284 research outputs found
No wisdom in the crowd: genome annotation at the time of big data - current status and future prospects
Science and engineering rely on the accumulation
and dissemination of knowledge to make discoveries
and create new designs. Discovery-driven genome
research rests on knowledge passed on via gene
annotations. In response to the deluge of sequencing
big data, standard annotation practice employs automated
procedures that rely on majority rules. We
argue this hinders progress through the generation
and propagation of errors, leading investigators into
blind alleys. More subtly, this inductive process discourages
the discovery of novelty, which remains
essential in biological research and reflects the nature
of biology itself. Annotation systems, rather than
being repositories of facts, should be tools that support
multiple modes of inference. By combining
deduction, induction and abduction, investigators can
generate hypotheses when accurate knowledge is
extracted from model databases. A key stance is to
depart from ‘the sequence tells the structure tells the
function’ fallacy, placing function first. We illustrate
our approach with examples of critical or unexpected
pathways, using MicroScope to demonstrate how
tools can be implemented following the principles we
advocate. We end with a challenge to the reader
Bacteria are not Lamarckian
Instructive influence of environment on heredity has been a debated topic for
centuries. Darwin's identification of natural selection coupled to chance
variation as the driving force for evolution, against a formal interpretation
proposed by Lamarck, convinced most scientists that environment does not
specifically instruct evolution in an oriented direction. This is true for
multicellular organisms. In contrast, bacteria were long thought of as prone to
receive oriented influences from their environment, although much was in favour
of the Darwinian route (1). In this context Cairns et al. raised a passionate
debate by suggesting that bacteria generate mutations oriented by the
environmental conditions (2). Several independent pieces of work subsequently
demonstrated that mutations overcoming specific defects arised as a consequence
of cultivation on specific media (3-7). Two diametrically opposed
interpretations were proposed to explain these observations : either induction
of mutations instructed by the environment (e.g. by a process involving a
putative reverse transcription) or selection of variants among a large set of
mutant bacteria generated when stress conditions are present. The experiments
presented below indicate that the Darwinian paradigm is the most plausible.Comment: Work performed to show that the interpretation of Cairns experiments
on adaptive mutations was wrong: bacteria are not lamarckian; the set up
provided shows that when submitted to some sort of starvation, individual
within colonies can find unexpected ways ou
Omnipresent Maxwell’s demons orchestrate information management in living cells
The development of synthetic biology calls for accurate
understanding of the critical functions that allow
construction and operation of a living cell. Besides
coding for ubiquitous structures, minimal genomes
encode a wealth of functions that dissipate energy in
an unanticipated way. Analysis of these functions
shows that they are meant to manage information
under conditions when discrimination of substrates
in a noisy background is preferred over a simple
recognition process. We show here that many of
these functions, including transporters and the ribosome
construction machinery, behave as would
behave a material implementation of the informationmanaging
agent theorized by Maxwell almost
150 years ago and commonly known as Maxwell’s
demon (MxD). A core gene set encoding these functions belongs to the minimal genome required
to allow the construction of an autonomous cell.
These MxDs allow the cell to perform computations
in an energy-efficient way that is vastly better than
our contemporary computers
The methionine salvage pathway in Bacillus subtilis
BACKGROUND: Polyamine synthesis produces methylthioadenosine, which has to be disposed of. The cell recycles it into methionine through methylthioribose (MTR). Very little was known about MTR recycling for methionine salvage in Bacillus subtilis. RESULTS: Using in silico genome analysis and transposon mutagenesis in B. subtilis we have experimentally uncovered the major steps of the dioxygen-dependent methionine salvage pathway, which, although similar to that found in Klebsiella pneumoniae, recruited for its implementation some entirely different proteins. The promoters of the genes have been identified by primer extension, and gene expression was analyzed by Northern blotting and lacZ reporter gene expression. Among the most remarkable discoveries in this pathway is the role of an analog of ribulose diphosphate carboxylase (Rubisco, the plant enzyme used in the Calvin cycle which recovers carbon dioxide from the atmosphere) as a major step in MTR recycling. CONCLUSIONS: A complete methionine salvage pathway exists in B. subtilis. This pathway is chemically similar to that in K. pneumoniae, but recruited different proteins to this purpose. In particular, a paralogue or Rubisco, MtnW, is used at one of the steps in the pathway. A major observation is that in the absence of MtnW, MTR becomes extremely toxic to the cell, opening an unexpected target for new antimicrobial drugs. In addition to methionine salvage, this pathway protects B. subtilis against dioxygen produced by its natural biotope, the surface of leaves (phylloplane)
Natural selection and immortality
Genomes replicate while the host cells reproduce. I explore the reproduction/replication dialogue, based on a deep analysis of bacterial genomes, in relation to ageing. Making young structures from aged ones implies creating information. I revisit Information Theory, showing that the laws of physics permit de novo creation of information, provided an energy-dependent process preserving functional entities makes room for entities accumulating information. I identify explicit functions involved in the process and characterise some of their genes. I suggest that the energy source necessary to establish reproduction while replication is temporarily stopped could be the ubiquitous polyphosphates. Finally, I show that rather than maintain and repair the original individual, organisms tend to metamorphose into young ones, sometimes totally, sometimes progressively. This permits living systems to accumulate information over generations, but has the drawback, in multicellular organisms, to open the door for immortalisation, leading to cancer
FRUSTRATION: PHYSICO-CHEMICAL PREREQUISITES FOR THE CONSTRUCTION OF A SYNTHETIC CELL
To construct a synthetic cell we need to understand the rules that
permit life. A central idea in modern biology is that in addition to
the four entities making reality, matter, energy, space and time, a fifth
one, information, plays a central role. As a consequence of this central
importance of the management of information, the bacterial cell is
organised as a Turing machine, where the machine, with its compartments
defining an inside and an outside and its metabolism, reads and
expresses the genetic program carried by the genome. This highly
abstract organisation is implemented using concrete objects and dynamics,
and this is at the cost of repeated incompatibilities (frustration),
which need to be sorted out by appropriate «patches». After describing
the organisation of the genome into the paleome (sustaining and propagating
life) and the cenome (permitting life in context), we describe
some chemical hurdles that the cell as to cope with, ending with the
specific case of the methionine salvage pathwa
Genomes are covered with ubiquitous 11 bp periodic patterns, the "class A flexible patterns"
BACKGROUND: The genomes of prokaryotes and lower eukaryotes display a very strong 11 bp periodic bias in the distribution of their nucleotides. This bias is present throughout a given genome, both in coding and non-coding sequences. Until now this bias remained of unknown origin. RESULTS: Using a technique for analysis of auto-correlations based on linear projection, we identified the sequences responsible for the bias. Prokaryotic and lower eukaryotic genomes are covered with ubiquitous patterns that we termed "class A flexible patterns". Each pattern is composed of up to ten conserved nucleotides or dinucleotides distributed into a discontinuous motif. Each occurrence spans a region up to 50 bp in length. They belong to what we named the "flexible pattern" type, in that there is some limited fluctuation in the distances between the nucleotides composing each occurrence of a given pattern. When taken together, these patterns cover up to half of the genome in the majority of prokaryotes. They generate the previously recognized 11 bp periodic bias. CONCLUSION: Judging from the structure of the patterns, we suggest that they may define a dense network of protein interaction sites in chromosomes
The logic of metabolism and its fuzzy consequences
Intermediary metabolism molecules are orchestrated into logical pathways stemming from history (L-amino acids, D-sugars) and dynamic constraints (hydrolysis of pyrophosphate or amide groups is the driving force of anabolism). Beside essential metabolites, numerous variants derive from programmed or accidental changes. Broken down, variants enter standard pathways, producing further variants. Macromolecule modification alters enzyme reactions specificity. Metabolism conform thermodynamic laws, precluding strict accuracy. Hence, for each regular pathway, a wealth of variants inputs and produces metabolites that are similar to but not the exact replicas of core metabolites. As corollary, a shadow, paralogous metabolism, is associated to standard metabolism. We focus on a logic of paralogous metabolism based on diversion of the core metabolic mimics into pathways where they are modified to minimize their input in the core pathways where they create havoc. We propose that a significant proportion of paralogues of well-characterized enzymes have evolved as the natural way to cope with paralogous metabolites. A second type of denouement uses a process where protecting/deprotecting unwanted metabolites – conceptually similar to the procedure used in the laboratory of an organic chemist – is used to enter a completely new catabolic pathway
Science, method and critical thinking
Science is founded on a method based on critical thinking. A prerequisite for this is not only a sufficient command of language but also the comprehension of the basic concepts underlying our understanding of reality. This constraint implies an awareness of the fact that the truth of the World is not directly accessible to us, but can only be glimpsed through the construction of mod- els designed to anticipate its behaviour. Because the relationship between models and reality rests on the interpretation of founding postulates and in- stantiations of their predictions (and is therefore deeply rooted in language and culture), there can be no demarcation between science and non-science. However, critical thinking is essential to ensure that the link between models and reality is gradually made more adequate to reality, based on what has already been established, thus guaranteeing that science progresses on this basis and excluding any form of relativism
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