIOCCS was able to achieve production rates (ie, to autocode) 31%-36% of entered variables at the “high confidence” level and 49%-58% at the “medium confidence” level. Autocoding (production) rates are somewhat lower than those reported by NIOSH. Agreement between manually coded and autocoded data are “substantial” at the 2-digit level, but only “fair” to “good” at the 4-digit level. Conclusions This work serves as a baseline for performance of NIOCCS by investigators in the field. Further field testing will clarify NIOCCS effectiveness in terms of ability to assign codes and coding accuracy and will clarify its value as inclusion of these occupational variables in the EHR is promoted. PMID:26878932

JavaGenes: Evolving Graphs with Crossover

NASA Technical Reports Server (NTRS)

Globus, Al; Atsatt, Sean; Lawton, John; Wipke, Todd

2000-01-01

Genetic algorithms usually use string or tree representations. We have developed a novel crossover operator for a directed and undirected graph representation, and used this operator to evolve molecules and circuits. Unlike strings or trees, a single point in the representation cannot divide every possible graph into two parts, because graphs may contain cycles. Thus, the crossover operator is non-trivial. A steady-state, tournament selection genetic algorithm code (JavaGenes) was written to implement and test the graph crossover operator. All runs were executed by cycle-scavagging on networked workstations using the Condor batch processing system. The JavaGenes code has evolved pharmaceutical drug molecules and simple digital circuits. Results to date suggest that JavaGenes can evolve moderate sized drug molecules and very small circuits in reasonable time. The algorithm has greater difficulty with somewhat larger circuits, suggesting that directed graphs (circuits) are more difficult to evolve than undirected graphs (molecules), although necessary differences in the crossover operator may also explain the results. In principle, JavaGenes should be able to evolve other graph-representable systems, such as transportation networks, metabolic pathways, and computer networks. However, large graphs evolve significantly slower than smaller graphs, presumably because the space-of-all-graphs explodes combinatorially with graph size. Since the representation strongly affects genetic algorithm performance, adding graphs to the evolutionary programmer's bag-of-tricks should be beneficial. Also, since graph evolution operates directly on the phenotype, the genotype-phenotype translation step, common in genetic algorithm work, is eliminated.

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.

Verification and Validation in a Rapid Software Development Process

NASA Technical Reports Server (NTRS)

Callahan, John R.; Easterbrook, Steve M.

1997-01-01

The high cost of software production is driving development organizations to adopt more automated design and analysis methods such as rapid prototyping, computer-aided software engineering (CASE) tools, and high-level code generators. Even developers of safety-critical software system have adopted many of these new methods while striving to achieve high levels Of quality and reliability. While these new methods may enhance productivity and quality in many cases, we examine some of the risks involved in the use of new methods in safety-critical contexts. We examine a case study involving the use of a CASE tool that automatically generates code from high-level system designs. We show that while high-level testing on the system structure is highly desirable, significant risks exist in the automatically generated code and in re-validating releases of the generated code after subsequent design changes. We identify these risks and suggest process improvements that retain the advantages of rapid, automated development methods within the quality and reliability contexts of safety-critical projects.

From chemical metabolism to life: the origin of the genetic coding process

PubMed Central

2017-01-01

Looking for origins is so much rooted in ideology that most studies reflect opinions that fail to explore the first realistic scenarios. To be sure, trying to understand the origins of life should be based on what we know of current chemistry in the solar system and beyond. There, amino acids and very small compounds such as carbon dioxide, dihydrogen or dinitrogen and their immediate derivatives are ubiquitous. Surface-based chemical metabolism using these basic chemicals is the most likely beginning in which amino acids, coenzymes and phosphate-based small carbon molecules were built up. Nucleotides, and of course RNAs, must have come to being much later. As a consequence, the key question to account for life is to understand how chemical metabolism that began with amino acids progressively shaped into a coding process involving RNAs. Here I explore the role of building up complementarity rules as the first information-based process that allowed for the genetic code to emerge, after RNAs were substituted to surfaces to carry over the basic metabolic pathways that drive the pursuit of life. PMID:28684991

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.

Opening up Architectures of Software-Intensive Systems: A Functional Decomposition to Support System Comprehension

DTIC Science & Technology

2007-10-01

Architecture ................................................................................ 14 Figure 2. Eclipse Java Model...16 Figure 3. Eclipse Java Model at the Source Code Level...24 Figure 9. Java Source Code

Mechanical code comparator

DOEpatents

Peter, Frank J.; Dalton, Larry J.; Plummer, David W.

2002-01-01

A new class of mechanical code comparators is described which have broad potential for application in safety, surety, and security applications. These devices can be implemented as micro-scale electromechanical systems that isolate a secure or otherwise controlled device until an access code is entered. This access code is converted into a series of mechanical inputs to the mechanical code comparator, which compares the access code to a pre-input combination, entered previously into the mechanical code comparator by an operator at the system security control point. These devices provide extremely high levels of robust security. Being totally mechanical in operation, an access control system properly based on such devices cannot be circumvented by software attack alone.

HERCULES: A Pattern Driven Code Transformation System

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

Kartsaklis, Christos; Hernandez, Oscar R; Hsu, Chung-Hsing

2012-01-01

New parallel computers are emerging, but developing efficient scientific code for them remains difficult. A scientist must manage not only the science-domain complexity but also the performance-optimization complexity. HERCULES is a code transformation system designed to help the scientist to separate the two concerns, which improves code maintenance, and facilitates performance optimization. The system combines three technologies, code patterns, transformation scripts and compiler plugins, to provide the scientist with an environment to quickly implement code transformations that suit his needs. Unlike existing code optimization tools, HERCULES is unique in its focus on user-level accessibility. In this paper we discuss themore » design, implementation and an initial evaluation of HERCULES.« less

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.

An overview on ethical considerations in stem cell research in Iran and ethical recommendations: A review.

PubMed

Farajkhoda, Tahmineh

2017-02-01

Conducting research on the stem cell lines might bring some worthy good to public. Human Stem Cells (hSCs) research has provided opportunities for scientific progresses and new therapies, but some complex ethical matters should be noticed to ensure that stem cell research is carried out in an ethically appropriate manner. The aim of this review article is to discuss the importance of stem cell research, code of ethics for stem cell research in Iran and ethical recommendation. Generation of stem cells for research from human embryo or adult stem cells, saving, maintenance and using of them are the main ethical, legal and jurisprudence concerns in Iran. Concerns regarding human reproduction or human cloning, breach of human dignity, genetic manipulation and probability of tumorogenisity are observed in adult/somatic stem cells. Destruction of embryo to generate stem cell is an important matter in Iran. In this regards, obtaining stem cell from donated frozen embryos through infertility treatment that would be discarded is an acceptable solution in Iran for generation of embryo for research. Ethical, legal, and jurisprudence strategies for using adult/somatic stem cells are determination of ownership of stem cells, trade prohibition of human body, supervision on bio banks and information of Oversight Committee on Stem Cell Research. Recommendations to handle ethical issues for conducting stem cell research are well-designed studies, compliance codes of ethics in biomedical research (specifically codes of ethics on stem cell research, codes of ethics on clinical trials studies and codes of ethics on animals studies), appropriate collaboration with ethics committees and respecting of rights of participants (including both of human and animal rights) in research. In addition, there is a necessity for extending global networks of bioethics for strengthening communications within organizations at both the regional and international level, strengthening legislation systems, designing and establishing convenient collaborative educational courses at different levels.

An overview on ethical considerations in stem cell research in Iran and ethical recommendations: A review

PubMed Central

Farajkhoda, Tahmineh

2017-01-01

Conducting research on the stem cell lines might bring some worthy good to public. Human Stem Cells (hSCs) research has provided opportunities for scientific progresses and new therapies, but some complex ethical matters should be noticed to ensure that stem cell research is carried out in an ethically appropriate manner. The aim of this review article is to discuss the importance of stem cell research, code of ethics for stem cell research in Iran and ethical recommendation. Generation of stem cells for research from human embryo or adult stem cells, saving, maintenance and using of them are the main ethical, legal and jurisprudence concerns in Iran. Concerns regarding human reproduction or human cloning, breach of human dignity, genetic manipulation and probability of tumorogenisity are observed in adult/somatic stem cells. Destruction of embryo to generate stem cell is an important matter in Iran. In this regards, obtaining stem cell from donated frozen embryos through infertility treatment that would be discarded is an acceptable solution in Iran for generation of embryo for research. Ethical, legal, and jurisprudence strategies for using adult/somatic stem cells are determination of ownership of stem cells, trade prohibition of human body, supervision on bio banks and information of Oversight Committee on Stem Cell Research. Recommendations to handle ethical issues for conducting stem cell research are well-designed studies, compliance codes of ethics in biomedical research (specifically codes of ethics on stem cell research, codes of ethics on clinical trials studies and codes of ethics on animals studies), appropriate collaboration with ethics committees and respecting of rights of participants (including both of human and animal rights) in research. In addition, there is a necessity for extending global networks of bioethics for strengthening communications within organizations at both the regional and international level, strengthening legislation systems, designing and establishing convenient collaborative educational courses at different levels. PMID:28462397

Severe Methanol Poisoning with Supralethal Serum Formate Concentration: A Case Report

PubMed Central

Nurieva, Olga; Kotikova, Katerina

2015-01-01

Objective To present a case of survival without visual and central nervous system sequelae at a formate concentration of twice the reported lethal level. Clinical Presentation and Intervention This was a case of a 33-year-old man who ingested 1 liter of a toxic mixture of methanol and ethanol. Upon admission, he presented with anxiety, tachycardia and hypertension and had a serum formate level of 1,400 mg/l (normal range 0.9–2.1 mg/l), a methanol level of 806 mg/l (normal range 2–30 mg/l), an undetectable ethanol concentration and a normal lactate level. A 10% solution of ethanol and folinic acid was administered intravenously and two 8-hour sessions of intermittent hemodialysis were performed. The patient was discharged on the fifth day without sequelae of poisoning. The follow-up examinations 3 months and 2 years later revealed no damage to the basal ganglia. The patient had normal visual-evoked potential and findings on optical coherence tomography. The genetic analysis revealed a rare minor allele for the gene coding CYP2E1 enzyme of the microsomal ethanol oxidizing system. Conclusion The patient survived acute methanol poisoning without long-term sequelae despite a high serum level of formic acid upon admission. PMID:26380973

The XylS/Pm regulator/promoter system and its use in fundamental studies of bacterial gene expression, recombinant protein production and metabolic engineering.

PubMed

Gawin, Agnieszka; Valla, Svein; Brautaset, Trygve

2017-07-01

The XylS/Pm regulator/promoter system originating from the Pseudomonas putida TOL plasmid pWW0 is widely used for regulated low- and high-level recombinant expression of genes and gene clusters in Escherichia coli and other bacteria. Induction of this system can be graded by using different cheap benzoic acid derivatives, which enter cells by passive diffusion, operate in a dose-dependent manner and are typically not metabolized by the host cells. Combinatorial mutagenesis and selection using the bla gene encoding β-lactamase as a reporter have demonstrated that the Pm promoter, the DNA sequence corresponding to the 5' untranslated end of its cognate mRNA and the xylS coding region can be modified and improved relative to various types of applications. By combining such mutant genetic elements, altered and extended expression profiles were achieved. Due to their unique properties, obtained systems serve as a genetic toolbox valuable for heterologous protein production and metabolic engineering, as well as for basic studies aiming at understanding fundamental parameters affecting bacterial gene expression. The approaches used to modify XylS/Pm should be adaptable for similar improvements also of other microbial expression systems. In this review, we summarize constructions, characteristics, refinements and applications of expression tools using the XylS/Pm system. © 2017 The Authors. Microbial Biotechnology published by John Wiley & Sons Ltd and Society for Applied Microbiology.

The GS (genetic selection) Principle.

PubMed

Abel, David L

2009-01-01

The GS (Genetic Selection) Principle states that biological selection must occur at the nucleotide-sequencing molecular-genetic level of 3'5' phosphodiester bond formation. After-the-fact differential survival and reproduction of already-living phenotypic organisms (ordinary natural selection) does not explain polynucleotide prescription and coding. All life depends upon literal genetic algorithms. Even epigenetic and "genomic" factors such as regulation by DNA methylation, histone proteins and microRNAs are ultimately instructed by prior linear digital programming. Biological control requires selection of particular configurable switch-settings to achieve potential function. This occurs largely at the level of nucleotide selection, prior to the realization of any integrated biofunction. Each selection of a nucleotide corresponds to the setting of two formal binary logic gates. The setting of these switches only later determines folding and binding function through minimum-free-energy sinks. These sinks are determined by the primary structure of both the protein itself and the independently prescribed sequencing of chaperones. The GS Principle distinguishes selection of existing function (natural selection) from selection for potential function (formal selection at decision nodes, logic gates and configurable switch-settings).

On decoding of multi-level MPSK modulation codes

NASA Technical Reports Server (NTRS)

Lin, Shu; Gupta, Alok Kumar

1990-01-01

The decoding problem of multi-level block modulation codes is investigated. The hardware design of soft-decision Viterbi decoder for some short length 8-PSK block modulation codes is presented. An effective way to reduce the hardware complexity of the decoder by reducing the branch metric and path metric, using a non-uniform floating-point to integer mapping scheme, is proposed and discussed. The simulation results of the design are presented. The multi-stage decoding (MSD) of multi-level modulation codes is also investigated. The cases of soft-decision and hard-decision MSD are considered and their performance are evaluated for several codes of different lengths and different minimum squared Euclidean distances. It is shown that the soft-decision MSD reduces the decoding complexity drastically and it is suboptimum. The hard-decision MSD further simplifies the decoding while still maintaining a reasonable coding gain over the uncoded system, if the component codes are chosen properly. Finally, some basic 3-level 8-PSK modulation codes using BCH codes as component codes are constructed and their coding gains are found for hard decision multistage decoding.

Genetic and morphological heterogeneity among populations of Eurytemora affinis (Crustacea: Copepoda: Temoridae) in European waters.

PubMed

Sukhikh, Natalia; Souissi, Anissa; Souissi, Sami; Winkler, Gesche; Castric, Vincent; Holl, Anne-Catherine; Alekseev, Victor

2016-01-01

Our understanding of the systematics of the Eurytemora affinis complex developed at a fast pace over the last decades. Formerly considered as a complex of cryptic species, it is now believed to include three valid species: E. affinis, Eurytemora carolleeae, and Eurytemora caspica. American and European representatives have been studied in detail with respect to fine-scale geographic distribution, levels of genetic subdivision, evolutionary and demographic histories. Morphological components have been less explored. In this study, an analysis of the phylogeny and morphology of E. affinis was done, with a special focus on European populations. A total of 447 individuals of E. affinis from Europe were analyzed with genetic tools and 170 individuals according to morphological criteria. Common and new morphological and genetic features were analyzed. For this, we used ML and Bayesian methods to analyze the bar coding mt-DNA gene cytochrome c oxidase I subunit. Both genetic and morphological analyses showed high heterogeneities among the E. affinis populations from Europe. As a result, three local populations of E. affinis in Western Europe, including the European part of Russia, were established. Their genetic and morphological heterogeneity corresponded to the subspecies level. Copyright © 2016 Académie des sciences. Published by Elsevier SAS. All rights reserved.

Biological Information Transfer Beyond the Genetic Code: The Sugar Code

NASA Astrophysics Data System (ADS)

Gabius, H.-J.

In the era of genetic engineering, cloning, and genome sequencing the focus of research on the genetic code has received an even further accentuation in the public eye. In attempting, however, to understand intra- and intercellular recognition processes comprehensively, the two biochemical dimensions established by nucleic acids and proteins are not sufficient to satisfactorily explain all molecular events in, for example, cell adhesion or routing. The consideration of further code systems is essential to bridge this gap. A third biochemical alphabet forming code words with an information storage capacity second to no other substance class in rather small units (words, sentences) is established by monosaccharides (letters). As hardware oligosaccharides surpass peptides by more than seven orders of magnitude in the theoretical ability to build isomers, when the total of conceivable hexamers is calculated. In addition to the sequence complexity, the use of magnetic resonance spectroscopy and molecular modeling has been instrumental in discovering that even small glycans can often reside in not only one but several distinct low-energy conformations (keys). Intriguingly, conformers can display notably different capacities to fit snugly into the binding site of nonhomologous receptors (locks). This process, experimentally verified for two classes of lectins, is termed "differential conformer selection." It adds potential for shifts of the conformer equilibrium to modulate ligand properties dynamically and reversibly to the well-known changes in sequence (including anomeric positioning and linkage points) and in pattern of substitution, for example, by sulfation. In the intimate interplay with sugar receptors (lectins, enzymes, and antibodies) the message of coding units of the sugar code is deciphered. Their recognition will trigger postbinding signaling and the intended biological response. Knowledge about the driving forces for the molecular rendezvous, i.e., contributions of bidentate or cooperative hydrogen bonds, dispersion forces, stacking, and solvent rearrangement, will enable the design of high-affinity ligands or mimetics thereof. They embody clinical applications reaching from receptor localization in diagnostic pathology to cell type-selective targeting of drugs and inhibition of undesired cell adhesion in bacterial/viral infections, inflammation, or metastasis.

Transmission over UWB channels with OFDM system using LDPC coding

NASA Astrophysics Data System (ADS)

Dziwoki, Grzegorz; Kucharczyk, Marcin; Sulek, Wojciech

2009-06-01

Hostile wireless environment requires use of sophisticated signal processing methods. The paper concerns on Ultra Wideband (UWB) transmission over Personal Area Networks (PAN) including MB-OFDM specification of physical layer. In presented work the transmission system with OFDM modulation was connected with LDPC encoder/decoder. Additionally the frame and bit error rate (FER and BER) of the system was decreased using results from the LDPC decoder in a kind of turbo equalization algorithm for better channel estimation. Computational block using evolutionary strategy, from genetic algorithms family, was also used in presented system. It was placed after SPA (Sum-Product Algorithm) decoder and is conditionally turned on in the decoding process. The result is increased effectiveness of the whole system, especially lower FER. The system was tested with two types of LDPC codes, depending on type of parity check matrices: randomly generated and constructed deterministically, optimized for practical decoder architecture implemented in the FPGA device.

Low cost and open source multi-fluorescence imaging system for teaching and research in biology and bioengineering.

PubMed

Nuñez, Isaac; Matute, Tamara; Herrera, Roberto; Keymer, Juan; Marzullo, Timothy; Rudge, Timothy; Federici, Fernán

2017-01-01

The advent of easy-to-use open source microcontrollers, off-the-shelf electronics and customizable manufacturing technologies has facilitated the development of inexpensive scientific devices and laboratory equipment. In this study, we describe an imaging system that integrates low-cost and open-source hardware, software and genetic resources. The multi-fluorescence imaging system consists of readily available 470 nm LEDs, a Raspberry Pi camera and a set of filters made with low cost acrylics. This device allows imaging in scales ranging from single colonies to entire plates. We developed a set of genetic components (e.g. promoters, coding sequences, terminators) and vectors following the standard framework of Golden Gate, which allowed the fabrication of genetic constructs in a combinatorial, low cost and robust manner. In order to provide simultaneous imaging of multiple wavelength signals, we screened a series of long stokes shift fluorescent proteins that could be combined with cyan/green fluorescent proteins. We found CyOFP1, mBeRFP and sfGFP to be the most compatible set for 3-channel fluorescent imaging. We developed open source Python code to operate the hardware to run time-lapse experiments with automated control of illumination and camera and a Python module to analyze data and extract meaningful biological information. To demonstrate the potential application of this integral system, we tested its performance on a diverse range of imaging assays often used in disciplines such as microbial ecology, microbiology and synthetic biology. We also assessed its potential use in a high school environment to teach biology, hardware design, optics, and programming. Together, these results demonstrate the successful integration of open source hardware, software, genetic resources and customizable manufacturing to obtain a powerful, low cost and robust system for education, scientific research and bioengineering. All the resources developed here are available under open source licenses.

Low cost and open source multi-fluorescence imaging system for teaching and research in biology and bioengineering

PubMed Central

Herrera, Roberto; Keymer, Juan; Marzullo, Timothy; Rudge, Timothy

2017-01-01

The advent of easy-to-use open source microcontrollers, off-the-shelf electronics and customizable manufacturing technologies has facilitated the development of inexpensive scientific devices and laboratory equipment. In this study, we describe an imaging system that integrates low-cost and open-source hardware, software and genetic resources. The multi-fluorescence imaging system consists of readily available 470 nm LEDs, a Raspberry Pi camera and a set of filters made with low cost acrylics. This device allows imaging in scales ranging from single colonies to entire plates. We developed a set of genetic components (e.g. promoters, coding sequences, terminators) and vectors following the standard framework of Golden Gate, which allowed the fabrication of genetic constructs in a combinatorial, low cost and robust manner. In order to provide simultaneous imaging of multiple wavelength signals, we screened a series of long stokes shift fluorescent proteins that could be combined with cyan/green fluorescent proteins. We found CyOFP1, mBeRFP and sfGFP to be the most compatible set for 3-channel fluorescent imaging. We developed open source Python code to operate the hardware to run time-lapse experiments with automated control of illumination and camera and a Python module to analyze data and extract meaningful biological information. To demonstrate the potential application of this integral system, we tested its performance on a diverse range of imaging assays often used in disciplines such as microbial ecology, microbiology and synthetic biology. We also assessed its potential use in a high school environment to teach biology, hardware design, optics, and programming. Together, these results demonstrate the successful integration of open source hardware, software, genetic resources and customizable manufacturing to obtain a powerful, low cost and robust system for education, scientific research and bioengineering. All the resources developed here are available under open source licenses. PMID:29140977

Modeling Host Genetic Regulation of Influenza Pathogenesis in the Collaborative Cross

PubMed Central

Ferris, Martin T.; Aylor, David L.; Bottomly, Daniel; Whitmore, Alan C.; Aicher, Lauri D.; Bell, Timothy A.; Bradel-Tretheway, Birgit; Bryan, Janine T.; Buus, Ryan J.; Gralinski, Lisa E.; Haagmans, Bart L.; McMillan, Leonard; Miller, Darla R.; Rosenzweig, Elizabeth; Valdar, William; Wang, Jeremy; Churchill, Gary A.; Threadgill, David W.; McWeeney, Shannon K.; Katze, Michael G.; Pardo-Manuel de Villena, Fernando; Baric, Ralph S.; Heise, Mark T.

2013-01-01

Genetic variation contributes to host responses and outcomes following infection by influenza A virus or other viral infections. Yet narrow windows of disease symptoms and confounding environmental factors have made it difficult to identify polymorphic genes that contribute to differential disease outcomes in human populations. Therefore, to control for these confounding environmental variables in a system that models the levels of genetic diversity found in outbred populations such as humans, we used incipient lines of the highly genetically diverse Collaborative Cross (CC) recombinant inbred (RI) panel (the pre-CC population) to study how genetic variation impacts influenza associated disease across a genetically diverse population. A wide range of variation in influenza disease related phenotypes including virus replication, virus-induced inflammation, and weight loss was observed. Many of the disease associated phenotypes were correlated, with viral replication and virus-induced inflammation being predictors of virus-induced weight loss. Despite these correlations, pre-CC mice with unique and novel disease phenotype combinations were observed. We also identified sets of transcripts (modules) that were correlated with aspects of disease. In order to identify how host genetic polymorphisms contribute to the observed variation in disease, we conducted quantitative trait loci (QTL) mapping. We identified several QTL contributing to specific aspects of the host response including virus-induced weight loss, titer, pulmonary edema, neutrophil recruitment to the airways, and transcriptional expression. Existing whole-genome sequence data was applied to identify high priority candidate genes within QTL regions. A key host response QTL was located at the site of the known anti-influenza Mx1 gene. We sequenced the coding regions of Mx1 in the eight CC founder strains, and identified a novel Mx1 allele that showed reduced ability to inhibit viral replication, while maintaining protection from weight loss. PMID:23468633

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

The emerging role of epigenetics in rheumatic diseases.

PubMed

Gay, Steffen; Wilson, Anthony G

2014-03-01

Epigenetics is a key mechanism regulating the expression of genes. There are three main and interrelated mechanisms: DNA methylation, post-translational modification of histone proteins and non-coding RNA. Gene activation is generally associated with lower levels of DNA methylation in promoters and with distinct histone marks such as acetylation of amino acids in histones. Unlike the genetic code, the epigenome is altered by endogenous (e.g. hormonal) and environmental (e.g. diet, exercise) factors and changes with age. Recent evidence implicates epigenetic mechanisms in the pathogenesis of common rheumatic disease, including RA, OA, SLE and scleroderma. Epigenetic drift has been implicated in age-related changes in the immune system that result in the development of a pro-inflammatory status termed inflammageing, potentially increasing the risk of age-related conditions such as polymyalgia rheumatica. Therapeutic targeting of the epigenome has shown promise in animal models of rheumatic diseases. Rapid advances in computational biology and DNA sequencing technology will lead to a more comprehensive understanding of the roles of epigenetics in the pathogenesis of common rheumatic diseases.

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.

Familial orthostatic tachycardia due to norepinephrine transporter deficiency

NASA Technical Reports Server (NTRS)

Robertson, D.; Flattem, N.; Tellioglu, T.; Carson, R.; Garland, E.; Shannon, J. R.; Jordan, J.; Jacob, G.; Blakely, R. D.; Biaggioni, I.

2001-01-01

Orthostatic intolerance (OI) or postural tachycardia syndrome (POTS) is a syndrome primarily affecting young females, and is characterized by lightheadedness, palpitations, fatigue, altered mentation, and syncope primarily occurring with upright posture and being relieved by lying down. There is typically tachycardia and raised plasma norepinephrine levels on upright posture, but little or no orthostatic hypotension. The pathophysiology of OI is believed to be very heterogeneous. Most studies of the syndrome have focused on abnormalities in norepinephrine release. Here the hypothesis that abnormal norepinephrine transporter (NET) function might contribute to the pathophysiology in some patients with OI was tested. In a proband with significant orthostatic symptoms and tachycardia, disproportionately elevated plasma norepinephrine with standing, impaired systemic, and local clearance of infused tritiated norepinephrine, impaired tyramine responsiveness, and a dissociation between stimulated plasma norepinephrine and DHPG elevation were found. Studies of NET gene structure in the proband revealed a coding mutation that converts a highly conserved transmembrane domain Ala residue to Pro. Analysis of the protein produced by the mutant cDNA in transfected cells demonstrated greater than 98% reduction in activity relative to normal. NE, DHPG/NE, and heart rate correlated with the mutant allele in this family. CONCLUSION: These results represent the first identification of a specific genetic defect in OI and the first disease linked to a coding alteration in a Na+/Cl(-)-dependent neurotransmitter transporter. Identification of this mechanism may facilitate our understanding of genetic causes of OI and lead to the development of more effective therapeutic modalities.

Genetic and epigenetic status of triple exotic consanguinity cotton introgression lines.

PubMed

He, S P; Sun, J L; Du, X M

2011-10-03

Introgression lines are some of the most important germplasm for breeding applications and other research conducted on cotton crops. The DNA methylation level among 10 introgression lines of cotton (Gossypium hirsutum) and three exotic parental species (G. arboreum, G. thurberi and G. barbadense) were assessed by methylation-sensitive amplified polymorphism (MSAP) technology. The methylation level in the introgression lines ranged from 33.3 to 51.5%. However, the lines PD0111 and PD0113 had the lowest methylation level (34.6 and 33.3%, respectively) due to demethylation of most non-coding sequences. Amplified fragment length polymorphism (AFLP) was used to evaluate the genetic polymorphism in the cotton introgression lines. A high degree of polymorphism was observed in all introgression lines (mean 47.2%) based on AFLP and MSAP analyses. This confirmed the effects of genetic improvement on cotton introgression lines. The low methylation varieties, PD0111 and PD0113 (introgression lines), clustered outside of the introgression lines based on MSAP data, which was incongruent with an AFLP-based dendrogram. This phenomenon could be caused by environmental changes or introgression of exotic DNA fragments.

Genetic and physical interaction of the B-cell systemic lupus erythematosus-associated genes BANK1 and BLK.

PubMed

Castillejo-López, Casimiro; Delgado-Vega, Angélica M; Wojcik, Jerome; Kozyrev, Sergey V; Thavathiru, Elangovan; Wu, Ying-Yu; Sánchez, Elena; Pöllmann, David; López-Egido, Juan R; Fineschi, Serena; Domínguez, Nicolás; Lu, Rufei; James, Judith A; Merrill, Joan T; Kelly, Jennifer A; Kaufman, Kenneth M; Moser, Kathy L; Gilkeson, Gary; Frostegård, Johan; Pons-Estel, Bernardo A; D'Alfonso, Sandra; Witte, Torsten; Callejas, José Luis; Harley, John B; Gaffney, Patrick M; Martin, Javier; Guthridge, Joel M; Alarcón-Riquelme, Marta E

2012-01-01

Altered signalling in B cells is a predominant feature of systemic lupus erythematosus (SLE). The genes BANK1 and BLK were recently described as associated with SLE. BANK1 codes for a B-cell-specific cytoplasmic protein involved in B-cell receptor signalling and BLK codes for an Src tyrosine kinase with important roles in B-cell development. To characterise the role of BANK1 and BLK in SLE, a genetic interaction analysis was performed hypothesising that genetic interactions could reveal functional pathways relevant to disease pathogenesis. The GPAT16 method was used to analyse the gene-gene interactions of BANK1 and BLK. Confocal microscopy was used to investigate co-localisation, and immunoprecipitation was used to verify the physical interaction of BANK1 and BLK. Epistatic interactions between BANK1 and BLK polymorphisms associated with SLE were observed in a discovery set of 279 patients and 515 controls from northern Europe. A meta-analysis with 4399 European individuals confirmed the genetic interactions between BANK1 and BLK. As BANK1 was identified as a binding partner of the Src tyrosine kinase LYN, the possibility that BANK1 and BLK could also show a protein-protein interaction was tested. The co-immunoprecipitation and co-localisation of BLK and BANK1 were demonstrated. In a Daudi cell line and primary naive B cells endogenous binding was enhanced upon B-cell receptor stimulation using anti-IgM antibodies. This study shows a genetic interaction between BANK1 and BLK, and demonstrates that these molecules interact physically. The results have important consequences for the understanding of SLE and other autoimmune diseases and identify a potential new signalling pathway.

Characterization of a genetically engineered mouse model of hemophilia A with complete deletion of the F8 gene.

PubMed

Chao, B N; Baldwin, W H; Healey, J F; Parker, E T; Shafer-Weaver, K; Cox, C; Jiang, P; Kanellopoulou, C; Lollar, P; Meeks, S L; Lenardo, M J

2016-02-01

ESSENTIALS: Anti-factor VIII (FVIII) inhibitory antibody formation is a severe complication in hemophilia A therapy. We genetically engineered and characterized a mouse model with complete deletion of the F8 coding region. F8(TKO) mice exhibit severe hemophilia, express no detectable F8 mRNA, and produce FVIII inhibitors. The defined background and lack of FVIII in F8(TKO) mice will aid in studying FVIII inhibitor formation. The most important complication in hemophilia A treatment is the development of inhibitory anti-Factor VIII (FVIII) antibodies in patients after FVIII therapy. Patients with severe hemophilia who express no endogenous FVIII (i.e. cross-reacting material, CRM) have the greatest incidence of inhibitor formation. However, current mouse models of severe hemophilia A produce low levels of truncated FVIII. The lack of a corresponding mouse model hampers the study of inhibitor formation in the complete absence of FVIII protein. We aimed to generate and characterize a novel mouse model of severe hemophilia A (designated the F8(TKO) strain) lacking the complete coding sequence of F8 and any FVIII CRM. Mice were created on a C57BL/6 background using Cre-Lox recombination and characterized using in vivo bleeding assays, measurement of FVIII activity by coagulation and chromogenic assays, and anti-FVIII antibody production using ELISA. All F8 exonic coding regions were deleted from the genome and no F8 mRNA was detected in F8(TKO) mice. The bleeding phenotype of F8(TKO) mice was comparable to E16 mice by measurements of factor activity and tail snip assay. Similar levels of anti-FVIII antibody titers after recombinant FVIII injections were observed between F8(TKO) and E16 mice. We describe a new C57BL/6 mouse model for severe hemophilia A patients lacking CRM. These mice can be directly bred to the many C57BL/6 strains of genetically engineered mice, which is valuable for studying the impact of a wide variety of genes on FVIII inhibitor formation on a defined genetic background. © 2015 International Society on Thrombosis and Haemostasis.

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

PubMed

Fleming, Damarius S; Miller, Laura C

2018-04-01

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 have emerged as having an important role in the immune system in humans. The study uses transcriptomic read counts to profile the type and quantity of both well and lesser characterized sncRNAs, such as microRNAs and small nucleolar RNAs to identify and quantify the classes of sncRNA expressed in whole blood between healthy and highly pathogenic PRRSV-infected pigs. Our results returned evidence on nine classes of sncRNA, four of which were consistently statistically significantly different based on Fisher's Exact Test, that can be detected and possibly interrogated for their effect on host dysregulation during PRRSV infections. Published by Elsevier Inc.

Epigenetic regulation in human melanoma: past and future.

PubMed

Sarkar, Debina; Leung, Euphemia Y; Baguley, Bruce C; Finlay, Graeme J; Askarian-Amiri, Marjan E

2015-01-01

The development and progression of melanoma have been attributed to independent or combined genetic and epigenetic events. There has been remarkable progress in understanding melanoma pathogenesis in terms of genetic alterations. However, recent studies have revealed a complex involvement of epigenetic mechanisms in the regulation of gene expression, including methylation, chromatin modification and remodeling, and the diverse activities of non-coding RNAs. The roles of gene methylation and miRNAs have been relatively well studied in melanoma, but other studies have shown that changes in chromatin status and in the differential expression of long non-coding RNAs can lead to altered regulation of key genes. Taken together, they affect the functioning of signaling pathways that influence each other, intersect, and form networks in which local perturbations disturb the activity of the whole system. Here, we focus on how epigenetic events intertwine with these pathways and contribute to the molecular pathogenesis of melanoma.

DNA as information.

PubMed

Wills, Peter R

2016-03-13

This article reviews contributions to this theme issue covering the topic 'DNA as information' in relation to the structure of DNA, the measure of its information content, the role and meaning of information in biology and the origin of genetic coding as a transition from uninformed to meaningful computational processes in physical systems. © 2016 The Author(s).

Examination of AVPR1a as an autism susceptibility gene.

PubMed

Wassink, T H; Piven, J; Vieland, V J; Pietila, J; Goedken, R J; Folstein, S E; Sheffield, V C

2004-10-01

Impaired reciprocal social interaction is one of the core features of autism. While its determinants are complex, one biomolecular pathway that clearly influences social behavior is the arginine-vasopressin (AVP) system. The behavioral effects of AVP are mediated through the AVP receptor 1a (AVPR1a), making the AVPR1a gene a reasonable candidate for autism susceptibility. We tested the gene's contribution to autism by screening its exons in 125 independent autistic probands and genotyping two promoter polymorphisms in 65 autism affected sibling pair (ASP) families. While we found no nonconservative coding sequence changes, we did identify evidence of linkage and of linkage disequilibrium. These results were most pronounced in a subset of the ASP families with relatively less severe impairment of language. Thus, though we did not demonstrate a disease-causing variant in the coding sequence, numerous nontraditional disease-causing genetic abnormalities are known to exist that would escape detection by traditional gene screening methods. Given the emerging biological, animal model, and now genetic data, AVPR1a and genes in the AVP system remain strong candidates for involvement in autism susceptibility and deserve continued scrutiny.

An att site-based recombination reporter system for genome engineering and synthetic DNA assembly.

PubMed

Bland, Michael J; Ducos-Galand, Magaly; Val, Marie-Eve; Mazel, Didier

2017-07-14

Direct manipulation of the genome is a widespread technique for genetic studies and synthetic biology applications. The tyrosine and serine site-specific recombination systems of bacteriophages HK022 and ΦC31 are widely used for stable directional exchange and relocation of DNA sequences, making them valuable tools in these contexts. We have developed site-specific recombination tools that allow the direct selection of recombination events by embedding the attB site from each system within the β-lactamase resistance coding sequence (bla). The HK and ΦC31 tools were developed by placing the attB sites from each system into the signal peptide cleavage site coding sequence of bla. All possible open reading frames (ORFs) were inserted and tested for recombination efficiency and bla activity. Efficient recombination was observed for all tested ORFs (3 for HK, 6 for ΦC31) as shown through a cointegrate formation assay. The bla gene with the embedded attB site was functional for eight of the nine constructs tested. The HK/ΦC31 att-bla system offers a simple way to directly select recombination events, thus enhancing the use of site-specific recombination systems for carrying out precise, large-scale DNA manipulation, and adding useful tools to the genetics toolbox. We further show the power and flexibility of bla to be used as a reporter for recombination.

Recurrent Coding Sequence Variation Explains Only A Small Fraction of the Genetic Architecture of Colorectal Cancer

PubMed Central

Timofeeva, Maria N.; Kinnersley, Ben; Farrington, Susan M.; Whiffin, Nicola; Palles, Claire; Svinti, Victoria; Lloyd, Amy; Gorman, Maggie; Ooi, Li-Yin; Hosking, Fay; Barclay, Ella; Zgaga, Lina; Dobbins, Sara; Martin, Lynn; Theodoratou, Evropi; Broderick, Peter; Tenesa, Albert; Smillie, Claire; Grimes, Graeme; Hayward, Caroline; Campbell, Archie; Porteous, David; Deary, Ian J.; Harris, Sarah E.; Northwood, Emma L.; Barrett, Jennifer H.; Smith, Gillian; Wolf, Roland; Forman, David; Morreau, Hans; Ruano, Dina; Tops, Carli; Wijnen, Juul; Schrumpf, Melanie; Boot, Arnoud; Vasen, Hans F A; Hes, Frederik J.; van Wezel, Tom; Franke, Andre; Lieb, Wolgang; Schafmayer, Clemens; Hampe, Jochen; Buch, Stephan; Propping, Peter; Hemminki, Kari; Försti, Asta; Westers, Helga; Hofstra, Robert; Pinheiro, Manuela; Pinto, Carla; Teixeira, Manuel; Ruiz-Ponte, Clara; Fernández-Rozadilla, Ceres; Carracedo, Angel; Castells, Antoni; Castellví-Bel, Sergi; Campbell, Harry; Bishop, D. Timothy; Tomlinson, Ian P M; Dunlop, Malcolm G.; Houlston, Richard S.

2015-01-01

Whilst common genetic variation in many non-coding genomic regulatory regions are known to impart risk of colorectal cancer (CRC), much of the heritability of CRC remains unexplained. To examine the role of recurrent coding sequence variation in CRC aetiology, we genotyped 12,638 CRCs cases and 29,045 controls from six European populations. Single-variant analysis identified a coding variant (rs3184504) in SH2B3 (12q24) associated with CRC risk (OR = 1.08, P = 3.9 × 10−7), and novel damaging coding variants in 3 genes previously tagged by GWAS efforts; rs16888728 (8q24) in UTP23 (OR = 1.15, P = 1.4 × 10−7); rs6580742 and rs12303082 (12q13) in FAM186A (OR = 1.11, P = 1.2 × 10−7 and OR = 1.09, P = 7.4 × 10−8); rs1129406 (12q13) in ATF1 (OR = 1.11, P = 8.3 × 10−9), all reaching exome-wide significance levels. Gene based tests identified associations between CRC and PCDHGA genes (P < 2.90 × 10−6). We found an excess of rare, damaging variants in base-excision (P = 2.4 × 10−4) and DNA mismatch repair genes (P = 6.1 × 10−4) consistent with a recessive mode of inheritance. This study comprehensively explores the contribution of coding sequence variation to CRC risk, identifying associations with coding variation in 4 genes and PCDHG gene cluster and several candidate recessive alleles. However, these findings suggest that recurrent, low-frequency coding variants account for a minority of the unexplained heritability of CRC. PMID:26553438

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.

Hsp90 and environmental stress transform the adaptive value of natural genetic variation.

PubMed

Jarosz, Daniel F; Lindquist, Susan

2010-12-24

How can species remain unaltered for long periods yet also undergo rapid diversification? By linking genetic variation to phenotypic variation via environmental stress, the Hsp90 protein-folding reservoir might promote both stasis and change. However, the nature and adaptive value of Hsp90-contingent traits remain uncertain. In ecologically and genetically diverse yeasts, we find such traits to be both common and frequently adaptive. Most are based on preexisting variation, with causative polymorphisms occurring in coding and regulatory sequences alike. A common temperature stress alters phenotypes similarly. Both selective inhibition of Hsp90 and temperature stress increase correlations between genotype and phenotype. This system broadly determines the adaptive value of standing genetic variation and, in so doing, has influenced the evolution of current genomes.

Multi-level Expression Design Language: Requirement level (MEDL-R) system evaluation

NASA Technical Reports Server (NTRS)

1980-01-01

An evaluation of the Multi-Level Expression Design Language Requirements Level (MEDL-R) system was conducted to determine whether it would be of use in the Goddard Space Flight Center Code 580 software development environment. The evaluation is based upon a study of the MEDL-R concept of requirement languages, the functions performed by MEDL-R, and the MEDL-R language syntax. Recommendations are made for changes to MEDL-R that would make it useful in the Code 580 environment.

Why Your ZIP Code Matters More Than Your Genetic Code: Promoting Healthy Outcomes from Mother to Child.

PubMed

Graham, Garth N

2016-10-01

Health equity has long been the dominant theme in the work of the Aetna Foundation. Recent data have focused on disparities through another lens, particularly the correlation between where people live (i.e., ZIP code) and their quality-and length-of life. In various cities across America, average life expectancies in certain communities are 20-30 years shorter than those mere miles away. In general, health disparities are founded on a complex interplay of racial, economic, educational, and other social factors. For example, breastfeeding rates in the United States differ significantly depending upon the race and income of the mother. Government policy makers are acutely aware of these disparities, but recent health system reforms have focused predominately on the processes used to administer, finance, and deliver care. What is needed is an approach that considers the health and wellness of all people in a geographic area, beyond established patients, and that measures more than clinical factors-such as genetics, environmental health, social circumstances, and individual behaviors. Solutions also must extend beyond the traditional healthcare arena. In particular, novel technological innovations show promise to bridge gaps between our healthcare capabilities and the needs of underserved populations. Digital tools are poised to revolutionize measurement, diagnostics, treatment, and global aspect of our healthcare system. The Aetna Foundation views technology as a core strategy in reducing health inequities through an approach that addresses both clinical and social factors in populations to dismantle the persistent paradigm of ZIP code as personal health destiny.

Observed positive parenting behaviors and youth genotype: evidence for gene-environment correlations and moderation by parent personality traits.

PubMed

Oppenheimer, Caroline W; Hankin, Benjamin L; Jenness, Jessica L; Young, Jami F; Smolen, Andrew

2013-02-01

Gene-environment correlations (rGE) have been demonstrated in behavioral genetic studies, but rGE have proven elusive in molecular genetic research. Significant gene-environment correlations may be difficult to detect because potential moderators could reduce correlations between measured genetic variants and the environment. Molecular genetic studies investigating moderated rGE are lacking. This study examined associations between child catechol-O-methyltransferase genotype and aspects of positive parenting (responsiveness and warmth), and whether these associations were moderated by parental personality traits (neuroticism and extraversion) among a general community sample of third, sixth, and ninth graders (N = 263) and their parents. Results showed that parent personality traits moderated the rGE association between youths' genotype and coded observations of positive parenting. Parents with low levels of neuroticism and high levels of extraversion exhibited greater sensitive responsiveness and warmth, respectively, to youth with the valine/valine genotype. Moreover, youth with this genotype exhibited lower levels of observed anger. There was no association between the catechol-O-methyltransferase genotype and parenting behaviors for parents high on neuroticism and low on extraversion. Findings highlight the importance of considering moderating variables that may influence child genetic effects on the rearing environment. Implications for developmental models of maladaptive and adaptive child outcomes, and interventions for psychopathology, are discussed within a developmental psychopathology framework.

Observed positive parenting behaviors and youth genotype: Evidence for gene–environment correlations and moderation by parent personality traits

PubMed Central

OPPENHEIMER, CAROLINE W.; HANKIN, BENJAMIN L.; JENNESS, JESSICA L.; YOUNG, JAMI F.; SMOLEN, ANDREW

2013-01-01

Gene–environment correlations (rGE) have been demonstrated in behavioral genetic studies, but rGE have proven elusive in molecular genetic research. Significant gene–environment correlations may be difficult to detect because potential moderators could reduce correlations between measured genetic variants and the environment. Molecular genetic studies investigating moderated rGE are lacking. This study examined associations between child catechol-O-methyltransferase genotype and aspects of positive parenting (responsiveness and warmth), and whether these associations were moderated by parental personality traits (neuroticism and extraversion) among a general community sample of third, sixth, and ninth graders (N = 263) and their parents. Results showed that parent personality traits moderated the rGE association between youths’ genotype and coded observations of positive parenting. Parents with low levels of neuroticism and high levels of extraversion exhibited greater sensitive responsiveness and warmth, respectively, to youth with the valine/valine genotype. Moreover, youth with this genotype exhibited lower levels of observed anger. There was no association between the catechol-O-methyltransferase genotype and parenting behaviors for parents high on neuroticism and low on extraversion. Findings highlight the importance of considering moderating variables that may influence child genetic effects on the rearing environment. Implications for developmental models of maladaptive and adaptive child outcomes, and interventions for psychopathology, are discussed within a developmental psychopathology framework. PMID:23398761

The Hmong Diaspora: preserved South-East Asian genetic ancestry in French Guianese Asians.

PubMed

Brucato, Nicolas; Mazières, Stéphane; Guitard, Evelyne; Giscard, Pierre-Henri; Bois, Etienne; Larrouy, Georges; Dugoujon, Jean-Michel

2012-01-01

The Hmong Diaspora is one of the widest modern human migrations. Mainly localised in South-East Asia, the United States of America, and metropolitan France, a small community has also settled the Amazonian forest of French Guiana. We have biologically analysed 62 individuals of this unique Guianese population through three complementary genetic markers: mitochondrial DNA (HVS-I/II and coding region SNPs), Y-chromosome (SNPs and STRs), and the Gm allotypic system. All genetic systems showed a high conservation of the Asian gene pool (Asian ancestry: mtDNA=100.0%; NRY=99.1%; Gm=96.6%), without a trace of founder effect. When compared across various Asian populations, the highest correlations were observed with Hmong-Mien groups still living in South-East Asia (Fst<0.05; P-value<0.05). Despite a long history punctuated by exodus, the French Guianese Hmong have maintained their original genetic diversity. Copyright © 2012 Académie des sciences. Published by Elsevier SAS. All rights reserved.

Signatures of selection in tilapia revealed by whole genome resequencing.

PubMed

Xia, Jun Hong; Bai, Zhiyi; Meng, Zining; Zhang, Yong; Wang, Le; Liu, Feng; Jing, Wu; Wan, Zi Yi; Li, Jiale; Lin, Haoran; Yue, Gen Hua

2015-09-16

Natural selection and selective breeding for genetic improvement have left detectable signatures within the genome of a species. Identification of selection signatures is important in evolutionary biology and for detecting genes that facilitate to accelerate genetic improvement. However, selection signatures, including artificial selection and natural selection, have only been identified at the whole genome level in several genetically improved fish species. Tilapia is one of the most important genetically improved fish species in the world. Using next-generation sequencing, we sequenced the genomes of 47 tilapia individuals. We identified a total of 1.43 million high-quality SNPs and found that the LD block sizes ranged from 10-100 kb in tilapia. We detected over a hundred putative selective sweep regions in each line of tilapia. Most selection signatures were located in non-coding regions of the tilapia genome. The Wnt signaling, gonadotropin-releasing hormone receptor and integrin signaling pathways were under positive selection in all improved tilapia lines. Our study provides a genome-wide map of genetic variation and selection footprints in tilapia, which could be important for genetic studies and accelerating genetic improvement of tilapia.

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 ...

Spectroscopy detection of green and red fluorescent proteins in genetically modified plants using a fiber optics system

NASA Astrophysics Data System (ADS)

Liew, Oi Wah; Asundi, Anand K.; Chen, Jun-Wei; Chew, Yiwen; Yu, Shangjuan; Yeo, Gare H.

2001-05-01

In this paper, fiber optic spectroscopy is developed to detect and quantify recombinant green (EGFP) and red (DsRED) fluorescent proteins in vitro and in vivo. The bacterial expression vectors carrying the coding regions of EGFP and DsRED were introduced into Escherichia coli host cells and fluorescent proteins were produced following induction with IPTG. Soluble EGFP and DsRED proteins were isolated from lysed bacterial cells and serially diluted for quantitative analysis by fiber optic spectroscopy. Fluorescence at the appropriate emission wavelengths could be detected up to 64X dilution for EGFP and 40X dilution for DsRED. To determine the capability of spectroscopy detection in vivo, transgenic potato hairy roots expressing EGFP and DsRED were regenerated. This was achieved by cloning the EGFP and DsRED genes into the plant binary vector, pTMV35S, to create the recombinant vectors pGLOWGreen and pGLOWRed. These latter binary vectors were introduced into Agrobacterium rhizogenes strain A4T. Infection of potato cells with transformed agrobacteria was used to insert the fluorescent protein genes into the potato genome. Genetically modified potato cells were then regenerated into hairy roots. A panel of transformed hairy roots expressing varying levels of fluorescent proteins was selected by fluorescence microscopy. We are now assessing the capability of spectroscopic detection system for in vivo quantification of green and red fluorescence levels in transformed roots.

Hfq Influences Multiple Transport Systems and Virulence in the Plant Pathogen Agrobacterium tumefaciens

PubMed Central

Wilms, Ina; Möller, Philip; Stock, Anna-Maria; Gurski, Rosemarie; Lai, Erh-Min

2012-01-01

The Hfq protein mediates gene regulation by small RNAs (sRNAs) in about 50% of all bacteria. Depending on the species, phenotypic defects of an hfq mutant range from mild to severe. Here, we document that the purified Hfq protein of the plant pathogen and natural genetic engineer Agrobacterium tumefaciens binds to the previously described sRNA AbcR1 and its target mRNA atu2422, which codes for the substrate binding protein of an ABC transporter taking up proline and γ-aminobutyric acid (GABA). Several other ABC transporter components were overproduced in an hfq mutant compared to their levels in the parental strain, suggesting that Hfq plays a major role in controlling the uptake systems and metabolic versatility of A. tumefaciens. The hfq mutant showed delayed growth, altered cell morphology, and reduced motility. Although the DNA-transferring type IV secretion system was produced, tumor formation by the mutant strain was attenuated, demonstrating an important contribution of Hfq to plant transformation by A. tumefaciens. PMID:22821981

[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.

Developing a contributing factor classification scheme for Rasmussen's AcciMap: Reliability and validity evaluation.

PubMed

Goode, N; Salmon, P M; Taylor, N Z; Lenné, M G; Finch, C F

2017-10-01

One factor potentially limiting the uptake of Rasmussen's (1997) Accimap method by practitioners is the lack of a contributing factor classification scheme to guide accident analyses. This article evaluates the intra- and inter-rater reliability and criterion-referenced validity of a classification scheme developed to support the use of Accimap by led outdoor activity (LOA) practitioners. The classification scheme has two levels: the system level describes the actors, artefacts and activity context in terms of 14 codes; the descriptor level breaks the system level codes down into 107 specific contributing factors. The study involved 11 LOA practitioners using the scheme on two separate occasions to code a pre-determined list of contributing factors identified from four incident reports. Criterion-referenced validity was assessed by comparing the codes selected by LOA practitioners to those selected by the method creators. Mean intra-rater reliability scores at the system (M = 83.6%) and descriptor (M = 74%) levels were acceptable. Mean inter-rater reliability scores were not consistently acceptable for both coding attempts at the system level (M T1  = 68.8%; M T2  = 73.9%), and were poor at the descriptor level (M T1  = 58.5%; M T2  = 64.1%). Mean criterion referenced validity scores at the system level were acceptable (M T1  = 73.9%; M T2  = 75.3%). However, they were not consistently acceptable at the descriptor level (M T1  = 67.6%; M T2  = 70.8%). Overall, the results indicate that the classification scheme does not currently satisfy reliability and validity requirements, and that further work is required. The implications for the design and development of contributing factors classification schemes are discussed. Copyright © 2017 Elsevier Ltd. All rights reserved.

System and method for embedding emotion in logic systems

NASA Technical Reports Server (NTRS)

Curtis, Steven A. (Inventor)

2012-01-01

A system, method, and computer readable-media for creating a stable synthetic neural system. The method includes training an intellectual choice-driven synthetic neural system (SNS), training an emotional rule-driven SNS by generating emotions from rules, incorporating the rule-driven SNS into the choice-driven SNS through an evolvable interface, and balancing the emotional SNS and the intellectual SNS to achieve stability in a nontrivial autonomous environment with a Stability Algorithm for Neural Entities (SANE). Generating emotions from rules can include coding the rules into the rule-driven SNS in a self-consistent way. Training the emotional rule-driven SNS can occur during a training stage in parallel with training the choice-driven SNS. The training stage can include a self assessment loop which measures performance characteristics of the rule-driven SNS against core genetic code. The method uses a stability threshold to measure stability of the incorporated rule-driven SNS and choice-driven SNS using SANE.

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

Next-generation mammalian genetics toward organism-level systems biology.

PubMed

Susaki, Etsuo A; Ukai, Hideki; Ueda, Hiroki R

2017-01-01

Organism-level systems biology in mammals aims to identify, analyze, control, and design molecular and cellular networks executing various biological functions in mammals. In particular, system-level identification and analysis of molecular and cellular networks can be accelerated by next-generation mammalian genetics. Mammalian genetics without crossing, where all production and phenotyping studies of genome-edited animals are completed within a single generation drastically reduce the time, space, and effort of conducting the systems research. Next-generation mammalian genetics is based on recent technological advancements in genome editing and developmental engineering. The process begins with introduction of double-strand breaks into genomic DNA by using site-specific endonucleases, which results in highly efficient genome editing in mammalian zygotes or embryonic stem cells. By using nuclease-mediated genome editing in zygotes, or ~100% embryonic stem cell-derived mouse technology, whole-body knock-out and knock-in mice can be produced within a single generation. These emerging technologies allow us to produce multiple knock-out or knock-in strains in high-throughput manner. In this review, we discuss the basic concepts and related technologies as well as current challenges and future opportunities for next-generation mammalian genetics in organism-level systems biology.

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.

Searching for Organics, Fossils, and Biology on Mars

NASA Technical Reports Server (NTRS)

McKay, Christopher P.; DeVincenzi, Donald (Technical Monitor)

2001-01-01

One of the goals of Astrobiology is to understand life on a fundamental level. All life on Earth is constructed from the same basic biochemical building blocks consisting of 20 amino acids with left handed symmetry, five nucleotides, a few sugars of right handed symmetry and some lipids. Using the metaphor of computers this is equivalent to saying that all life shares the same hardware. Beyond hardware similarity, it is now known that all life has fundamentally the same software. The genetic code of life is common to all organisms. Some have argued that the "hammer of evolution is heavy" and life anywhere is likely to be composed of identical biochemical and genetic patterns. However, in a system as complex as biochemistry it is likely that there are numerous local optima and the details of the optimum found by evolutionary selection on another world would likely depend on the initial conditions and random developments in the early biological history on that world. To address these fundamental questions in Astrobiology we need a second example of life: a second genesis.

'Faceness' and affectivity: evidence for genetic contributions to distinct components of electrocortical response to human faces.

PubMed

Shannon, Robert W; Patrick, Christopher J; Venables, Noah C; He, Sheng

2013-12-01

The ability to recognize a variety of different human faces is undoubtedly one of the most important and impressive functions of the human perceptual system. Neuroimaging studies have revealed multiple brain regions (including the FFA, STS, OFA) and electrophysiological studies have identified differing brain event-related potential (ERP) components (e.g., N170, P200) possibly related to distinct types of face information processing. To evaluate the heritability of ERP components associated with face processing, including N170, P200, and LPP, we examined ERP responses to fearful and neutral face stimuli in monozygotic (MZ) and dizygotic (DZ) twins. Concordance levels for early brain response indices of face processing (N170, P200) were found to be stronger for MZ than DZ twins, providing evidence of a heritable basis to each. These findings support the idea that certain key neural mechanisms for face processing are genetically coded. Implications for understanding individual differences in recognition of facial identity and the emotional content of faces are discussed. Copyright © 2013 Elsevier Inc. All rights reserved.

Comparative Mitogenomics of Plant Bugs (Hemiptera: Miridae): Identifying the AGG Codon Reassignments between Serine and Lysine

PubMed Central

Wang, Pei; Song, Fan; Cai, Wanzhi

2014-01-01

Insect mitochondrial genomes are very important to understand the molecular evolution as well as for phylogenetic and phylogeographic studies of the insects. The Miridae are the largest family of Heteroptera encompassing more than 11,000 described species and of great economic importance. For better understanding the diversity and the evolution of plant bugs, we sequence five new mitochondrial genomes and present the first comparative analysis of nine mitochondrial genomes of mirids available to date. Our result showed that gene content, gene arrangement, base composition and sequences of mitochondrial transcription termination factor were conserved in plant bugs. Intra-genus species shared more conserved genomic characteristics, such as nucleotide and amino acid composition of protein-coding genes, secondary structure and anticodon mutations of tRNAs, and non-coding sequences. Control region possessed several distinct characteristics, including: variable size, abundant tandem repetitions, and intra-genus conservation; and was useful in evolutionary and population genetic studies. The AGG codon reassignments were investigated between serine and lysine in the genera Adelphocoris and other cimicomorphans. Our analysis revealed correlated evolution between reassignments of the AGG codon and specific point mutations at the antidocons of tRNALys and tRNASer(AGN). Phylogenetic analysis indicated that mitochondrial genome sequences were useful in resolving family level relationship of Cimicomorpha. Comparative evolutionary analysis of plant bug mitochondrial genomes allowed the identification of previously neglected coding genes or non-coding regions as potential molecular markers. The finding of the AGG codon reassignments between serine and lysine indicated the parallel evolution of the genetic code in Hemiptera mitochondrial genomes. PMID:24988409

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 application of coded excitation technology in medical ultrasonic Doppler imaging

NASA Astrophysics Data System (ADS)

Li, Weifeng; Chen, Xiaodong; Bao, Jing; Yu, Daoyin

2008-03-01

Medical ultrasonic Doppler imaging is one of the most important domains of modern medical imaging technology. The application of coded excitation technology in medical ultrasonic Doppler imaging system has the potential of higher SNR and deeper penetration depth than conventional pulse-echo imaging system, it also improves the image quality, and enhances the sensitivity of feeble signal, furthermore, proper coded excitation is beneficial to received spectrum of Doppler signal. Firstly, this paper analyzes the application of coded excitation technology in medical ultrasonic Doppler imaging system abstractly, showing the advantage and bright future of coded excitation technology, then introduces the principle and the theory of coded excitation. Secondly, we compare some coded serials (including Chirp and fake Chirp signal, Barker codes, Golay's complementary serial, M-sequence, etc). Considering Mainlobe Width, Range Sidelobe Level, Signal-to-Noise Ratio and sensitivity of Doppler signal, we choose Barker codes as coded serial. At last, we design the coded excitation circuit. The result in B-mode imaging and Doppler flow measurement coincided with our expectation, which incarnated the advantage of application of coded excitation technology in Digital Medical Ultrasonic Doppler Endoscope Imaging System.

Molecular and neurochemical substrates of the audiogenic seizure strains: The GASH:Sal model.

PubMed

Prieto-Martín, Ana I; Aroca-Aguilar, J Daniel; Sánchez-Sánchez, Francisco; Muñoz, Luis J; López, Dolores E; Escribano, Julio; de Cabo, Carlos

2017-06-01

Animal models of audiogenic epilepsy are useful tools to understand the mechanisms underlying human reflex epilepsies. There is accumulating evidence regarding behavioral, anatomical, electrophysiological, and genetic substrates of audiogenic seizure strains, but there are still aspects concerning their neurochemical basis that remain to be elucidated. Previous studies have shown the involved of γ-amino butyric acid (GABA) in audiogenic seizures. The aim of our research was to clarify the role of the GABAergic system in the generation of epileptic seizures in the genetic audiogenic seizure-prone hamster (GASH:Sal) strain. We studied the K + /Cl - cotransporter KCC2 and β2-GABAA-type receptor (GABAAR) and β3-GABAAR subunit expressions in the GASH:Sal both at rest and after repeated sound-induced seizures in different brain regions using the Western blot technique. We also sequenced the coding region for the KCC2 gene both in wild- type and GASH:Sal hamsters. Lower expression of KCC2 protein was found in GASH:Sal when compared with controls at rest in several brain areas: hippocampus, cortex, cerebellum, hypothalamus, pons-medulla, and mesencephalon. Repeated induction of seizures caused a decrease in KCC2 protein content in the inferior colliculus and hippocampus and an increase in the pons-medulla. When compared to controls, the basal β 2 -GABA A R subunit in the GASH:Sal was overexpressed in the inferior colliculus, rest of the mesencephalon, and cerebellum, whereas basal β 3 subunit levels were lower in the inferior colliculus and rest of the mesencephalon. Repeated seizures increased β2 both in the inferior colliculus and in the hypothalamus and β 3 in the hypothalamus. No differences in the KCC2 gene-coding region were found between GASH:Sal and wild-type hamsters. These data indicate that GABAergic system functioning is impaired in the GASH:Sal strain, and repeated seizures seem to aggravate this dysfunction. These results have potential clinical relevance and support the validity of employing the GASH:Sal strain as a model to study the neurochemistry of genetic reflex epilepsy. This article is part of a Special Issue entitled "Genetic and Reflex Epilepsies, Audiogenic Seizures and Strains: From Experimental Models to the Clinic". Copyright © 2015 Elsevier Inc. All rights reserved.

[Data coding in the Israeli healthcare system - do choices provide the answers to our system's needs?].

PubMed

Zelingher, Julian; Ash, Nachman

2013-05-01

The IsraeLi healthcare system has undergone major processes for the adoption of health information technologies (HIT), and enjoys high Levels of utilization in hospital and ambulatory care. Coding is an essential infrastructure component of HIT, and ts purpose is to represent data in a simplified and common format, enhancing its manipulation by digital systems. Proper coding of data enables efficient identification, storage, retrieval and communication of data. UtiLization of uniform coding systems by different organizations enables data interoperability between them, facilitating communication and integrating data elements originating in different information systems from various organizations. Current needs in Israel for heaLth data coding include recording and reporting of diagnoses for hospitalized patients, outpatients and visitors of the Emergency Department, coding of procedures and operations, coding of pathology findings, reporting of discharge diagnoses and causes of death, billing codes, organizational data warehouses and national registries. New national projects for cLinicaL data integration, obligatory reporting of quality indicators and new Ministry of Health (MOH) requirements for HIT necessitate a high Level of interoperability that can be achieved only through the adoption of uniform coding. Additional pressures were introduced by the USA decision to stop the maintenance of the ICD-9-CM codes that are also used by Israeli healthcare, and the adoption of ICD-10-C and ICD-10-PCS as the main coding system for billing purpose. The USA has also mandated utilization of SNOMED-CT as the coding terminology for the ELectronic Health Record problem list, and for reporting quality indicators to the CMS. Hence, the Israeli MOH has recently decided that discharge diagnoses will be reported using ICD-10-CM codes, and SNOMED-CT will be used to code the cLinical information in the EHR. We reviewed the characteristics, strengths and weaknesses of these two coding systems. In summary, the adoption of ICD-10-CM is in line with the USA decision to abandon ICD-9-CM, and the Israeli heaLthcare system could benefit from USA heaLthcare efforts in this direction. The Large content of SNOMED-CT and its sophisticated hierarchical data structure will enable advanced cLinicaL decision support and quality improvement applications.

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.

Optimal lightpath placement on a metropolitan-area network linked with optical CDMA local nets

NASA Astrophysics Data System (ADS)

Wang, Yih-Fuh; Huang, Jen-Fa

2008-01-01

A flexible optical metropolitan-area network (OMAN) [J.F. Huang, Y.F. Wang, C.Y. Yeh, Optimal configuration of OCDMA-based MAN with multimedia services, in: 23rd Biennial Symposium on Communications, Queen's University, Kingston, Canada, May 29-June 2, 2006, pp. 144-148] structured with OCDMA linkage is proposed to support multimedia services with multi-rate or various qualities of service. To prioritize transmissions in OCDMA, the orthogonal variable spreading factor (OVSF) codes widely used in wireless CDMA are adopted. In addition, for feasible multiplexing, unipolar OCDMA modulation [L. Nguyen, B. Aazhang, J.F. Young, All-optical CDMA with bipolar codes, IEEE Electron. Lett. 31 (6) (1995) 469-470] is used to generate the code selector of multi-rate OMAN, and a flexible fiber-grating-based system is used for the equipment on OCDMA-OVSF code. These enable an OMAN to assign suitable OVSF codes when creating different-rate lightpaths. How to optimally configure a multi-rate OMAN is a challenge because of displaced lightpaths. In this paper, a genetically modified genetic algorithm (GMGA) [L.R. Chen, Flexible fiber Bragg grating encoder/decoder for hybrid wavelength-time optical CDMA, IEEE Photon. Technol. Lett. 13 (11) (2001) 1233-1235] is used to preplan lightpaths in order to optimally configure an OMAN. To evaluate the performance of the GMGA, we compared it with different preplanning optimization algorithms. Simulation results revealed that the GMGA very efficiently solved the problem.

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.

Selection of a computer code for Hanford low-level waste engineered-system performance assessment

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

McGrail, B.P.; Mahoney, L.A.

Planned performance assessments for the proposed disposal of low-level waste (LLW) glass produced from remediation of wastes stored in underground tanks at Hanford, Washington will require calculations of radionuclide release rates from the subsurface disposal facility. These calculations will be done with the aid of computer codes. Currently available computer codes were ranked in terms of the feature sets implemented in the code that match a set of physical, chemical, numerical, and functional capabilities needed to assess release rates from the engineered system. The needed capabilities were identified from an analysis of the important physical and chemical process expected tomore » affect LLW glass corrosion and the mobility of radionuclides. The highest ranked computer code was found to be the ARES-CT code developed at PNL for the US Department of Energy for evaluation of and land disposal sites.« less

Functional annotation of the vlinc class of non-coding RNAs using systems biology approach

PubMed Central

Laurent, Georges St.; Vyatkin, Yuri; Antonets, Denis; Ri, Maxim; Qi, Yao; Saik, Olga; Shtokalo, Dmitry; de Hoon, Michiel J.L.; Kawaji, Hideya; Itoh, Masayoshi; Lassmann, Timo; Arner, Erik; Forrest, Alistair R.R.; Nicolas, Estelle; McCaffrey, Timothy A.; Carninci, Piero; Hayashizaki, Yoshihide; Wahlestedt, Claes; Kapranov, Philipp

2016-01-01

Functionality of the non-coding transcripts encoded by the human genome is the coveted goal of the modern genomics research. While commonly relied on the classical methods of forward genetics, integration of different genomics datasets in a global Systems Biology fashion presents a more productive avenue of achieving this very complex aim. Here we report application of a Systems Biology-based approach to dissect functionality of a newly identified vast class of very long intergenic non-coding (vlinc) RNAs. Using highly quantitative FANTOM5 CAGE dataset, we show that these RNAs could be grouped into 1542 novel human genes based on analysis of insulators that we show here indeed function as genomic barrier elements. We show that vlincRNAs genes likely function in cis to activate nearby genes. This effect while most pronounced in closely spaced vlincRNA–gene pairs can be detected over relatively large genomic distances. Furthermore, we identified 101 vlincRNA genes likely involved in early embryogenesis based on patterns of their expression and regulation. We also found another 109 such genes potentially involved in cellular functions also happening at early stages of development such as proliferation, migration and apoptosis. Overall, we show that Systems Biology-based methods have great promise for functional annotation of non-coding RNAs. PMID:27001520

A Response Surface Methodology for Bi-Level Integrated System Synthesis (BLISS)

NASA Technical Reports Server (NTRS)

Altus, Troy David; Sobieski, Jaroslaw (Technical Monitor)

2002-01-01

The report describes a new method for optimization of engineering systems such as aerospace vehicles whose design must harmonize a number of subsystems and various physical phenomena, each represented by a separate computer code, e.g., aerodynamics, structures, propulsion, performance, etc. To represent the system internal couplings, the codes receive output from other codes as part of their inputs. The system analysis and optimization task is decomposed into subtasks that can be executed concurrently, each subtask conducted using local state and design variables and holding constant a set of the system-level design variables. The subtasks results are stored in form of the Response Surfaces (RS) fitted in the space of the system-level variables to be used as the subtask surrogates in a system-level optimization whose purpose is to optimize the system objective(s) and to reconcile the system internal couplings. By virtue of decomposition and execution concurrency, the method enables a broad workfront in organization of an engineering project involving a number of specialty groups that might be geographically dispersed, and it exploits the contemporary computing technology of massively concurrent and distributed processing. The report includes a demonstration test case of supersonic business jet design.

Multilevel Parallelization of AutoDock 4.2.

PubMed

Norgan, Andrew P; Coffman, Paul K; Kocher, Jean-Pierre A; Katzmann, David J; Sosa, Carlos P

2011-04-28

Virtual (computational) screening is an increasingly important tool for drug discovery. AutoDock is a popular open-source application for performing molecular docking, the prediction of ligand-receptor interactions. AutoDock is a serial application, though several previous efforts have parallelized various aspects of the program. In this paper, we report on a multi-level parallelization of AutoDock 4.2 (mpAD4). Using MPI and OpenMP, AutoDock 4.2 was parallelized for use on MPI-enabled systems and to multithread the execution of individual docking jobs. In addition, code was implemented to reduce input/output (I/O) traffic by reusing grid maps at each node from docking to docking. Performance of mpAD4 was examined on two multiprocessor computers. Using MPI with OpenMP multithreading, mpAD4 scales with near linearity on the multiprocessor systems tested. In situations where I/O is limiting, reuse of grid maps reduces both system I/O and overall screening time. Multithreading of AutoDock's Lamarkian Genetic Algorithm with OpenMP increases the speed of execution of individual docking jobs, and when combined with MPI parallelization can significantly reduce the execution time of virtual screens. This work is significant in that mpAD4 speeds the execution of certain molecular docking workloads and allows the user to optimize the degree of system-level (MPI) and node-level (OpenMP) parallelization to best fit both workloads and computational resources.

Engineering posttranslational proofreading to discriminate nonstandard amino acids

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

Kunjapur, Aditya M.; Stork, Devon A.; Kuru, Erkin

Accurate incorporation of nonstandard amino acids (nsAAs) is central for genetic code expansion to increase the chemical diversity of proteins. However, aminoacyl-tRNA synthetases are polyspecific and facilitate incorporation of multiple nsAAs. We investigated and repurposed a natural protein degradation pathway, the N-end rule pathway, to devise an innovative system for rapid assessment of the accuracy of nsAA incorporation. Using this tool to monitor incorporation of the nsAA biphenylalanine allowed the identification of tyrosyl-tRNA synthetase (TyrRS) variants with improved amino acid specificity. The evolved TyrRS variants enhanced our ability to contain unwanted proliferation of genetically modified organisms. In conclusion, this posttranslationalmore » proofreading system will aid the evolution of orthogonal translation systems for specific incorporation of diverse nsAAs.« less

Engineering posttranslational proofreading to discriminate nonstandard amino acids

DOE PAGES

Kunjapur, Aditya M.; Stork, Devon A.; Kuru, Erkin; ...

2018-01-04

Accurate incorporation of nonstandard amino acids (nsAAs) is central for genetic code expansion to increase the chemical diversity of proteins. However, aminoacyl-tRNA synthetases are polyspecific and facilitate incorporation of multiple nsAAs. We investigated and repurposed a natural protein degradation pathway, the N-end rule pathway, to devise an innovative system for rapid assessment of the accuracy of nsAA incorporation. Using this tool to monitor incorporation of the nsAA biphenylalanine allowed the identification of tyrosyl-tRNA synthetase (TyrRS) variants with improved amino acid specificity. The evolved TyrRS variants enhanced our ability to contain unwanted proliferation of genetically modified organisms. In conclusion, this posttranslationalmore » proofreading system will aid the evolution of orthogonal translation systems for specific incorporation of diverse nsAAs.« less

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.

Performance Enhancement by Threshold Level Control of a Receiver in WDM-PON System with Manchester Coded Downstream and NRZ Upstream Re-Modulation

NASA Astrophysics Data System (ADS)

Kim, Bong Kyu; Chung, Hwan Seok; Chang, Sun Hyok; Park, Sangjo

We propose and demonstrate a scheme enhancing the performance of optical access networks with Manchester coded downstream and re-modulated NRZ coded upstream. It is achieved by threshold level control of a limiting amplifier at a receiver, and the minimum sensitivity of upstream is significantly improved for the re-modulation scheme with 5Gb/s Manchester coded downstream and 2.488Gb/s NRZ upstream data rates.

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.

National Underground Mines Inventory

DTIC Science & Technology

1983-10-01

system is well designed to minimize water accumulation on the drift levels. In many areas, sufficient water has accumulated to make the use of boots a...four characters designate Field office. 17-18 State Code Pic 99 FIPS code for state in which minets located. 19-21 County Code Plc 999 FIPS code for... Designate a general product class based onSIC code. 28-29 Nine Type Plc 99 Natal/Nonmetal mine type code. Based on subunit operations code and canvass code

Development of a Gene Cloning System in Methanogens.

DTIC Science & Technology

1987-03-27

Genetic transfer via DNA-dependent natural transformation was achieved for two markers, 5-fluorouracil-resistance, and 6- mercaptopurine resistance...resistance genes, and genes coding for enzymes that produce colored products will be tested as markers for plasmid transformation. A functional plasmid...clones, which include resistances to mercaptopurine , azahypoxanthine, diazauracil, kanamycin, mitomycin C, and fluorouracil- mercaptopurine and

Effect of strain and diet on growth performance characteristics and relative expression of genes coding for electron transport chain in channel catfish

USDA-ARS?s Scientific Manuscript database

The major cost in aquaculture production systems is feed, and the use of biotechnology approaches to identify fishes with superior feed efficiency (FE) may have a positive influence on profitability. There been little use of genetically based technologies to assess FE in culture fishes. Mitochondria...

MS-READ: Quantitative measurement of amino acid incorporation.

PubMed

Mohler, Kyle; Aerni, Hans-Rudolf; Gassaway, Brandon; Ling, Jiqiang; Ibba, Michael; Rinehart, Jesse

2017-11-01

Ribosomal protein synthesis results in the genetically programmed incorporation of amino acids into a growing polypeptide chain. Faithful amino acid incorporation that accurately reflects the genetic code is critical to the structure and function of proteins as well as overall proteome integrity. Errors in protein synthesis are generally detrimental to cellular processes yet emerging evidence suggest that proteome diversity generated through mistranslation may be beneficial under certain conditions. Cumulative translational error rates have been determined at the organismal level, however codon specific error rates and the spectrum of misincorporation errors from system to system remain largely unexplored. In particular, until recently technical challenges have limited the ability to detect and quantify comparatively rare amino acid misincorporation events, which occur orders of magnitude less frequently than canonical amino acid incorporation events. We now describe a technique for the quantitative analysis of amino acid incorporation that provides the sensitivity necessary to detect mistranslation events during translation of a single codon at frequencies as low as 1 in 10,000 for all 20 proteinogenic amino acids, as well as non-proteinogenic and modified amino acids. 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.

Airport-Noise Levels and Annoyance Model (ALAMO) system's reference manual

NASA Technical Reports Server (NTRS)

Deloach, R.; Donaldson, J. L.; Johnson, M. J.

1986-01-01

The airport-noise levels and annoyance model (ALAMO) is described in terms of the constituent modules, the execution of ALAMO procedure files, necessary for system execution, and the source code documentation associated with code development at Langley Research Center. The modules constituting ALAMO are presented both in flow graph form, and through a description of the subroutines and functions that comprise them.

Variation in the Oxytocin Receptor Gene Predicts Brain Region Specific Expression and Social Attachment

PubMed Central

King, Lanikea B.; Walum, Hasse; Inoue, Kiyoshi; Eyrich, Nicholas W.; Young, Larry J.

2015-01-01

Background Oxytocin (OXT) modulates several aspects of social behavior. Intranasal OXT is a leading candidate for treating social deficits in autism spectrum disorder (ASD) and common genetic variants in the human oxytocin receptor (OXTR) are associated with emotion recognition, relationship quality and ASD. Animal models have revealed that individual differences in Oxtr expression in the brain drive social behavior variation. Our understanding of how genetic variation contributes to brain OXTR expression is very limited. Methods We investigated Oxtr expression in monogamous prairie voles, which have a well characterized OXT system. We quantified brain region-specific levels of Oxtr mRNA and OXTR protein with established neuroanatomical methods. We used pyrosequencing to investigate allelic imbalance of Oxtr mRNA, a molecular signature of polymorphic genetic regulatory elements. We performed next-generation sequencing to discover variants in and near the Oxtr gene. We investigated social attachment using the partner preference test. Results Our allelic imbalance data demonstrates that genetic variants contribute to individual differences in Oxtr expression, but only in particular brain regions, including the nucleus accumbens (NAcc), where OXTR signaling facilitates social attachment. Next-generation sequencing identified one polymorphism in the Oxtr intron, near a putative cis-regulatory element, explaining 74% of the variance in striatal Oxtr expression specifically. Males homozygous for the high expressing allele display enhanced social attachment. Discussion Taken together, these findings provide convincing evidence for robust genetic influence on Oxtr expression and provide novel insights into how non-coding polymorphisms in the OXTR might influence individual differences in human social cognition and behavior PMID:26893121

Distribution and localization of microsatellites in the Perigord black truffle genome and identification of new molecular markers (2010) Fungal Genetics and Biology

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

Murat, Claude; Riccioni, C; Belfiori, B

The level of genetic diversity and genetic structure in the Perigord black truffle (Tuber melanosporum Vittad.) has been debated for several years, mainly due to the lack of appropriate genetic markers. Microsatellites or simple sequence repeats (SSRs) are important for the genome organisation, phenotypic diversity and are one of the most popular molecular markers. In this study, we surveyed the T. melanosporum genome (1) to characterise its SSR pattern; (2) to compare it with SSR patterns found in 48 other fungal and three oomycetes genomes and (3) to identify new polymorphic SSR markers for population genetics. The T. melanosporum genomemore » is rich in SSRs with 22,425 SSRs with mono-nucleotides being the most frequent motifs. SSRs were found in all genomic regions although they are more frequent in non-coding regions (introns and intergenic regions). Sixty out of 135 PCR-amplified mono-, di-, tri-, tetra, penta, and hexanucleotides were polymorphic (44%) within black truffle populations and 27 were randomly selected and analysed on 139 T. melanosporum isolates from France, Italy and Spain. The number of alleles varied from 2 to 18 and the expected heterozygosity from 0.124 to 0.815. One hundred and thirty-two different multilocus genotypes out of the 139 T. melanosporum isolates were identified and the genotypic diversity was high (0.999). Polymorphic SSRs were found in UTR regulatory regions of fruiting bodies and ectomycorrhiza regulated genes, suggesting that they may play a role in phenotypic variation. In conclusion, SSRs developed in this study were highly polymorphic and our results showed that T. melanosporum is a species with an important genetic diversity, which is in agreement with its recently uncovered heterothallic mating system.« less

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

Genomic and Epigenomic Insights into Nutrition and Brain Disorders

PubMed Central

Dauncey, Margaret Joy

2013-01-01

Considerable evidence links many neuropsychiatric, neurodevelopmental and neurodegenerative disorders with multiple complex interactions between genetics and environmental factors such as nutrition. Mental health problems, autism, eating disorders, Alzheimer’s disease, schizophrenia, Parkinson’s disease and brain tumours are related to individual variability in numerous protein-coding and non-coding regions of the genome. However, genotype does not necessarily determine neurological phenotype because the epigenome modulates gene expression in response to endogenous and exogenous regulators, throughout the life-cycle. Studies using both genome-wide analysis of multiple genes and comprehensive analysis of specific genes are providing new insights into genetic and epigenetic mechanisms underlying nutrition and neuroscience. This review provides a critical evaluation of the following related areas: (1) recent advances in genomic and epigenomic technologies, and their relevance to brain disorders; (2) the emerging role of non-coding RNAs as key regulators of transcription, epigenetic processes and gene silencing; (3) novel approaches to nutrition, epigenetics and neuroscience; (4) gene-environment interactions, especially in the serotonergic system, as a paradigm of the multiple signalling pathways affected in neuropsychiatric and neurological disorders. Current and future advances in these four areas should contribute significantly to the prevention, amelioration and treatment of multiple devastating brain disorders. PMID:23503168

Transcriptional landscapes of Axolotl (Ambystoma mexicanum).

PubMed

Caballero-Pérez, Juan; Espinal-Centeno, Annie; Falcon, Francisco; García-Ortega, Luis F; Curiel-Quesada, Everardo; Cruz-Hernández, Andrés; Bako, Laszlo; Chen, Xuemei; Martínez, Octavio; Alberto Arteaga-Vázquez, Mario; Herrera-Estrella, Luis; Cruz-Ramírez, Alfredo

2018-01-15

The axolotl (Ambystoma mexicanum) is the vertebrate model system with the highest regeneration capacity. Experimental tools established over the past 100 years have been fundamental to start unraveling the cellular and molecular basis of tissue and limb regeneration. In the absence of a reference genome for the Axolotl, transcriptomic analysis become fundamental to understand the genetic basis of regeneration. Here we present one of the most diverse transcriptomic data sets for Axolotl by profiling coding and non-coding RNAs from diverse tissues. We reconstructed a population of 115,906 putative protein coding mRNAs as full ORFs (including isoforms). We also identified 352 conserved miRNAs and 297 novel putative mature miRNAs. Systematic enrichment analysis of gene expression allowed us to identify tissue-specific protein-coding transcripts. We also found putative novel and conserved microRNAs which potentially target mRNAs which are reported as important disease candidates in heart and liver. Copyright © 2017 Elsevier Inc. All rights reserved.

More Than Bar Codes: Integrating Global Standards-Based Bar Code Technology Into National Health Information Systems in Ethiopia and Pakistan to Increase End-to-End Supply Chain Visibility.

PubMed

Hara, Liuichi; Guirguis, Ramy; Hummel, Keith; Villanueva, Monica

2017-12-28

The United Nations Population Fund (UNFPA) and the United States Agency for International Development (USAID) DELIVER PROJECT work together to strengthen public health commodity supply chains by standardizing bar coding under a single set of global standards. From 2015, UNFPA and USAID collaborated to pilot test how tracking and tracing of bar coded health products could be operationalized in the public health supply chains of Ethiopia and Pakistan and inform the ecosystem needed to begin full implementation. Pakistan had been using proprietary bar codes for inventory management of contraceptive supplies but transitioned to global standards-based bar codes during the pilot. The transition allowed Pakistan to leverage the original bar codes that were preprinted by global manufacturers as opposed to printing new bar codes at the central warehouse. However, barriers at lower service delivery levels prevented full realization of end-to-end data visibility. Key barriers at the district level were the lack of a digital inventory management system and absence of bar codes at the primary-level packaging level, such as single blister packs. The team in Ethiopia developed an open-sourced smartphone application that allowed the team to scan bar codes using the mobile phone's camera and to push the captured data to the country's data mart. Real-time tracking and tracing occurred from the central warehouse to the Addis Ababa distribution hub and to 2 health centers. These pilots demonstrated that standardized product identification and bar codes can significantly improve accuracy over manual stock counts while significantly streamlining the stock-taking process, resulting in efficiencies. The pilots also showed that bar coding technology by itself is not sufficient to ensure data visibility. Rather, by using global standards for identification and data capture of pharmaceuticals and medical devices, and integrating the data captured into national and global tracking systems, countries are able to lay the foundation for interoperability and ensure a harmonized language between global health stakeholders. © Hara et al.

More Than Bar Codes: Integrating Global Standards-Based Bar Code Technology Into National Health Information Systems in Ethiopia and Pakistan to Increase End-to-End Supply Chain Visibility

PubMed Central

Hara, Liuichi; Guirguis, Ramy; Hummel, Keith; Villanueva, Monica

2017-01-01

The United Nations Population Fund (UNFPA) and the United States Agency for International Development (USAID) DELIVER PROJECT work together to strengthen public health commodity supply chains by standardizing bar coding under a single set of global standards. From 2015, UNFPA and USAID collaborated to pilot test how tracking and tracing of bar coded health products could be operationalized in the public health supply chains of Ethiopia and Pakistan and inform the ecosystem needed to begin full implementation. Pakistan had been using proprietary bar codes for inventory management of contraceptive supplies but transitioned to global standards-based bar codes during the pilot. The transition allowed Pakistan to leverage the original bar codes that were preprinted by global manufacturers as opposed to printing new bar codes at the central warehouse. However, barriers at lower service delivery levels prevented full realization of end-to-end data visibility. Key barriers at the district level were the lack of a digital inventory management system and absence of bar codes at the primary-level packaging level, such as single blister packs. The team in Ethiopia developed an open-sourced smartphone application that allowed the team to scan bar codes using the mobile phone's camera and to push the captured data to the country's data mart. Real-time tracking and tracing occurred from the central warehouse to the Addis Ababa distribution hub and to 2 health centers. These pilots demonstrated that standardized product identification and bar codes can significantly improve accuracy over manual stock counts while significantly streamlining the stock-taking process, resulting in efficiencies. The pilots also showed that bar coding technology by itself is not sufficient to ensure data visibility. Rather, by using global standards for identification and data capture of pharmaceuticals and medical devices, and integrating the data captured into national and global tracking systems, countries are able to lay the foundation for interoperability and ensure a harmonized language between global health stakeholders. PMID:29284701

Increased registration of hypertension and cancer diagnoses after the introduction of a new reimbursement system.

PubMed

Hjerpe, Per; Boström, Kristina Bengtsson; Lindblad, Ulf; Merlo, Juan

2012-12-01

To investigate the impact on ICD coding behaviour of a new case-mix reimbursement system based on coded patient diagnoses. The main hypothesis was that after the introduction of the new system the coding of chronic diseases like hypertension and cancer would increase and the variance in propensity for coding would decrease on both physician and health care centre (HCC) levels. Cross-sectional multilevel logistic regression analyses were performed in periods covering the time before and after the introduction of the new reimbursement system. Skaraborg primary care, Sweden. All patients (n = 76 546 to 79 826) 50 years of age and older visiting 468 to 627 physicians at the 22 public HCCs in five consecutive time periods of one year each. Registered codes for hypertension and cancer diseases in Skaraborg primary care database (SPCD). After the introduction of the new reimbursement system the adjusted prevalence of hypertension and cancer in SPCD increased from 17.4% to 32.2% and from 0.79% to 2.32%, respectively, probably partly due to an increased diagnosis coding of indirect patient contacts. The total variance in the propensity for coding declined simultaneously at the physician level for both diagnosis groups. Changes in the healthcare reimbursement system may directly influence the contents of a research database that retrieves data from clinical practice. This should be taken into account when using such a database for research purposes, and the data should be validated for each diagnosis.

Cohort-specific imputation of gene expression improves prediction of warfarin dose for African Americans.

PubMed

Gottlieb, Assaf; Daneshjou, Roxana; DeGorter, Marianne; Bourgeois, Stephane; Svensson, Peter J; Wadelius, Mia; Deloukas, Panos; Montgomery, Stephen B; Altman, Russ B

2017-11-24

Genome-wide association studies are useful for discovering genotype-phenotype associations but are limited because they require large cohorts to identify a signal, which can be population-specific. Mapping genetic variation to genes improves power and allows the effects of both protein-coding variation as well as variation in expression to be combined into "gene level" effects. Previous work has shown that warfarin dose can be predicted using information from genetic variation that affects protein-coding regions. Here, we introduce a method that improves dose prediction by integrating tissue-specific gene expression. In particular, we use drug pathways and expression quantitative trait loci knowledge to impute gene expression-on the assumption that differential expression of key pathway genes may impact dose requirement. We focus on 116 genes from the pharmacokinetic and pharmacodynamic pathways of warfarin within training and validation sets comprising both European and African-descent individuals. We build gene-tissue signatures associated with warfarin dose in a cohort-specific manner and identify a signature of 11 gene-tissue pairs that significantly augments the International Warfarin Pharmacogenetics Consortium dosage-prediction algorithm in both populations. Our results demonstrate that imputed expression can improve dose prediction and bridge population-specific compositions. MATLAB code is available at https://github.com/assafgo/warfarin-cohort.

Identification and Functional Characterization of G6PC2 Coding Variants Influencing Glycemic Traits Define an Effector Transcript at the G6PC2-ABCB11 Locus

PubMed Central

Mahajan, Anubha; Sim, Xueling; Ng, Hui Jin; Manning, Alisa; Rivas, Manuel A.; Highland, Heather M.; Locke, Adam E.; Grarup, Niels; Im, Hae Kyung; Cingolani, Pablo; Flannick, Jason; Fontanillas, Pierre; Fuchsberger, Christian; Gaulton, Kyle J.; Teslovich, Tanya M.; Rayner, N. William; Robertson, Neil R.; Beer, Nicola L.; Rundle, Jana K.; Bork-Jensen, Jette; Ladenvall, Claes; Blancher, Christine; Buck, David; Buck, Gemma; Burtt, Noël P.; Gabriel, Stacey; Gjesing, Anette P.; Groves, Christopher J.; Hollensted, Mette; Huyghe, Jeroen R.; Jackson, Anne U.; Jun, Goo; Justesen, Johanne Marie; Mangino, Massimo; Murphy, Jacquelyn; Neville, Matt; Onofrio, Robert; Small, Kerrin S.; Stringham, Heather M.; Syvänen, Ann-Christine; Trakalo, Joseph; Abecasis, Goncalo; Bell, Graeme I.; Blangero, John; Cox, Nancy J.; Duggirala, Ravindranath; Hanis, Craig L.; Seielstad, Mark; Wilson, James G.; Christensen, Cramer; Brandslund, Ivan; Rauramaa, Rainer; Surdulescu, Gabriela L.; Doney, Alex S. F.; Lannfelt, Lars; Linneberg, Allan; Isomaa, Bo; Tuomi, Tiinamaija; Jørgensen, Marit E.; Jørgensen, Torben; Kuusisto, Johanna; Uusitupa, Matti; Salomaa, Veikko; Spector, Timothy D.; Morris, Andrew D.; Palmer, Colin N. A.; Collins, Francis S.; Mohlke, Karen L.; Bergman, Richard N.; Ingelsson, Erik; Lind, Lars; Tuomilehto, Jaakko; Hansen, Torben; Watanabe, Richard M.; Prokopenko, Inga; Dupuis, Josee; Karpe, Fredrik; Groop, Leif; Laakso, Markku; Pedersen, Oluf; Florez, Jose C.; Morris, Andrew P.; Altshuler, David; Meigs, James B.; Boehnke, Michael; McCarthy, Mark I.; Lindgren, Cecilia M.; Gloyn, Anna L.

2015-01-01

Genome wide association studies (GWAS) for fasting glucose (FG) and insulin (FI) have identified common variant signals which explain 4.8% and 1.2% of trait variance, respectively. It is hypothesized that low-frequency and rare variants could contribute substantially to unexplained genetic variance. To test this, we analyzed exome-array data from up to 33,231 non-diabetic individuals of European ancestry. We found exome-wide significant (P<5×10-7) evidence for two loci not previously highlighted by common variant GWAS: GLP1R (p.Ala316Thr, minor allele frequency (MAF)=1.5%) influencing FG levels, and URB2 (p.Glu594Val, MAF = 0.1%) influencing FI levels. Coding variant associations can highlight potential effector genes at (non-coding) GWAS signals. At the G6PC2/ABCB11 locus, we identified multiple coding variants in G6PC2 (p.Val219Leu, p.His177Tyr, and p.Tyr207Ser) influencing FG levels, conditionally independent of each other and the non-coding GWAS signal. In vitro assays demonstrate that these associated coding alleles result in reduced protein abundance via proteasomal degradation, establishing G6PC2 as an effector gene at this locus. Reconciliation of single-variant associations and functional effects was only possible when haplotype phase was considered. In contrast to earlier reports suggesting that, paradoxically, glucose-raising alleles at this locus are protective against type 2 diabetes (T2D), the p.Val219Leu G6PC2 variant displayed a modest but directionally consistent association with T2D risk. Coding variant associations for glycemic traits in GWAS signals highlight PCSK1, RREB1, and ZHX3 as likely effector transcripts. These coding variant association signals do not have a major impact on the trait variance explained, but they do provide valuable biological insights. PMID:25625282

Identification and functional characterization of G6PC2 coding variants influencing glycemic traits define an effector transcript at the G6PC2-ABCB11 locus.

PubMed

Mahajan, Anubha; Sim, Xueling; Ng, Hui Jin; Manning, Alisa; Rivas, Manuel A; Highland, Heather M; Locke, Adam E; Grarup, Niels; Im, Hae Kyung; Cingolani, Pablo; Flannick, Jason; Fontanillas, Pierre; Fuchsberger, Christian; Gaulton, Kyle J; Teslovich, Tanya M; Rayner, N William; Robertson, Neil R; Beer, Nicola L; Rundle, Jana K; Bork-Jensen, Jette; Ladenvall, Claes; Blancher, Christine; Buck, David; Buck, Gemma; Burtt, Noël P; Gabriel, Stacey; Gjesing, Anette P; Groves, Christopher J; Hollensted, Mette; Huyghe, Jeroen R; Jackson, Anne U; Jun, Goo; Justesen, Johanne Marie; Mangino, Massimo; Murphy, Jacquelyn; Neville, Matt; Onofrio, Robert; Small, Kerrin S; Stringham, Heather M; Syvänen, Ann-Christine; Trakalo, Joseph; Abecasis, Goncalo; Bell, Graeme I; Blangero, John; Cox, Nancy J; Duggirala, Ravindranath; Hanis, Craig L; Seielstad, Mark; Wilson, James G; Christensen, Cramer; Brandslund, Ivan; Rauramaa, Rainer; Surdulescu, Gabriela L; Doney, Alex S F; Lannfelt, Lars; Linneberg, Allan; Isomaa, Bo; Tuomi, Tiinamaija; Jørgensen, Marit E; Jørgensen, Torben; Kuusisto, Johanna; Uusitupa, Matti; Salomaa, Veikko; Spector, Timothy D; Morris, Andrew D; Palmer, Colin N A; Collins, Francis S; Mohlke, Karen L; Bergman, Richard N; Ingelsson, Erik; Lind, Lars; Tuomilehto, Jaakko; Hansen, Torben; Watanabe, Richard M; Prokopenko, Inga; Dupuis, Josee; Karpe, Fredrik; Groop, Leif; Laakso, Markku; Pedersen, Oluf; Florez, Jose C; Morris, Andrew P; Altshuler, David; Meigs, James B; Boehnke, Michael; McCarthy, Mark I; Lindgren, Cecilia M; Gloyn, Anna L

2015-01-01

Genome wide association studies (GWAS) for fasting glucose (FG) and insulin (FI) have identified common variant signals which explain 4.8% and 1.2% of trait variance, respectively. It is hypothesized that low-frequency and rare variants could contribute substantially to unexplained genetic variance. To test this, we analyzed exome-array data from up to 33,231 non-diabetic individuals of European ancestry. We found exome-wide significant (P<5×10-7) evidence for two loci not previously highlighted by common variant GWAS: GLP1R (p.Ala316Thr, minor allele frequency (MAF)=1.5%) influencing FG levels, and URB2 (p.Glu594Val, MAF = 0.1%) influencing FI levels. Coding variant associations can highlight potential effector genes at (non-coding) GWAS signals. At the G6PC2/ABCB11 locus, we identified multiple coding variants in G6PC2 (p.Val219Leu, p.His177Tyr, and p.Tyr207Ser) influencing FG levels, conditionally independent of each other and the non-coding GWAS signal. In vitro assays demonstrate that these associated coding alleles result in reduced protein abundance via proteasomal degradation, establishing G6PC2 as an effector gene at this locus. Reconciliation of single-variant associations and functional effects was only possible when haplotype phase was considered. In contrast to earlier reports suggesting that, paradoxically, glucose-raising alleles at this locus are protective against type 2 diabetes (T2D), the p.Val219Leu G6PC2 variant displayed a modest but directionally consistent association with T2D risk. Coding variant associations for glycemic traits in GWAS signals highlight PCSK1, RREB1, and ZHX3 as likely effector transcripts. These coding variant association signals do not have a major impact on the trait variance explained, but they do provide valuable biological insights.

Responses of chub (Leuciscus cephalus) populations to chemical stress, assessed by genetic markers, DNA damage and cytochrome P4501A induction.

PubMed

Larno, V; Laroche, J; Launey, S; Flammarion, P; Devaux, A

2001-06-01

Indicators of effects at the population level (genetic variation using allozymes) and early indicators of pollution (EROD activity and DNA strand break formation) were analysed in chub (Leuciscus cephalus) living in weakly and heavily contaminated stations of the Rhône River watershed. The genetic erosion was mainly detected in a fish population living in a contaminated small river system, through modifications in allelic and genotypic frequencies for PGM-2 locus and could be linked to a genetic bottleneck and to the reduced gene flow from upstream unable to maintain or restore the genetic diversity. In a contaminated large river system, the genetic diversity for PGM-2 and other loci was maintained and was probably the consequence of a high gene flow from upstream, linked to a sustained drift of larvae and juveniles in the system. A convergent increase of the frequency of the 90 allele at PGM-2 was observed in two contaminated stations compared with the reference station, this trend being confirmed on a more extensive geographic scale over the Rhône River basin. A high level of EROD activity was detected in both contaminated sites but only the fish in the large river system showed a significant DNA damage level compared to the reference population. The low DNA damage level and high hepato-somatic ratio characterized the impacted population of the small river system and could be associated to a chronic high-level exposure of fish to pollutants which selected individuals exhibiting a high level of DNA damage repair. In the two contaminated systems, some genotypes at the PGM-2 and EST-2 loci showed a low level of DNA damage and/or a high EROD activity and may be considered as being tolerant to pollutants. A higher tolerance of the most heterozygous fish was also detected in the contaminated large system and confirmed that a high level of heterozygosity may be necessary for survival in such a system.

[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.

New genetic variants of LATS1 detected in urinary bladder and colon cancer.

PubMed

Saadeldin, Mona K; Shawer, Heba; Mostafa, Ahmed; Kassem, Neemat M; Amleh, Asma; Siam, Rania

2014-01-01

LATS1, the large tumor suppressor 1 gene, encodes for a serine/threonine kinase protein and is implicated in cell cycle progression. LATS1 is down-regulated in various human cancers, such as breast cancer, and astrocytoma. Point mutations in LATS1 were reported in human sarcomas. Additionally, loss of heterozygosity of LATS1 chromosomal region predisposes to breast, ovarian, and cervical tumors. In the current study, we investigated LATS1 genetic variations including single nucleotide polymorphisms (SNPs), in 28 Egyptian patients with either urinary bladder or colon cancers. The LATS1 gene was amplified and sequenced and the expression of LATS1 at the RNA level was assessed in 12 urinary bladder cancer samples. We report, the identification of a total of 29 variants including previously identified SNPs within LATS1 coding and non-coding sequences. A total of 18 variants were novel. Majority of the novel variants, 13, were mapped to intronic sequences and un-translated regions of the gene. Four of the five novel variants located in the coding region of the gene, represented missense mutations within the serine/threonine kinase catalytic domain. Interestingly, LATS1 RNA steady state levels was lost in urinary bladder cancerous tissue harboring four specific SNPs (16045 + 41736 + 34614 + 56177) positioned in the 5'UTR, intron 6, and two silent mutations within exon 4 and exon 8, respectively. This study identifies novel single-base-sequence alterations in the LATS1 gene. These newly identified variants could potentially be used as novel diagnostic or prognostic tools in cancer.

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.

Hanford business structure for HANDI 2000 business management system

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

Wilson, D.

The Hanford Business Structure integrates the project`s technical, schedule, and cost baselines; implements the use of a standard code of accounts; and streamlines performance reporting and cost collection. Technical requirements drive the technical functions and come from the RDD 100 database. The functions will be identified in the P3 scheduling system and also in the PeopleSoft system. Projects will break their work down from the technical requirements in the P3 schedules. When the level at which they want to track cost via the code of accounts is reached, a Project ID will be generated in the PeopleSoft system. P3 maymore » carry more detailed schedules below the Project ID level. The standard code of accounts will identify discrete work activities done across the site and various projects. They will include direct and overhead type work scopes. Activities in P3 will roll up to this standard code of accounts. The field that will be used to record this in PeopleSoft is ``Activity``. In Passport it is a user-defined field. It will have to be added to other feeder systems. Project ID and code of accounts are required fields on all cost records.« less

Power optimization of wireless media systems with space-time block codes.

PubMed

Yousefi'zadeh, Homayoun; Jafarkhani, Hamid; Moshfeghi, Mehran

2004-07-01

We present analytical and numerical solutions to the problem of power control in wireless media systems with multiple antennas. We formulate a set of optimization problems aimed at minimizing total power consumption of wireless media systems subject to a given level of QoS and an available bit rate. Our formulation takes into consideration the power consumption related to source coding, channel coding, and transmission of multiple-transmit antennas. In our study, we consider Gauss-Markov and video source models, Rayleigh fading channels along with the Bernoulli/Gilbert-Elliott loss models, and space-time block codes.

Unexpected allelic heterogeneity and spectrum of mutations in Fowler syndrome revealed by next-generation exome sequencing.

PubMed

Lalonde, Emilie; Albrecht, Steffen; Ha, Kevin C H; Jacob, Karine; Bolduc, Nathalie; Polychronakos, Constantin; Dechelotte, Pierre; Majewski, Jacek; Jabado, Nada

2010-08-01

Protein coding genes constitute approximately 1% of the human genome but harbor 85% of the mutations with large effects on disease-related traits. Therefore, efficient strategies for selectively sequencing complete coding regions (i.e., "whole exome") have the potential to contribute our understanding of human diseases. We used a method for whole-exome sequencing coupling Agilent whole-exome capture to the Illumina DNA-sequencing platform, and investigated two unrelated fetuses from nonconsanguineous families with Fowler Syndrome (FS), a stereotyped phenotype lethal disease. We report novel germline mutations in feline leukemia virus subgroup C cellular-receptor-family member 2, FLVCR2, which has recently been shown to cause FS. Using this technology, we identified three types of genetic abnormalities: point-mutations, insertions-deletions, and intronic splice-site changes (first pathogenic report using this technology), in the fetuses who both were compound heterozygotes for the disease. Although revealing a high level of allelic heterogeneity and mutational spectrum in FS, this study further illustrates the successful application of whole-exome sequencing to uncover genetic defects in rare Mendelian disorders. Of importance, we show that we can identify genes underlying rare, monogenic and recessive diseases using a limited number of patients (n=2), in the absence of shared genetic heritage and in the presence of allelic heterogeneity.

A volcanic activity alert-level system for aviation: Review of its development and application in Alaska

USGS Publications Warehouse

Guffanti, Marianne C.; Miller, Thomas

2013-01-01

An alert-level system for communicating volcano hazard information to the aviation industry was devised by the Alaska Volcano Observatory (AVO) during the 1989–1990 eruption of Redoubt Volcano. The system uses a simple, color-coded ranking that focuses on volcanic ash emissions: Green—normal background; Yellow—signs of unrest; Orange—precursory unrest or minor ash eruption; Red—major ash eruption imminent or underway. The color code has been successfully applied on a regional scale in Alaska for a sustained period. During 2002–2011, elevated color codes were assigned by AVO to 13 volcanoes, eight of which erupted; for that decade, one or more Alaskan volcanoes were at Yellow on 67 % of days and at Orange or Red on 12 % of days. As evidence of its utility, the color code system is integrated into procedures of agencies responsible for air-traffic management and aviation meteorology in Alaska. Furthermore, it is endorsed as a key part of globally coordinated protocols established by the International Civil Aviation Organization to provide warnings of ash hazards to aviation worldwide. The color code and accompanying structured message (called a Volcano Observatory Notice for Aviation) comprise an effective early-warning message system according to the United Nations International Strategy for Disaster Reduction. The aviation color code system currently is used in the United States, Russia, New Zealand, Iceland, and partially in the Philippines, Papua New Guinea, and Indonesia. Although there are some barriers to implementation, with continued education and outreach to Volcano Observatories worldwide, greater use of the aviation color code system is achievable.

A volcanic activity alert-level system for aviation: review of its development and application in Alaska

USGS Publications Warehouse

Guffanti, Marianne; Miller, Thomas P.

2013-01-01

An alert-level system for communicating volcano hazard information to the aviation industry was devised by the Alaska Volcano Observatory (AVO) during the 1989–1990 eruption of Redoubt Volcano. The system uses a simple, color-coded ranking that focuses on volcanic ash emissions: Green—normal background; Yellow—signs of unrest; Orange—precursory unrest or minor ash eruption; Red—major ash eruption imminent or underway. The color code has been successfully applied on a regional scale in Alaska for a sustained period. During 2002–2011, elevated color codes were assigned by AVO to 13 volcanoes, eight of which erupted; for that decade, one or more Alaskan volcanoes were at Yellow on 67 % of days and at Orange or Red on 12 % of days. As evidence of its utility, the color code system is integrated into procedures of agencies responsible for air-traffic management and aviation meteorology in Alaska. Furthermore, it is endorsed as a key part of globally coordinated protocols established by the International Civil Aviation Organization to provide warnings of ash hazards to aviation worldwide. The color code and accompanying structured message (called a Volcano Observatory Notice for Aviation) comprise an effective early-warning message system according to the United Nations International Strategy for Disaster Reduction. The aviation color code system currently is used in the United States, Russia, New Zealand, Iceland, and partially in the Philippines, Papua New Guinea, and Indonesia. Although there are some barriers to implementation, with continued education and outreach to Volcano Observatories worldwide, greater use of the aviation color code system is achievable.

Promoter analysis reveals globally differential regulation of human long non-coding RNA and protein-coding genes

DOE PAGES

Alam, Tanvir; Medvedeva, Yulia A.; Jia, Hui; ...

2014-10-02

Transcriptional regulation of protein-coding genes is increasingly well-understood on a global scale, yet no comparable information exists for long non-coding RNA (lncRNA) genes, which were recently recognized to be as numerous as protein-coding genes in mammalian genomes. We performed a genome-wide comparative analysis of the promoters of human lncRNA and protein-coding genes, finding global differences in specific genetic and epigenetic features relevant to transcriptional regulation. These two groups of genes are hence subject to separate transcriptional regulatory programs, including distinct transcription factor (TF) proteins that significantly favor lncRNA, rather than coding-gene, promoters. We report a specific signature of promoter-proximal transcriptionalmore » regulation of lncRNA genes, including several distinct transcription factor binding sites (TFBS). Experimental DNase I hypersensitive site profiles are consistent with active configurations of these lncRNA TFBS sets in diverse human cell types. TFBS ChIP-seq datasets confirm the binding events that we predicted using computational approaches for a subset of factors. For several TFs known to be directly regulated by lncRNAs, we find that their putative TFBSs are enriched at lncRNA promoters, suggesting that the TFs and the lncRNAs may participate in a bidirectional feedback loop regulatory network. Accordingly, cells may be able to modulate lncRNA expression levels independently of mRNA levels via distinct regulatory pathways. Our results also raise the possibility that, given the historical reliance on protein-coding gene catalogs to define the chromatin states of active promoters, a revision of these chromatin signature profiles to incorporate expressed lncRNA genes is warranted in the future.« less

Promoter analysis reveals globally differential regulation of human long non-coding RNA and protein-coding genes

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

Alam, Tanvir; Medvedeva, Yulia A.; Jia, Hui

Transcriptional regulation of protein-coding genes is increasingly well-understood on a global scale, yet no comparable information exists for long non-coding RNA (lncRNA) genes, which were recently recognized to be as numerous as protein-coding genes in mammalian genomes. We performed a genome-wide comparative analysis of the promoters of human lncRNA and protein-coding genes, finding global differences in specific genetic and epigenetic features relevant to transcriptional regulation. These two groups of genes are hence subject to separate transcriptional regulatory programs, including distinct transcription factor (TF) proteins that significantly favor lncRNA, rather than coding-gene, promoters. We report a specific signature of promoter-proximal transcriptionalmore » regulation of lncRNA genes, including several distinct transcription factor binding sites (TFBS). Experimental DNase I hypersensitive site profiles are consistent with active configurations of these lncRNA TFBS sets in diverse human cell types. TFBS ChIP-seq datasets confirm the binding events that we predicted using computational approaches for a subset of factors. For several TFs known to be directly regulated by lncRNAs, we find that their putative TFBSs are enriched at lncRNA promoters, suggesting that the TFs and the lncRNAs may participate in a bidirectional feedback loop regulatory network. Accordingly, cells may be able to modulate lncRNA expression levels independently of mRNA levels via distinct regulatory pathways. Our results also raise the possibility that, given the historical reliance on protein-coding gene catalogs to define the chromatin states of active promoters, a revision of these chromatin signature profiles to incorporate expressed lncRNA genes is warranted in the future.« less

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

The genomic signature of sexual selection in the genetic diversity of the sex chromosomes and autosomes.

PubMed

Corl, Ammon; Ellegren, Hans

2012-07-01

Genomic levels of variation can help reveal the selective and demographic forces that have affected a species during its history. The relative amount of genetic diversity observed on the sex chromosomes as compared to the autosomes is predicted to differ among monogamous and polygynous species. Many species show departures from the expectation for monogamy, but it can be difficult to conclude that this pattern results from variation in mating system because forces other than sexual selection can act upon sex chromosome genetic diversity. As a critical test of the role of mating system, we compared levels of genetic diversity on the Z chromosome and autosomes of phylogenetically independent pairs of shorebirds that differed in their mating systems. We found general support for sexual selection shaping sex chromosome diversity because most polygynous species showed relatively reduced genetic variation on their Z chromosomes as compared to monogamous species. Differences in levels of genetic diversity between the sex chromosomes and autosomes may therefore contribute to understanding the long-term history of sexual selection experienced by a species. © 2012 The Author(s).

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

Dynamic response analysis of a 24-story damped steel structure

NASA Astrophysics Data System (ADS)

Feng, Demin; Miyama, Takafumi

2017-10-01

In Japanese and Chinese building codes, a two-stage design philosophy, damage limitation (small earthquake, Level 1) and life safety (extreme large earthquake, Level 2), is adopted. It is very interesting to compare the design method of a damped structure based on the two building codes. In the Chinese code, in order to be consistent with the conventional seismic design method, the damped structure is also designed at the small earthquake level. The effect of damper systems is considered by the additional damping ratio concept. The design force will be obtained from the damped design spectrum considering the reduction due to the additional damping ratio. The additional damping ratio by the damper system is usually calculated by a time history analysis method at the small earthquake level. The velocity dependent type dampers such as viscous dampers can function well even in the small earthquake level. But, if steel damper is used, which usually remains elastic in the small earthquake, there will be no additional damping ratio achieved. On the other hand, a time history analysis is used in Japan both for small earthquake and extreme large earthquake level. The characteristics of damper system and ductility of the structure can be modelled well. An existing 24-story steel frame is modified to demonstrate the design process of the damped structure based on the two building codes. Viscous wall type damper and low yield steel panel dampers are studied as the damper system.

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.

Systems Genetics as a Tool to Identify Master Genetic Regulators in Complex Disease.

PubMed

Moreno-Moral, Aida; Pesce, Francesco; Behmoaras, Jacques; Petretto, Enrico

2017-01-01

Systems genetics stems from systems biology and similarly employs integrative modeling approaches to describe the perturbations and phenotypic effects observed in a complex system. However, in the case of systems genetics the main source of perturbation is naturally occurring genetic variation, which can be analyzed at the systems-level to explain the observed variation in phenotypic traits. In contrast with conventional single-variant association approaches, the success of systems genetics has been in the identification of gene networks and molecular pathways that underlie complex disease. In addition, systems genetics has proven useful in the discovery of master trans-acting genetic regulators of functional networks and pathways, which in many cases revealed unexpected gene targets for disease. Here we detail the central components of a fully integrated systems genetics approach to complex disease, starting from assessment of genetic and gene expression variation, linking DNA sequence variation to mRNA (expression QTL mapping), gene regulatory network analysis and mapping the genetic control of regulatory networks. By summarizing a few illustrative (and successful) examples, we highlight how different data-modeling strategies can be effectively integrated in a systems genetics study.

Geographical distance and barriers explain population genetic patterns in an endangered island perennial

PubMed Central

Dias, Elisabete F.; Moura, M.; Schaefer, H.; Silva, Luís

2016-01-01

Island plants are frequently used as model systems in evolutionary biology to understand factors that might explain genetic diversity and population differentiation levels. Theory suggests that island plants should have lower levels of genetic diversity than their continental relatives, but this hypothesis has been rejected in several recent studies. In the Azores, the population level genetic diversity is generally low. However, like in most island systems, there are high levels of genetic differentiation between different islands. The Azores lettuce, Lactuca watsoniana, is an endangered Asteraceae with small population sizes. Therefore, we expect to find a lower level of genetic diversity than in the other more common endemic Asteraceae. The intra- and interpopulation genetic structure and diversity of L. watsoniana was assessed using eight newly developed microsatellite markers. We included 135 individuals, from all 13 known populations in the study. Because our microsatellite results suggested that the species is tetraploid, we analysed the microsatellite data (i) in codominant format using PolySat (Principal Coordinate Analysis, PCoA) and SPAgedi (genetic diversity indexes) and (ii) in dominant format using Arlequin (AMOVA) and STRUCTURE (Bayesian genetic cluster analysis). A total of 129 alleles were found for all L. watsoniana populations. In contrast to our expectations, we found a high level of intrapopulation genetic diversity (total heterozigosity = 0.85; total multilocus average proportion of private alleles per population = 26.5 %, Fis = −0.19). Our results show the existence of five well-defined genetic groups, one for each of the three islands São Miguel, Terceira and Faial, plus two groups for the East and West side of Pico Island (Fst = 0.45). The study revealed the existence of high levels of genetic diversity, which should be interpreted taking into consideration the ploidy level of this rare taxon. PMID:27742648

Multi-level of Fidelity Multi-Disciplinary Design Optimization of Small, Solid-Propellant Launch Vehicles

NASA Astrophysics Data System (ADS)

Roshanian, Jafar; Jodei, Jahangir; Mirshams, Mehran; Ebrahimi, Reza; Mirzaee, Masood

A new automated multi-level of fidelity Multi-Disciplinary Design Optimization (MDO) methodology has been developed at the MDO Laboratory of K.N. Toosi University of Technology. This paper explains a new design approach by formulation of developed disciplinary modules. A conceptual design for a small, solid-propellant launch vehicle was considered at two levels of fidelity structure. Low and medium level of fidelity disciplinary codes were developed and linked. Appropriate design and analysis codes were defined according to their effect on the conceptual design process. Simultaneous optimization of the launch vehicle was performed at the discipline level and system level. Propulsion, aerodynamics, structure and trajectory disciplinary codes were used. To reach the minimum launch weight, the Low LoF code first searches the whole design space to achieve the mission requirements. Then the medium LoF code receives the output of the low LoF and gives a value near the optimum launch weight with more details and higher fidelity.

Signatures of selection in tilapia revealed by whole genome resequencing

PubMed Central

Hong Xia, Jun; Bai, Zhiyi; Meng, Zining; Zhang, Yong; Wang, Le; Liu, Feng; Jing, Wu; Yi Wan, Zi; Li, Jiale; Lin, Haoran; Hua Yue, Gen

2015-01-01

Natural selection and selective breeding for genetic improvement have left detectable signatures within the genome of a species. Identification of selection signatures is important in evolutionary biology and for detecting genes that facilitate to accelerate genetic improvement. However, selection signatures, including artificial selection and natural selection, have only been identified at the whole genome level in several genetically improved fish species. Tilapia is one of the most important genetically improved fish species in the world. Using next-generation sequencing, we sequenced the genomes of 47 tilapia individuals. We identified a total of 1.43 million high-quality SNPs and found that the LD block sizes ranged from 10–100 kb in tilapia. We detected over a hundred putative selective sweep regions in each line of tilapia. Most selection signatures were located in non-coding regions of the tilapia genome. The Wnt signaling, gonadotropin-releasing hormone receptor and integrin signaling pathways were under positive selection in all improved tilapia lines. Our study provides a genome-wide map of genetic variation and selection footprints in tilapia, which could be important for genetic studies and accelerating genetic improvement of tilapia. PMID:26373374

Development of a PCR-Based Reverse Genetics System for an Attenuated Duck Tembusu Virus Strain

PubMed Central

Wu, Xiaogang; Shi, Ying; Yan, Dawei; Li, Xuesong; Yan, Pixi; Gao, Xuyuan; Zhang, Yuee; Yu, Lei; Ren, Chaochao; Li, Guoxin; Yan, Liping; Teng, Qiaoyang; Li, Zejun

2016-01-01

The infectious disease caused by the duck Tembusu virus (DTMUV) has resulted in massive economic losses to the Chinese duck industry in China since 2010. Research on the molecular basis of DTMUV pathogenicity has been hampered by the lack of a reliable reverse genetics system for this virus. Here we developed a PCR-based reverse genetics system with high fidelity for the attenuated DTMUV strain FX2010-180P. The rescued virus was characterized by using both indirect immunofluorescence assays (IFA) and whole genome sequencing. The rescued virus (rFX2010-180P) grew to similar titers as compared with the wild-type virus in DF-1 cells, and had similar replication and immunogenicity properties in ducks. To determine whether exogenous proteins could be expressed from DTMUV, both an internal ribosomal entry site (IRES) and the enhanced green fluorescent protein (eGFP) gene were introduced between the NS5 gene and the 3' non-coding sequence of FX2010-180P. A recombinant DTMUV expressing eGFP was rescued, but eGFP expression was unstable after 4 passages in DF-1 cells due to a deletion of 1,294 nucleotides. The establishment of a reliable reverse genetics system for FX2010-180P provides a foundation for future studies of DTMUV. PMID:27248497

Development of a PCR-Based Reverse Genetics System for an Attenuated Duck Tembusu Virus Strain.

PubMed

Wu, Xiaogang; Shi, Ying; Yan, Dawei; Li, Xuesong; Yan, Pixi; Gao, Xuyuan; Zhang, Yuee; Yu, Lei; Ren, Chaochao; Li, Guoxin; Yan, Liping; Teng, Qiaoyang; Li, Zejun

2016-01-01

The infectious disease caused by the duck Tembusu virus (DTMUV) has resulted in massive economic losses to the Chinese duck industry in China since 2010. Research on the molecular basis of DTMUV pathogenicity has been hampered by the lack of a reliable reverse genetics system for this virus. Here we developed a PCR-based reverse genetics system with high fidelity for the attenuated DTMUV strain FX2010-180P. The rescued virus was characterized by using both indirect immunofluorescence assays (IFA) and whole genome sequencing. The rescued virus (rFX2010-180P) grew to similar titers as compared with the wild-type virus in DF-1 cells, and had similar replication and immunogenicity properties in ducks. To determine whether exogenous proteins could be expressed from DTMUV, both an internal ribosomal entry site (IRES) and the enhanced green fluorescent protein (eGFP) gene were introduced between the NS5 gene and the 3' non-coding sequence of FX2010-180P. A recombinant DTMUV expressing eGFP was rescued, but eGFP expression was unstable after 4 passages in DF-1 cells due to a deletion of 1,294 nucleotides. The establishment of a reliable reverse genetics system for FX2010-180P provides a foundation for future studies of DTMUV.

Programming biological operating systems: genome design, assembly and activation.

PubMed

Gibson, Daniel G

2014-05-01

The DNA technologies developed over the past 20 years for reading and writing the genetic code converged when the first synthetic cell was created 4 years ago. An outcome of this work has been an extraordinary set of tools for synthesizing, assembling, engineering and transplanting whole bacterial genomes. Technical progress, options and applications for bacterial genome design, assembly and activation are discussed.

Chromatin accessibility prediction via a hybrid deep convolutional neural network.

PubMed

Liu, Qiao; Xia, Fei; Yin, Qijin; Jiang, Rui

2018-03-01

A majority of known genetic variants associated with human-inherited diseases lie in non-coding regions that lack adequate interpretation, making it indispensable to systematically discover functional sites at the whole genome level and precisely decipher their implications in a comprehensive manner. Although computational approaches have been complementing high-throughput biological experiments towards the annotation of the human genome, it still remains a big challenge to accurately annotate regulatory elements in the context of a specific cell type via automatic learning of the DNA sequence code from large-scale sequencing data. Indeed, the development of an accurate and interpretable model to learn the DNA sequence signature and further enable the identification of causative genetic variants has become essential in both genomic and genetic studies. We proposed Deopen, a hybrid framework mainly based on a deep convolutional neural network, to automatically learn the regulatory code of DNA sequences and predict chromatin accessibility. In a series of comparison with existing methods, we show the superior performance of our model in not only the classification of accessible regions against background sequences sampled at random, but also the regression of DNase-seq signals. Besides, we further visualize the convolutional kernels and show the match of identified sequence signatures and known motifs. We finally demonstrate the sensitivity of our model in finding causative noncoding variants in the analysis of a breast cancer dataset. We expect to see wide applications of Deopen with either public or in-house chromatin accessibility data in the annotation of the human genome and the identification of non-coding variants associated with diseases. Deopen is freely available at https://github.com/kimmo1019/Deopen. ruijiang@tsinghua.edu.cn. Supplementary data are available at Bioinformatics online. © The Author (2017). Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com

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.

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.

Medical decision making: guide to improved CPT coding.

PubMed

Holt, Jim; Warsy, Ambreen; Wright, Paula

2010-04-01

The Current Procedural Terminology (CPT) coding system for office visits, which has been in use since 1995, has not been well studied, but it is generally agreed that the system contains much room for error. In fact, the available literature suggests that only slightly more than half of physicians will agree on the same CPT code for a given visit, and only 60% of professional coders will agree on the same code for a particular visit. In addition, the criteria used to assign a code are often related to the amount of written documentation. The goal of this study was to evaluate two novel methods to assess if the most appropriate CPT code is used: the level of medical decision making, or the sum of all problems mentioned by the patient during the visit. The authors-a professional coder, a residency faculty member, and a PGY-3 family medicine resident-reviewed 351 randomly selected visit notes from two residency programs in the Northeast Tennessee region for the level of documentation, the level of medical decision making, and the total number of problems addressed. The authors assigned appropriate CPT codes at each of those three levels. Substantial undercoding occurred at each of the three levels. Approximately 33% of visits were undercoded based on the written documentation. Approximately 50% of the visits were undercoded based on the level of documented medical decision making. Approximately 80% of the visits were undercoded based on the total number of problems which the patient presented during the visit. Interrater agreement was fair, and similar to that noted in other coding studies. Undercoding is not only common in a family medicine residency program but it also occurs at levels that would not be evident from a simple audit of the documentation on the visit note. Undercoding also occurs from not exploring problems mentioned by the patient and not documenting additional work that was performed. Family physicians may benefit from minor alterations in their documentation of office visit notes.

Non-coding variants contribute to the clinical heterogeneity of TTR amyloidosis.

PubMed

Iorio, Andrea; De Lillo, Antonella; De Angelis, Flavio; Di Girolamo, Marco; Luigetti, Marco; Sabatelli, Mario; Pradotto, Luca; Mauro, Alessandro; Mazzeo, Anna; Stancanelli, Claudia; Perfetto, Federico; Frusconi, Sabrina; My, Filomena; Manfellotto, Dario; Fuciarelli, Maria; Polimanti, Renato

2017-09-01

Coding mutations in TTR gene cause a rare hereditary form of systemic amyloidosis, which has a complex genotype-phenotype correlation. We investigated the role of non-coding variants in regulating TTR gene expression and consequently amyloidosis symptoms. We evaluated the genotype-phenotype correlation considering the clinical information of 129 Italian patients with TTR amyloidosis. Then, we conducted a re-sequencing of TTR gene to investigate how non-coding variants affect TTR expression and, consequently, phenotypic presentation in carriers of amyloidogenic mutations. Polygenic scores for genetically determined TTR expression were constructed using data from our re-sequencing analysis and the GTEx (Genotype-Tissue Expression) project. We confirmed a strong phenotypic heterogeneity across coding mutations causing TTR amyloidosis. Considering the effects of non-coding variants on TTR expression, we identified three patient clusters with specific expression patterns associated with certain phenotypic presentations, including late onset, autonomic neurological involvement, and gastrointestinal symptoms. This study provides novel data regarding the role of non-coding variation and the gene expression profiles in patients affected by TTR amyloidosis, also putting forth an approach that could be used to investigate the mechanisms at the basis of the genotype-phenotype correlation of the disease.

Genetic variability, individuality and the evolution of the mammalian brain.

PubMed

Lipp, H P

1995-12-01

The neo-Darwinian theory of evolution has difficulty in explaining the rapid evolution of mammalian brain and behavior. I shall argue that the plasticity mechanisms of the brain (i.e., system homeostasis, developmental reorganization, structural adult plasticity, and cognition and learning) have evolved primarily as genetic buffer systems which protect subtle mutations influencing brain structures from natural selection. These buffer systems permit accumulation of genetic variation in the higher system levels of the brain (simply defined as structures with late differentiation), while low-level systems are kept constant by natural selection. The organization of this intrinsic genetic buffering system provides several features facilitating neo-Darwinian evolution: In conclusion, the evolutionary appearance of cognition and intelligence is an ordinary biological mechanism compensating evolutionary drags such as long lifespans and fewer offspring. The concept has heuristic value for identifying gene-brain-behavior relationships and for explaining behavioral consequences of artifical gene deletions.

Genome-wide association study identifies common and low-frequency variants at the AMH gene locus that strongly predict serum AMH levels in males.

PubMed

Perry, John R B; McMahon, George; Day, Felix R; Ring, Susan M; Nelson, Scott M; Lawlor, Debbie A

2016-01-15

Anti-Müllerian hormone (AMH) is an essential messenger of sexual differentiation in the foetus and is an emerging biomarker of postnatal reproductive function in females. Due to a paucity of adequately sized studies, the genetic determinants of circulating AMH levels are poorly characterized. In samples from 2815 adolescents aged 15 from the ALSPAC study, we performed the first genome-wide association study of serum AMH levels across a set of ∼9 m '1000 Genomes Reference Panel' imputed genetic variants. Genetic variants at the AMH protein-coding gene showed considerable allelic heterogeneity, with both common variants [rs4807216 (P(Male) = 2 × 10(-49), Beta: ∼0.9 SDs per allele), rs8112524 (P(Male) = 3 × 10(-8), Beta: ∼0.25)] and low-frequency variants [rs2385821 (P(Male) = 6 × 10(-31), Beta: ∼1.2, frequency 3.6%)] independently associated with apparently large effect sizes in males, but not females. For all three SNPs, we highlight mechanistic links to AMH gene function and demonstrate highly significant sex interactions (P(Het) 0.0003-6.3 × 10(-12)), culminating in contrasting estimates of trait variance explained (24.5% in males versus 0.8% in females). Using these SNPs as a genetic proxy for AMH levels, we found no evidence in additional datasets to support a biological role for AMH in complex traits and diseases in men. © The Author 2015. Published by Oxford University Press.

Origins of the Human Genome Project

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

Cook-Deegan, Robert

1993-07-01

The human genome project was borne of technology, grew into a science bureaucracy in the US and throughout the world, and is now being transformed into a hybrid academic and commercial enterprise. The next phase of the project promises to veer more sharply toward commercial application, harnessing both the technical prowess of molecular biology and the rapidly growing body of knowledge about DNA structure to the pursuit of practical benefits. Faith that the systematic analysis of DNA structure will prove to be a powerful research tool underlies the rationale behind the genome project. The notion that most genetic information ismore » embedded in the sequence of CNA base pairs comprising chromosomes is a central tenet. A rough analogy is to liken an organism's genetic code to computer code. The coal of the genome project, in this parlance, is to identify and catalog 75,000 or more files (genes) in the software that directs construction of a self-modifying and self-replicating system -- a living organism.« less

Origins of the Human Genome Project

DOE R&D Accomplishments Database

Cook-Deegan, Robert (Affiliation: Institute of Medicine, National Academy of Sciences)

1993-07-01

The human genome project was borne of technology, grew into a science bureaucracy in the United States and throughout the world, and is now being transformed into a hybrid academic and commercial enterprise. The next phase of the project promises to veer more sharply toward commercial application, harnessing both the technical prowess of molecular biology and the rapidly growing body of knowledge about DNA structure to the pursuit of practical benefits. Faith that the systematic analysis of DNA structure will prove to be a powerful research tool underlies the rationale behind the genome project. The notion that most genetic information is embedded in the sequence of CNA base pairs comprising chromosomes is a central tenet. A rough analogy is to liken an organism's genetic code to computer code. The coal of the genome project, in this parlance, is to identify and catalog 75,000 or more files (genes) in the software that directs construction of a self-modifying and self-replicating system -- a living organism.

Amino acid fermentation at the origin of the genetic code.

PubMed

de Vladar, Harold P

2012-02-10

There is evidence that the genetic code was established prior to the existence of proteins, when metabolism was powered by ribozymes. Also, early proto-organisms had to rely on simple anaerobic bioenergetic processes. In this work I propose that amino acid fermentation powered metabolism in the RNA world, and that this was facilitated by proto-adapters, the precursors of the tRNAs. Amino acids were used as carbon sources rather than as catalytic or structural elements. In modern bacteria, amino acid fermentation is known as the Stickland reaction. This pathway involves two amino acids: the first undergoes oxidative deamination, and the second acts as an electron acceptor through reductive deamination. This redox reaction results in two keto acids that are employed to synthesise ATP via substrate-level phosphorylation. The Stickland reaction is the basic bioenergetic pathway of some bacteria of the genus Clostridium. Two other facts support Stickland fermentation in the RNA world. First, several Stickland amino acid pairs are synthesised in abiotic amino acid synthesis. This suggests that amino acids that could be used as an energy substrate were freely available. Second, anticodons that have complementary sequences often correspond to amino acids that form Stickland pairs. The main hypothesis of this paper is that pairs of complementary proto-adapters were assigned to Stickland amino acids pairs. There are signatures of this hypothesis in the genetic code. Furthermore, it is argued that the proto-adapters formed double strands that brought amino acid pairs into proximity to facilitate their mutual redox reaction, structurally constraining the anticodon pairs that are assigned to these amino acid pairs. Significance tests which randomise the code are performed to study the extent of the variability of the energetic (ATP) yield. Random assignments can lead to a substantial yield of ATP and maintain enough variability, thus selection can act and refine the assignments into a proto-code that optimises the energetic yield. Monte Carlo simulations are performed to evaluate the establishment of these simple proto-codes, based on amino acid substitutions and codon swapping. In all cases, donor amino acids are assigned to anticodons composed of U+G, and have low redundancy (1-2 codons), whereas acceptor amino acids are assigned to the the remaining codons. These bioenergetic and structural constraints allow for a metabolic role for amino acids before their co-option as catalyst cofactors.

Increased registration of hypertension and cancer diagnoses after the introduction of a new reimbursement system

PubMed Central

Hjerpe, Per; Boström, Kristina Bengtsson; Lindblad, Ulf; Merlo, Juan

2012-01-01

Objective To investigate the impact on ICD coding behaviour of a new case-mix reimbursement system based on coded patient diagnoses. The main hypothesis was that after the introduction of the new system the coding of chronic diseases like hypertension and cancer would increase and the variance in propensity for coding would decrease on both physician and health care centre (HCC) levels. Design Cross-sectional multilevel logistic regression analyses were performed in periods covering the time before and after the introduction of the new reimbursement system. Setting Skaraborg primary care, Sweden. Subjects All patients (n = 76 546 to 79 826) 50 years of age and older visiting 468 to 627 physicians at the 22 public HCCs in five consecutive time periods of one year each. Main outcome measures Registered codes for hypertension and cancer diseases in Skaraborg primary care database (SPCD). Results After the introduction of the new reimbursement system the adjusted prevalence of hypertension and cancer in SPCD increased from 17.4% to 32.2% and from 0.79% to 2.32%, respectively, probably partly due to an increased diagnosis coding of indirect patient contacts. The total variance in the propensity for coding declined simultaneously at the physician level for both diagnosis groups. Conclusions Changes in the healthcare reimbursement system may directly influence the contents of a research database that retrieves data from clinical practice. This should be taken into account when using such a database for research purposes, and the data should be validated for each diagnosis. PMID:23130878

Complete coding sequence characterization and comparative analysis of the putative novel human rhinovirus (HRV) species C and B

PubMed Central

2011-01-01

Background Human Rhinoviruses (HRVs) are well recognized viral pathogens associated with acute respiratory tract illnesses (RTIs) abundant worldwide. Although recent studies have phylogenetically identified the new HRV species (HRV-C), data on molecular epidemiology, genetic diversity, and clinical manifestation have been limited. Result To gain new insight into HRV genetic diversity, we determined the complete coding sequences of putative new members of HRV species C (HRV-CU072 with 1% prevalence) and HRV-B (HRV-CU211) identified from clinical specimens collected from pediatric patients diagnosed with a symptom of acute lower RTI. Complete coding sequence and phylogenetic analysis revealed that the HRV-CU072 strain shared a recent common ancestor with most closely related Chinese strain (N4). Comparative analysis at the protein level showed that HRV-CU072 might accumulate substitutional mutations in structural proteins, as well as nonstructural proteins 3C and 3 D. Comparative analysis of all available HRVs and HEVs indicated that HRV-C contains a relatively high G+C content and is more closely related to HEV-D. This might be correlated to their replication and capability to adapt to the high temperature environment of the human lower respiratory tract. We herein report an infrequently occurring intra-species recombination event in HRV-B species (HRV-CU211) with a crossing over having taken place at the boundary of VP2 and VP3 genes. Moreover, we observed phylogenetic compatibility in all HRV species and suggest that dynamic mechanisms for HRV evolution seem to be related to recombination events. These findings indicated that the elementary units shaping the genetic diversity of HRV-C could be found in the nonstructural 2A and 3D genes. Conclusion This study provides information for understanding HRV genetic diversity and insight into the role of selection pressure and recombination mechanisms influencing HRV evolution. PMID:21214911

Complete coding sequence characterization and comparative analysis of the putative novel human rhinovirus (HRV) species C and B.

PubMed

Linsuwanon, Piyada; Payungporn, Sunchai; Suwannakarn, Kamol; Chieochansin, Thaweesak; Theamboonlers, Apiradee; Poovorawan, Yong

2011-01-07

Human Rhinoviruses (HRVs) are well recognized viral pathogens associated with acute respiratory tract illnesses (RTIs) abundant worldwide. Although recent studies have phylogenetically identified the new HRV species (HRV-C), data on molecular epidemiology, genetic diversity, and clinical manifestation have been limited. To gain new insight into HRV genetic diversity, we determined the complete coding sequences of putative new members of HRV species C (HRV-CU072 with 1% prevalence) and HRV-B (HRV-CU211) identified from clinical specimens collected from pediatric patients diagnosed with a symptom of acute lower RTI. Complete coding sequence and phylogenetic analysis revealed that the HRV-CU072 strain shared a recent common ancestor with most closely related Chinese strain (N4). Comparative analysis at the protein level showed that HRV-CU072 might accumulate substitutional mutations in structural proteins, as well as nonstructural proteins 3C and 3 D. Comparative analysis of all available HRVs and HEVs indicated that HRV-C contains a relatively high G+C content and is more closely related to HEV-D. This might be correlated to their replication and capability to adapt to the high temperature environment of the human lower respiratory tract. We herein report an infrequently occurring intra-species recombination event in HRV-B species (HRV-CU211) with a crossing over having taken place at the boundary of VP2 and VP3 genes. Moreover, we observed phylogenetic compatibility in all HRV species and suggest that dynamic mechanisms for HRV evolution seem to be related to recombination events. These findings indicated that the elementary units shaping the genetic diversity of HRV-C could be found in the nonstructural 2A and 3D genes. This study provides information for understanding HRV genetic diversity and insight into the role of selection pressure and recombination mechanisms influencing HRV evolution.

Functional annotation of the vlinc class of non-coding RNAs using systems biology approach.

PubMed

St Laurent, Georges; Vyatkin, Yuri; Antonets, Denis; Ri, Maxim; Qi, Yao; Saik, Olga; Shtokalo, Dmitry; de Hoon, Michiel J L; Kawaji, Hideya; Itoh, Masayoshi; Lassmann, Timo; Arner, Erik; Forrest, Alistair R R; Nicolas, Estelle; McCaffrey, Timothy A; Carninci, Piero; Hayashizaki, Yoshihide; Wahlestedt, Claes; Kapranov, Philipp

2016-04-20

Functionality of the non-coding transcripts encoded by the human genome is the coveted goal of the modern genomics research. While commonly relied on the classical methods of forward genetics, integration of different genomics datasets in a global Systems Biology fashion presents a more productive avenue of achieving this very complex aim. Here we report application of a Systems Biology-based approach to dissect functionality of a newly identified vast class of very long intergenic non-coding (vlinc) RNAs. Using highly quantitative FANTOM5 CAGE dataset, we show that these RNAs could be grouped into 1542 novel human genes based on analysis of insulators that we show here indeed function as genomic barrier elements. We show that vlinc RNAs genes likely function in cisto activate nearby genes. This effect while most pronounced in closely spaced vlinc RNA-gene pairs can be detected over relatively large genomic distances. Furthermore, we identified 101 vlinc RNA genes likely involved in early embryogenesis based on patterns of their expression and regulation. We also found another 109 such genes potentially involved in cellular functions also happening at early stages of development such as proliferation, migration and apoptosis. Overall, we show that Systems Biology-based methods have great promise for functional annotation of non-coding RNAs. © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

Genome sequences of two closely related strains of Escherichia coli K-12 GM4792.

PubMed

Zhang, Yan-Cong; Zhang, Yan; Zhu, Bi-Ru; Zhang, Bo-Wen; Ni, Chuan; Zhang, Da-Yong; Huang, Ying; Pang, Erli; Lin, Kui

2015-01-01

Escherichia coli lab strains K-12 GM4792 Lac(+) and GM4792 Lac(-) carry opposite lactose markers, which are useful for distinguishing evolved lines as they produce different colored colonies. The two closely related strains are chosen as ancestors for our ongoing studies of experimental evolution. Here, we describe the genome sequences, annotation, and features of GM4792 Lac(+) and GM4792 Lac(-). GM4792 Lac(+) has a 4,622,342-bp long chromosome with 4,061 protein-coding genes and 83 RNA genes. Similarly, the genome of GM4792 Lac(-) consists of a 4,621,656-bp chromosome containing 4,043 protein-coding genes and 74 RNA genes. Genome comparison analysis reveals that the differences between GM4792 Lac(+) and GM4792 Lac(-) are minimal and limited to only the targeted lac region. Moreover, a previous study on competitive experimentation indicates the two strains are identical or nearly identical in survivability except for lactose utilization in a nitrogen-limited environment. Therefore, at both a genetic and a phenotypic level, GM4792 Lac(+) and GM4792 Lac(-), with opposite neutral markers, are ideal systems for future experimental evolution studies.

Multi-Platform Next-Generation Sequencing of the Domestic Turkey (Meleagris gallopavo): Genome Assembly and Analysis

PubMed Central

Aslam, Luqman; Beal, Kathryn; Ann Blomberg, Le; Bouffard, Pascal; Burt, David W.; Crasta, Oswald; Crooijmans, Richard P. M. A.; Cooper, Kristal; Coulombe, Roger A.; De, Supriyo; Delany, Mary E.; Dodgson, Jerry B.; Dong, Jennifer J.; Evans, Clive; Frederickson, Karin M.; Flicek, Paul; Florea, Liliana; Folkerts, Otto; Groenen, Martien A. M.; Harkins, Tim T.; Herrero, Javier; Hoffmann, Steve; Megens, Hendrik-Jan; Jiang, Andrew; de Jong, Pieter; Kaiser, Pete; Kim, Heebal; Kim, Kyu-Won; Kim, Sungwon; Langenberger, David; Lee, Mi-Kyung; Lee, Taeheon; Mane, Shrinivasrao; Marcais, Guillaume; Marz, Manja; McElroy, Audrey P.; Modise, Thero; Nefedov, Mikhail; Notredame, Cédric; Paton, Ian R.; Payne, William S.; Pertea, Geo; Prickett, Dennis; Puiu, Daniela; Qioa, Dan; Raineri, Emanuele; Ruffier, Magali; Salzberg, Steven L.; Schatz, Michael C.; Scheuring, Chantel; Schmidt, Carl J.; Schroeder, Steven; Searle, Stephen M. J.; Smith, Edward J.; Smith, Jacqueline; Sonstegard, Tad S.; Stadler, Peter F.; Tafer, Hakim; Tu, Zhijian (Jake); Van Tassell, Curtis P.; Vilella, Albert J.; Williams, Kelly P.; Yorke, James A.; Zhang, Liqing; Zhang, Hong-Bin; Zhang, Xiaojun; Zhang, Yang; Reed, Kent M.

2010-01-01

A synergistic combination of two next-generation sequencing platforms with a detailed comparative BAC physical contig map provided a cost-effective assembly of the genome sequence of the domestic turkey (Meleagris gallopavo). Heterozygosity of the sequenced source genome allowed discovery of more than 600,000 high quality single nucleotide variants. Despite this heterozygosity, the current genome assembly (∼1.1 Gb) includes 917 Mb of sequence assigned to specific turkey chromosomes. Annotation identified nearly 16,000 genes, with 15,093 recognized as protein coding and 611 as non-coding RNA genes. Comparative analysis of the turkey, chicken, and zebra finch genomes, and comparing avian to mammalian species, supports the characteristic stability of avian genomes and identifies genes unique to the avian lineage. Clear differences are seen in number and variety of genes of the avian immune system where expansions and novel genes are less frequent than examples of gene loss. The turkey genome sequence provides resources to further understand the evolution of vertebrate genomes and genetic variation underlying economically important quantitative traits in poultry. This integrated approach may be a model for providing both gene and chromosome level assemblies of other species with agricultural, ecological, and evolutionary interest. PMID:20838655

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

Conserved syntenic clusters of protein coding genes are missing in birds.

PubMed

Lovell, Peter V; Wirthlin, Morgan; Wilhelm, Larry; Minx, Patrick; Lazar, Nathan H; Carbone, Lucia; Warren, Wesley C; Mello, Claudio V

2014-01-01

Birds are one of the most highly successful and diverse groups of vertebrates, having evolved a number of distinct characteristics, including feathers and wings, a sturdy lightweight skeleton and unique respiratory and urinary/excretion systems. However, the genetic basis of these traits is poorly understood. Using comparative genomics based on extensive searches of 60 avian genomes, we have found that birds lack approximately 274 protein coding genes that are present in the genomes of most vertebrate lineages and are for the most part organized in conserved syntenic clusters in non-avian sauropsids and in humans. These genes are located in regions associated with chromosomal rearrangements, and are largely present in crocodiles, suggesting that their loss occurred subsequent to the split of dinosaurs/birds from crocodilians. Many of these genes are associated with lethality in rodents, human genetic disorders, or biological functions targeting various tissues. Functional enrichment analysis combined with orthogroup analysis and paralog searches revealed enrichments that were shared by non-avian species, present only in birds, or shared between all species. Together these results provide a clearer definition of the genetic background of extant birds, extend the findings of previous studies on missing avian genes, and provide clues about molecular events that shaped avian evolution. They also have implications for fields that largely benefit from avian studies, including development, immune system, oncogenesis, and brain function and cognition. With regards to the missing genes, birds can be considered ‘natural knockouts’ that may become invaluable model organisms for several human diseases.

Advanced technology development for image gathering, coding, and processing

NASA Technical Reports Server (NTRS)

Huck, Friedrich O.

1990-01-01

Three overlapping areas of research activities are presented: (1) Information theory and optimal filtering are extended to visual information acquisition and processing. The goal is to provide a comprehensive methodology for quantitatively assessing the end-to-end performance of image gathering, coding, and processing. (2) Focal-plane processing techniques and technology are developed to combine effectively image gathering with coding. The emphasis is on low-level vision processing akin to the retinal processing in human vision. (3) A breadboard adaptive image-coding system is being assembled. This system will be used to develop and evaluate a number of advanced image-coding technologies and techniques as well as research the concept of adaptive image coding.

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

The paternal ancestry of Uttarakhand does not imitate the classical caste system of India.

PubMed

Negi, Neetu; Tamang, Rakesh; Pande, Veena; Sharma, Amrita; Shah, Anish; Reddy, Alla G; Vishnupriya, Satti; Singh, Lalji; Chaubey, Gyaneshwer; Thangaraj, Kumarasamy

2016-02-01

Although, there have been rigorous research on the Indian caste system by several disciplines, it is still one of the most controversial socioscientific topic. Previous genetic studies on the subcontinent have supported a classical hierarchal sharing of genetic component by various castes of India. In the present study, we have used high-resolution mtDNA and Y chromosomal markers to characterize the genetic structuring of the Uttarakhand populations in the context of neighboring regions. Furthermore, we have tested whether the genetic structuring of caste populations at different social levels of this region, follow the classical chaturvarna system. Interestingly, we found that this region showed a high level of variation for East Eurasian ancestry in both maternal and paternal lines of descent. Moreover, the intrapopulation comparison showed a high level of heterogeneity, likely because of different caste hierarchy, interpolated on asymmetric admixture of populations inhabiting on both sides of the Himalayas.

Charge scheduling of an energy storage system under time-of-use pricing and a demand charge.

PubMed

Yoon, Yourim; Kim, Yong-Hyuk

2014-01-01

A real-coded genetic algorithm is used to schedule the charging of an energy storage system (ESS), operated in tandem with renewable power by an electricity consumer who is subject to time-of-use pricing and a demand charge. Simulations based on load and generation profiles of typical residential customers show that an ESS scheduled by our algorithm can reduce electricity costs by approximately 17%, compared to a system without an ESS and by 8% compared to a scheduling algorithm based on net power.

Charge Scheduling of an Energy Storage System under Time-of-Use Pricing and a Demand Charge

PubMed Central

Yoon, Yourim

2014-01-01

A real-coded genetic algorithm is used to schedule the charging of an energy storage system (ESS), operated in tandem with renewable power by an electricity consumer who is subject to time-of-use pricing and a demand charge. Simulations based on load and generation profiles of typical residential customers show that an ESS scheduled by our algorithm can reduce electricity costs by approximately 17%, compared to a system without an ESS and by 8% compared to a scheduling algorithm based on net power. PMID:25197720

Towards a global IT system for personalized medicine: the Medicine Safety Code initiative.

PubMed

Samwald, Matthias; Minarro-Giménez, José Antonio; Blagec, Kathrin; Adlassnig, Klaus-Peter

2014-01-01

The availability of pharmacogenomic data of individual patients can significantly improve physicians' prescribing behavior, lead to a reduced incidence of adverse drug events and an improvement of effectiveness of treatment. The Medicine Safety Code (MSC) initiative is an effort to improve the ability of clinicians and patients to share pharmacogenomic data and to use it at the point of care. The MSC is a standardized two-dimensional barcode that captures individual pharmacogenomic data. The system is backed by a web service that allows the decoding and interpretation of anonymous MSCs without requiring the installation of dedicated software. The system is based on a curated, ontology-based knowledge base representing pharmacogenomic definitions and clinical guidelines. The MSC system performed well in preliminary tests. To evaluate the system in realistic health care settings and to translate it into practical applications, the future participation of stakeholders in clinical institutions, researchers, pharmaceutical companies, genetic testing providers, health IT companies and health insurance organizations will be essential.

Towards a global IT system for personalized medicine: the Medicine Safety Code initiative.

PubMed

Samwald, Matthias; Minarro-Giménez, José Antonio; Blagec, Kathrin; Adlassnig, Klaus-Peter

2014-01-01

The availability of pharmacogenomic data of individual patients can significantly improve physicians' prescribing behavior, lead to a reduced incidence of adverse drug events and an improvement of effectiveness of treatment. The Medicine Safety Code (MSC) initiative is an effort to improve the ability of clinicians and patients to share pharmacogenomic data and to use it at the point of care. The MSC is a standardized two-dimensional barcode that captures individual pharmacogenomic data. The system is backed by a web service that allows the decoding and interpretation of anonymous MSCs without requiring the installation of dedicated software. The system is based on a curated, ontology-based knowledge base representing pharmacogenomic definitions and clinical guidelines. The MSC system performed well in preliminary tests. To evaluate the system in realistic health care settings and to translate it into practical applications, the future participation of stakeholders in clinical institutions, medical researchers, pharmaceutical companies, genetic testing providers, health IT companies and health insurance organizations will be essential.

Model annotation for synthetic biology: automating model to nucleotide sequence conversion

PubMed Central

Misirli, Goksel; Hallinan, Jennifer S.; Yu, Tommy; Lawson, James R.; Wimalaratne, Sarala M.; Cooling, Michael T.; Wipat, Anil

2011-01-01

Motivation: The need for the automated computational design of genetic circuits is becoming increasingly apparent with the advent of ever more complex and ambitious synthetic biology projects. Currently, most circuits are designed through the assembly of models of individual parts such as promoters, ribosome binding sites and coding sequences. These low level models are combined to produce a dynamic model of a larger device that exhibits a desired behaviour. The larger model then acts as a blueprint for physical implementation at the DNA level. However, the conversion of models of complex genetic circuits into DNA sequences is a non-trivial undertaking due to the complexity of mapping the model parts to their physical manifestation. Automating this process is further hampered by the lack of computationally tractable information in most models. Results: We describe a method for automatically generating DNA sequences from dynamic models implemented in CellML and Systems Biology Markup Language (SBML). We also identify the metadata needed to annotate models to facilitate automated conversion, and propose and demonstrate a method for the markup of these models using RDF. Our algorithm has been implemented in a software tool called MoSeC. Availability: The software is available from the authors' web site http://research.ncl.ac.uk/synthetic_biology/downloads.html. Contact: anil.wipat@ncl.ac.uk Supplementary information: Supplementary data are available at Bioinformatics online. PMID:21296753

The grout/glass performance assessment code system (GPACS) with verification and benchmarking

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

Piepho, M.G.; Sutherland, W.H.; Rittmann, P.D.

1994-12-01

GPACS is a computer code system for calculating water flow (unsaturated or saturated), solute transport, and human doses due to the slow release of contaminants from a waste form (in particular grout or glass) through an engineered system and through a vadose zone to an aquifer, well and river. This dual-purpose document is intended to serve as a user`s guide and verification/benchmark document for the Grout/Glass Performance Assessment Code system (GPACS). GPACS can be used for low-level-waste (LLW) Glass Performance Assessment and many other applications including other low-level-waste performance assessments and risk assessments. Based on all the cses presented, GPACSmore » is adequate (verified) for calculating water flow and contaminant transport in unsaturated-zone sediments and for calculating human doses via the groundwater pathway.« less

High-Penetration Photovoltaics Standards and Codes Workshop, Denver, Colorado, May 20, 2010: Workshop Proceedings

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

Coddington, M.; Kroposki, B.; Basso, T.

Effectively interconnecting high-level penetration of photovoltaic (PV) systems requires careful technical attention to ensuring compatibility with electric power systems. Standards, codes, and implementation have been cited as major impediments to widespread use of PV within electric power systems. On May 20, 2010, in Denver, Colorado, the National Renewable Energy Laboratory, in conjunction with the U.S. Department of Energy (DOE) Office of Energy Efficiency and Renewable Energy (EERE), held a workshop to examine the key technical issues and barriers associated with high PV penetration levels with an emphasis on codes and standards. This workshop included building upon results of the Highmore » Penetration of Photovoltaic (PV) Systems into the Distribution Grid workshop held in Ontario California on February 24-25, 2009, and upon the stimulating presentations of the diverse stakeholder presentations.« less

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

Rapid and Parallel Adaptive Evolution of the Visual System of Neotropical Midas Cichlid Fishes.

PubMed

Torres-Dowdall, Julián; Pierotti, Michele E R; Härer, Andreas; Karagic, Nidal; Woltering, Joost M; Henning, Frederico; Elmer, Kathryn R; Meyer, Axel

2017-10-01

Midas cichlid fish are a Central American species flock containing 13 described species that has been dated to only a few thousand years old, a historical timescale infrequently associated with speciation. Their radiation involved the colonization of several clear water crater lakes from two turbid great lakes. Therefore, Midas cichlids have been subjected to widely varying photic conditions during their radiation. Being a primary signal relay for information from the environment to the organism, the visual system is under continuing selective pressure and a prime organ system for accumulating adaptive changes during speciation, particularly in the case of dramatic shifts in photic conditions. Here, we characterize the full visual system of Midas cichlids at organismal and genetic levels, to determine what types of adaptive changes evolved within the short time span of their radiation. We show that Midas cichlids have a diverse visual system with unexpectedly high intra- and interspecific variation in color vision sensitivity and lens transmittance. Midas cichlid populations in the clear crater lakes have convergently evolved visual sensitivities shifted toward shorter wavelengths compared with the ancestral populations from the turbid great lakes. This divergence in sensitivity is driven by changes in chromophore usage, differential opsin expression, opsin coexpression, and to a lesser degree by opsin coding sequence variation. The visual system of Midas cichlids has the evolutionary capacity to rapidly integrate multiple adaptations to changing light environments. Our data may indicate that, in early stages of divergence, changes in opsin regulation could precede changes in opsin coding sequence evolution. © The Author 2017. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

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.

The Genetic Privacy Act and commentary

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

Annas, G.J.; Glantz, L.H.; Roche, P.A.

1995-02-28

The Genetic Privacy Act is a proposal for federal legislation. The Act is based on the premise that genetic information is different from other types of personal information in ways that require special protection. The DNA molecule holds an extensive amount of currently indecipherable information. The major goal of the Human Genome Project is to decipher this code so that the information it contains is accessible. The privacy question is, accessible to whom? The highly personal nature of the information contained in DNA can be illustrated by thinking of DNA as containing an individual`s {open_quotes}future diary.{close_quotes} A diary is perhapsmore » the most personal and private document a person can create. It contains a person`s innermost thoughts and perceptions, and is usually hidden and locked to assure its secrecy. Diaries describe the past. The information in one`s genetic code can be thought of as a coded probabilistic future diary because it describes an important part of a unique and personal future. This document presents an introduction to the proposal for federal legislation `the Genetic Privacy Act`; a copy of the proposed act; and comment.« less

Job coding (PCS 2003): feedback from a study conducted in an Occupational Health Service

PubMed

Henrotin, Jean-Bernard; Vaissière, Monique; Etaix, Maryline; Malard, Stéphane; Dziurla, Mathieu; Lafon, Dominique

2016-10-19

Aim: To examine the quality of manual job coding carried out by occupational health teams with access to a software application that provides assistance in job and business sector coding (CAPS). Methods: Data from a study conducted in an Occupational Health Service were used to examine the first-level coding of 1,495 jobs by occupational health teams according to the French job classification entitled “PSC- Professions and socio-professional categories” (INSEE, 2003 version). A second level of coding was also performed by an experienced coder and the first and second level codes were compared. Agreement between the two coding systems was studied using the kappa coefficient (κ) and frequencies were compared by Chi2 tests. Results: Missing data or incorrect codes were observed for 14.5% of social groups (1 digit) and 25.7% of job codes (4 digits). While agreement between the first two levels of PCS 2003 appeared to be satisfactory (κ=0.73 and κ=0.75), imbalances in reassignment flows were effectively noted. The divergent job code rate was 48.2%. Variation in the frequency of socio-occupational variables was as high as 8.6% after correcting for missing data and divergent codes. Conclusions: Compared with other studies, the use of the CAPS tool appeared to provide effective coding assistance. However, our results indicate that job coding based on PSC 2003 should be conducted using ancillary data by personnel trained in the use of this tool.

We Are Not Numbers: The Use of Identification Codes in Online Learning

ERIC Educational Resources Information Center

Francis-Poscente, Krista; Moisey, Susan Darlene

2012-01-01

This paper discusses students' experiences with the use of identification codes in a graduate course delivered asynchronously via the Internet. While teaching an introductory masters level graduate course in distance learning, the authors discovered that the learning management system, Moodle, was programmed to display identification codes rather…

Computer algorithm for coding gain

NASA Technical Reports Server (NTRS)

Dodd, E. E.

1974-01-01

Development of a computer algorithm for coding gain for use in an automated communications link design system. Using an empirical formula which defines coding gain as used in space communications engineering, an algorithm is constructed on the basis of available performance data for nonsystematic convolutional encoding with soft-decision (eight-level) Viterbi decoding.

The positive financial impact of using an Intensive Care Information System in a tertiary Intensive Care Unit.

PubMed

Levesque, Eric; Hoti, Emir; de La Serna, Sofia; Habouchi, Houssam; Ichai, Philippe; Saliba, Faouzi; Samuel, Didier; Azoulay, Daniel

2013-03-01

In the French healthcare system, the intensive care budget allocated is directly dependent on the activity level of the center. To evaluate this activity level, it is necessary to code the medical diagnoses and procedures performed on Intensive Care Unit (ICU) patients. The aim of this study was to evaluate the effects of using an Intensive Care Information System (ICIS) on the incidence of coding errors and its impact on the ICU budget allocated. Since 2005, the documentation on and monitoring of every patient admitted to our ICU has been carried out using an ICIS. However, the coding process was performed manually until 2008. This study focused on two periods: the period of manual coding (year 2007) and the period of computerized coding (year 2008) which covered a total of 1403 ICU patients. The time spent on the coding process, the rate of coding errors (defined as patients missed/not coded or wrongly identified as undergoing major procedure/s) and the financial impact were evaluated for these two periods. With computerized coding, the time per admission decreased significantly (from 6.8 ± 2.8 min in 2007 to 3.6 ± 1.9 min in 2008, p<0.001). Similarly, a reduction in coding errors was observed (7.9% vs. 2.2%, p<0.001). This decrease in coding errors resulted in a reduced difference between the potential and real ICU financial supplements obtained in the respective years (€194,139 loss in 2007 vs. a €1628 loss in 2008). Using specific computer programs improves the intensive process of manual coding by shortening the time required as well as reducing errors, which in turn positively impacts the ICU budget allocation. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Genome-wide and gene-centric analyses of circulating myeloperoxidase levels in the charge and care consortia.

PubMed

Reiner, Alexander P; Hartiala, Jaana; Zeller, Tanja; Bis, Joshua C; Dupuis, Josée; Fornage, Myriam; Baumert, Jens; Kleber, Marcus E; Wild, Philipp S; Baldus, Stephan; Bielinski, Suzette J; Fontes, João D; Illig, Thomas; Keating, Brendan J; Lange, Leslie A; Ojeda, Francisco; Müller-Nurasyid, Martina; Munzel, Thomas F; Psaty, Bruce M; Rice, Kenneth; Rotter, Jerome I; Schnabel, Renate B; Tang, W H Wilson; Thorand, Barbara; Erdmann, Jeanette; Jacobs, David R; Wilson, James G; Koenig, Wolfgang; Tracy, Russell P; Blankenberg, Stefan; März, Winfried; Gross, Myron D; Benjamin, Emelia J; Hazen, Stanley L; Allayee, Hooman

2013-08-15

Increased systemic levels of myeloperoxidase (MPO) are associated with the risk of coronary artery disease (CAD). To identify the genetic factors that are associated with circulating MPO levels, we carried out a genome-wide association study (GWAS) and a gene-centric analysis in subjects of European ancestry and African Americans (AAs). A locus on chromosome 1q31.1 containing the complement factor H (CFH) gene was strongly associated with serum MPO levels in 9305 subjects of European ancestry (lead SNP rs800292; P = 4.89 × 10(-41)) and in 1690 AA subjects (rs505102; P = 1.05 × 10(-8)). Gene-centric analyses in 8335 subjects of European ancestry additionally identified two rare MPO coding sequence variants that were associated with serum MPO levels (rs28730837, P = 5.21 × 10(-12); rs35897051, P = 3.32 × 10(-8)). A GWAS for plasma MPO levels in 9260 European ancestry subjects identified a chromosome 17q22 region near MPO that was significantly associated (lead SNP rs6503905; P = 2.94 × 10(-12)), but the CFH locus did not exhibit evidence of association with plasma MPO levels. Functional analyses revealed that rs800292 was associated with levels of complement proteins in serum. Variants at chromosome 17q22 also had pleiotropic cis effects on gene expression. In a case-control analysis of ∼80 000 subjects from CARDIoGRAM, none of the identified single-nucleotide polymorphisms (SNPs) were associated with CAD. These results suggest that distinct genetic factors regulate serum and plasma MPO levels, which may have relevance for various acute and chronic inflammatory disorders. The clinical implications for CAD and a better understanding of the functional basis for the association of CFH and MPO variants with circulating MPO levels require further study.

Chemical and Biological Tools for the Preparation of Modified Histone Proteins

PubMed Central

Howard, Cecil J.; Yu, Ruixuan R.; Gardner, Miranda L.; Shimko, John C.; Ottesen, Jennifer J.

2016-01-01

Eukaryotic chromatin is a complex and dynamic system in which the DNA double helix is organized and protected by interactions with histone proteins. This system is regulated through, a large network of dynamic post-translational modifications (PTMs) exists to ensure proper gene transcription, DNA repair, and other processes involving DNA. Homogenous protein samples with precisely characterized modification sites are necessary to better understand the functions of modified histone proteins. Here, we discuss sets of chemical and biological tools that have been developed for the preparation of modified histones, with a focus on the appropriate choice of tool for a given target. We start with genetic approaches for the creation of modified histones, including the incorporation of genetic mimics of histone modifications, chemical installation of modification analogs, and the use of the expanded genetic code to incorporate modified amino acids. Additionally, we will cover the chemical ligation techniques that have been invaluable in the generation of complex modified histones that are indistinguishable from the natural counterparts. Finally, we will end with a prospectus on future directions of synthetic chromatin in living systems. PMID:25863817

Information theory and the ethylene genetic network.

PubMed

González-García, José S; Díaz, José

2011-10-01

The original aim of the Information Theory (IT) was to solve a purely technical problem: to increase the performance of communication systems, which are constantly affected by interferences that diminish the quality of the transmitted information. That is, the theory deals only with the problem of transmitting with the maximal precision the symbols constituting a message. In Shannon's theory messages are characterized only by their probabilities, regardless of their value or meaning. As for its present day status, it is generally acknowledged that Information Theory has solid mathematical foundations and has fruitful strong links with Physics in both theoretical and experimental areas. However, many applications of Information Theory to Biology are limited to using it as a technical tool to analyze biopolymers, such as DNA, RNA or protein sequences. The main point of discussion about the applicability of IT to explain the information flow in biological systems is that in a classic communication channel, the symbols that conform the coded message are transmitted one by one in an independent form through a noisy communication channel, and noise can alter each of the symbols, distorting the message; in contrast, in a genetic communication channel the coded messages are not transmitted in the form of symbols but signaling cascades transmit them. Consequently, the information flow from the emitter to the effector is due to a series of coupled physicochemical processes that must ensure the accurate transmission of the message. In this review we discussed a novel proposal to overcome this difficulty, which consists of the modeling of gene expression with a stochastic approach that allows Shannon entropy (H) to be directly used to measure the amount of uncertainty that the genetic machinery has in relation to the correct decoding of a message transmitted into the nucleus by a signaling pathway. From the value of H we can define a function I that measures the amount of information content in the input message that the cell's genetic machinery is processing during a given time interval. Furthermore, combining Information Theory with the frequency response analysis of dynamical systems we can examine the cell's genetic response to input signals with varying frequencies, amplitude and form, in order to determine if the cell can distinguish between different regimes of information flow from the environment. In the particular case of the ethylene signaling pathway, the amount of information managed by the root cell of Arabidopsis can be correlated with the frequency of the input signal. The ethylene signaling pathway cuts off very low and very high frequencies, allowing a window of frequency response in which the nucleus reads the incoming message as a varying input. Outside of this window the nucleus reads the input message as an approximately non-varying one. This frequency response analysis is also useful to estimate the rate of information transfer during the transport of each new ERF1 molecule into the nucleus. Additionally, application of Information Theory to analysis of the flow of information in the ethylene signaling pathway provides a deeper insight in the form in which the transition between auxin and ethylene hormonal activity occurs during a circadian cycle. An ambitious goal for the future would be to use Information Theory as a theoretical foundation for a suitable model of the information flow that runs at each level and through all levels of biological organization.

Dissecting the genetics of the human transcriptome identifies novel trait-related trans-eQTLs and corroborates the regulatory relevance of non-protein coding loci†

PubMed Central

Kirsten, Holger; Al-Hasani, Hoor; Holdt, Lesca; Gross, Arnd; Beutner, Frank; Krohn, Knut; Horn, Katrin; Ahnert, Peter; Burkhardt, Ralph; Reiche, Kristin; Hackermüller, Jörg; Löffler, Markus; Teupser, Daniel; Thiery, Joachim; Scholz, Markus

2015-01-01

Genetics of gene expression (eQTLs or expression QTLs) has proved an indispensable tool for understanding biological pathways and pathomechanisms of trait-associated SNPs. However, power of most genome-wide eQTL studies is still limited. We performed a large eQTL study in peripheral blood mononuclear cells of 2112 individuals increasing the power to detect trans-effects genome-wide. Going beyond univariate SNP-transcript associations, we analyse relations of eQTLs to biological pathways, polygenetic effects of expression regulation, trans-clusters and enrichment of co-localized functional elements. We found eQTLs for about 85% of analysed genes, and 18% of genes were trans-regulated. Local eSNPs were enriched up to a distance of 5 Mb to the transcript challenging typically implemented ranges of cis-regulations. Pathway enrichment within regulated genes of GWAS-related eSNPs supported functional relevance of identified eQTLs. We demonstrate that nearest genes of GWAS-SNPs might frequently be misleading functional candidates. We identified novel trans-clusters of potential functional relevance for GWAS-SNPs of several phenotypes including obesity-related traits, HDL-cholesterol levels and haematological phenotypes. We used chromatin immunoprecipitation data for demonstrating biological effects. Yet, we show for strongly heritable transcripts that still little trans-chromosomal heritability is explained by all identified trans-eSNPs; however, our data suggest that most cis-heritability of these transcripts seems explained. Dissection of co-localized functional elements indicated a prominent role of SNPs in loci of pseudogenes and non-coding RNAs for the regulation of coding genes. In summary, our study substantially increases the catalogue of human eQTLs and improves our understanding of the complex genetic regulation of gene expression, pathways and disease-related processes. PMID:26019233

Use of Contemporary Genetics in Cardiovascular Diagnosis

PubMed Central

George, Alfred L.

2015-01-01

An explosion of knowledge regarding the genetic and genomic basis for rare and common diseases has provided a framework for revolutionizing the practice of medicine. Achieving the reality of a genomic medicine era requires that basic discoveries are effectively translated into clinical practice through implementation of genetic and genomic testing. Clinical genetic tests have become routine for many inherited disorders and can be regarded as the standard-of-care in many circumstances including disorders affecting the cardiovascular system. New, high-throughput methods for determining the DNA sequence of all coding exons or complete genomes are being adopted for clinical use to expand the speed and breadth of genetic testing. Along with these extraordinary advances have emerged new challenges to practicing physicians for understanding when and how to use genetic testing along with how to appropriately interpret test results. This review will acquaint readers with general principles of genetic testing including newer technologies, test interpretation and pitfalls. The focus will be on testing genes responsible for monogenic disorders and on other emerging applications such as pharmacogenomic profiling. The discussion will be extended to the new paradigm of direct-to-consumer genetic testing and the value of assessing genomic risk for common diseases. PMID:25421045

Application of the Linux cluster for exhaustive window haplotype analysis using the FBAT and Unphased programs.

PubMed

Mishima, Hiroyuki; Lidral, Andrew C; Ni, Jun

2008-05-28

Genetic association studies have been used to map disease-causing genes. A newly introduced statistical method, called exhaustive haplotype association study, analyzes genetic information consisting of different numbers and combinations of DNA sequence variations along a chromosome. Such studies involve a large number of statistical calculations and subsequently high computing power. It is possible to develop parallel algorithms and codes to perform the calculations on a high performance computing (HPC) system. However, most existing commonly-used statistic packages for genetic studies are non-parallel versions. Alternatively, one may use the cutting-edge technology of grid computing and its packages to conduct non-parallel genetic statistical packages on a centralized HPC system or distributed computing systems. In this paper, we report the utilization of a queuing scheduler built on the Grid Engine and run on a Rocks Linux cluster for our genetic statistical studies. Analysis of both consecutive and combinational window haplotypes was conducted by the FBAT (Laird et al., 2000) and Unphased (Dudbridge, 2003) programs. The dataset consisted of 26 loci from 277 extended families (1484 persons). Using the Rocks Linux cluster with 22 compute-nodes, FBAT jobs performed about 14.4-15.9 times faster, while Unphased jobs performed 1.1-18.6 times faster compared to the accumulated computation duration. Execution of exhaustive haplotype analysis using non-parallel software packages on a Linux-based system is an effective and efficient approach in terms of cost and performance.

Application of the Linux cluster for exhaustive window haplotype analysis using the FBAT and Unphased programs

PubMed Central

Mishima, Hiroyuki; Lidral, Andrew C; Ni, Jun

2008-01-01

Background Genetic association studies have been used to map disease-causing genes. A newly introduced statistical method, called exhaustive haplotype association study, analyzes genetic information consisting of different numbers and combinations of DNA sequence variations along a chromosome. Such studies involve a large number of statistical calculations and subsequently high computing power. It is possible to develop parallel algorithms and codes to perform the calculations on a high performance computing (HPC) system. However, most existing commonly-used statistic packages for genetic studies are non-parallel versions. Alternatively, one may use the cutting-edge technology of grid computing and its packages to conduct non-parallel genetic statistical packages on a centralized HPC system or distributed computing systems. In this paper, we report the utilization of a queuing scheduler built on the Grid Engine and run on a Rocks Linux cluster for our genetic statistical studies. Results Analysis of both consecutive and combinational window haplotypes was conducted by the FBAT (Laird et al., 2000) and Unphased (Dudbridge, 2003) programs. The dataset consisted of 26 loci from 277 extended families (1484 persons). Using the Rocks Linux cluster with 22 compute-nodes, FBAT jobs performed about 14.4–15.9 times faster, while Unphased jobs performed 1.1–18.6 times faster compared to the accumulated computation duration. Conclusion Execution of exhaustive haplotype analysis using non-parallel software packages on a Linux-based system is an effective and efficient approach in terms of cost and performance. PMID:18541045

Reading the Second Code: Mapping Epigenomes to Understand Plant Growth, Development, and Adaptation to the Environment[OA

PubMed Central

2012-01-01

We have entered a new era in agricultural and biomedical science made possible by remarkable advances in DNA sequencing technologies. The complete sequence of an individual’s set of chromosomes (collectively, its genome) provides a primary genetic code for what makes that individual unique, just as the contents of every personal computer reflect the unique attributes of its owner. But a second code, composed of “epigenetic” layers of information, affects the accessibility of the stored information and the execution of specific tasks. Nature’s second code is enigmatic and must be deciphered if we are to fully understand and optimize the genetic potential of crop plants. The goal of the Epigenomics of Plants International Consortium is to crack this second code, and ultimately master its control, to help catalyze a new green revolution. PMID:22751210

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.

Data compression for satellite images

NASA Technical Reports Server (NTRS)

Chen, P. H.; Wintz, P. A.

1976-01-01

An efficient data compression system is presented for satellite pictures and two grey level pictures derived from satellite pictures. The compression techniques take advantages of the correlation between adjacent picture elements. Several source coding methods are investigated. Double delta coding is presented and shown to be the most efficient. Both predictive differential quantizing technique and double delta coding can be significantly improved by applying a background skipping technique. An extension code is constructed. This code requires very little storage space and operates efficiently. Simulation results are presented for various coding schemes and source codes.

One-way quantum repeaters with quantum Reed-Solomon codes

NASA Astrophysics Data System (ADS)

Muralidharan, Sreraman; Zou, Chang-Ling; Li, Linshu; Jiang, Liang

2018-05-01

We show that quantum Reed-Solomon codes constructed from classical Reed-Solomon codes can approach the capacity on the quantum erasure channel of d -level systems for large dimension d . We study the performance of one-way quantum repeaters with these codes and obtain a significant improvement in key generation rate compared to previously investigated encoding schemes with quantum parity codes and quantum polynomial codes. We also compare the three generations of quantum repeaters using quantum Reed-Solomon codes and identify parameter regimes where each generation performs the best.

Association of genetic variants of GRIN2B with autism.

PubMed

Pan, Yongcheng; Chen, Jingjing; Guo, Hui; Ou, Jianjun; Peng, Yu; Liu, Qiong; Shen, Yidong; Shi, Lijuan; Liu, Yalan; Xiong, Zhimin; Zhu, Tengfei; Luo, Sanchuan; Hu, Zhengmao; Zhao, Jingping; Xia, Kun

2015-02-06

Autism (MIM 209850) is a complex neurodevelopmental disorder characterized by social communication impairments and restricted repetitive behaviors. It has a high heritability, although much remains unclear. To evaluate genetic variants of GRIN2B in autism etiology, we performed a system association study of common and rare variants of GRIN2B and autism in cohorts from a Chinese population, involving a total sample of 1,945 subjects. Meta-analysis of a triad family cohort and a case-control cohort identified significant associations of multiple common variants and autism risk (Pmin = 1.73 × 10(-4)). Significantly, the haplotype involved with the top common variants also showed significant association (P = 1.78 × 10(-6)). Sanger sequencing of 275 probands from a triad cohort identified several variants in coding regions, including four common variants and seven rare variants. Two of the common coding variants were located in the autism-related linkage disequilibrium (LD) block, and both were significantly associated with autism (P < 9 × 10(-3)) using an independent control cohort. Burden analysis and case-only analysis of rare coding variants identified by Sanger sequencing did not find this association. Our study for the first time reveals that common variants and related haplotypes of GRIN2B are associated with autism risk.

Regulation of mammalian cell differentiation by long non-coding RNAs

PubMed Central

Hu, Wenqian; Alvarez-Dominguez, Juan R; Lodish, Harvey F

2012-01-01

Differentiation of specialized cell types from stem and progenitor cells is tightly regulated at several levels, both during development and during somatic tissue homeostasis. Many long non-coding RNAs have been recognized as an additional layer of regulation in the specification of cellular identities; these non-coding species can modulate gene-expression programmes in various biological contexts through diverse mechanisms at the transcriptional, translational or messenger RNA stability levels. Here, we summarize findings that implicate long non-coding RNAs in the control of mammalian cell differentiation. We focus on several representative differentiation systems and discuss how specific long non-coding RNAs contribute to the regulation of mammalian development. PMID:23070366

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.

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.

IDENTIFYING GENETIC ASSOCIATIONS WITH VARIABILITY IN METABOLIC HEALTH AND BLOOD COUNT LABORATORY VALUES: DIVING INTO THE QUANTITATIVE TRAITS BY LEVERAGING LONGITUDINAL DATA FROM AN EHR.

PubMed

Verma, Shefali S; Lucas, Anastasia M; Lavage, Daniel R; Leader, Joseph B; Metpally, Raghu; Krishnamurthy, Sarathbabu; Dewey, Frederick; Borecki, Ingrid; Lopez, Alexander; Overton, John; Penn, John; Reid, Jeffrey; Pendergrass, Sarah A; Breitwieser, Gerda; Ritchie, Marylyn D

2017-01-01

A wide range of patient health data is recorded in Electronic Health Records (EHR). This data includes diagnosis, surgical procedures, clinical laboratory measurements, and medication information. Together this information reflects the patient's medical history. Many studies have efficiently used this data from the EHR to find associations that are clinically relevant, either by utilizing International Classification of Diseases, version 9 (ICD-9) codes or laboratory measurements, or by designing phenotype algorithms to extract case and control status with accuracy from the EHR. Here we developed a strategy to utilize longitudinal quantitative trait data from the EHR at Geisinger Health System focusing on outpatient metabolic and complete blood panel data as a starting point. Comprehensive Metabolic Panel (CMP) as well as Complete Blood Counts (CBC) are parts of routine care and provide a comprehensive picture from high level screening of patients' overall health and disease. We randomly split our data into two datasets to allow for discovery and replication. We first conducted a genome-wide association study (GWAS) with median values of 25 different clinical laboratory measurements to identify variants from Human Omni Express Exome beadchip data that are associated with these measurements. We identified 687 variants that associated and replicated with the tested clinical measurements at p<5×10-08. Since longitudinal data from the EHR provides a record of a patient's medical history, we utilized this information to further investigate the ICD-9 codes that might be associated with differences in variability of the measurements in the longitudinal dataset. We identified low and high variance patients by looking at changes within their individual longitudinal EHR laboratory results for each of the 25 clinical lab values (thus creating 50 groups - a high variance and a low variance for each lab variable). We then performed a PheWAS analysis with ICD-9 diagnosis codes, separately in the high variance group and the low variance group for each lab variable. We found 717 PheWAS associations that replicated at a p-value less than 0.001. Next, we evaluated the results of this study by comparing the association results between the high and low variance groups. For example, we found 39 SNPs (in multiple genes) associated with ICD-9 250.01 (Type-I diabetes) in patients with high variance of plasma glucose levels, but not in patients with low variance in plasma glucose levels. Another example is the association of 4 SNPs in UMOD with chronic kidney disease in patients with high variance for aspartate aminotransferase (discovery p-value: 8.71×10-09 and replication p-value: 2.03×10-06). In general, we see a pattern of many more statistically significant associations from patients with high variance in the quantitative lab variables, in comparison with the low variance group across all of the 25 laboratory measurements. This study is one of the first of its kind to utilize quantitative trait variance from longitudinal laboratory data to find associations among genetic variants and clinical phenotypes obtained from an EHR, integrating laboratory values and diagnosis codes to understand the genetic complexities of common diseases.

Parallel Grand Canonical Monte Carlo (ParaGrandMC) Simulation Code

NASA Technical Reports Server (NTRS)

Yamakov, Vesselin I.

2016-01-01

This report provides an overview of the Parallel Grand Canonical Monte Carlo (ParaGrandMC) simulation code. This is a highly scalable parallel FORTRAN code for simulating the thermodynamic evolution of metal alloy systems at the atomic level, and predicting the thermodynamic state, phase diagram, chemical composition and mechanical properties. The code is designed to simulate multi-component alloy systems, predict solid-state phase transformations such as austenite-martensite transformations, precipitate formation, recrystallization, capillary effects at interfaces, surface absorption, etc., which can aid the design of novel metallic alloys. While the software is mainly tailored for modeling metal alloys, it can also be used for other types of solid-state systems, and to some degree for liquid or gaseous systems, including multiphase systems forming solid-liquid-gas interfaces.

GENET note no. 1

NASA Technical Reports Server (NTRS)

Yeh, J. W.

1971-01-01

The general features of the GENET system for simulating networks are described. A set of features is presented which are desirable for network simulations and which are expected to be achieved by this system. Among these features are: (1) two level network modeling; and (2) problem oriented operations. Several typical network systems are modeled in GENET framework to illustrate various of the features and to show its applicability.

Real-time data compression of broadcast video signals

NASA Technical Reports Server (NTRS)

Shalkauser, Mary Jo W. (Inventor); Whyte, Wayne A., Jr. (Inventor); Barnes, Scott P. (Inventor)

1991-01-01

A non-adaptive predictor, a nonuniform quantizer, and a multi-level Huffman coder are incorporated into a differential pulse code modulation system for coding and decoding broadcast video signals in real time.

Changes in the Coding and Non-coding Transcriptome and DNA Methylome that Define the Schwann Cell Repair Phenotype after Nerve Injury.

PubMed

Arthur-Farraj, Peter J; Morgan, Claire C; Adamowicz, Martyna; Gomez-Sanchez, Jose A; Fazal, Shaline V; Beucher, Anthony; Razzaghi, Bonnie; Mirsky, Rhona; Jessen, Kristjan R; Aitman, Timothy J

2017-09-12

Repair Schwann cells play a critical role in orchestrating nerve repair after injury, but the cellular and molecular processes that generate them are poorly understood. Here, we perform a combined whole-genome, coding and non-coding RNA and CpG methylation study following nerve injury. We show that genes involved in the epithelial-mesenchymal transition are enriched in repair cells, and we identify several long non-coding RNAs in Schwann cells. We demonstrate that the AP-1 transcription factor C-JUN regulates the expression of certain micro RNAs in repair Schwann cells, in particular miR-21 and miR-34. Surprisingly, unlike during development, changes in CpG methylation are limited in injury, restricted to specific locations, such as enhancer regions of Schwann cell-specific genes (e.g., Nedd4l), and close to local enrichment of AP-1 motifs. These genetic and epigenomic changes broaden our mechanistic understanding of the formation of repair Schwann cell during peripheral nervous system tissue repair. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Dichotomy in the definition of prescriptive information suggests both prescribed data and prescribed algorithms: biosemiotics applications in genomic systems.

PubMed

D'Onofrio, David J; Abel, David L; Johnson, Donald E

2012-03-14

The fields of molecular biology and computer science have cooperated over recent years to create a synergy between the cybernetic and biosemiotic relationship found in cellular genomics to that of information and language found in computational systems. Biological information frequently manifests its "meaning" through instruction or actual production of formal bio-function. Such information is called prescriptive information (PI). PI programs organize and execute a prescribed set of choices. Closer examination of this term in cellular systems has led to a dichotomy in its definition suggesting both prescribed data and prescribed algorithms are constituents of PI. This paper looks at this dichotomy as expressed in both the genetic code and in the central dogma of protein synthesis. An example of a genetic algorithm is modeled after the ribosome, and an examination of the protein synthesis process is used to differentiate PI data from PI algorithms.

Preliminary Classification of Army and Navy Entry-Level Occupations by the Holland Coding System.

DTIC Science & Technology

1986-12-01

Dictionary of Holland Occupational Codes (DOHC; see Gottfredson , Holland, & Ogawa, 1982) either directly or through expert judgment. Results...publications: The Dictionary of Holland Occupational Codes (DHOC; Gottfredson , Holland, & Ogawa, 192) and The Occupations Finder (Holland, 1978). The...occupational categories ( Gottfredson et al., 1982). The agreement between the first letters codes obtained from the 1977 Occupations Finder and the

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.

Concatenated coding for low date rate space communications.

NASA Technical Reports Server (NTRS)

Chen, C. H.

1972-01-01

In deep space communications with distant planets, the data rate as well as the operating SNR may be very low. To maintain the error rate also at a very low level, it is necessary to use a sophisticated coding system (longer code) without excessive decoding complexity. The concatenated coding has been shown to meet such requirements in that the error rate decreases exponentially with the overall length of the code while the decoder complexity increases only algebraically. Three methods of concatenating an inner code with an outer code are considered. Performance comparison of the three concatenated codes is made.

Blood pressure regulation via the epithelial sodium channel: from gene to kidney and beyond.

PubMed

Büsst, Cara J

2013-08-01

The epithelial sodium channel (ENaC) has long been recognized as playing a vital role in blood pressure (BP) regulation due to its involvement in fluid balance. The genes encoding the three ENaC subunits are likewise important contributors to hypertension, both in rare monogenic diseases and in the general population. The unusually high numbers of genetic variants associated with complex traits, including BP, that are located in non-coding areas suggest an involvement of these variants in regulatory functions. This may involve differential regulation of expression in different tissues. Emerging evidence indicates that the ENaC plays an important role in BP determination not only via its actions in the kidney, but also in other tissues commonly involved in BP regulation. The ENaC in the central nervous system is proposed to regulate BP via sympathetic nervous system activity. Recent evidence suggests that the ENaC contributes to vascular function and the myogenic response. Additional roles potentially include initiation of the baroreceptor reflex via ENaC in the baroreceptors and driving high salt intake with a 'taste for salt' via ENaC in the tongue. The present review describes the involvement of the ENaC in the determination of BP at a genetic and physiological level, detailing recent evidence for its role in the kidney and in other pertinent tissues. © 2013 Wiley Publishing Asia Pty Ltd.

Endogenous voltage gradients as mediators of cell-cell communication: strategies for investigating bioelectrical signals during pattern formation

PubMed Central

Adams, Dany S.; Levin, Michael

2013-01-01

Alongside the well-known chemical modes of cell-cell communication, we find an important and powerful system of bioelectrical signaling: changes in the resting voltage potential (Vmem) of the plasma membrane driven by ion channels, pumps and gap junctions. Slow Vmem changes in all cells serve as a highly conserved, information-bearing pathway that regulates cell proliferation, migration and differentiation. In embryonic and regenerative pattern formation and in the disorganization of neoplasia, bioelectrical cues serve as mediators of large-scale anatomical polarity, organ identity and positional information. Recent developments have resulted in tools that enable a high-resolution analysis of these biophysical signals and their linkage with upstream and downstream canonical genetic pathways. Here, we provide an overview for the study of bioelectric signaling, focusing on state-of-the-art approaches that use molecular physiology and developmental genetics to probe the roles of bioelectric events functionally. We highlight the logic, strategies and well-developed technologies that any group of researchers can employ to identify and dissect ionic signaling components in their own work and thus to help crack the bioelectric code. The dissection of bioelectric events as instructive signals enabling the orchestration of cell behaviors into large-scale coherent patterning programs will enrich on-going work in diverse areas of biology, as biophysical factors become incorporated into our systems-level understanding of cell interactions. PMID:22350846

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

Assume-Guarantee Verification of Source Code with Design-Level Assumptions

NASA Technical Reports Server (NTRS)

Giannakopoulou, Dimitra; Pasareanu, Corina S.; Cobleigh, Jamieson M.

2004-01-01

Model checking is an automated technique that can be used to determine whether a system satisfies certain required properties. To address the 'state explosion' problem associated with this technique, we propose to integrate assume-guarantee verification at different phases of system development. During design, developers build abstract behavioral models of the system components and use them to establish key properties of the system. To increase the scalability of model checking at this level, we have developed techniques that automatically decompose the verification task by generating component assumptions for the properties to hold. The design-level artifacts are subsequently used to guide the implementation of the system, but also to enable more efficient reasoning at the source code-level. In particular we propose to use design-level assumptions to similarly decompose the verification of the actual system implementation. We demonstrate our approach on a significant NASA application, where design-level models were used to identify; and correct a safety property violation, and design-level assumptions allowed us to check successfully that the property was presented by the implementation.

Pragmatic turn in biology: From biological molecules to genetic content operators.

PubMed

Witzany, Guenther

2014-08-26

Erwin Schrödinger's question "What is life?" received the answer for decades of "physics + chemistry". The concepts of Alain Turing and John von Neumann introduced a third term: "information". This led to the understanding of nucleic acid sequences as a natural code. Manfred Eigen adapted the concept of Hammings "sequence space". Similar to Hilbert space, in which every ontological entity could be defined by an unequivocal point in a mathematical axiomatic system, in the abstract "sequence space" concept each point represents a unique syntactic structure and the value of their separation represents their dissimilarity. In this concept molecular features of the genetic code evolve by means of self-organisation of matter. Biological selection determines the fittest types among varieties of replication errors of quasi-species. The quasi-species concept dominated evolution theory for many decades. In contrast to this, recent empirical data on the evolution of DNA and its forerunners, the RNA-world and viruses indicate cooperative agent-based interactions. Group behaviour of quasi-species consortia constitute de novo and arrange available genetic content for adaptational purposes within real-life contexts that determine epigenetic markings. This review focuses on some fundamental changes in biology, discarding its traditional status as a subdiscipline of physics and chemistry.

Interactive searching of facial image databases

NASA Astrophysics Data System (ADS)

Nicholls, Robert A.; Shepherd, John W.; Shepherd, Jean

1995-09-01

A set of psychological facial descriptors has been devised to enable computerized searching of criminal photograph albums. The descriptors have been used to encode image databased of up to twelve thousand images. Using a system called FACES, the databases are searched by translating a witness' verbal description into corresponding facial descriptors. Trials of FACES have shown that this coding scheme is more productive and efficient than searching traditional photograph albums. An alternative method of searching the encoded database using a genetic algorithm is currenly being tested. The genetic search method does not require the witness to verbalize a description of the target but merely to indicate a degree of similarity between the target and a limited selection of images from the database. The major drawback of FACES is that is requires a manual encoding of images. Research is being undertaken to automate the process, however, it will require an algorithm which can predict human descriptive values. Alternatives to human derived coding schemes exist using statistical classifications of images. Since databases encoded using statistical classifiers do not have an obvious direct mapping to human derived descriptors, a search method which does not require the entry of human descriptors is required. A genetic search algorithm is being tested for such a purpose.

Antibiotics reduce genetic diversity of core species in the honeybee gut microbiome.

PubMed

Raymann, Kasie; Bobay, Louis-Marie; Moran, Nancy A

2018-04-01

The gut microbiome plays a key role in animal health, and perturbing it can have detrimental effects. One major source of perturbation to microbiomes, in humans and human-associated animals, is exposure to antibiotics. Most studies of how antibiotics affect the microbiome have used amplicon sequencing of highly conserved 16S rRNA sequences, as in a recent study showing that antibiotic treatment severely alters the species-level composition of the honeybee gut microbiome. But because the standard 16S rRNA-based methods cannot resolve closely related strains, strain-level changes could not be evaluated. To address this gap, we used amplicon sequencing of protein-coding genes to assess effects of antibiotics on fine-scale genetic diversity of the honeybee gut microbiota. We followed the population dynamics of alleles within two dominant core species of the bee gut community, Gilliamella apicola and Snodgrassella alvi, following antibiotic perturbation. Whereas we observed a large reduction in genetic diversity in G. apicola, S. alvi diversity was mostly unaffected. The reduction in G. apicola diversity accompanied an increase in the frequency of several alleles, suggesting resistance to antibiotic treatment. We find that antibiotic perturbation can cause major shifts in diversity and that the extent of these shifts can vary substantially across species. Thus, antibiotics impact not only species composition, but also allelic diversity within species, potentially affecting hosts if variants with particular functions are reduced or eliminated. Overall, we show that amplicon sequencing of protein-coding genes, without clustering into operational taxonomic units, provides an accurate picture of the fine-scale dynamics of microbial communities over time. © 2017 John Wiley & Sons Ltd.

Nutrigenetics and modulation of oxidative stress.

PubMed

Da Costa, Laura A; Badawi, Alaa; El-Sohemy, Ahmed

2012-01-01

Oxidative stress develops as a result of an imbalance between the production and accumulation of reactive species and the body's ability to manage them using exogenous and endogenous antioxidants. Exogenous antioxidants obtained from the diet, including vitamin C, vitamin E, and carotenoids, have important roles in preventing and reducing oxidative stress. Individual genetic variation affecting proteins involved in the uptake, utilization and metabolism of these antioxidants may alter their serum levels, exposure to target cells and subsequent contribution to the extent of oxidative stress. Endogenous antioxidants include the antioxidant enzymes superoxide dismutase, catalase, glutathione peroxidase, paraoxanase, and glutathione S-transferase. These enzymes metabolize reactive species and their by-products, reducing oxidative stress. Variation in the genes coding these enzymes may impact their enzymatic antioxidant activity and, thus, the levels of reactive species, oxidative stress, and risk of disease development. Oxidative stress may contribute to the development of chronic disease, including osteoporosis, type 2 diabetes, neurodegenerative diseases, cardiovascular disease, and cancer. Indeed, polymorphisms in most of the genes that code for antioxidant enzymes have been associated with several types of cancer, although inconsistent findings between studies have been reported. These inconsistencies may, in part, be explained by interactions with the environment, such as modification by diet. In this review, we highlight some of the recent studies in the field of nutrigenetics, which have examined interactions between diet, genetic variation in antioxidant enzymes, and oxidative stress. Copyright © 2012 S. Karger AG, Basel.

Double silencing of relevant genes suggests the existence of the direct link between DNA replication/repair and central carbon metabolism in human fibroblasts.

PubMed

Wieczorek, Aneta; Fornalewicz, Karolina; Mocarski, Łukasz; Łyżeń, Robert; Węgrzyn, Grzegorz

2018-04-15

Genetic evidence for a link between DNA replication and glycolysis has been demonstrated a decade ago in Bacillus subtilis, where temperature-sensitive mutations in genes coding for replication proteins could be suppressed by mutations in genes of glycolytic enzymes. Then, a strong influence of dysfunctions of particular enzymes from the central carbon metabolism (CCM) on DNA replication and repair in Escherichia coli was reported. Therefore, we asked if such a link occurs only in bacteria or it is a more general phenomenon. Here, we demonstrate that effects of silencing (provoked by siRNA) of expression of genes coding for proteins involved in DNA replication and repair (primase, DNA polymerase ι, ligase IV, and topoisomerase IIIβ) on these processes (less efficient entry into the S phase of the cell cycle and decreased level of DNA synthesis) could be suppressed by silencing of specific genes of enzymes from CMM. Silencing of other pairs of replication/repair and CMM genes resulted in enhancement of the negative effects of lower expression levels of replication/repair genes. We suggest that these results may be proposed as a genetic evidence for the link between DNA replication/repair and CMM in human cells, indicating that it is a common biological phenomenon, occurring from bacteria to humans. Copyright © 2018 Elsevier B.V. All rights reserved.

Genotyping of single spore isolates of a Pasteuria penetrans population occurring in Florida using SNP-based markers.

PubMed

Joseph, S; Schmidt, L M; Danquah, W B; Timper, P; Mekete, T

2017-02-01

To generate single spore lines of a population of bacterial parasite of root-knot nematode (RKN), Pasteuria penetrans, isolated from Florida and examine genotypic variation and virulence characteristics exist within the population. Six single spore lines (SSP), 16SSP, 17SSP, 18SSP, 25SSP, 26SSP and 30SSP were generated. Genetic variability was evaluated by comparing single-nucleotide polymorphisms (SNPs) in six protein-coding genes and the 16S rRNA gene. An average of one SNP was observed for every 69 bp in the 16S rRNA, whereas no SNPs were observed in the protein-coding sequences. Hierarchical cluster analysis of 16S rRNA sequences placed the clones into three distinct clades. Bio-efficacy analysis revealed significant heterogeneity in the level virulence and host specificity between the individual clones. The SNP markers developed to the 5' hypervariable region of the 16S rRNA gene may be useful in biotype differentiation within a population of P. penetrans. This study demonstrates an efficient method for generating single spore lines of P. penetrans and gives a deep insight into genetic heterogeneity and varying level of virulence exists within a population parasitizing a specific Meloidogyne sp. host. The results also suggest that the application of generalist spore lines in nematode management may achieve broad RKN control. © 2016 The Society for Applied Microbiology.

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

Thermal hydraulic-severe accident code interfaces for SCDAP/RELAP5/MOD3.2

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

Coryell, E.W.; Siefken, L.J.; Harvego, E.A.

1997-07-01

The SCDAP/RELAP5 computer code is designed to describe the overall reactor coolant system thermal-hydraulic response, core damage progression, and fission product release during severe accidents. The code is being developed at the Idaho National Engineering Laboratory under the primary sponsorship of the Office of Nuclear Regulatory Research of the U.S. Nuclear Regulatory Commission. The code is the result of merging the RELAP5, SCDAP, and COUPLE codes. The RELAP5 portion of the code calculates the overall reactor coolant system, thermal-hydraulics, and associated reactor system responses. The SCDAP portion of the code describes the response of the core and associated vessel structures.more » The COUPLE portion of the code describes response of lower plenum structures and debris and the failure of the lower head. The code uses a modular approach with the overall structure, input/output processing, and data structures following the pattern established for RELAP5. The code uses a building block approach to allow the code user to easily represent a wide variety of systems and conditions through a powerful input processor. The user can represent a wide variety of experiments or reactor designs by selecting fuel rods and other assembly structures from a range of representative core component models, and arrange them in a variety of patterns within the thermalhydraulic network. The COUPLE portion of the code uses two-dimensional representations of the lower plenum structures and debris beds. The flow of information between the different portions of the code occurs at each system level time step advancement. The RELAP5 portion of the code describes the fluid transport around the system. These fluid conditions are used as thermal and mass transport boundary conditions for the SCDAP and COUPLE structures and debris beds.« less

The partitioning and copy number control systems of the selfish yeast plasmid: an optimized molecular design for stable persistence in host cells

PubMed Central

Yen-Ting-Liu; Sau, Saumitra; Ma, Chien-Hui; Kachroo, Aashiq H; Rowley, Paul A; Chang, Keng-Ming; Fan, Hsiu-Fang; Jayaram, Makkuni

2014-01-01

Summary The multi-copy 2 micron plasmid of Saccharomyces cerevisiae, a resident of the nucleus, is remarkable for its high chromosome-like stability. The plasmid does not appear to contribute to the fitness of the host, nor does it impose a significant metabolic burden on the host at its steady state copy number. The plasmid may be viewed as a highly optimized selfish DNA element whose genome design is devoted entirely towards efficient replication, equal segregation and copy number maintenance. A partitioning system comprised of two plasmid coded proteins, Rep1 and Rep2, and a partitioning locus STB is responsible for equal or nearly equal segregation of plasmid molecules to mother and daughter cells. Current evidence supports a model in which the Rep-STB system promotes the physical association of the plasmid with chromosomes and thus plasmid segregation by a hitchhiking mechanism. The Flp site-specific recombination system housed by the plasmid plays a critical role in maintaining steady state plasmid copy number. A decrease in plasmid population due to rare missegregation events is rectified by plasmid amplification via a recombination induced rolling circle replication mechanism. Appropriate plasmid amplification, without runaway increase in copy number, is ensured by positive and negative regulation of FLP gene expression by plasmid coded proteins and by the control of Flp level/activity through host mediated post-translational modification(s) of Flp. The Flp system has been successfully utilized to understand mechanisms of site-specific recombination, to bring about directed genetic alterations for addressing fundamental problems in biology, and as a tool in biotechnological applications. PMID:25541598

The partitioning and copy number control systems of the selfish yeast plasmid: an optimized molecular design for stable persistence in host cells.

PubMed

Yen-Ting-Liu; Sau, Saumitra; Ma, Chien-Hui; Kachroo, Aashiq H; Rowley, Paul A; Chang, Keng-Ming; Fan, Hsiu-Fang; Jayaram, Makkuni

2014-10-01

The multi-copy 2 micron plasmid of Saccharomyces cerevisiae, a resident of the nucleus, is remarkable for its high chromosome-like stability. The plasmid does not appear to contribute to the fitness of the host, nor does it impose a significant metabolic burden on the host at its steady state copy number. The plasmid may be viewed as a highly optimized selfish DNA element whose genome design is devoted entirely towards efficient replication, equal segregation and copy number maintenance. A partitioning system comprised of two plasmid coded proteins, Rep1 and Rep2, and a partitioning locus STB is responsible for equal or nearly equal segregation of plasmid molecules to mother and daughter cells. Current evidence supports a model in which the Rep-STB system promotes the physical association of the plasmid with chromosomes and thus plasmid segregation by a hitchhiking mechanism. The Flp site-specific recombination system housed by the plasmid plays a critical role in maintaining steady state plasmid copy number. A decrease in plasmid population due to rare missegregation events is rectified by plasmid amplification via a recombination induced rolling circle replication mechanism. Appropriate plasmid amplification, without runaway increase in copy number, is ensured by positive and negative regulation of FLP gene expression by plasmid coded proteins and by the control of Flp level/activity through host mediated post-translational modification(s) of Flp. The Flp system has been successfully utilized to understand mechanisms of site-specific recombination, to bring about directed genetic alterations for addressing fundamental problems in biology, and as a tool in biotechnological applications.

New knowledge-based genetic algorithm for excavator boom structural optimization

NASA Astrophysics Data System (ADS)

Hua, Haiyan; Lin, Shuwen

2014-03-01

Due to the insufficiency of utilizing knowledge to guide the complex optimal searching, existing genetic algorithms fail to effectively solve excavator boom structural optimization problem. To improve the optimization efficiency and quality, a new knowledge-based real-coded genetic algorithm is proposed. A dual evolution mechanism combining knowledge evolution with genetic algorithm is established to extract, handle and utilize the shallow and deep implicit constraint knowledge to guide the optimal searching of genetic algorithm circularly. Based on this dual evolution mechanism, knowledge evolution and population evolution can be connected by knowledge influence operators to improve the configurability of knowledge and genetic operators. Then, the new knowledge-based selection operator, crossover operator and mutation operator are proposed to integrate the optimal process knowledge and domain culture to guide the excavator boom structural optimization. Eight kinds of testing algorithms, which include different genetic operators, are taken as examples to solve the structural optimization of a medium-sized excavator boom. By comparing the results of optimization, it is shown that the algorithm including all the new knowledge-based genetic operators can more remarkably improve the evolutionary rate and searching ability than other testing algorithms, which demonstrates the effectiveness of knowledge for guiding optimal searching. The proposed knowledge-based genetic algorithm by combining multi-level knowledge evolution with numerical optimization provides a new effective method for solving the complex engineering optimization problem.

SGO: A fast engine for ab initio atomic structure global optimization by differential evolution

NASA Astrophysics Data System (ADS)

Chen, Zhanghui; Jia, Weile; Jiang, Xiangwei; Li, Shu-Shen; Wang, Lin-Wang

2017-10-01

As the high throughout calculations and material genome approaches become more and more popular in material science, the search for optimal ways to predict atomic global minimum structure is a high research priority. This paper presents a fast method for global search of atomic structures at ab initio level. The structures global optimization (SGO) engine consists of a high-efficiency differential evolution algorithm, accelerated local relaxation methods and a plane-wave density functional theory code running on GPU machines. The purpose is to show what can be achieved by combining the superior algorithms at the different levels of the searching scheme. SGO can search the global-minimum configurations of crystals, two-dimensional materials and quantum clusters without prior symmetry restriction in a relatively short time (half or several hours for systems with less than 25 atoms), thus making such a task a routine calculation. Comparisons with other existing methods such as minima hopping and genetic algorithm are provided. One motivation of our study is to investigate the properties of magnetic systems in different phases. The SGO engine is capable of surveying the local minima surrounding the global minimum, which provides the information for the overall energy landscape of a given system. Using this capability we have found several new configurations for testing systems, explored their energy landscape, and demonstrated that the magnetic moment of metal clusters fluctuates strongly in different local minima.

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.

Long distance quantum communication with quantum Reed-Solomon codes

NASA Astrophysics Data System (ADS)

Muralidharan, Sreraman; Zou, Chang-Ling; Li, Linshu; Jiang, Liang; Jianggroup Team

We study the construction of quantum Reed Solomon codes from classical Reed Solomon codes and show that they achieve the capacity of quantum erasure channel for multi-level quantum systems. We extend the application of quantum Reed Solomon codes to long distance quantum communication, investigate the local resource overhead needed for the functioning of one-way quantum repeaters with these codes, and numerically identify the parameter regime where these codes perform better than the known quantum polynomial codes and quantum parity codes . Finally, we discuss the implementation of these codes into time-bin photonic states of qubits and qudits respectively, and optimize the performance for one-way quantum repeaters.

38. DETAIL OF CYLINDER LEVELING SYSTEM SHOWING TYPICAL UPPER AND ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

38. DETAIL OF CYLINDER LEVELING SYSTEM SHOWING TYPICAL UPPER AND LOWER PULLEY BRACKET. F.C. TORKELSON DRAWING NUMBER 842-ARVFS-701-S-8. INEL INDEX CODE - Idaho National Engineering Laboratory, Advanced Reentry Vehicle Fusing System, Scoville, Butte County, ID

Longevity and aging. Mechanisms and perspectives.

PubMed

Labat-Robert, J; Robert, L

2015-12-01

Longevity can mostly be determined with relative accuracy from birth and death registers when available. Aging is a multifactorial process, much more difficult to quantitate. Every measurable physiological function declines with specific speeds over a wide range. The mechanisms involved are also different, genetic factors are of importance for longevity determinations. The best-known genes involved are the Sirtuins, active at the genetic and epigenetic level. Aging is multifactorial, not "coded" in the genome. There are, however, a number of well-studied physical and biological parameters involved in aging, which can be determined and quantitated. We shall try to identify parameters affecting longevity as well as aging and suggest some reasonable predictions for the future. Copyright © 2015 Elsevier Masson SAS. 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

Genetically elevated non-fasting triglycerides and calculated remnant cholesterol as causal risk factors for myocardial infarction.

PubMed

Jørgensen, Anders Berg; Frikke-Schmidt, Ruth; West, Anders Sode; Grande, Peer; Nordestgaard, Børge G; Tybjærg-Hansen, Anne

2013-06-01

Elevated non-fasting triglycerides mark elevated levels of remnant cholesterol. Using a Mendelian randomization approach, we tested whether genetically increased remnant cholesterol in hypertriglyceridaemia due to genetic variation in the apolipoprotein A5 gene (APOA5) associates with an increased risk of myocardial infarction (MI). We resequenced the core promoter and coding regions of APOA5 in individuals with the lowest 1% (n = 95) and highest 2% (n = 190) triglyceride levels in the Copenhagen City Heart Study (CCHS, n = 10 391). Genetic variants which differed in frequency between the two extreme triglyceride groups (c.-1131T > C, S19W, and c.*31C > T; P-value: 0.06 to <0.001), thus suggesting an effect on triglyceride levels, were genotyped in the Copenhagen General Population Study (CGPS), the CCHS, and the Copenhagen Ischemic Heart Disease Study (CIHDS), comprising a total of 5705 MI cases and 54 408 controls. Genotype combinations of these common variants associated with increases in non-fasting triglycerides and calculated remnant cholesterol of, respectively, up to 68% (1.10 mmol/L) and 56% (0.40 mmol/L) (P < 0.001), and with a corresponding odds ratio for MI of 1.87 (95% confidence interval: 1.25-2.81). Using APOA5 genotypes in instrumental variable analysis, the observational hazard ratio for a doubling in non-fasting triglycerides was 1.57 (1.32-2.68) compared with a causal genetic odds ratio of 1.94 (1.40-1.85) (P for comparison = 0.28). For calculated remnant cholesterol, the corresponding values were 1.67(1.38-2.02) observational and 2.23(1.48-3.35) causal (P for comparison = 0.21). These data are consistent with a causal association between elevated levels of remnant cholesterol in hypertriglyceridaemia and an increased risk of MI. Limitations include that remnants were not measured directly, and that APOA5 genetic variants may influence other lipoprotein parameters.

Holonomic surface codes for fault-tolerant quantum computation

NASA Astrophysics Data System (ADS)

Zhang, Jiang; Devitt, Simon J.; You, J. Q.; Nori, Franco

2018-02-01

Surface codes can protect quantum information stored in qubits from local errors as long as the per-operation error rate is below a certain threshold. Here we propose holonomic surface codes by harnessing the quantum holonomy of the system. In our scheme, the holonomic gates are built via auxiliary qubits rather than the auxiliary levels in multilevel systems used in conventional holonomic quantum computation. The key advantage of our approach is that the auxiliary qubits are in their ground state before and after each gate operation, so they are not involved in the operation cycles of surface codes. This provides an advantageous way to implement surface codes for fault-tolerant quantum computation.

Genetic algorithm with maximum-minimum crossover (GA-MMC) applied in optimization of radiation pattern control of phased-array radars for rocket tracking systems.

PubMed

Silva, Leonardo W T; Barros, Vitor F; Silva, Sandro G

2014-08-18

In launching operations, Rocket Tracking Systems (RTS) process the trajectory data obtained by radar sensors. In order to improve functionality and maintenance, radars can be upgraded by replacing antennas with parabolic reflectors (PRs) with phased arrays (PAs). These arrays enable the electronic control of the radiation pattern by adjusting the signal supplied to each radiating element. However, in projects of phased array radars (PARs), the modeling of the problem is subject to various combinations of excitation signals producing a complex optimization problem. In this case, it is possible to calculate the problem solutions with optimization methods such as genetic algorithms (GAs). For this, the Genetic Algorithm with Maximum-Minimum Crossover (GA-MMC) method was developed to control the radiation pattern of PAs. The GA-MMC uses a reconfigurable algorithm with multiple objectives, differentiated coding and a new crossover genetic operator. This operator has a different approach from the conventional one, because it performs the crossover of the fittest individuals with the least fit individuals in order to enhance the genetic diversity. Thus, GA-MMC was successful in more than 90% of the tests for each application, increased the fitness of the final population by more than 20% and reduced the premature convergence.

Genetic Algorithm with Maximum-Minimum Crossover (GA-MMC) Applied in Optimization of Radiation Pattern Control of Phased-Array Radars for Rocket Tracking Systems

PubMed Central

Silva, Leonardo W. T.; Barros, Vitor F.; Silva, Sandro G.

2014-01-01

In launching operations, Rocket Tracking Systems (RTS) process the trajectory data obtained by radar sensors. In order to improve functionality and maintenance, radars can be upgraded by replacing antennas with parabolic reflectors (PRs) with phased arrays (PAs). These arrays enable the electronic control of the radiation pattern by adjusting the signal supplied to each radiating element. However, in projects of phased array radars (PARs), the modeling of the problem is subject to various combinations of excitation signals producing a complex optimization problem. In this case, it is possible to calculate the problem solutions with optimization methods such as genetic algorithms (GAs). For this, the Genetic Algorithm with Maximum-Minimum Crossover (GA-MMC) method was developed to control the radiation pattern of PAs. The GA-MMC uses a reconfigurable algorithm with multiple objectives, differentiated coding and a new crossover genetic operator. This operator has a different approach from the conventional one, because it performs the crossover of the fittest individuals with the least fit individuals in order to enhance the genetic diversity. Thus, GA-MMC was successful in more than 90% of the tests for each application, increased the fitness of the final population by more than 20% and reduced the premature convergence. PMID:25196013

Research on Formation of Microsatellite Communication with Genetic Algorithm

PubMed Central

Wu, Guoqiang; Bai, Yuguang; Sun, Zhaowei

2013-01-01

For the formation of three microsatellites which fly in the same orbit and perform three-dimensional solid mapping for terra, this paper proposes an optimizing design method of space circular formation order based on improved generic algorithm and provides an intersatellite direct spread spectrum communication system. The calculating equation of LEO formation flying satellite intersatellite links is guided by the special requirements of formation-flying microsatellite intersatellite links, and the transmitter power is also confirmed throughout the simulation. The method of space circular formation order optimizing design based on improved generic algorithm is given, and it can keep formation order steady for a long time under various absorb impetus. The intersatellite direct spread spectrum communication system is also provided. It can be found that, when the distance is 1 km and the data rate is 1 Mbps, the input wave matches preferably with the output wave. And LDPC code can improve the communication performance. The correct capability of (512, 256) LDPC code is better than (2, 1, 7) convolution code, distinctively. The design system can satisfy the communication requirements of microsatellites. So, the presented method provides a significant theory foundation for formation-flying and intersatellite communication. PMID:24078796

Research on formation of microsatellite communication with genetic algorithm.

PubMed

Wu, Guoqiang; Bai, Yuguang; Sun, Zhaowei

2013-01-01

For the formation of three microsatellites which fly in the same orbit and perform three-dimensional solid mapping for terra, this paper proposes an optimizing design method of space circular formation order based on improved generic algorithm and provides an intersatellite direct spread spectrum communication system. The calculating equation of LEO formation flying satellite intersatellite links is guided by the special requirements of formation-flying microsatellite intersatellite links, and the transmitter power is also confirmed throughout the simulation. The method of space circular formation order optimizing design based on improved generic algorithm is given, and it can keep formation order steady for a long time under various absorb impetus. The intersatellite direct spread spectrum communication system is also provided. It can be found that, when the distance is 1 km and the data rate is 1 Mbps, the input wave matches preferably with the output wave. And LDPC code can improve the communication performance. The correct capability of (512, 256) LDPC code is better than (2, 1, 7) convolution code, distinctively. The design system can satisfy the communication requirements of microsatellites. So, the presented method provides a significant theory foundation for formation-flying and intersatellite communication.

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

An Adaptive Source-Channel Coding with Feedback for Progressive Transmission of Medical Images

PubMed Central

Lo, Jen-Lung; Sanei, Saeid; Nazarpour, Kianoush

2009-01-01

A novel adaptive source-channel coding with feedback for progressive transmission of medical images is proposed here. In the source coding part, the transmission starts from the region of interest (RoI). The parity length in the channel code varies with respect to both the proximity of the image subblock to the RoI and the channel noise, which is iteratively estimated in the receiver. The overall transmitted data can be controlled by the user (clinician). In the case of medical data transmission, it is vital to keep the distortion level under control as in most of the cases certain clinically important regions have to be transmitted without any visible error. The proposed system significantly reduces the transmission time and error. Moreover, the system is very user friendly since the selection of the RoI, its size, overall code rate, and a number of test features such as noise level can be set by the users in both ends. A MATLAB-based TCP/IP connection has been established to demonstrate the proposed interactive and adaptive progressive transmission system. The proposed system is simulated for both binary symmetric channel (BSC) and Rayleigh channel. The experimental results verify the effectiveness of the design. PMID:19190770

A good performance watermarking LDPC code used in high-speed optical fiber communication system

NASA Astrophysics Data System (ADS)

Zhang, Wenbo; Li, Chao; Zhang, Xiaoguang; Xi, Lixia; Tang, Xianfeng; He, Wenxue

2015-07-01

A watermarking LDPC code, which is a strategy designed to improve the performance of the traditional LDPC code, was introduced. By inserting some pre-defined watermarking bits into original LDPC code, we can obtain a more correct estimation about the noise level in the fiber channel. Then we use them to modify the probability distribution function (PDF) used in the initial process of belief propagation (BP) decoding algorithm. This algorithm was tested in a 128 Gb/s PDM-DQPSK optical communication system and results showed that the watermarking LDPC code had a better tolerances to polarization mode dispersion (PMD) and nonlinearity than that of traditional LDPC code. Also, by losing about 2.4% of redundancy for watermarking bits, the decoding efficiency of the watermarking LDPC code is about twice of the traditional one.

From Physics Model to Results: An Optimizing Framework for Cross-Architecture Code Generation

DOE PAGES

Blazewicz, Marek; Hinder, Ian; Koppelman, David M.; ...

2013-01-01

Starting from a high-level problem description in terms of partial differential equations using abstract tensor notation, the Chemora framework discretizes, optimizes, and generates complete high performance codes for a wide range of compute architectures. Chemora extends the capabilities of Cactus, facilitating the usage of large-scale CPU/GPU systems in an efficient manner for complex applications, without low-level code tuning. Chemora achieves parallelism through MPI and multi-threading, combining OpenMP and CUDA. Optimizations include high-level code transformations, efficient loop traversal strategies, dynamically selected data and instruction cache usage strategies, and JIT compilation of GPU code tailored to the problem characteristics. The discretization ismore » based on higher-order finite differences on multi-block domains. Chemora's capabilities are demonstrated by simulations of black hole collisions. This problem provides an acid test of the framework, as the Einstein equations contain hundreds of variables and thousands of terms.« less

Structuring and coding in health care records: a qualitative analysis using diabetes as a case study.

PubMed

Robertson, Ann R R; Fernando, Bernard; Morrison, Zoe; Kalra, Dipak; Sheikh, Aziz

2015-03-27

Globally, diabetes mellitus presents a substantial and increasing burden to individuals, health care systems and society. Structuring and coding of information in the electronic health record underpin attempts to improve sharing and searching for information. Digital records for those with long-term conditions are expected to bring direct and secondary uses benefits, and potentially to support patient self-management. We sought to investigate if how and why records for adults with diabetes were structured and coded and to explore a range of UK stakeholders' perceptions of current practice in the National Health Service. We carried out a qualitative, theoretically informed case study of documenting health care information for diabetes in family practice and hospital settings in England, using semi-structured interviews, observations, systems demonstrations and documentary data. We conducted 22 interviews and four on-site observations. With respect to secondary uses - research, audit, public health and service planning - interviewees clearly articulated the benefits of highly structured and coded diabetes data and it was believed that benefits would expand through linkage to other datasets. Direct, more marginal, clinical benefits in terms of managing and monitoring diabetes and perhaps encouraging patient self-management were also reported. We observed marked differences in levels of record structuring and/or coding between family practices, where it was high, and the hospital. We found little evidence that structured and coded data were being exploited to improve information sharing between care settings. Using high levels of data structuring and coding in records for diabetes patients has the potential to be exploited more fully, and lessons might be learned from successful developments elsewhere in the UK. A first step would be for hospitals to attain levels of health information technology infrastructure and systems use commensurate with family practices.

The Role of Ontologies in Schema-based Program Synthesis

NASA Technical Reports Server (NTRS)

Bures, Tomas; Denney, Ewen; Fischer, Bernd; Nistor, Eugen C.

2004-01-01

Program synthesis is the process of automatically deriving executable code from (non-executable) high-level specifications. It is more flexible and powerful than conventional code generation techniques that simply translate algorithmic specifications into lower-level code or only create code skeletons from structural specifications (such as UML class diagrams). Key to building a successful synthesis system is specializing to an appropriate application domain. The AUTOBAYES and AUTOFILTER systems, under development at NASA Ames, operate in the two domains of data analysis and state estimation, respectively. The central concept of both systems is the schema, a representation of reusable computational knowledge. This can take various forms, including high-level algorithm templates, code optimizations, datatype refinements, or architectural information. A schema also contains applicability conditions that are used to determine when it can be applied safely. These conditions can refer to the initial specification, to intermediate results, or to elements of the partially-instantiated code. Schema-based synthesis uses AI technology to recursively apply schemas to gradually refine a specification into executable code. This process proceeds in two main phases. A front-end gradually transforms the problem specification into a program represented in an abstract intermediate code. A backend then compiles this further down into a concrete target programming language of choice. A core engine applies schemas on the initial problem specification, then uses the output of those schemas as the input for other schemas, until the full implementation is generated. Since there might be different schemas that implement different solutions to the same problem this process can generate an entire solution tree. AUTOBAYES and AUTOFILTER have reached the level of maturity where they enable users to solve interesting application problems, e.g., the analysis of Hubble Space Telescope images. They are large (in total around 100kLoC Prolog), knowledge intensive systems that employ complex symbolic reasoning to generate a wide range of non-trivial programs for complex application do- mains. Their schemas can have complex interactions, which make it hard to change them in isolation or even understand what an existing schema actually does. Adding more capabilities by increasing the number of schemas will only worsen this situation, ultimately leading to the entropy death of the synthesis system. The root came of this problem is that the domain knowledge is scattered throughout the entire system and only represented implicitly in the schema implementations. In our current work, we are addressing this problem by making explicit the knowledge from Merent parts of the synthesis system. Here; we discuss how Gruber's definition of an ontology as an explicit specification of a conceptualization matches our efforts in identifying and explicating the domain-specific concepts. We outline the dual role ontologies play in schema-based synthesis and argue that they address different audiences and serve different purposes. Their first role is descriptive: they serve as explicit documentation, and help to understand the internal structure of the system. Their second role is prescriptive: they provide the formal basis against which the other parts of the system (e.g., schemas) can be checked. Their final role is referential: ontologies also provide semantically meaningful "hooks" which allow schemas and tools to access the internal state of the program derivation process (e.g., fragments of the generated code) in domain-specific rather than language-specific terms, and thus to modify it in a controlled fashion. For discussion purposes we use AUTOLINEAR, a small synthesis system we are currently experimenting with, which can generate code for solving a system of linear equations, Az = b.

[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.

The implementation of thermal image visualization by HDL based on pseudo-color

NASA Astrophysics Data System (ADS)

Zhu, Yong; Zhang, JiangLing

2004-11-01

The pseudo-color method which maps the sampled data to intuitive perception colors is a kind of powerful visualization way. And the all-around system of pseudo-color visualization, which includes the primary principle, model and HDL (Hardware Description Language) implementation for the thermal images, is expatiated on in the paper. The thermal images whose signal is modulated as video reflect the temperature distribution of measured object, so they have the speciality of mass and real-time. The solution to the intractable problem is as follows: First, the reasonable system, i.e. the combining of global pseudo-color visualization and local special area accurate measure, muse be adopted. Then, the HDL pseudo-color algorithms in SoC (System on Chip) carry out the system to ensure the real-time. Finally, the key HDL algorithms for direct gray levels connection coding, proportional gray levels map coding and enhanced gray levels map coding are presented, and its simulation results are showed. The pseudo-color visualization of thermal images implemented by HDL in the paper has effective application in the aspect of electric power equipment test and medical health diagnosis.

Universal biology and the statistical mechanics of early life.

PubMed

Goldenfeld, Nigel; Biancalani, Tommaso; Jafarpour, Farshid

2017-12-28

All known life on the Earth exhibits at least two non-trivial common features: the canonical genetic code and biological homochirality, both of which emerged prior to the Last Universal Common Ancestor state. This article describes recent efforts to provide a narrative of this epoch using tools from statistical mechanics. During the emergence of self-replicating life far from equilibrium in a period of chemical evolution, minimal models of autocatalysis show that homochirality would have necessarily co-evolved along with the efficiency of early-life self-replicators. Dynamical system models of the evolution of the genetic code must explain its universality and its highly refined error-minimization properties. These have both been accounted for in a scenario where life arose from a collective, networked phase where there was no notion of species and perhaps even individuality itself. We show how this phase ultimately terminated during an event sometimes known as the Darwinian transition, leading to the present epoch of tree-like vertical descent of organismal lineages. These examples illustrate concrete examples of universal biology: the quest for a fundamental understanding of the basic properties of living systems, independent of precise instantiation in chemistry or other media.This article is part of the themed issue 'Reconceptualizing the origins of life'. © 2017 The Author(s).

Universal biology and the statistical mechanics of early life

NASA Astrophysics Data System (ADS)

Goldenfeld, Nigel; Biancalani, Tommaso; Jafarpour, Farshid

2017-11-01

All known life on the Earth exhibits at least two non-trivial common features: the canonical genetic code and biological homochirality, both of which emerged prior to the Last Universal Common Ancestor state. This article describes recent efforts to provide a narrative of this epoch using tools from statistical mechanics. During the emergence of self-replicating life far from equilibrium in a period of chemical evolution, minimal models of autocatalysis show that homochirality would have necessarily co-evolved along with the efficiency of early-life self-replicators. Dynamical system models of the evolution of the genetic code must explain its universality and its highly refined error-minimization properties. These have both been accounted for in a scenario where life arose from a collective, networked phase where there was no notion of species and perhaps even individuality itself. We show how this phase ultimately terminated during an event sometimes known as the Darwinian transition, leading to the present epoch of tree-like vertical descent of organismal lineages. These examples illustrate concrete examples of universal biology: the quest for a fundamental understanding of the basic properties of living systems, independent of precise instantiation in chemistry or other media. This article is part of the themed issue 'Reconceptualizing the origins of life'.

Selection signatures in four lignin genes from switchgrass populations divergently selected for in vitro dry matter digestibility

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

Chen, Shiyu; Kaeppler, Shawn M.; Vogel, Kenneth P.

Switchgrass is undergoing development as a dedicated cellulosic bioenergy crop. Fermentation of lignocellulosic biomass to ethanol in a bioenergy system or to volatile fatty acids in a livestock production system is strongly and negatively influenced by lignification of cell walls. This study detects specific loci that exhibit selection signatures across switchgrass breeding populations that differ in in vitro dry matter digestibility (IVDMD), ethanol yield, and lignin concentration. Allele frequency changes in candidate genes were used to detect loci under selection. Out of the 183 polymorphisms identified in the four candidate genes, twenty-five loci in the intron regions and four locimore » in coding regions were found to display a selection signature. All loci in the coding regions are synonymous substitutions. Selection in both directions were observed on polymorphisms that appeared to be under selection. Genetic diversity and linkage disequilibrium within the candidate genes were low. The recurrent divergent selection caused excessive moderate allele frequencies in the cycle 3 reduced lignin population as compared to the base population. As a result, this study provides valuable insight on genetic changes occurring in short-term selection in the polyploid populations, and discovered potential markers for breeding switchgrass with improved biomass quality.« less

Selection signatures in four lignin genes from switchgrass populations divergently selected for in vitro dry matter digestibility

DOE PAGES

Chen, Shiyu; Kaeppler, Shawn M.; Vogel, Kenneth P.; ...

2016-11-28

Switchgrass is undergoing development as a dedicated cellulosic bioenergy crop. Fermentation of lignocellulosic biomass to ethanol in a bioenergy system or to volatile fatty acids in a livestock production system is strongly and negatively influenced by lignification of cell walls. This study detects specific loci that exhibit selection signatures across switchgrass breeding populations that differ in in vitro dry matter digestibility (IVDMD), ethanol yield, and lignin concentration. Allele frequency changes in candidate genes were used to detect loci under selection. Out of the 183 polymorphisms identified in the four candidate genes, twenty-five loci in the intron regions and four locimore » in coding regions were found to display a selection signature. All loci in the coding regions are synonymous substitutions. Selection in both directions were observed on polymorphisms that appeared to be under selection. Genetic diversity and linkage disequilibrium within the candidate genes were low. The recurrent divergent selection caused excessive moderate allele frequencies in the cycle 3 reduced lignin population as compared to the base population. As a result, this study provides valuable insight on genetic changes occurring in short-term selection in the polyploid populations, and discovered potential markers for breeding switchgrass with improved biomass quality.« less

QR codes: next level of social media.

PubMed

Gottesman, Wesley; Baum, Neil

2013-01-01

The OR code, which is short for quick response code, system was invented in Japan for the auto industry. Its purpose was to track vehicles during manufacture; it was designed to allow high-speed component scanning. Now the scanning can be easily accomplished via cell phone, making the technology useful and within reach of your patients. There are numerous applications for OR codes in the contemporary medical practice. This article describes QR codes and how they might be applied for marketing and practice management.

Study of an External Neutron Source for an Accelerator-Driven System using the PHITS Code

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

Sugawara, Takanori; Iwasaki, Tomohiko; Chiba, Takashi

A code system for the Accelerator Driven System (ADS) has been under development for analyzing dynamic behaviors of a subcritical core coupled with an accelerator. This code system named DSE (Dynamics calculation code system for a Subcritical system with an External neutron source) consists of an accelerator part and a reactor part. The accelerator part employs a database, which is calculated by using PHITS, for investigating the effect related to the accelerator such as the changes of beam energy, beam diameter, void generation, and target level. This analysis method using the database may introduce some errors into dynamics calculations sincemore » the neutron source data derived from the database has some errors in fitting or interpolating procedures. In this study, the effects of various events are investigated to confirm that the method based on the database is appropriate.« less

International cooperation and networking in genetic health care provision: issues arising from the genetic services plan for the Emilia-Romagna region, Italy.

PubMed

Calzolari, E; Baroncini, A

2005-01-01

The aims of this report are to describe the genetic plan for Emilia-Romagna, a region in Italy, and to contribute to the international exchange of information on developing and applying policy frameworks to provide high-quality and comprehensive genetic health care in the publicly funded health systems. At the present time there is no national policy for genetic medicine in Italy, and only two regions, Emilia-Romagna and Liguria, have formally agreed to a strategic plan for health care in genetics. The current provision of genetic services in Emilia-Romagna is described focusing on the intra- and inter-organizational linkages to ensure a comprehensive system of coordinated activities. Strengths and implementation areas are highlighted. Points that must be solved within the regional or national context are the definition of the level of assistance required in genetic medicine, the formal professional recognition of the genetic counselor and the adjustment of the billing mechanisms to the complexities of clinical genetic services. Issues that need to be addressed at a wider level include full assessment of genetic tests before their introduction into clinical practice, networking to provide tests for the rarest genetic diseases, consensus on fundamental terminology and clinical and administrative data sets to promote a cohesive framework for the flow of information throughout the health care systems with respect to genetics. Copyright 2005 S. Karger AG, Basel.

The Study on Network Examinational Database based on ASP Technology

NASA Astrophysics Data System (ADS)

Zhang, Yanfu; Han, Yuexiao; Zhou, Yanshuang

This article introduces the structure of the general test base system based on .NET technology, discussing the design of the function modules and its implementation methods. It focuses on key technology of the system, proposing utilizing the WEB online editor control to solve the input problem and regular expression to solve the problem HTML code, making use of genetic algorithm to optimize test paper and the automated tools of WORD to solve the problem of exporting papers and others. Practical effective design and implementation technology can be used as reference for the development of similar systems.

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.

Implementation of Finite Volume based Navier Stokes Algorithm Within General Purpose Flow Network Code

NASA Technical Reports Server (NTRS)

Schallhorn, Paul; Majumdar, Alok

2012-01-01

This paper describes a finite volume based numerical algorithm that allows multi-dimensional computation of fluid flow within a system level network flow analysis. There are several thermo-fluid engineering problems where higher fidelity solutions are needed that are not within the capacity of system level codes. The proposed algorithm will allow NASA's Generalized Fluid System Simulation Program (GFSSP) to perform multi-dimensional flow calculation within the framework of GFSSP s typical system level flow network consisting of fluid nodes and branches. The paper presents several classical two-dimensional fluid dynamics problems that have been solved by GFSSP's multi-dimensional flow solver. The numerical solutions are compared with the analytical and benchmark solution of Poiseulle, Couette and flow in a driven cavity.

An engineer's view on genetic information and biological evolution.

PubMed

Battail, Gérard

2004-01-01

We develop ideas on genome replication introduced in Battail [Europhys. Lett. 40 (1997) 343]. Starting with the hypothesis that the genome replication process uses error-correcting means, and the auxiliary one that nested codes are used to this end, we first review the concepts of redundancy and error-correcting codes. Then we show that these hypotheses imply that: distinct species exist with a hierarchical taxonomy, there is a trend of evolution towards complexity, and evolution proceeds by discrete jumps. At least the first two features above may be considered as biological facts so, in the absence of direct evidence, they provide an indirect proof in favour of the hypothesized error-correction system. The very high redundancy of genomes makes it possible. In order to explain how it is implemented, we suggest that soft codes and replication decoding, to be briefly described, are plausible candidates. Experimentally proven properties of long-range correlation of the DNA message substantiate this claim.

Life is physics and chemistry and communication.

PubMed

Witzany, Guenther

2015-04-01

Manfred Eigen extended Erwin Schroedinger's concept of "life is physics and chemistry" through the introduction of information theory and cybernetic systems theory into "life is physics and chemistry and information." Based on this assumption, Eigen developed the concepts of quasispecies and hypercycles, which have been dominant in molecular biology and virology ever since. He insisted that the genetic code is not just used metaphorically: it represents a real natural language. However, the basics of scientific knowledge changed dramatically within the second half of the 20th century. Unfortunately, Eigen ignored the results of the philosophy of science discourse on essential features of natural languages and codes: a natural language or code emerges from populations of living agents that communicate. This contribution will look at some of the highlights of this historical development and the results relevant for biological theories about life. © 2014 New York Academy of Sciences.

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

A Unifying Mathematical Framework for Genetic Robustness, Environmental Robustness, Network Robustness and their Trade-off on Phenotype Robustness in Biological Networks Part I: Gene Regulatory Networks in Systems and Evolutionary Biology

PubMed Central

Chen, Bor-Sen; Lin, Ying-Po

2013-01-01

Robust stabilization and environmental disturbance attenuation are ubiquitous systematic properties observed in biological systems at different levels. The underlying principles for robust stabilization and environmental disturbance attenuation are universal to both complex biological systems and sophisticated engineering systems. In many biological networks, network robustness should be enough to confer intrinsic robustness in order to tolerate intrinsic parameter fluctuations, genetic robustness for buffering genetic variations, and environmental robustness for resisting environmental disturbances. With this, the phenotypic stability of biological network can be maintained, thus guaranteeing phenotype robustness. This paper presents a survey on biological systems and then develops a unifying mathematical framework for investigating the principles of both robust stabilization and environmental disturbance attenuation in systems and evolutionary biology. Further, from the unifying mathematical framework, it was discovered that the phenotype robustness criterion for biological networks at different levels relies upon intrinsic robustness + genetic robustness + environmental robustness ≦ network robustness. When this is true, the phenotype robustness can be maintained in spite of intrinsic parameter fluctuations, genetic variations, and environmental disturbances. Therefore, the trade-offs between intrinsic robustness, genetic robustness, environmental robustness, and network robustness in systems and evolutionary biology can also be investigated through their corresponding phenotype robustness criterion from the systematic point of view. PMID:23515240

A Unifying Mathematical Framework for Genetic Robustness, Environmental Robustness, Network Robustness and their Trade-off on Phenotype Robustness in Biological Networks Part I: Gene Regulatory Networks in Systems and Evolutionary Biology.

PubMed

Chen, Bor-Sen; Lin, Ying-Po

2013-01-01

Robust stabilization and environmental disturbance attenuation are ubiquitous systematic properties observed in biological systems at different levels. The underlying principles for robust stabilization and environmental disturbance attenuation are universal to both complex biological systems and sophisticated engineering systems. In many biological networks, network robustness should be enough to confer intrinsic robustness in order to tolerate intrinsic parameter fluctuations, genetic robustness for buffering genetic variations, and environmental robustness for resisting environmental disturbances. With this, the phenotypic stability of biological network can be maintained, thus guaranteeing phenotype robustness. This paper presents a survey on biological systems and then develops a unifying mathematical framework for investigating the principles of both robust stabilization and environmental disturbance attenuation in systems and evolutionary biology. Further, from the unifying mathematical framework, it was discovered that the phenotype robustness criterion for biological networks at different levels relies upon intrinsic robustness + genetic robustness + environmental robustness ≦ network robustness. When this is true, the phenotype robustness can be maintained in spite of intrinsic parameter fluctuations, genetic variations, and environmental disturbances. Therefore, the trade-offs between intrinsic robustness, genetic robustness, environmental robustness, and network robustness in systems and evolutionary biology can also be investigated through their corresponding phenotype robustness criterion from the systematic point of view.

A Locus Encoding Variable Defense Systems against Invading DNA Identified in Streptococcus suis

PubMed Central

Okura, Masatoshi; Nozawa, Takashi; Watanabe, Takayasu; Murase, Kazunori; Nakagawa, Ichiro; Takamatsu, Daisuke; Osaki, Makoto; Sekizaki, Tsutomu; Gottschalk, Marcelo; Hamada, Shigeyuki

2017-01-01

Streptococcus suis, an important zoonotic pathogen, is known to have an open pan-genome and to develop a competent state. In S. suis, limited genetic lineages are suggested to be associated with zoonosis. However, little is known about the evolution of diversified lineages and their respective phenotypic or ecological characteristics. In this study, we performed comparative genome analyses of S. suis, with a focus on the competence genes, mobile genetic elements, and genetic elements related to various defense systems against exogenous DNAs (defense elements) that are associated with gene gain/loss/exchange mediated by horizontal DNA movements and their restrictions. Our genome analyses revealed a conserved competence-inducing peptide type (pherotype) of the competence system and large-scale genome rearrangements in certain clusters based on the genome phylogeny of 58 S. suis strains. Moreover, the profiles of the defense elements were similar or identical to each other among the strains belonging to the same genomic clusters. Our findings suggest that these genetic characteristics of each cluster might exert specific effects on the phenotypic or ecological differences between the clusters. We also found certain loci that shift several types of defense elements in S. suis. Of note, one of these loci is a previously unrecognized variable region in bacteria, at which strains of distinct clusters code for different and various defense elements. This locus might represent a novel defense mechanism that has evolved through an arms race between bacteria and invading DNAs, mediated by mobile genetic elements and genetic competence. PMID:28379509

On Francis Crick, the genetic code, and a clever kid.

PubMed

Goldstein, Bob

2018-04-02

A few years ago, Francis Crick's son told me a story that I can't get out of my mind. I had contacted Michael Crick by email while digging through the background of the researchers who had cracked the genetic code in the 1960s. Francis had died in 2004, and I was contacting some of the people who knew him when he was struggling to decipher the code. Francis didn't appear to struggle often - he is known mostly for his successes - and, as it turns out, this one well-known struggle may have had a clue sitting just barely out of sight. Copyright © 2018 Elsevier Ltd. All rights reserved.

Genetic and Physical Interaction of the B-Cell SLE-Associated Genes BANK1 and BLK

PubMed Central

Castillejo-López, Casimiro; Delgado-Vega, Angélica M.; Wojcik, Jerome; Kozyrev, Sergey V.; Thavathiru, Elangovan; Wu, Ying-Yu; Sánchez, Elena; Pöllmann, David; López-Egido, Juan R.; Fineschi, Serena; Domínguez, Nicolás; Lu, Rufei; James, Judith A.; Merrill, Joan T.; Kelly, Jennifer A.; Kaufman, Kenneth M.; Moser, Kathy; Gilkeson, Gary; Frostegård, Johan; Pons-Estel, Bernardo A.; D’Alfonso, Sandra; Witte, Torsten; Callejas, José Luis; Harley, John B.; Gaffney, Patrick; Martin, Javier; Guthridge, Joel M.; Alarcón-Riquelme, Marta E.

2012-01-01

Objectives Altered signaling in B-cells is a predominant feature of systemic lupus erythematosus (SLE). The genes BANK1 and BLK were recently described as associated with SLE. BANK1 codes for a B-cell-specific cytoplasmic protein involved in B-cell receptor signaling and BLK codes for an Src tyrosine kinase with important roles in B-cell development. To characterize the role of BANK1 and BLK in SLE, we performed a genetic interaction analysis hypothesizing that genetic interactions could reveal functional pathways relevant to disease pathogenesis. Methods We Used the method GPAT16 to analyze the gene-gene interactions of BANK1 and BLK. Confocal microscopy was used to investigate co-localization, and immunoprecipitation was used to verify the physical interaction of BANK1 and BLK. Results Epistatic interactions between BANK1 and BLK polymorphisms associated with SLE were observed in a discovery set of 279 patients and 515 controls from Northern Europe. A meta-analysis with 4399 European individuals confirmed the genetic interactions between BANK1 and BLK. As BANK1 was identified as a binding partner of the Src tyrosine kinase LYN, we tested the possibility that BANK1 and BLK could also show a protein-protein interaction. We demonstrated co-immunoprecipitation and co-localization of BLK and BANK1. In a Daudi cell line and primary naïve B-cells the endogenous binding was enhanced upon B-cell receptor stimulation using anti-IgM antibodies. Conclusions Here, we show a genetic interaction between BANK1 and BLK, and demonstrate that these molecules interact physically. Our results have important consequences for the understanding of SLE and other autoimmune diseases and identify a potential new signaling pathway. PMID:21978998

The First AO Classification System for Fractures of the Craniomaxillofacial Skeleton: Rationale, Methodological Background, Developmental Process, and Objectives

PubMed Central

Audigé, Laurent; Cornelius, Carl-Peter; Ieva, Antonio Di; Prein, Joachim

2014-01-01

Validated trauma classification systems are the sole means to provide the basis for reliable documentation and evaluation of patient care, which will open the gateway to evidence-based procedures and healthcare in the coming years. With the support of AO Investigation and Documentation, a classification group was established to develop and evaluate a comprehensive classification system for craniomaxillofacial (CMF) fractures. Blueprints for fracture classification in the major constituents of the human skull were drafted and then evaluated by a multispecialty group of experienced CMF surgeons and a radiologist in a structured process during iterative agreement sessions. At each session, surgeons independently classified the radiological imaging of up to 150 consecutive cases with CMF fractures. During subsequent review meetings, all discrepancies in the classification outcome were critically appraised for clarification and improvement until consensus was reached. The resulting CMF classification system is structured in a hierarchical fashion with three levels of increasing complexity. The most elementary level 1 simply distinguishes four fracture locations within the skull: mandible (code 91), midface (code 92), skull base (code 93), and cranial vault (code 94). Levels 2 and 3 focus on further defining the fracture locations and for fracture morphology, achieving an almost individual mapping of the fracture pattern. This introductory article describes the rationale for the comprehensive AO CMF classification system, discusses the methodological framework, and provides insight into the experiences and interactions during the evaluation process within the core groups. The details of this system in terms of anatomy and levels are presented in a series of focused tutorials illustrated with case examples in this special issue of the Journal. PMID:25489387

The First AO Classification System for Fractures of the Craniomaxillofacial Skeleton: Rationale, Methodological Background, Developmental Process, and Objectives.

PubMed

Audigé, Laurent; Cornelius, Carl-Peter; Di Ieva, Antonio; Prein, Joachim

2014-12-01

Validated trauma classification systems are the sole means to provide the basis for reliable documentation and evaluation of patient care, which will open the gateway to evidence-based procedures and healthcare in the coming years. With the support of AO Investigation and Documentation, a classification group was established to develop and evaluate a comprehensive classification system for craniomaxillofacial (CMF) fractures. Blueprints for fracture classification in the major constituents of the human skull were drafted and then evaluated by a multispecialty group of experienced CMF surgeons and a radiologist in a structured process during iterative agreement sessions. At each session, surgeons independently classified the radiological imaging of up to 150 consecutive cases with CMF fractures. During subsequent review meetings, all discrepancies in the classification outcome were critically appraised for clarification and improvement until consensus was reached. The resulting CMF classification system is structured in a hierarchical fashion with three levels of increasing complexity. The most elementary level 1 simply distinguishes four fracture locations within the skull: mandible (code 91), midface (code 92), skull base (code 93), and cranial vault (code 94). Levels 2 and 3 focus on further defining the fracture locations and for fracture morphology, achieving an almost individual mapping of the fracture pattern. This introductory article describes the rationale for the comprehensive AO CMF classification system, discusses the methodological framework, and provides insight into the experiences and interactions during the evaluation process within the core groups. The details of this system in terms of anatomy and levels are presented in a series of focused tutorials illustrated with case examples in this special issue of the Journal.

A survey to identify the clinical coding and classification systems currently in use across Europe.

PubMed

de Lusignan, S; Minmagh, C; Kennedy, J; Zeimet, M; Bommezijn, H; Bryant, J

2001-01-01

This is a survey to identify what clinical coding systems are currently in use across the European Union, and the states seeking membership to it. We sought to identify what systems are currently used and to what extent they were subject to local adaptation. Clinical coding should facilitate identifying key medical events in a computerised medical record, and aggregating information across groups of records. The emerging new driver is as the enabler of the life-long computerised medical record. A prerequisite for this level of functionality is the transfer of information between different computer systems. This transfer can be facilitated either by working on the interoperability problems between disparate systems or by harmonising the underlying data. This paper examines the extent to which the latter has occurred across Europe. Literature and Internet search. Requests for information via electronic mail to pan-European mailing lists of health informatics professionals. Coding systems are now a de facto part of health information systems across Europe. There are relatively few coding systems in existence across Europe. ICD9 and ICD 10, ICPC and Read were the most established. However the local adaptation of these classification systems either on a by country or by computer software manufacturer basis; significantly reduces the ability for the meaning coded with patients computer records to be easily transferred from one medical record system to another. There is no longer any debate as to whether a coding or classification system should be used. Convergence of different classifications systems should be encouraged. Countries and computer manufacturers within the EU should be encouraged to stop making local modifications to coding and classification systems, as this practice risks significantly slowing progress towards easy transfer of records between computer systems.

Amino acid fermentation at the origin of the genetic code

PubMed Central

2012-01-01

There is evidence that the genetic code was established prior to the existence of proteins, when metabolism was powered by ribozymes. Also, early proto-organisms had to rely on simple anaerobic bioenergetic processes. In this work I propose that amino acid fermentation powered metabolism in the RNA world, and that this was facilitated by proto-adapters, the precursors of the tRNAs. Amino acids were used as carbon sources rather than as catalytic or structural elements. In modern bacteria, amino acid fermentation is known as the Stickland reaction. This pathway involves two amino acids: the first undergoes oxidative deamination, and the second acts as an electron acceptor through reductive deamination. This redox reaction results in two keto acids that are employed to synthesise ATP via substrate-level phosphorylation. The Stickland reaction is the basic bioenergetic pathway of some bacteria of the genus Clostridium. Two other facts support Stickland fermentation in the RNA world. First, several Stickland amino acid pairs are synthesised in abiotic amino acid synthesis. This suggests that amino acids that could be used as an energy substrate were freely available. Second, anticodons that have complementary sequences often correspond to amino acids that form Stickland pairs. The main hypothesis of this paper is that pairs of complementary proto-adapters were assigned to Stickland amino acids pairs. There are signatures of this hypothesis in the genetic code. Furthermore, it is argued that the proto-adapters formed double strands that brought amino acid pairs into proximity to facilitate their mutual redox reaction, structurally constraining the anticodon pairs that are assigned to these amino acid pairs. Significance tests which randomise the code are performed to study the extent of the variability of the energetic (ATP) yield. Random assignments can lead to a substantial yield of ATP and maintain enough variability, thus selection can act and refine the assignments into a proto-code that optimises the energetic yield. Monte Carlo simulations are performed to evaluate the establishment of these simple proto-codes, based on amino acid substitutions and codon swapping. In all cases, donor amino acids are assigned to anticodons composed of U+G, and have low redundancy (1-2 codons), whereas acceptor amino acids are assigned to the the remaining codons. These bioenergetic and structural constraints allow for a metabolic role for amino acids before their co-option as catalyst cofactors. Reviewers: this article was reviewed by Prof. William Martin, Prof. Eörs Szathmáry (nominated by Dr. Gáspár Jékely) and Dr. Ádám Kun (nominated by Dr. Sandor Pongor) PMID:22325238

Genome-wide survey and analysis of microsatellites in giant panda (Ailuropoda melanoleuca), with a focus on the applications of a novel microsatellite marker system.

PubMed

Huang, Jie; Li, Yu-Zhi; Du, Lian-Ming; Yang, Bo; Shen, Fu-Jun; Zhang, He-Min; Zhang, Zhi-He; Zhang, Xiu-Yue; Yue, Bi-Song

2015-02-07

The giant panda (Ailuropoda melanoleuca) is a critically endangered species endemic to China. Microsatellites have been preferred as the most popular molecular markers and proven effective in estimating population size, paternity test, genetic diversity for the critically endangered species. The availability of the giant panda complete genome sequences provided the opportunity to carry out genome-wide scans for all types of microsatellites markers, which now opens the way for the analysis and development of microsatellites in giant panda. By screening the whole genome sequence of giant panda in silico mining, we identified microsatellites in the genome of giant panda and analyzed their frequency and distribution in different genomic regions. Based on our search criteria, a repertoire of 855,058 SSRs was detected, with mono-nucleotides being the most abundant. SSRs were found in all genomic regions and were more abundant in non-coding regions than coding regions. A total of 160 primer pairs were designed to screen for polymorphic microsatellites using the selected tetranucleotide microsatellite sequences. The 51 novel polymorphic tetranucleotide microsatellite loci were discovered based on genotyping blood DNA from 22 captive giant pandas in this study. Finally, a total of 15 markers, which showed good polymorphism, stability, and repetition in faecal samples, were used to establish the novel microsatellite marker system for giant panda. Meanwhile, a genotyping database for Chengdu captive giant pandas (n = 57) were set up using this standardized system. What's more, a universal individual identification method was established and the genetic diversity were analysed in this study as the applications of this marker system. The microsatellite abundance and diversity were characterized in giant panda genomes. A total of 154,677 tetranucleotide microsatellites were identified and 15 of them were discovered as the polymorphic and stable loci. The individual identification method and the genetic diversity analysis method in this study provided adequate material for the future study of giant panda.

Avoidance of truncated proteins from unintended ribosome binding sites within heterologous protein coding sequences.

PubMed

Whitaker, Weston R; Lee, Hanson; Arkin, Adam P; Dueber, John E

2015-03-20

Genetic sequences ported into non-native hosts for synthetic biology applications can gain unexpected properties. In this study, we explored sequences functioning as ribosome binding sites (RBSs) within protein coding DNA sequences (CDSs) that cause internal translation, resulting in truncated proteins. Genome-wide prediction of bacterial RBSs, based on biophysical calculations employed by the RBS calculator, suggests a selection against internal RBSs within CDSs in Escherichia coli, but not those in Saccharomyces cerevisiae. Based on these calculations, silent mutations aimed at removing internal RBSs can effectively reduce truncation products from internal translation. However, a solution for complete elimination of internal translation initiation is not always feasible due to constraints of available coding sequences. Fluorescence assays and Western blot analysis showed that in genes with internal RBSs, increasing the strength of the intended upstream RBS had little influence on the internal translation strength. Another strategy to minimize truncated products from an internal RBS is to increase the relative strength of the upstream RBS with a concomitant reduction in promoter strength to achieve the same protein expression level. Unfortunately, lower transcription levels result in increased noise at the single cell level due to stochasticity in gene expression. At the low expression regimes desired for many synthetic biology applications, this problem becomes particularly pronounced. We found that balancing promoter strengths and upstream RBS strengths to intermediate levels can achieve the target protein concentration while avoiding both excessive noise and truncated protein.

PDE Nozzle Optimization Using a Genetic Algorithm

NASA Technical Reports Server (NTRS)

Billings, Dana; Turner, James E. (Technical Monitor)

2000-01-01

Genetic algorithms, which simulate evolution in natural systems, have been used to find solutions to optimization problems that seem intractable to standard approaches. In this study, the feasibility of using a GA to find an optimum, fixed profile nozzle for a pulse detonation engine (PDE) is demonstrated. The objective was to maximize impulse during the detonation wave passage and blow-down phases of operation. Impulse of each profile variant was obtained by using the CFD code Mozart/2.0 to simulate the transient flow. After 7 generations, the method has identified a nozzle profile that certainly is a candidate for optimum solution. The constraints on the generality of this possible solution remain to be clarified.

X-linked Charcot-Marie-Tooth (CMT) neuropathies (CMTX1, CMTX2, CMTX3) show different clinical phenotype and molecular genetics

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

Ionasescu, V.V.; Searby, C.C.; Ionasescu, R.

1994-09-01

The purpose of this study was to compare the X-linked dominant type CMTX1 (20 families) with X-linked recessive types CMTX2 and CMTX3 (2 families). The clinical phenotype was consistent with CMT peripheral neuropathy in all cases including distal weakness, atrophy and sensory loss, pes cavus and areflexia. Additional clinicial involvement of the central nervous system was present in one family with CMTX2 (mental retardation) and one family with CMTX3 (spastic paraparesis). Tight genetic linkage to Xq13.1 was present in 20 families with CMTX1 (Z=34.07 at {theta}=0) for the marker DXS453. Fifteen of the CMTX1 families showed point mutations of themore » connexin 32 coding region (5 nonsense mutations, 8 missense mutations, 2 deletions). Five CMTX1 neuropathy families showed no evidence of point mutations of the CX32 coding sequence. These findings suggest that the CMTX1 neuropathy genotype in these families may be the result of promoter mutations, 3{prime}-untranslated region mutations or exon/intron splice site mutations or a mutation with a different type of connexin but which has close structural similarities to CX32. No mutations of the CX32 coding region were found in the CMTX2 or CMTX3 families. Linkage to Xq13.1 was excluded in both families. Genetic linkage to Xp22.2 was present in the CMTX2 family (Z=3.54 at {theta}=0) for the markers DXS987 and DXS999. Suggestion of linkage to Xq26 (Z=1.81 at {theta}=0) for the marker DXS86 was present in the CMTX3 family.« less

Practical guide to bar coding for patient medication safety.

PubMed

Neuenschwander, Mark; Cohen, Michael R; Vaida, Allen J; Patchett, Jeffrey A; Kelly, Jamie; Trohimovich, Barbara

2003-04-15

Bar coding for the medication administration step of the drug-use process is discussed. FDA will propose a rule in 2003 that would require bar-code labels on all human drugs and biologicals. Even with an FDA mandate, manufacturer procrastination and possible shifts in product availability are likely to slow progress. Such delays should not preclude health systems from adopting bar-code-enabled point-of-care (BPOC) systems to achieve gains in patient safety. Bar-code technology is a replacement for traditional keyboard data entry. The elements of bar coding are content, which determines the meaning; data format, which refers to the embedded data and symbology, which describes the "font" in which the machine-readable code is written. For a BPOC system to deliver an acceptable level of patient protection, the hospital must first establish reliable processes for a patient identification band, caregiver badge, and medication bar coding. Medications can have either drug-specific or patient-specific bar codes. Both varieties result in the desired code that supports patient's five rights of drug administration. When medications are not available from the manufacturer in immediate-container bar-coded packaging, other means of applying the bar code must be devised, including the use of repackaging equipment, overwrapping, manual bar coding, and outsourcing. Virtually all medications should be bar coded, the bar code on the label should be easily readable, and appropriate policies, procedures, and checks should be in place. Bar coding has the potential to be not only cost-effective but to produce a return on investment. By bar coding patient identification tags, caregiver badges, and immediate-container medications, health systems can substantially increase patient safety during medication administration.

Extremely high genetic diversity in a single tumor points to prevalence of non-Darwinian cell evolution.

PubMed

Ling, Shaoping; Hu, Zheng; Yang, Zuyu; Yang, Fang; Li, Yawei; Lin, Pei; Chen, Ke; Dong, Lili; Cao, Lihua; Tao, Yong; Hao, Lingtong; Chen, Qingjian; Gong, Qiang; Wu, Dafei; Li, Wenjie; Zhao, Wenming; Tian, Xiuyun; Hao, Chunyi; Hungate, Eric A; Catenacci, Daniel V T; Hudson, Richard R; Li, Wen-Hsiung; Lu, Xuemei; Wu, Chung-I

2015-11-24

The prevailing view that the evolution of cells in a tumor is driven by Darwinian selection has never been rigorously tested. Because selection greatly affects the level of intratumor genetic diversity, it is important to assess whether intratumor evolution follows the Darwinian or the non-Darwinian mode of evolution. To provide the statistical power, many regions in a single tumor need to be sampled and analyzed much more extensively than has been attempted in previous intratumor studies. Here, from a hepatocellular carcinoma (HCC) tumor, we evaluated multiregional samples from the tumor, using either whole-exome sequencing (WES) (n = 23 samples) or genotyping (n = 286) under both the infinite-site and infinite-allele models of population genetics. In addition to the many single-nucleotide variations (SNVs) present in all samples, there were 35 "polymorphic" SNVs among samples. High genetic diversity was evident as the 23 WES samples defined 20 unique cell clones. With all 286 samples genotyped, clonal diversity agreed well with the non-Darwinian model with no evidence of positive Darwinian selection. Under the non-Darwinian model, MALL (the number of coding region mutations in the entire tumor) was estimated to be greater than 100 million in this tumor. DNA sequences reveal local diversities in small patches of cells and validate the estimation. In contrast, the genetic diversity under a Darwinian model would generally be orders of magnitude smaller. Because the level of genetic diversity will have implications on therapeutic resistance, non-Darwinian evolution should be heeded in cancer treatments even for microscopic tumors.

Extremely high genetic diversity in a single tumor points to prevalence of non-Darwinian cell evolution

PubMed Central

Ling, Shaoping; Hu, Zheng; Yang, Zuyu; Yang, Fang; Li, Yawei; Lin, Pei; Chen, Ke; Dong, Lili; Cao, Lihua; Tao, Yong; Hao, Lingtong; Chen, Qingjian; Gong, Qiang; Wu, Dafei; Li, Wenjie; Zhao, Wenming; Tian, Xiuyun; Hao, Chunyi; Hungate, Eric A.; Catenacci, Daniel V. T.; Hudson, Richard R.; Li, Wen-Hsiung; Lu, Xuemei; Wu, Chung-I

2015-01-01

The prevailing view that the evolution of cells in a tumor is driven by Darwinian selection has never been rigorously tested. Because selection greatly affects the level of intratumor genetic diversity, it is important to assess whether intratumor evolution follows the Darwinian or the non-Darwinian mode of evolution. To provide the statistical power, many regions in a single tumor need to be sampled and analyzed much more extensively than has been attempted in previous intratumor studies. Here, from a hepatocellular carcinoma (HCC) tumor, we evaluated multiregional samples from the tumor, using either whole-exome sequencing (WES) (n = 23 samples) or genotyping (n = 286) under both the infinite-site and infinite-allele models of population genetics. In addition to the many single-nucleotide variations (SNVs) present in all samples, there were 35 “polymorphic” SNVs among samples. High genetic diversity was evident as the 23 WES samples defined 20 unique cell clones. With all 286 samples genotyped, clonal diversity agreed well with the non-Darwinian model with no evidence of positive Darwinian selection. Under the non-Darwinian model, MALL (the number of coding region mutations in the entire tumor) was estimated to be greater than 100 million in this tumor. DNA sequences reveal local diversities in small patches of cells and validate the estimation. In contrast, the genetic diversity under a Darwinian model would generally be orders of magnitude smaller. Because the level of genetic diversity will have implications on therapeutic resistance, non-Darwinian evolution should be heeded in cancer treatments even for microscopic tumors. PMID:26561581

A New Operating System for Security Tagged Architecture Hardware in Support of Multiple Independent Levels of Security (MILS) Compliant System

DTIC Science & Technology

2014-04-01

important data structures of RTEMS are introduced. Section 3.2.2 discusses the problems we found in RTEMS that may cause security vulnerabilities...the important data structures in RTEMS: Object, which is a critical data structure in the SCORE, tasks threads. Approved for Public Release...these important system codes. The example code shows a possibility that a user can delete a system thread. Therefore, in order to protect system

The Effects of Predator Evolution and Genetic Variation on Predator-Prey Population-Level Dynamics.

PubMed

Cortez, Michael H; Patel, Swati

2017-07-01

This paper explores how predator evolution and the magnitude of predator genetic variation alter the population-level dynamics of predator-prey systems. We do this by analyzing a general eco-evolutionary predator-prey model using four methods: Method 1 identifies how eco-evolutionary feedbacks alter system stability in the fast and slow evolution limits; Method 2 identifies how the amount of standing predator genetic variation alters system stability; Method 3 identifies how the phase lags in predator-prey cycles depend on the amount of genetic variation; and Method 4 determines conditions for different cycle shapes in the fast and slow evolution limits using geometric singular perturbation theory. With these four methods, we identify the conditions under which predator evolution alters system stability and shapes of predator-prey cycles, and how those effect depend on the amount of genetic variation in the predator population. We discuss the advantages and disadvantages of each method and the relations between the four methods. This work shows how the four methods can be used in tandem to make general predictions about eco-evolutionary dynamics and feedbacks.

Combined sequence and sequence-structure-based methods for analyzing RAAS gene SNPs: a computational approach.

PubMed

Singh, Kh Dhanachandra; Karthikeyan, Muthusamy

2014-12-01

The renin-angiotensin-aldosterone system (RAAS) plays a key role in the regulation of blood pressure (BP). Mutations on the genes that encode components of the RAAS have played a significant role in genetic susceptibility to hypertension and have been intensively scrutinized. The identification of such probably causal mutations not only provides insight into the RAAS but may also serve as antihypertensive therapeutic targets and diagnostic markers. The methods for analyzing the SNPs from the huge dataset of SNPs, containing both functional and neutral SNPs is challenging by the experimental approach on every SNPs to determine their biological significance. To explore the functional significance of genetic mutation (SNPs), we adopted combined sequence and sequence-structure-based SNP analysis algorithm. Out of 3864 SNPs reported in dbSNP, we found 108 missense SNPs in the coding region and remaining in the non-coding region. In this study, we are reporting only those SNPs in coding region to be deleterious when three or more tools are predicted to be deleterious and which have high RMSD from the native structure. Based on these analyses, we have identified two SNPs of REN gene, eight SNPs of AGT gene, three SNPs of ACE gene, two SNPs of AT1R gene, three SNPs of CYP11B2 gene and three SNPs of CMA1 gene in the coding region were found to be deleterious. Further this type of study will be helpful in reducing the cost and time for identification of potential SNP and also helpful in selecting potential SNP for experimental study out of SNP pool.

Understanding the potential of state-based public health genomics programs to mitigate disparities in access to clinical genetic services.

PubMed

Senier, Laura; Tan, Catherine; Smollin, Leandra; Lee, Rachael

2018-06-12

State health agencies (SHAs) have developed public health genomics (PHG) programs that play an instrumental role in advancing precision public health, but there is limited research on their approaches. This study examines how PHG programs attempt to mitigate or forestall health disparities and inequities in the utilization of genomic medicine. We compared PHG programs in three states: Connecticut, Michigan, and Utah. We analyzed 85 in-depth interviews with SHA internal and external collaborators and program documents. We employed a qualitative coding process to capture themes relating to health disparities and inequities. Each SHA implemented population-level approaches to identify individuals who carry genetic variants that increase risk of hereditary cancers. However, each SHA developed a unique strategy-which we label public health action repertoires-to reach specific subgroups who faced barriers in accessing genetic services. These strategies varied across states given demographics of the state population, state-level partnerships, and availability of healthcare services. Our findings illustrate the imperative of tailoring PHG programs to local demographic characteristics and existing community resources. Furthermore, our study highlights how integrating genomics into precision public health will require multilevel, multisector collaboration to optimize efficacy and equity.

Arduino-based automation of a DNA extraction system.

PubMed

Kim, Kyung-Won; Lee, Mi-So; Ryu, Mun-Ho; Kim, Jong-Won

2015-01-01

There have been many studies to detect infectious diseases with the molecular genetic method. This study presents an automation process for a DNA extraction system based on microfluidics and magnetic bead, which is part of a portable molecular genetic test system. This DNA extraction system consists of a cartridge with chambers, syringes, four linear stepper actuators, and a rotary stepper actuator. The actuators provide a sequence of steps in the DNA extraction process, such as transporting, mixing, and washing for the gene specimen, magnetic bead, and reagent solutions. The proposed automation system consists of a PC-based host application and an Arduino-based controller. The host application compiles a G code sequence file and interfaces with the controller to execute the compiled sequence. The controller executes stepper motor axis motion, time delay, and input-output manipulation. It drives the stepper motor with an open library, which provides a smooth linear acceleration profile. The controller also provides a homing sequence to establish the motor's reference position, and hard limit checking to prevent any over-travelling. The proposed system was implemented and its functionality was investigated, especially regarding positioning accuracy and velocity profile.

Prophage-mediated defense against viral attack and viral counter-defense

PubMed Central

Dedrick, Rebekah M.; Jacobs-Sera, Deborah; Guerrero Bustamante, Carlos A.; Garlena, Rebecca A.; Mavrich, Travis N.; Pope, Welkin H.; Reyes, Juan C Cervantes; Russell, Daniel A.; Adair, Tamarah; Alvey, Richard; Bonilla, J. Alfred; Bricker, Jerald S.; Brown, Bryony R.; Byrnes, Deanna; Cresawn, Steven G.; Davis, William B.; Dickson, Leon A.; Edgington, Nicholas P.; Findley, Ann M.; Golebiewska, Urszula; Grose, Julianne H.; Hayes, Cory F.; Hughes, Lee E.; Hutchison, Keith W.; Isern, Sharon; Johnson, Allison A.; Kenna, Margaret A.; Klyczek, Karen K.; Mageeney, Catherine M.; Michael, Scott F.; Molloy, Sally D.; Montgomery, Matthew T.; Neitzel, James; Page, Shallee T.; Pizzorno, Marie C.; Poxleitner, Marianne K.; Rinehart, Claire A.; Robinson, Courtney J.; Rubin, Michael R.; Teyim, Joseph N.; Vazquez, Edwin; Ware, Vassie C.; Washington, Jacqueline; Hatfull, Graham F.

2017-01-01

Temperate phages are common and prophages are abundant residents of sequenced bacterial genomes. Mycobacteriophages are viruses infecting mycobacterial hosts including Mycobacterium tuberculosis and Mycobacterium smegmatis, encompass substantial genetic diversity, and are commonly temperate. Characterization of ten Cluster N temperate mycobacteriophages reveals at least five distinct prophage-expressed viral defense systems that interfere with infection of lytic and temperate phages that are either closely-related (homotypic defense) or unrelated (heterotypic defense). Target specificity is unpredictable, ranging from a single target phage to one-third of those tested. The defense systems include a single-subunit restriction system, a heterotypic exclusion system, and a predicted (p)ppGpp synthetase, which blocks lytic phage growth, promotes bacterial survival, and enables efficient lysogeny. The predicted (p)ppGpp synthetase coded by the Phrann prophage defends against phage Tweety infection, but Tweety codes for a tetrapeptide repeat protein, gp54, that acts as a highly effective counter-defense system. Prophage-mediated viral defense offers an efficient mechanism for bacterial success in host-virus dynamics, and counter-defense promotes phage co-evolution. PMID:28067906

Trends in genetic patent applications: the commercialization of academic intellectual property

PubMed Central

Kers, Jannigje G; Van Burg, Elco; Stoop, Tom; Cornel, Martina C

2014-01-01

We studied trends in genetic patent applications in order to identify the trends in the commercialization of research findings in genetics. To define genetic patent applications, the European version (ECLA) of the International Patent Classification (IPC) codes was used. Genetic patent applications data from the PATSTAT database from 1990 until 2009 were analyzed for time trends and regional distribution. Overall, the number of patent applications has been growing. In 2009, 152 000 patent applications were submitted under the Patent Cooperation Treaty (PCT) and within the EP (European Patent) system of the European Patent Office (EPO). The number of genetic patent applications increased until a peak was reached in the year 2000, with >8000 applications, after which it declined by almost 50%. Continents show different patterns over time, with the global peak in 2000 mainly explained by the USA and Europe, while Asia shows a stable number of >1000 per year. Nine countries together account for 98.9% of the total number of genetic patent applications. In The Netherlands, 26.7% of the genetic patent applications originate from public research institutions. After the year 2000, the number of genetic patent applications dropped significantly. Academic leadership and policy as well as patent regulations seem to have an important role in the trend differences. The ongoing investment in genetic research in the past decade is not reflected by an increase of patent applications. PMID:24448546

Trends in genetic patent applications: the commercialization of academic intellectual property.

PubMed

Kers, Jannigje G; Van Burg, Elco; Stoop, Tom; Cornel, Martina C

2014-10-01

We studied trends in genetic patent applications in order to identify the trends in the commercialization of research findings in genetics. To define genetic patent applications, the European version (ECLA) of the International Patent Classification (IPC) codes was used. Genetic patent applications data from the PATSTAT database from 1990 until 2009 were analyzed for time trends and regional distribution. Overall, the number of patent applications has been growing. In 2009, 152 000 patent applications were submitted under the Patent Cooperation Treaty (PCT) and within the EP (European Patent) system of the European Patent Office (EPO). The number of genetic patent applications increased until a peak was reached in the year 2000, with >8000 applications, after which it declined by almost 50%. Continents show different patterns over time, with the global peak in 2000 mainly explained by the USA and Europe, while Asia shows a stable number of >1000 per year. Nine countries together account for 98.9% of the total number of genetic patent applications. In The Netherlands, 26.7% of the genetic patent applications originate from public research institutions. After the year 2000, the number of genetic patent applications dropped significantly. Academic leadership and policy as well as patent regulations seem to have an important role in the trend differences. The ongoing investment in genetic research in the past decade is not reflected by an increase of patent applications.

Automation and validation of DNA-banking systems.

PubMed

Thornton, Melissa; Gladwin, Amanda; Payne, Robin; Moore, Rachael; Cresswell, Carl; McKechnie, Douglas; Kelly, Steve; March, Ruth

2005-10-15

DNA banking is one of the central capabilities on which modern genetic research rests. The DNA-banking system plays an essential role in the flow of genetic data from patients and genetics researchers to the application of genetic research in the clinic. Until relatively recently, large collections of DNA samples were not common in human genetics. Now, collections of hundreds of thousands of samples are common in academic institutions and private companies. Automation of DNA banking can dramatically increase throughput, eliminate manual errors and improve the productivity of genetics research. An increased emphasis on pharmacogenetics and personalized medicine has highlighted the need for genetics laboratories to operate within the principles of a recognized quality system such as good laboratory practice (GLP). Automated systems are suitable for such laboratories but require a level of validation that might be unfamiliar to many genetics researchers. In this article, we use the AstraZeneca automated DNA archive and reformatting system (DART) as a case study of how such a system can be successfully developed and validated within the principles of GLP.

Genetic structure of the mating-type locus of Chlamydomonas reinhardtii.

PubMed Central

Ferris, Patrick J; Armbrust, E Virginia; Goodenough, Ursula W

2002-01-01

Portions of the cloned mating-type (MT) loci (mt(+) and mt(-)) of Chlamydomonas reinhardtii, defined as the approximately 1-Mb domains of linkage group VI that are under recombinational suppression, were subjected to Northern analysis to elucidate their coding capacity. The four central rearranged segments of the loci were found to contain both housekeeping genes (expressed during several life-cycle stages) and mating-related genes, while the sequences unique to mt(+) or mt(-) carried genes expressed only in the gametic or zygotic phases of the life cycle. One of these genes, Mtd1, is a candidate participant in gametic cell fusion; two others, Mta1 and Ezy2, are candidate participants in the uniparental inheritance of chloroplast DNA. The identified housekeeping genes include Pdk, encoding pyruvate dehydrogenase kinase, and GdcH, encoding glycine decarboxylase complex subunit H. Unusual genetic configurations include three genes whose sequences overlap, one gene that has inserted into the coding region of another, several genes that have been inactivated by rearrangements in the region, and genes that have undergone tandem duplication. This report extends our original conclusion that the MT locus has incurred high levels of mutational change. PMID:11805055

The impact of mating systems and dispersal on fine-scale genetic structure at maternally, paternally and biparentally inherited markers.

PubMed

Shaw, Robyn E; Banks, Sam C; Peakall, Rod

2018-01-01

For decades, studies have focused on how dispersal and mating systems influence genetic structure across populations or social groups. However, we still lack a thorough understanding of how these processes and their interaction shape spatial genetic patterns over a finer scale (tens-hundreds of metres). Using uniparentally inherited markers may help answer these questions, yet their potential has not been fully explored. Here, we use individual-level simulations to investigate the effects of dispersal and mating system on fine-scale genetic structure at autosomal, mitochondrial and Y chromosome markers. Using genetic spatial autocorrelation analysis, we found that dispersal was the major driver of fine-scale genetic structure across maternally, paternally and biparentally inherited markers. However, when dispersal was restricted (mean distance = 100 m), variation in mating behaviour created strong differences in the comparative level of structure detected at maternally and paternally inherited markers. Promiscuity reduced spatial genetic structure at Y chromosome loci (relative to monogamy), whereas structure increased under polygyny. In contrast, mitochondrial and autosomal markers were robust to differences in the specific mating system, although genetic structure increased across all markers when reproductive success was skewed towards fewer individuals. Comparing males and females at Y chromosome vs. mitochondrial markers, respectively, revealed that some mating systems can generate similar patterns to those expected under sex-biased dispersal. This demonstrates the need for caution when inferring ecological and behavioural processes from genetic results. Comparing patterns between the sexes, across a range of marker types, may help us tease apart the processes shaping fine-scale genetic structure. © 2017 John Wiley & Sons Ltd.

The Sphagnome Project: enabling ecological and evolutionary insights through a genus-level sequencing project

DOE PAGES

Weston, David J.; Turetsky, Merritt R.; Johnson, Matthew G.; ...

2017-10-27

Considerable progress has been made in ecological and evolutionary genetics with studies demonstrating how genes underlying plant and microbial traits can influence adaptation and even ‘extend’ to influence community structure and ecosystem level processes. The progress in this area is limited to model systems with deep genetic and genomic resources that often have negligible ecological impact or interest. Therefore, important linkages between genetic adaptations and their consequences at organismal and ecological scales are often lacking. We introduce the Sphagnome Project, which incorporates genomics into a long-running history of Sphagnum research that has documented unparalleled contributions to peatland ecology, carbon sequestration,more » biogeochemistry, microbiome research, niche construction, and ecosystem engineering. The Sphagnome Project encompasses a genus-level sequencing effort that represents a new type of model system driven not only by genetic tractability, but by ecologically relevant questions and hypotheses.« less

The Sphagnome Project: enabling ecological and evolutionary insights through a genus-level sequencing project

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

Weston, David J.; Turetsky, Merritt R.; Johnson, Matthew G.

Considerable progress has been made in ecological and evolutionary genetics with studies demonstrating how genes underlying plant and microbial traits can influence adaptation and even ‘extend’ to influence community structure and ecosystem level processes. The progress in this area is limited to model systems with deep genetic and genomic resources that often have negligible ecological impact or interest. Therefore, important linkages between genetic adaptations and their consequences at organismal and ecological scales are often lacking. We introduce the Sphagnome Project, which incorporates genomics into a long-running history of Sphagnum research that has documented unparalleled contributions to peatland ecology, carbon sequestration,more » biogeochemistry, microbiome research, niche construction, and ecosystem engineering. The Sphagnome Project encompasses a genus-level sequencing effort that represents a new type of model system driven not only by genetic tractability, but by ecologically relevant questions and hypotheses.« less

The Sphagnome Project: enabling ecological and evolutionary insights through a genus-level sequencing project.

PubMed

Weston, David J; Turetsky, Merritt R; Johnson, Matthew G; Granath, Gustaf; Lindo, Zoë; Belyea, Lisa R; Rice, Steven K; Hanson, David T; Engelhardt, Katharina A M; Schmutz, Jeremy; Dorrepaal, Ellen; Euskirchen, Eugénie S; Stenøien, Hans K; Szövényi, Péter; Jackson, Michelle; Piatkowski, Bryan T; Muchero, Wellington; Norby, Richard J; Kostka, Joel E; Glass, Jennifer B; Rydin, Håkan; Limpens, Juul; Tuittila, Eeva-Stiina; Ullrich, Kristian K; Carrell, Alyssa; Benscoter, Brian W; Chen, Jin-Gui; Oke, Tobi A; Nilsson, Mats B; Ranjan, Priya; Jacobson, Daniel; Lilleskov, Erik A; Clymo, R S; Shaw, A Jonathan

2018-01-01

Considerable progress has been made in ecological and evolutionary genetics with studies demonstrating how genes underlying plant and microbial traits can influence adaptation and even 'extend' to influence community structure and ecosystem level processes. Progress in this area is limited to model systems with deep genetic and genomic resources that often have negligible ecological impact or interest. Thus, important linkages between genetic adaptations and their consequences at organismal and ecological scales are often lacking. Here we introduce the Sphagnome Project, which incorporates genomics into a long-running history of Sphagnum research that has documented unparalleled contributions to peatland ecology, carbon sequestration, biogeochemistry, microbiome research, niche construction, and ecosystem engineering. The Sphagnome Project encompasses a genus-level sequencing effort that represents a new type of model system driven not only by genetic tractability, but by ecologically relevant questions and hypotheses. © 2017 UT-Battelle New Phytologist © 2017 New Phytologist Trust.

Coding and Plasticity in the Mammalian Thermosensory System.

PubMed

Yarmolinsky, David A; Peng, Yueqing; Pogorzala, Leah A; Rutlin, Michael; Hoon, Mark A; Zuker, Charles S

2016-12-07

Perception of the thermal environment begins with the activation of peripheral thermosensory neurons innervating the body surface. To understand how temperature is represented in vivo, we used genetically encoded calcium indicators to measure temperature-evoked responses in hundreds of neurons across the trigeminal ganglion. Our results show how warm, hot, and cold stimuli are represented by distinct population responses, uncover unique functional classes of thermosensory neurons mediating heat and cold sensing, and reveal the molecular logic for peripheral warmth sensing. Next, we examined how the peripheral somatosensory system is functionally reorganized to produce altered perception of the thermal environment after injury. We identify fundamental transformations in sensory coding, including the silencing and recruitment of large ensembles of neurons, providing a cellular basis for perceptual changes in temperature sensing, including heat hypersensitivity, persistence of heat perception, cold hyperalgesia, and cold analgesia. Copyright © 2016 Elsevier Inc. All rights reserved.

Analysis of mitochondrial DNA in Bolivian llama, alpaca and vicuna populations: a contribution to the phylogeny of the South American camelids.

PubMed

Barreta, J; Gutiérrez-Gil, B; Iñiguez, V; Saavedra, V; Chiri, R; Latorre, E; Arranz, J J

2013-04-01

The objectives of this work were to assess the mtDNA diversity of Bolivian South American camelid (SAC) populations and to shed light on the evolutionary relationships between the Bolivian camelids and other populations of SACs. We have analysed two different mtDNA regions: the complete coding region of the MT-CYB gene and 513 bp of the D-loop region. The populations sampled included Bolivian llamas, alpacas and vicunas, and Chilean guanacos. High levels of genetic diversity were observed in the studied populations. In general, MT-CYB was more variable than D-loop. On a species level, the vicunas showed the lowest genetic variability, followed by the guanacos, alpacas and llamas. Phylogenetic analyses performed by including additional available mtDNA sequences from the studied species confirmed the existence of the two monophyletic clades previously described by other authors for guanacos (G) and vicunas (V). Significant levels of mtDNA hybridization were found in the domestic species. Our sequence analyses revealed significant sequence divergence within clade G, and some of the Bolivian llamas grouped with the majority of the southern guanacos. This finding supports the existence of more than the one llama domestication centre in South America previously suggested on the basis of archaeozoological evidence. Additionally, analysis of D-loop sequences revealed two new matrilineal lineages that are distinct from the previously reported G and V clades. The results presented here represent the first report on the population structure and genetic variability of Bolivian camelids and may help to elucidate the complex and dynamic domestication process of SAC populations. © 2012 The Authors, Animal Genetics © 2012 Stichting International Foundation for Animal Genetics.

Comparative genetic structure of two mangrove species in Caribbean and Pacific estuaries of Panama

PubMed Central

2012-01-01

Background Mangroves are ecologically important and highly threatened forest communities. Observational and genetic evidence has confirmed the long distance dispersal capacity of water-dispersed mangrove seeds, but less is known about the relative importance of pollen vs. seed gene flow in connecting populations. We analyzed 980 Avicennia germinans for 11 microsatellite loci and 940 Rhizophora mangle for six microsatellite loci and subsampled two non-coding cpDNA regions in order to understand population structure, and gene flow within and among four major estuaries on the Caribbean and Pacific coasts of Panama. Results Both species showed similar rates of outcrossing (t= 0.7 in A. germinans and 0.8 in R. mangle) and strong patterns of spatial genetic structure within estuaries, although A. germinans had greater genetic structure in nuclear and cpDNA markers (7 demes > 4 demes and Sp= 0.02 > 0.002), and much greater cpDNA diversity (Hd= 0.8 > 0.2) than R. mangle. The Central American Isthmus serves as an exceptionally strong barrier to gene flow, with high levels nuclear (FST= 0.3-0.5) and plastid (FST= 0.5-0.8) genetic differentiation observed within each species between coasts and no shared cpDNA haplotypes between species on each coast. Finally, evidence of low ratios of pollen to seed dispersal (r = −0.6 in A. germinans and 7.7 in R. mangle), coupled with the strong observed structure in nuclear and plastid DNA among most estuaries, suggests low levels of gene flow in these mangrove species. Conclusions We conclude that gene dispersal in mangroves is usually limited within estuaries and that coastal geomorphology and rare long distance dispersal events could also influence levels of structure. PMID:23078287

Exome-wide association study identifies genetic polymorphisms of C12orf51, MYL2, and ALDH2 associated with blood lead levels in the general Korean population.

PubMed

Eom, Sang-Yong; Hwang, Myung Sil; Lim, Ji-Ae; Choi, Byung-Sun; Kwon, Ho-Jang; Park, Jung-Duck; Kim, Yong-Dae; Kim, Heon

2017-02-17

Lead (Pb) is a ubiquitous toxic metal present in the environment that poses adverse health effects to humans. Inter-individual variation in blood Pb levels is affected by various factors, including genetic makeup. However, limited data are available on the association between genetic variation and blood Pb levels. The purpose of this study was to identify the genetic markers associated with blood Pb levels in the Korean population. The study subjects consisted of 1,483 healthy adults with no history of occupational exposure to Pb. We measured blood Pb levels and calculated probable daily intake of Pb according to dietary data collected using 24-hour recall. We conducted exome-wide association screening using Illumina Human Exome-12v1.2 platform (n = 500) and a replication analysis using VeraCode Goldengate assay (n = 1,483). Among the 244,770 single nucleotide polymorphisms (SNPs) tested, 12 SNPs associated with blood Pb level were identified, with suggestive significance level (P < 1 × 10 -4 ). In the Goldengate assay for replication, three SNPs (C12orf51 rs11066280, MYL2 rs12229654, and ALDH2 rs671) were associated with statistically suggestively significant differences in blood Pb levels. When stratified by drinking status, a potential association of C12orf51 rs11066280, MYL2 rs12229654, and ALDH2 rs671 with blood Pb level was observed only in drinkers. A marginally significant gene-environment interaction between ALDH2 rs671 and alcohol consumption was observed in relation to blood Pb levels. The effects of the three suggestively significant SNPs on blood Pb levels was dependent on daily calcium intake amounts. This exome-wide association study indicated that C12orf51 rs11066280, MYL2 rs12229654, and ALDH2 rs671 polymorphisms are linked to blood Pb levels in the Korean population. Our results suggest that these three SNPs are involved in the determination of Pb levels in Koreans via the regulation of alcohol drinking behavior, and that their negative effects may be compensated by appropriate calcium intake.

Genetic variation and population structure of the mixed-mating cactus, Melocactus curvispinus (Cactaceae).

PubMed

Nassar, J M; Hamrick, J L; Fleming, T H

2001-07-01

Genetic diversity was measured in the mixed-mating cactus, Melocactus curvispinus, in Venezuela. Allozyme diversity was surveyed in 19 putative loci over 18 populations. Compared to other plant taxa, this cactus is rich in polymorphic loci (Ps=89.5%), with high numbers of alleles per polymorphic locus (APs=3.82), but moderate levels of heterozygosity (Hes=0.145). Substantial levels of inbreeding were detected across loci and populations at macrogeographic (FIS=0.348) and regional levels (FIS=0.194-0.402). Moderate levels of genetic differentiation among populations were detected at macrogeographical (FST=0.193) and regional (FST=0.084-0.187) scales, suggesting that gene flow is relatively restricted, but increases within regions without topographic barriers. The population genetic structure observed for this cactus was attributed to, at least, three factors: short-distance pollination and seed dispersal, the mixed-mating condition of the species, and genetic drift. High genetic identities between populations (I=0.942) supported the conspecific nature of all populations surveyed. The levels and patterns of genetic structure observed for M. curvispinus were consistent with its mating system and gene dispersal mechanisms.

Viterbi decoding for satellite and space communication.

NASA Technical Reports Server (NTRS)

Heller, J. A.; Jacobs, I. M.

1971-01-01

Convolutional coding and Viterbi decoding, along with binary phase-shift keyed modulation, is presented as an efficient system for reliable communication on power limited satellite and space channels. Performance results, obtained theoretically and through computer simulation, are given for optimum short constraint length codes for a range of code constraint lengths and code rates. System efficiency is compared for hard receiver quantization and 4 and 8 level soft quantization. The effects on performance of varying of certain parameters relevant to decoder complexity and cost are examined. Quantitative performance degradation due to imperfect carrier phase coherence is evaluated and compared to that of an uncoded system. As an example of decoder performance versus complexity, a recently implemented 2-Mbit/sec constraint length 7 Viterbi decoder is discussed. Finally a comparison is made between Viterbi and sequential decoding in terms of suitability to various system requirements.

How Color Coding Formulaic Writing Enhances Organization: A Qualitative Approach for Measuring Student Affect

ERIC Educational Resources Information Center

Geigle, Bryce A.

2014-01-01

The aim of this thesis is to investigate and present the status of student synthesis with color coded formula writing for grade level six through twelve, and to make recommendations for educators to teach writing structure through a color coded formula system in order to increase classroom engagement and lower students' affect. The thesis first…

[Complexity level simulation in the German diagnosis-related groups system: the financial effect of coding of comorbidity diagnostics in urology].

PubMed

Wenke, A; Gaber, A; Hertle, L; Roeder, N; Pühse, G

2012-07-01

Precise and complete coding of diagnoses and procedures is of value for optimizing revenues within the German diagnosis-related groups (G-DRG) system. The implementation of effective structures for coding is cost-intensive. The aim of this study was to prove whether higher costs can be refunded by complete acquisition of comorbidities and complications. Calculations were based on DRG data of the Department of Urology, University Hospital of Münster, Germany, covering all patients treated in 2009. The data were regrouped and subjected to a process of simulation (increase and decrease of patient clinical complexity levels, PCCL) with the help of recently developed software. In urology a strong dependency of quantity and quality of coding of secondary diagnoses on PCCL and subsequent profits was found. Departmental budgetary procedures can be optimized when coding is effective. The new simulation tool can be a valuable aid to improve profits available for distribution. Nevertheless, calculation of time use and financial needs by this procedure are subject to specific departmental terms and conditions. Completeness of coding of (secondary) diagnoses must be the ultimate administrative goal of patient case documentation in urology.

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.

Design of two-dimensional zero reference codes with cross-entropy method.

PubMed

Chen, Jung-Chieh; Wen, Chao-Kai

2010-06-20

We present a cross-entropy (CE)-based method for the design of optimum two-dimensional (2D) zero reference codes (ZRCs) in order to generate a zero reference signal for a grating measurement system and achieve absolute position, a coordinate origin, or a machine home position. In the absence of diffraction effects, the 2D ZRC design problem is known as the autocorrelation approximation. Based on the properties of the autocorrelation function, the design of the 2D ZRC is first formulated as a particular combination optimization problem. The CE method is then applied to search for an optimal 2D ZRC and thus obtain the desirable zero reference signal. Computer simulation results indicate that there are 15.38% and 14.29% reductions in the second maxima value for the 16x16 grating system with n(1)=64 and the 100x100 grating system with n(1)=300, respectively, where n(1) is the number of transparent pixels, compared with those of the conventional genetic algorithm.

Acquisition Handbook - Update. Comprehensive Approach to Reusable Defensive Software (CARDS)

DTIC Science & Technology

1994-03-25

designs, and implementation components (source code, test plans, procedures and results, and system/software documentation). This handbook provides a...activities where software components are acquired, evaluated, tested and sometimes modified. In addition to serving as a facility for the acquisition and...systems from such components [1]. Implementation components are at the lowest level and consist of: specifications; detailed designs; code, test

NATURAL AND ENGINEERED CODING VARIATION IN ANTIDEPRESSANT-SENSITIVE SEROTONIN TRANSPORTERS

PubMed Central

YE, R.; BLAKELY, R. D.

2013-01-01

The presynaptic serotonin (5-HT) transporter (SERT) is a key regulator of 5-HT signaling and is a major target for antidepressant medications and psychostimulants. In recent years, studies of natural and engineered genetic variation in SERT have provided new opportunities to understand structural dimensions of drug interactions and regulation of the transporter, to explore 5-HT contributions to antidepressant action, and to assess the impact of SERT-mediated 5-HT contributions to neuropsychiatric disorders. Here we review three examples from our recent studies where genetic changes in SERT, identified or engineered, have led to new models, findings, and theories that cast light on new dimensions of 5-HT action in the CNS and periphery. First, we review our work to identify specific residues through which SERT recognizes antagonists, and the conversion of this knowledge to the creation of mice lacking high-affinity antidepressant and cocaine sensitivity. Second, we discuss our studies of functional coding variation in SERT that exists in commonly used strains of inbred mice, and how this variation is beginning to reveal novel 5-HT-associated phenotypes. Third, we review our identification and functional characterization of multiple, hyperactive SERT coding variants in subjects with autism. Each of these activities has driven the development of new model systems that can be further exploited to understand the contribution of 5-HT signaling to risk for neuropsychiatric disorders and their treatment. PMID:21893166

Advanced Design of Dumbbell-shaped Genetic Minimal Vectors Improves Non-coding and Coding RNA Expression.

PubMed

Jiang, Xiaoou; Yu, Han; Teo, Cui Rong; Tan, Genim Siu Xian; Goh, Sok Chin; Patel, Parasvi; Chua, Yiqiang Kevin; Hameed, Nasirah Banu Sahul; Bertoletti, Antonio; Patzel, Volker

2016-09-01

Dumbbell-shaped DNA minimal vectors lacking nontherapeutic genes and bacterial sequences are considered a stable, safe alternative to viral, nonviral, and naked plasmid-based gene-transfer systems. We investigated novel molecular features of dumbbell vectors aiming to reduce vector size and to improve the expression of noncoding or coding RNA. We minimized small hairpin RNA (shRNA) or microRNA (miRNA) expressing dumbbell vectors in size down to 130 bp generating the smallest genetic expression vectors reported. This was achieved by using a minimal H1 promoter with integrated transcriptional terminator transcribing the RNA hairpin structure around the dumbbell loop. Such vectors were generated with high conversion yields using a novel protocol. Minimized shRNA-expressing dumbbells showed accelerated kinetics of delivery and transcription leading to enhanced gene silencing in human tissue culture cells. In primary human T cells, minimized miRNA-expressing dumbbells revealed higher stability and triggered stronger target gene suppression as compared with plasmids and miRNA mimics. Dumbbell-driven gene expression was enhanced up to 56- or 160-fold by implementation of an intron and the SV40 enhancer compared with control dumbbells or plasmids. Advanced dumbbell vectors may represent one option to close the gap between durable expression that is achievable with integrating viral vectors and short-term effects triggered by naked RNA.

Gene and genon concept: coding versus regulation

PubMed Central

2007-01-01

We analyse here the definition of the gene in order to distinguish, on the basis of modern insight in molecular biology, what the gene is coding for, namely a specific polypeptide, and how its expression is realized and controlled. Before the coding role of the DNA was discovered, a gene was identified with a specific phenotypic trait, from Mendel through Morgan up to Benzer. Subsequently, however, molecular biologists ventured to define a gene at the level of the DNA sequence in terms of coding. As is becoming ever more evident, the relations between information stored at DNA level and functional products are very intricate, and the regulatory aspects are as important and essential as the information coding for products. This approach led, thus, to a conceptual hybrid that confused coding, regulation and functional aspects. In this essay, we develop a definition of the gene that once again starts from the functional aspect. A cellular function can be represented by a polypeptide or an RNA. In the case of the polypeptide, its biochemical identity is determined by the mRNA prior to translation, and that is where we locate the gene. The steps from specific, but possibly separated sequence fragments at DNA level to that final mRNA then can be analysed in terms of regulation. For that purpose, we coin the new term “genon”. In that manner, we can clearly separate product and regulative information while keeping the fundamental relation between coding and function without the need to introduce a conceptual hybrid. In mRNA, the program regulating the expression of a gene is superimposed onto and added to the coding sequence in cis - we call it the genon. The complementary external control of a given mRNA by trans-acting factors is incorporated in its transgenon. A consequence of this definition is that, in eukaryotes, the gene is, in most cases, not yet present at DNA level. Rather, it is assembled by RNA processing, including differential splicing, from various pieces, as steered by the genon. It emerges finally as an uninterrupted nucleic acid sequence at mRNA level just prior to translation, in faithful correspondence with the amino acid sequence to be produced as a polypeptide. After translation, the genon has fulfilled its role and expires. The distinction between the protein coding information as materialised in the final polypeptide and the processing information represented by the genon allows us to set up a new information theoretic scheme. The standard sequence information determined by the genetic code expresses the relation between coding sequence and product. Backward analysis asks from which coding region in the DNA a given polypeptide originates. The (more interesting) forward analysis asks in how many polypeptides of how many different types a given DNA segment is expressed. This concerns the control of the expression process for which we have introduced the genon concept. Thus, the information theoretic analysis can capture the complementary aspects of coding and regulation, of gene and genon. PMID:18087760

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.

Temporal Code-Driven Stimulation: Definition and Application to Electric Fish Signaling

PubMed Central

Lareo, Angel; Forlim, Caroline G.; Pinto, Reynaldo D.; Varona, Pablo; Rodriguez, Francisco de Borja

2016-01-01

Closed-loop activity-dependent stimulation is a powerful methodology to assess information processing in biological systems. In this context, the development of novel protocols, their implementation in bioinformatics toolboxes and their application to different description levels open up a wide range of possibilities in the study of biological systems. We developed a methodology for studying biological signals representing them as temporal sequences of binary events. A specific sequence of these events (code) is chosen to deliver a predefined stimulation in a closed-loop manner. The response to this code-driven stimulation can be used to characterize the system. This methodology was implemented in a real time toolbox and tested in the context of electric fish signaling. We show that while there are codes that evoke a response that cannot be distinguished from a control recording without stimulation, other codes evoke a characteristic distinct response. We also compare the code-driven response to open-loop stimulation. The discussed experiments validate the proposed methodology and the software toolbox. PMID:27766078

Temporal Code-Driven Stimulation: Definition and Application to Electric Fish Signaling.

PubMed

Lareo, Angel; Forlim, Caroline G; Pinto, Reynaldo D; Varona, Pablo; Rodriguez, Francisco de Borja

2016-01-01

Closed-loop activity-dependent stimulation is a powerful methodology to assess information processing in biological systems. In this context, the development of novel protocols, their implementation in bioinformatics toolboxes and their application to different description levels open up a wide range of possibilities in the study of biological systems. We developed a methodology for studying biological signals representing them as temporal sequences of binary events. A specific sequence of these events (code) is chosen to deliver a predefined stimulation in a closed-loop manner. The response to this code-driven stimulation can be used to characterize the system. This methodology was implemented in a real time toolbox and tested in the context of electric fish signaling. We show that while there are codes that evoke a response that cannot be distinguished from a control recording without stimulation, other codes evoke a characteristic distinct response. We also compare the code-driven response to open-loop stimulation. The discussed experiments validate the proposed methodology and the software toolbox.

Plenary III-04: Media Messages and Public Perceptions of Direct-to-Consumer Genetics: Results of a Media Analysis and Focus Group Study

PubMed Central

Rahm, Alanna Kulchak; Dearing, James; Feigelson, Heather Spencer; Tracer, David; Bull, Sheana

2011-01-01

Background Information about genetics and the promise of genomic medicine is commonplace in the mass media. How the mass media themselves contribute – or not – to the persistence of this issue and its perception by the public is the topic of this presentation. The purpose of this study is to investigate the structural and individual perspectives on the issue of direct-to-consumer (DTC) genetics, and assess the degree of correspondence across these perspectives. Methods I conducted a media analysis to determine how the issue of DTC genetics has been framed in mass media stories and the salient topics related to the issue. I conducted focus groups to determine individual knowledge, attitudes and beliefs about the issue of DTC genetics. Results A final sample of 398 mass media stories of DTC genetics from Lexis-Nexis Academic archives between September 1, 2007 and September 30, 2009 were coded for salience and frames. Fourteen focus groups were conducted between October, 2009 and March, 2010 with Kaiser Permanente Colorado members and medical staff. Focus group transcripts were coded for salience and framing of the issue and compared with the media analysis results.Study results found that the issue of DTC genetics was not very important to focus group participants except as it related to the topic of breast cancer. Mass media message topics and frames showed differences over time. Focus group participants were generally negative towards the issue while the mass media was mostly positive towards DTC genetics. Focus group participants used some of the many frames to understand the issue that were utilized by the mass media to package the issue, but participants mainly framed the issue in terms of prevention and a pandora’s box, while the mass media presented the issue more in terms of progressive and discrimination frames. Conclusions The mass media appears to function as a field of power for the issue of DTC genetics with the consumers in the middle of the contests. A higher-level concept of an “informed consumer” emerged from the focus groups that appears to provide consumers a degree of power in this battlefield as well.

Evolvable Neural Software System

NASA Technical Reports Server (NTRS)

Curtis, Steven A.

2009-01-01

The Evolvable Neural Software System (ENSS) is composed of sets of Neural Basis Functions (NBFs), which can be totally autonomously created and removed according to the changing needs and requirements of the software system. The resulting structure is both hierarchical and self-similar in that a given set of NBFs may have a ruler NBF, which in turn communicates with other sets of NBFs. These sets of NBFs may function as nodes to a ruler node, which are also NBF constructs. In this manner, the synthetic neural system can exhibit the complexity, three-dimensional connectivity, and adaptability of biological neural systems. An added advantage of ENSS over a natural neural system is its ability to modify its core genetic code in response to environmental changes as reflected in needs and requirements. The neural system is fully adaptive and evolvable and is trainable before release. It continues to rewire itself while on the job. The NBF is a unique, bilevel intelligence neural system composed of a higher-level heuristic neural system (HNS) and a lower-level, autonomic neural system (ANS). Taken together, the HNS and the ANS give each NBF the complete capabilities of a biological neural system to match sensory inputs to actions. Another feature of the NBF is the Evolvable Neural Interface (ENI), which links the HNS and ANS. The ENI solves the interface problem between these two systems by actively adapting and evolving from a primitive initial state (a Neural Thread) to a complicated, operational ENI and successfully adapting to a training sequence of sensory input. This simulates the adaptation of a biological neural system in a developmental phase. Within the greater multi-NBF and multi-node ENSS, self-similar ENI s provide the basis for inter-NBF and inter-node connectivity.

Genome-wide association meta-analysis in 269,867 individuals identifies new genetic and functional links to intelligence.

PubMed

Savage, Jeanne E; Jansen, Philip R; Stringer, Sven; Watanabe, Kyoko; Bryois, Julien; de Leeuw, Christiaan A; Nagel, Mats; Awasthi, Swapnil; Barr, Peter B; Coleman, Jonathan R I; Grasby, Katrina L; Hammerschlag, Anke R; Kaminski, Jakob A; Karlsson, Robert; Krapohl, Eva; Lam, Max; Nygaard, Marianne; Reynolds, Chandra A; Trampush, Joey W; Young, Hannah; Zabaneh, Delilah; Hägg, Sara; Hansell, Narelle K; Karlsson, Ida K; Linnarsson, Sten; Montgomery, Grant W; Muñoz-Manchado, Ana B; Quinlan, Erin B; Schumann, Gunter; Skene, Nathan G; Webb, Bradley T; White, Tonya; Arking, Dan E; Avramopoulos, Dimitrios; Bilder, Robert M; Bitsios, Panos; Burdick, Katherine E; Cannon, Tyrone D; Chiba-Falek, Ornit; Christoforou, Andrea; Cirulli, Elizabeth T; Congdon, Eliza; Corvin, Aiden; Davies, Gail; Deary, Ian J; DeRosse, Pamela; Dickinson, Dwight; Djurovic, Srdjan; Donohoe, Gary; Conley, Emily Drabant; Eriksson, Johan G; Espeseth, Thomas; Freimer, Nelson A; Giakoumaki, Stella; Giegling, Ina; Gill, Michael; Glahn, David C; Hariri, Ahmad R; Hatzimanolis, Alex; Keller, Matthew C; Knowles, Emma; Koltai, Deborah; Konte, Bettina; Lahti, Jari; Le Hellard, Stephanie; Lencz, Todd; Liewald, David C; London, Edythe; Lundervold, Astri J; Malhotra, Anil K; Melle, Ingrid; Morris, Derek; Need, Anna C; Ollier, William; Palotie, Aarno; Payton, Antony; Pendleton, Neil; Poldrack, Russell A; Räikkönen, Katri; Reinvang, Ivar; Roussos, Panos; Rujescu, Dan; Sabb, Fred W; Scult, Matthew A; Smeland, Olav B; Smyrnis, Nikolaos; Starr, John M; Steen, Vidar M; Stefanis, Nikos C; Straub, Richard E; Sundet, Kjetil; Tiemeier, Henning; Voineskos, Aristotle N; Weinberger, Daniel R; Widen, Elisabeth; Yu, Jin; Abecasis, Goncalo; Andreassen, Ole A; Breen, Gerome; Christiansen, Lene; Debrabant, Birgit; Dick, Danielle M; Heinz, Andreas; Hjerling-Leffler, Jens; Ikram, M Arfan; Kendler, Kenneth S; Martin, Nicholas G; Medland, Sarah E; Pedersen, Nancy L; Plomin, Robert; Polderman, Tinca J C; Ripke, Stephan; van der Sluis, Sophie; Sullivan, Patrick F; Vrieze, Scott I; Wright, Margaret J; Posthuma, Danielle

2018-06-25

Intelligence is highly heritable 1 and a major determinant of human health and well-being 2 . Recent genome-wide meta-analyses have identified 24 genomic loci linked to variation in intelligence 3-7 , but much about its genetic underpinnings remains to be discovered. Here, we present a large-scale genetic association study of intelligence (n = 269,867), identifying 205 associated genomic loci (190 new) and 1,016 genes (939 new) via positional mapping, expression quantitative trait locus (eQTL) mapping, chromatin interaction mapping, and gene-based association analysis. We find enrichment of genetic effects in conserved and coding regions and associations with 146 nonsynonymous exonic variants. Associated genes are strongly expressed in the brain, specifically in striatal medium spiny neurons and hippocampal pyramidal neurons. Gene set analyses implicate pathways related to nervous system development and synaptic structure. We confirm previous strong genetic correlations with multiple health-related outcomes, and Mendelian randomization analysis results suggest protective effects of intelligence for Alzheimer's disease and ADHD and bidirectional causation with pleiotropic effects for schizophrenia. These results are a major step forward in understanding the neurobiology of cognitive function as well as genetically related neurological and psychiatric disorders.

Breeding system and demography shape population genetic structure across ecological and climatic zones in the African freshwater snail, Bulinus forskalii (Gastropoda, Pulmonata), intermediate host for schistosomes.

PubMed

Gow, J L; Noble, L R; Rollinson, D; Mimpfoundi, R; Jones, C S

2004-11-01

The role of breeding system and population bottlenecks in shaping the distribution of neutral genetic variation among populations inhabiting patchily distributed, ephemeral water bodies was examined for the hermaphroditic freshwater snail Bulinus forskalii, intermediate host for the medically important trematode Schistosoma guineensis. Levels of genetic variation at 11 microsatellite loci were assessed for 600 individuals sampled from 19 populations that span three ecological and climatic zones (ecozones) in Cameroon, West Africa. Significant heterozygote deficiencies and linkage disequilibria indicated very high selfing rates in these populations. Despite this and the large genetic differentiation detected between populations, high levels of genetic variation were harboured within these populations. The high level of gene flow inferred from assignment tests may be responsible for this pattern. Indeed, metapopulation dynamics, including high levels of gene flow as well as extinction/contraction and recolonization events, are invoked to account for the observed population structuring, which was not a consequence of isolation-by-distance. Because B. forskalii populations inhabiting the northern, Sahelian area are subject to more pronounced annual cycles of drought and flood than the southern equatorial ones, they were expected to be subject to population bottlenecks of increased frequency and severity and, therefore, show reduced genetic variability and elevated population differentiation. Contrary to predictions, the populations inhabiting the most northerly ecozone exhibited higher genetic diversity and lower genetic differentiation than those in the most southerly one, suggesting that elevated gene flow in this region is counteracting genetic drift.

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.

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

Automated Translation of Safety Critical Application Software Specifications into PLC Ladder Logic

NASA Technical Reports Server (NTRS)

Leucht, Kurt W.; Semmel, Glenn S.

2008-01-01

The numerous benefits of automatic application code generation are widely accepted within the software engineering community. A few of these benefits include raising the abstraction level of application programming, shorter product development time, lower maintenance costs, and increased code quality and consistency. Surprisingly, code generation concepts have not yet found wide acceptance and use in the field of programmable logic controller (PLC) software development. Software engineers at the NASA Kennedy Space Center (KSC) recognized the need for PLC code generation while developing their new ground checkout and launch processing system. They developed a process and a prototype software tool that automatically translates a high-level representation or specification of safety critical application software into ladder logic that executes on a PLC. This process and tool are expected to increase the reliability of the PLC code over that which is written manually, and may even lower life-cycle costs and shorten the development schedule of the new control system at KSC. This paper examines the problem domain and discusses the process and software tool that were prototyped by the KSC software engineers.

A Secure and Robust Approach to Software Tamper Resistance

NASA Astrophysics Data System (ADS)

Ghosh, Sudeep; Hiser, Jason D.; Davidson, Jack W.

Software tamper-resistance mechanisms have increasingly assumed significance as a technique to prevent unintended uses of software. Closely related to anti-tampering techniques are obfuscation techniques, which make code difficult to understand or analyze and therefore, challenging to modify meaningfully. This paper describes a secure and robust approach to software tamper resistance and obfuscation using process-level virtualization. The proposed techniques involve novel uses of software check summing guards and encryption to protect an application. In particular, a virtual machine (VM) is assembled with the application at software build time such that the application cannot run without the VM. The VM provides just-in-time decryption of the program and dynamism for the application's code. The application's code is used to protect the VM to ensure a level of circular protection. Finally, to prevent the attacker from obtaining an analyzable snapshot of the code, the VM periodically discards all decrypted code. We describe a prototype implementation of these techniques and evaluate the run-time performance of applications using our system. We also discuss how our system provides stronger protection against tampering attacks than previously described tamper-resistance approaches.