Refatoração do código genético para aumento da capacidade evolutiva

terça-feira, agosto 14, 2018

Refactoring the Genetic Code for Increased Evolvability

Gur Pines a,b, James D. Winkler a,b*, Assaf Pines, Ryan T. Gilla, b

a Renewable and Sustainable Energy Institute, University of Colorado Boulder, Boulder, Colorado, USA

b Department of Chemical and Biological Engineering, University of Colorado Boulder, Boulder, Colorado, USA

Sang Yup Lee, Editor

- Author Affiliations

Korea Advanced Institute of Science and Technology

+ Author Notes

↵* Present address: James D. Winkler, Shell Biodomain, Houston, Texas, USA.

Address correspondence to Gur Pines, gur.pines@colorado.edu.

G.P. and J.D.W. contributed equally to this work.


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 single 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.

KEYWORDS evolution genetic code genome synthesis saturation mutagenesis

FOOTNOTES

Citation Pines G, Winkler JD, Pines A, Gill RT. 2017. Refactoring the genetic code for increased evolvability. mBio 8:e01654-17.

Received 7 September 2017 Accepted 10 October 2017 Published 14 November 2017

Copyright © 2017 Pines et al.

This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

FREE PDF GRATIS: mBio

Defendendo o paradigma dos três domínios de vida de Carl Woese

In defence of the three-domains of life paradigm

P.T.S. van der Gulik, W.D. Hoff and D. Speijer

BMC Evolutionary BiologyBMC series – open, inclusive and trusted 201717:218


Received: 27 April 2017 Accepted: 1 September 2017 Published: 19 September 2017

Source/Fonte: OpenI

Abstract

Background

Recently, important discoveries regarding the archaeon that functioned as the “host” in the merger with a bacterium that led to the eukaryotes, its “complex” nature, and its phylogenetic relationship to eukaryotes, have been reported. Based on these new insights proposals have been put forward to get rid of the three-domain Model of life, and replace it with a two-domain model.

Results

We present arguments (both regarding timing, complexity, and chemical nature of specific evolutionary processes, as well as regarding genetic structure) to resist such proposals. The three-domain Model represents an accurate description of the differences at the most fundamental level of living organisms, as the eukaryotic lineage that arose from this unique merging event is distinct from both Archaea and Bacteria in a myriad of crucial ways.

Conclusions

We maintain that “a natural system of organisms”, as proposed when the three-domain Model of life was introduced, should not be revised when considering the recent discoveries, however exciting they may be.

Keywords Eucarya LECA Phylogenetics Eukaryogenesis Three-domain model

FREE PDF GRATIS: BMC Evolutionary Biology

Carl R. Woese, o cientista que mexeu profundamente na árvore da vida de Darwin e no entendimento da origem e evolução da vida

The Scientist Who Scrambled Darwin’s Tree of Life

How the microbiologist Carl Woese fundamentally changed the way we think about evolution and the origins of life.

By David Quammen

Source/Fonte: Science

Aug. 13, 2018

On Nov. 3, 1977, a new scientific revolution was heralded to the world — but it came cryptically, in slightly confused form. The front page of that day’s New York Times carried a headline: “Scientists Discover a Form of Life That Predates Higher Organisms.” A photograph showed a man named Carl R. Woese, a microbiologist at the University of Illinois in Urbana, with his feet up on his office desk. He was 50ish, with unruly hair, wearing a sport shirt and Adidas sneakers. Behind him was a blackboard, on which was scrawled a simple treelike figure in chalk. The article, by a veteran Times reporter named Richard D. Lyons, began:

Scientists studying the evolution of primitive organisms reported today the existence of a separate form of life that is hard to find in nature. They described it as a “third kingdom” of living material, composed of ancestral cells that abhor oxygen, digest carbon dioxide and produce methane.

This “separate form of life” would become known as the archaea, reflecting the impression that these organisms were primitive, primordial, especially old. They were single-celled creatures, simple in structure, with no cell nucleus. Through a microscope, they looked like bacteria, and they had been mistaken for bacteria by all earlier microbiologists. They lived in extreme environments, at least some of them — hot springs, salty lakes, sewage — and some had unusual metabolic habits, such as metabolizing without oxygen and, as the Times account said, producing methane.

But these archaea, these whatevers, were drastically unlike bacteria if you looked at their DNA, which is what (indirectly) Woese had done. They lacked certain bits that characterized all bacteria, and they contained other bits that shouldn’t have been present. They constituted a “third kingdom” of living creatures because they fit within neither of the existing two, the bacterial kingdom (bacteria) and the kingdom of everything else (eukarya), including animals and plants, amoebas and fungi, you and me.

Charles Darwin himself suggested (first in an early notebook, later in “On the Origin of Species”) that the history of life could be drawn as a tree — all creatures originating in a single trunk, then diverging into different lineages like major limbs, branches and twigs, with leaves of the canopy representing the multiplicity of living species. But if that simile was valid, then the prevailing tree of 1977, the orthodox image of life’s history, was wrong. It showed two major limbs arising from the trunk. According to what Woese had just announced to the world, it ought to show three.

...

Read more here: The New York Times

Um cálculo do DNA total na biosfera: um número fantástico!!!

segunda-feira, agosto 13, 2018

An Estimate of the Total DNA in the Biosphere

Hanna K. E. Landenmark , Duncan H. Forgan, Charles S. Cockell


Fig 1. Storing the total amount of information encoded in DNA in the biosphere, 5.3 × 1031 megabases (Mb), would require approximately 1021 supercomputers with the average storage capacity of the world’s four most powerful supercomputers.

Abstract


Modern whole-organism genome analysis, in combination with biomass estimates, allows us to estimate a lower bound on the total information content in the biosphere: 5.3 × 1031 (±3.6 × 1031) megabases (Mb) of DNA. Given conservative estimates regarding DNA transcription rates, this information content suggests biosphere processing speeds exceeding yottaNOPS values (1024 Nucleotide Operations Per Second). Although prokaryotes evolved at least 3 billion years before plants and animals, we find that the information content of prokaryotes is similar to plants and animals at the present day. This information-based approach offers a new way to quantify anthropogenic and natural processes in the biosphere and its information diversity over time.
Citation: Landenmark HKE, Forgan DH, Cockell CS (2015) An Estimate of the Total DNA in the Biosphere. PLoS Biol 13(6): e1002168. https://doi.org/10.1371/journal.pbio.1002168
Published: June 11, 2015
Copyright: © 2015 Landenmark et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
Funding: The authors received no specific funding for this work.
Competing interests: The authors have declared that no competing interests exist.
FREE PDF GRATIS: PLoS Biology
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Uma brecha para a Teoria do Design Inteligente???
We note that the approach that we propose here (and the analogy of supercomputers) does not necessarily imply a global, Gaia-like superorganism. We merely observe that ultimately all organisms interact with each other and the environment. Thus, the information being processed in the biosphere is interlinked in a large mass of organisms, however one chooses to conceptualise this. It does not have to be considered as a single, self-regulating organism. The manner in which the total information in the biosphere is processed, and the degree to which it is coordinated and interlinked in feedback processes, is another matter, but one that could be investigated using an information-based approach.

Sobre a eficiência do código genético após mutações frameshift

On the efficiency of the genetic code after frameshift mutations

Regine Geyer​, Amir Madany Mamlouk​​

Published May 21, 2018

Author and article information

Institute for Neuro- and Bioinformatics, University of Lübeck, Lübeck, Germany


Published 2018-05-21 Accepted 2018-05-02 Received 2017-10-02

Academic Editor Thomas Tullius

Subject Areas Bioinformatics, Evolutionary Studies, Genetics

Keywords Standard genetic code, Overlapping codes, Frameshift mutation, Polar requirement

Copyright

© 2018 Geyer and Madany Mamlouk

Licence

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, reproduction and adaptation in any medium and for any purpose provided that it is properly attributed. For attribution, the original author(s), title, publication source (PeerJ) and either DOI or URL of the article must be cited.

Cite this article

Geyer R, Madany Mamlouk A. (2018) On the efficiency of the genetic code after frameshift mutations. PeerJ 6:e4825 https://doi.org/10.7717/peerj.4825


Abstract

Statistical and biochemical studies of the standard genetic code (SGC) have found evidence that the impact of mistranslations is minimized in a way that erroneous codes are either synonymous or code for an amino acid with similar polarity as the originally coded amino acid. It could be quantified that the SGC is optimized to protect this specific chemical property as good as possible. In recent work, it has been speculated that the multilevel optimization of the genetic code stands in the wider context of overlapping codes. This work tries to follow the systematic approach on mistranslations and to extend those analyses to the general effect of frameshift mutations on the polarity conservation of amino acids. We generated one million random codes and compared their average polarity change over all triplets and the whole set of possible frameshift mutations. While the natural code—just as for the point mutations—appears to be competitively robust against frameshift mutations as well, we found that both optimizations appear to be independent of each other. For both, better codes can be found, but it becomes significantly more difficult to find candidates that optimize all of these features—just like the SGC does. We conclude that the SGC is not only very efficient in minimizing the consequences of mistranslations, but rather optimized in amino acid polarity conservation for all three effects of code alteration, namely translational errors, point and frameshift mutations. In other words, our result demonstrates that the SGC appears to be much more than just “one in a million”.

Cite this as

Geyer R, Madany Mamlouk A. (2018) On the efficiency of the genetic code after frameshift mutations. PeerJ 6:e4825 https://doi.org/10.7717/peerj.4825

FREE PDF GRATIS: PeerJ

Essas criaturas de 635 milhões de anos eram animais diferentes de quaisquer animais conhecidos hoje

quinta-feira, agosto 09, 2018

Cambrian petalonamid Stromatoveris phylogenetically links Ediacaran biota to later animals


Jennifer F. Hoyal Cuthill Jian Han


First published: 07 August 2018 https://doi.org/10.1111/pala.12393


Data archiving statementData and supplementary information (including character–taxon matrix and reconstructed phylogenetic trees) for this study are available in MorphoBank: http://morphobank.org/permalink/?P2695 and the Dryad Digital Repository: https://doi.org/10.5061/dryad.5pv4qm3.



Artist’s reconstruction of Stromatoveris, an ancient marine animal
J. HOYAL CUTHILL
Source/Fonte: Science

Abstract

Macro‐organisms of the Ediacaran period (635–541 Ma) were large and morphologically complex, with some living in aphotic habitats, presenting the possibility that they were early animals. However, ‘bizarre’ Ediacaran morphologies and mouldic preservation have frustrated comparison to later taxa. Consequently, both the positions of Ediacaran biota in the tree of life and the origins of the Metazoa have remained disputed. Here we provide phylogenetic evidence to identify Ediacaran macro‐biota as animals, based on 206 new fossils of Stromatoveris psygmoglena from the lower Cambrian Chengjiang Lagerstätte. Exceptionally preserved soft‐tissue anatomy shows that Stromatoveris was a soft‐bodied, radially symmetric animal with multiple, sub‐branched petaloids and a differentiated holdfast. Photo‐referenced morphological character analysis enables phylogenetic reconstruction of a monophyletic clade designated Petalonamae, that unites Stromatoveris with iconic Ediacaran genera (Rangea, Pteridinium, Ernietta, Swartpuntia, Arborea, Pambikalbae and Dickinsonia) and is placed as sister‐group to the Eumetazoa. Therefore, based on phylogenetic bracketing within the Metazoa, the Ediacaran petalonamids are established as animals. From these findings, it follows that petalonamids remained an important component of Cambrian marine ecosystems and that the metazoan radiation can be dated to a minimum age of between 558 and 571 myr.


FREE PDF GRATIS: Palaeontology

Navegação de redes cerebrais: mero acaso, fortuita necessidade ou design inteligente?

quarta-feira, agosto 08, 2018

Navigation of brain networks

Caio Seguin, Martijn P. van den Heuvel, and Andrew Zalesky

PNAS June 12, 2018. 115 (24) 6297-6302; published ahead of print May 30, 2018. https://doi.org/10.1073/pnas.1801351115

Edited by Edward T. Bullmore, University of Cambridge, Cambridge, United Kingdom, and accepted by Editorial Board Member Michael S. Gazzaniga May 7, 2018 (received for review January 24, 2018)


Significance

We show that the combination of topology and geometry in mammalian cortical networks allows for near-optimal decentralized communication under navigation routing. Following a simple propagation rule based on local knowledge of the distance between cortical regions, we demonstrate that brain networks can be successfully navigated with efficiency that is comparable to shortest paths routing. This finding helps to conciliate the major progress achieved over more than a decade of connectomics research, under the assumption of communication via shortest paths, with recent questions raised by the biologically unrealistic requirements involved in the computation of optimal routes. Our results reiterate the importance of the brain’s spatial embedding, suggesting a three-way relationship between connectome geometry, topology, and communication.

Abstract

Understanding the mechanisms of neural communication in large-scale brain networks remains a major goal in neuroscience. We investigated whether navigation is a parsimonious routing model for connectomics. Navigating a network involves progressing to the next node that is closest in distance to a desired destination. We developed a measure to quantify navigation efficiency and found that connectomes in a range of mammalian species (human, mouse, and macaque) can be successfully navigated with near-optimal efficiency (>80% of optimal efficiency for typical connection densities). Rewiring network topology or repositioning network nodes resulted in 45–60% reductions in navigation performance. We found that the human connectome cannot be progressively randomized or clusterized to result in topologies with substantially improved navigation performance (>5%), suggesting a topological balance between regularity and randomness that is conducive to efficient navigation. Navigation was also found to (i) promote a resource-efficient distribution of the information traffic load, potentially relieving communication bottlenecks, and (ii) explain significant variation in functional connectivity. Unlike commonly studied communication strategies in connectomics, navigation does not mandate assumptions about global knowledge of network topology. We conclude that the topology and geometry of brain networks are conducive to efficient decentralized communication.

connectome neural communication network navigation complex networks

FREE PDF GRATIS: PNAS Sup. Info.

Pesquisa lança dúvidas sobre a ideia de que o gene FOXP2 - ligado à evolução da linguagem - seja especial para os humanos modernos

Cell

No Evidence for Recent Selection at FOXP2 among Diverse Human Populations

Elizabeth Grace Atkinson 8, 9, 10 Amanda Jane Audesse Julia Adela Palacios Dean Michael Bobo Ashley Elizabeth Webb Sohini Ramachandran Brenna Mariah Henn Show footnotes

Published:August 02, 2018 DOI:https://doi.org/10.1016/j.cell.2018.06.048


Highlights

No support for positive selection at FOXP2 in large genomic datasets

Sample composition and genomic scale significantly affect selection scans

An intronic ROI within FOXP2 is expressed in human brain cells and cortical tissue

This ROI contains a large amount of constrained, human-specific polymorphisms

Summary

FOXP2, initially identified for its role in human speech, contains two nonsynonymous substitutions derived in the human lineage. Evidence for a recent selective sweep in Homo sapiens, however, is at odds with the presence of these substitutions in archaic hominins. Here, we comprehensively reanalyze FOXP2 in hundreds of globally distributed genomes to test for recent selection. We do not find evidence of recent positive or balancing selection at FOXP2. Instead, the original signal appears to have been due to sample composition. Our tests do identify an intronic region that is enriched for highly conserved sites that are polymorphic among humans, compatible with a loss of function in humans. This region is lowly expressed in relevant tissue types that were tested via RNA-seq in human prefrontal cortex and RT-PCR in immortalized human brain cells. Our results represent a substantial revision to the adaptive history of FOXP2, a gene regarded as vital to human evolution.

Keywords
FOXP2 human evolution population structure natural selection language demography human brain

FREE PDF GRATIS: Cell

Darwin não explica a origem e evolução da linguagem humana

terça-feira, agosto 07, 2018

Front. Psychol., 07 May 2014 | https://doi.org/10.3389/fpsyg.2014.00401

The mystery of language evolution

Marc D. Hauser1*, Charles Yang2, Robert C. Berwick3, Ian Tattersall4, Michael J. Ryan5, Jeffrey Watumull6, Noam Chomsky7 and Richard C. Lewontin8

1Risk-Eraser, LLC, West Falmouth, MA, USA

2Department of Linguistics and Computer and Information Sciences, University of Pennsylvania, Philadelphia, PA, USA

3Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, MA, USA

4Division of Anthropology, American Museum of Natural History, New York, NY, USA

5Department of Integrative Biology, University of Texas, Austin, TX, USA

6Department of Theoretical and Applied Linguistics, Cambridge University, Cambridge, UK

7Department of Linguistics and Philosophy, Massachusetts Institute of Technology, Cambridge, MA, USA

8Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA, USA



Understanding the evolution of language requires evidence regarding origins and processes that led to change. In the last 40 years, there has been an explosion of research on this problem as well as a sense that considerable progress has been made. We argue instead that the richness of ideas is accompanied by a poverty of evidence, with essentially no explanation of how and why our linguistic computations and representations evolved. We show that, to date, (1) studies of nonhuman animals provide virtually no relevant parallels to human linguistic communication, and none to the underlying biological capacity; (2) the fossil and archaeological evidence does not inform our understanding of the computations and representations of our earliest ancestors, leaving details of origins and selective pressure unresolved; (3) our understanding of the genetics of language is so impoverished that there is little hope of connecting genes to linguistic processes any time soon; (4) all modeling attempts have made unfounded assumptions, and have provided no empirical tests, thus leaving any insights into language's origins unverifiable. Based on the current state of evidence, we submit that the most fundamental questions about the origins and evolution of our linguistic capacity remain as mysterious as ever, with considerable uncertainty about the discovery of either relevant or conclusive evidence that can adjudicate among the many open hypotheses. We conclude by presenting some suggestions about possible paths forward.

FREE PDF GRATIS: Frontiers in Psychology

Escutoides - um bloco de construção de organismos multicellulares: sem ele a vida complexa não poderia ter surgido na Terra! Mero acaso, fortuita necessidade ou design inteligente?

Scutoids are a geometrical solution to three-dimensional packing of epithelia

Pedro Gómez-Gálvez, Pablo Vicente-Munuera, Antonio Tagua, Cristina Forja, Ana M. Castro, Marta Letrán, Andrea Valencia-Expósito, Clara Grima, Marina Bermúdez-Gallardo, Óscar Serrano-Pérez-Higueras, Florencia Cavodeassi, Sol Sotillos, María D. Martín-Bermudo, Alberto Márquez, Javier Buceta & Luis M. Escudero 

Nature Communications volume 9, Article number: 2960 (2018) 


Abstract

As animals develop, tissue bending contributes to shape the organs into complex three-dimensional structures. However, the architecture and packing of curved epithelia remains largely unknown. Here we show by means of mathematical modelling that cells in bent epithelia can undergo intercalations along the apico-basal axis. This phenomenon forces cells to have different neighbours in their basal and apical surfaces. As a consequence, epithelial cells adopt a novel shape that we term “scutoid”. The detailed analysis of diverse tissues confirms that generation of apico-basal intercalations between cells is a common feature during morphogenesis. Using biophysical arguments, we propose that scutoids make possible the minimization of the tissue energy and stabilize three-dimensional packing. Hence, we conclude that scutoids are one of nature's solutions to achieve epithelial bending. Our findings pave the way to understand the three-dimensional organization of epithelial organs.

Acknowledgements

M.D.M.-B. and A.V.-E. work was funded by the Ministerio Español de Ciencia y Tecnología (grants numbers BFU2013-48988-C2-1-P and BFU2016-80797 to M.D.M.-B.). A.V.-E. is supported by a FPI studentship (BES-2014-068850) from the Ministerio de Economía y Competitividad. S.S. is supported by grant of the MICINN/FEDER to J.C.-G. Hombría (BFU2016-76528-P). F.C. work is funded by Spanish Government Grant BFU2014-55918 and BBVA Foundation Personal Grant IN[16]_BBM_BAS_0078. J.B. acknowledges core funding by Lehigh University. L.M.E. and P.G.-G. are supported by the Ramón y Cajal program (PI13/01347); L.M.E., A.M., and C.G. work is funded by the Ministry of Economy, Industry, and Competitiveness grant BFU2016-74975-P co-funded by FEDER funds. P.V.-M. is supported by a contract co-funded by the Asociación Fundación Española contra el Cáncer and the Seville University. A.M.C. is supported by Fundación Pública Andaluza Progreso y Salud (Consejería de Salud), ref. PI-0033-2014. C.F. and A.T. is supported by a contract from Sistema Nacional de Garantía Juvenil and Programa Operativo de Empleo Juvenil 2014–2020. We are thankful to Dr. Nicolas Gompel for the picture of the Cetoniidae: Protaetia (Potosia) speciose to illustrate the term “scutoid”. We thank Dr. Paco Martín, Dr. José López-Barneo, Dr. Alberto Pascual, Dr. Colin Adrain and Dr. Matthew Freeman for helpful comments and corrections to the manuscript.

Author information

Author notes

These authors contributed equally: Pedro Gómez-Gálvez, Pablo Vicente-Munuera.

Affiliations

Departamento de Biología Celular, Universidad de Sevilla and Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, 41013, Seville, Spain

Pedro Gómez-Gálvez, Pablo Vicente-Munuera, Antonio Tagua, Cristina Forja, Ana M. Castro, Marta Letrán, Marina Bermúdez-Gallardo, Óscar Serrano-Pérez-Higueras & Luis M. Escudero

CABD, CSIC/JA/UPO, Campus Universidad Pablo de Olavide, 41013, Seville, Spain

Andrea Valencia-Expósito, Sol Sotillos & María D. Martín-Bermudo

Departamento de Matemática Aplicada I, Universidad de Sevilla, 41012, Seville, Spain

Clara Grima & Alberto Márquez

Centro de Biología Molecular Severo Ochoa and CIBER de Enfermedades Raras. C/ Nicolás Cabrera 1, 28049, Madrid, Spain

Florencia Cavodeassi

St. George’s, University of London, Cranmer Terrace, SW17 0RE, London, UK

Florencia Cavodeassi

Bioengineering Department, Lehigh University, Bethlehem, PA, 18018, USA

Javier Buceta

Chemical and Biomolecular Engineering Department, Lehigh University, Bethlehem, PA, 18018, USA

Javier Buceta

Contributions

L.M.E. designed the study with help from A.M., C.G., and J.B. P.G.-G. and P.V.-M. wrote the software for the mathematical model and performed analyses. A.T., C.F., A.M.C., M.L., A.V.-E., M.B.-G., O.S.-P.-H., F.C., S.S., and M.D.M.-B., collaborated in the obtaining, measurement of parameters and analysis of the confocal images. All authors participated in the interpretation of results, discussions, and the development of the project. J.B. and L.M.E. wrote the manuscript with input from all authors.

Competing interests

The authors declare no competing interests.

Corresponding authors

Correspondence to Javier Buceta or Luis M. Escudero.

A maquinaria majestosa e complexa do espliceossomo: mero acaso, fortuita necessidade ou design inteligente?

segunda-feira, agosto 06, 2018

All-atom simulations disentangle the functional dynamics underlying gene maturation in the intron lariat spliceosome

Lorenzo Casalino, Giulia Palermo, Angelo Spinello, Ursula Rothlisberger, and Alessandra Magistrato

PNAS June 26, 2018. 115 (26) 6584-6589; published ahead of print June 11, 2018. https://doi.org/10.1073/pnas.1802963115

Edited by Michael L. Klein, Temple University, Philadelphia, PA, and approved May 15, 2018 (received for review February 16, 2018)



Significance

Precursor messenger RNA (pre-mRNA) splicing is a crucial step of gene expression, enabling the maturation of pre-mRNA transcripts into protein-coding mRNAs. In humans, a majestic ribonucleoprotein machinery—the spliceosome—governs this fundamental process, the defects and misregulation of which lead to over 200 human diseases. A thorough understanding of splicing is pivotal for biology and medicine, holding the promise of harnessing it for genome modulation applications. Despite the recent breakthroughs gained by cryo-EM, an atomic-resolution picture of the spliceosome functional plasticity is still missing. Here, all-atom simulations elucidate the cooperative motions underlying the functional dynamics of the spliceosome at a late stage of the splicing cycle, suggesting the role of specific proteins involved in the spliceosome disassembly from an atomic-level perspective.

Abstract

The spliceosome (SPL) is a majestic macromolecular machinery composed of five small nuclear RNAs and hundreds of proteins. SPL removes noncoding introns from precursor messenger RNAs (pre-mRNAs) and ligates coding exons, giving rise to functional mRNAs. Building on the first SPL structure solved at near–atomic-level resolution, here we elucidate the functional dynamics of the intron lariat spliceosome (ILS) complex through multi-microsecond-long molecular-dynamics simulations of ∼1,000,000 atoms models. The ILS essential dynamics unveils (i) the leading role of the Spp42 protein, which heads the gene maturation by tuning the motions of distinct SPL components, and (ii) the critical participation of the Cwf19 protein in displacing the intron lariat/U2 branch helix. These findings provide unprecedented details on the SPL functional dynamics, thus contributing to move a step forward toward a thorough understanding of eukaryotic pre-mRNA splicing.

spliceosome splicing molecular dynamics RNA gene maturation

Footnotes

↵1To whom correspondence should be addressed. 
Email: alessandra.magistrato@sissa.it.

Author contributions: A.M. designed research; L.C. performed research; L.C., G.P., and A.S. analyzed data; U.R. participated in the discussion of the results; and L.C., G.P., U.R., and A.M. wrote the paper.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1802963115/-/DCSupplementa

Published under the PNAS license.


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Professores, pesquisadores e alunos de universidades públicas e privadas com acesso ao Portal Periódicos CAPES-MEC podem acessar gratuitamente este artigo do PNAS e de mais 33.000 publicações científicas.

O fim do conceito anatômico de homologia da teoria da evolução de Darwin???

quinta-feira, agosto 02, 2018

Evolution of limb development in cephalopod mollusks

Oscar A. Tarazona, Davys H. Lopez, Leslie A Slota, View ORCID ProfileMartin J. Cohn


This article is a preprint and has not been peer-reviewed [what does this mean?].


Abstract

Cephalopod mollusks evolved numerous anatomical innovations, including specialized arms and tentacles, but little is known about the developmental mechanisms underlying the evolution of cephalopod limbs. Here we report that all three axes of cuttlefish limbs are patterned by the same signaling networks that act in vertebrates and arthropods, although they evolved limbs independently. In cuttlefish limb buds, Hedgehog is expressed anteriorly. Posterior transplantation of Hedgehog-expressing cells induced mirror-image limb duplications. Bmp and Wnt signaling, which establishes dorsoventral polarity in vertebrate and arthropod limbs, is similarly polarized in cuttlefish. Inhibition of the dorsal Bmp signal caused ectopic expression of Notum, a ventral sucker field marker, and development of ectopic suckers. Cuttlefish limbs also show proximodistally regionalized expression of Htx, Exd, Dll, Dac, Sp8, and Wnt genes, which delineate arm and tentacle sucker fields. These results suggest that cephalopod limbs evolved by parallel activation of an ancient developmental genetic program that was present in the bilaterian common ancestor

Copyright 

The copyright holder for this preprint is the author/funder. All rights reserved. No reuse allowed without permission.

FREE PREPRINT: bioRxiv

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Comentário de um gigante em Biologia:

"Se os resultados reportados neste trabalho se sustentarem, eles adicionam para a quase completa destruição do conceito neodarwinista de homologia anatômica. Hoje, a homologia significa quase que muita coisa na biologia evolucionária. Este conceito tem se livrado de quaisquer âncoras evidenciais consistentes, por contra-exemplos tão numerosos que eles poderiam encher um livro-texto dedicado simplesmente por sua diversidade taxonômica, abundância, e valor de impacto.

Se você tivesse perguntado um biólogo evolucionário nos anos 1980s se os membros de cefalópodos, artrópodes, e vertebrados usariam os mesmos elementos reguladores de desenvolvimento, ele teria dito “Com os diabos, não! — essas são estruturas classicamente não homólogas.”

Pano rápido!

Carl Woese acreditava em Deus e chamou Darwin de bastardo!!!

BOOKS AND ARTS 31 JULY 2018

The band of biologists who redrew the tree of life

John Archibald praises a compelling guide to the past 3 billion years — and its molecular historians.

John Archibald

Carl Woese discovered the ‘third domain’ of life — the Archaea.
Credit: Jason Lindley/LAS, Univ. Illinois at Urbana-Champaign

The Tangled Tree: A Radical New History of Life David Quammen Simon & Schuster (2018)

In The Tangled Tree, celebrated science writer David Quammen tells perhaps the grandest tale in biology: how scientists used gene sequencing to elucidate the evolutionary relationships between living beings. Charles Darwin called it the ‘great Tree of Life’. But as Quammen reveals, at the molecular level, life’s history is more accurately depicted as a network, a tangled web through which organisms have been exchanging genes for more than 3 billion years. This perspective is indeed radical, and he presents the science — and the scientists involved — with patience, candour and flair.

Centre stage in Quammen’s narrative is Carl Woese (1928–2012), the US microbiologist best known as the discoverer of the Archaea (Archaebacteria) — the ‘third domain’ of life. Inspired by the visionary musings of Francis Crick, Linus Pauling and Emile Zuckerkandl, Woese committed himself to molecular phylogenetics at a time when this powerful approach to the study of evolution was in its infancy. During the 1960s and 1970s, the Woese Laboratory at the University of Illinois at Urbana–Champaign developed and refined techniques for deriving sequence information from molecules of ribosomal RNA (core components of the cell’s protein-synthesizing factory, the ribosome). Sequences were painstakingly obtained from diverse microbes and used as molecular yardsticks to infer how the organisms were related to one another and to animals and plants. Through the following two decades, as molecular sequencing got easier and cheaper, Woese’s ‘three-domains’ tree — comprising archaea, bacteria and the nucleus-containing eukaryotes — served as the definitive road map for the field of comparative genomics. In many ways, it still does.

But life is complicated, and so are the scientists who study it. In his breezy, conversational style, Quammen shepherds us up and down life’s vast timeline, and across 150-plus years of exciting, often controversial discoveries. He handles the complexities with humour and clarity (he’s right: some ribosomes do look like rubber ducks). We learn about the seeds of “tree thinking” in biology, before and after Darwin’s 1859 On the Origin of Species. We learn of a time when a natural classification of microorganisms was considered impossible (they were deemed morphologically too simple, physiologically too variable). We learn how molecular sequencing helped test and eventually prove the endosymbiont hypothesis for the origin of mitochondria and chloroplasts; these eukaryotic organelles are now known to have evolved from once free-living bacteria.

...

Woese’s last months and weeks with pancreatic cancer, as revealed by those closest to him, make for painful, albeit illuminating reading. I was surprised, for instance, to learn that Woese believed in a deity.

Around 2010, Woese and Canadian science historian Jan Sapp began to collaborate on a book tentatively entitled Beyond God and Darwin. The project never moved beyond Sapp’s draft introduction, on which Woese wrote: “Jan, you accord Darwin so much more substance than the bastard deserves.”

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Capacitar revisores paritários com uma lista de verificação para melhorar a transparência

quarta-feira, agosto 01, 2018

Empowering peer reviewers with a checklist to improve transparency

Timothy H. Parker, Simon C. Griffith, Judith L. Bronstein, Fiona Fidler, Susan Foster, Hannah Fraser, Wolfgang Forstmeier, Jessica Gurevitch, Julia Koricheva, Ralf Seppelt, Morgan W. Tingley & Shinichi Nakagawa 

Nature Ecology & Evolution volume 2, pages929–935 (2018) | Download Citation

Source/Fonte: Editage

Abstract

Peer review is widely considered fundamental to maintaining the rigour of science, but it often fails to ensure transparency and reduce bias in published papers, and this systematically weakens the quality of published inferences. In part, this is because many reviewers are unaware of important questions to ask with respect to the soundness of the design and analyses, and the presentation of the methods and results; also some reviewers may expect others to be responsible for these tasks. We therefore present a reviewers’ checklist of ten questions that address these critical components. Checklists are commonly used by practitioners of other complex tasks, and we see great potential for the wider adoption of checklists for peer review, especially to reduce bias and facilitate transparency in published papers. We expect that such checklists will be well received by many reviewers.

Mapeamento das partículas magnéticas no cérebro humano

Distribution of magnetic remanence carriers in the human brain

Stuart A. Gilder, Michael Wack, Leon Kaub, Sophie C. Roud, Nikolai Petersen, Helmut Heinsen, Peter Hillenbrand, Stefan Milz & Christoph Schmitz 

Scientific Reports volume 8, Article number: 11363 (2018) | Download Citation


Abstract

That the human brain contains magnetite is well established; however, its spatial distribution in the brain has remained unknown. We present room temperature, remanent magnetization measurements on 822 specimens from seven dissected whole human brains in order to systematically map concentrations of magnetic remanence carriers. Median saturation remanent magnetizations from the cerebellum were approximately twice as high as those from the cerebral cortex in all seven cases (statistically significantly distinct, p = 0.016). Brain stems were over two times higher in magnetization on average than the cerebral cortex. The ventral (lowermost) horizontal layer of the cerebral cortex was consistently more magnetic than the average cerebral cortex in each of the seven studied cases. Although exceptions existed, the reproducible magnetization patterns lead us to conclude that magnetite is preferentially partitioned in the human brain, specifically in the cerebellum and brain stem.

Acknowledgements

We thank Josef Jezek for advice on the statistical analyses. This work was kindly funded by the Volkswagen Foundation Experiment! program.

Author information

Affiliations

Department of Earth and Environmental Sciences, Ludwig-Maximilians University of Munich, Theresienstrasse 41, Munich, 80333, Germany

Stuart A. Gilder, Michael Wack, Leon Kaub, Sophie C. Roud & Nikolai Petersen

Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital Würzburg, Würzburg, 97080, Germany

Helmut Heinsen

Ageing Brain Study Group, Department of Pathology, LIM 22, University of São Paulo Medical School, São Paulo, Brazil

Helmut Heinsen

Department of Neuroanatomy, Ludwig-Maximilians University of Munich, Pettenkoferstrasse 11, Munich, 80336, Germany

Peter Hillenbrand, Stefan Milz & Christoph Schmitz

Contributions

H.H. provided the brain specimens to C.S., S.M. cut all brains with assistance from P.H., L.K., S.R., S.G. and M.W. S.G. made all magnetic measurements with assistance from P.H., L.K., S.R., M.W. and S.M. Data treatment and interpretation were done by M.W., S.R. and S.G. with contributions from C.S., S.M., P.H., L.K. and N.P. Figures were drafted by S.R., S.G., S.M. and M.W. S.G. wrote the paper and all authors read and contributed comments to the work.

Competing Interests

The authors declare no competing interests.

Corresponding author

Correspondence to Stuart A. Gilder.

FREE PDF GRATIS: Scientific Reports