5,445 research outputs found
Molecular dynamics recipes for genome research
Molecular dynamics (MD) simulation allows one to predict the time evolution of a system of interacting particles. It is widely used in physics, chemistry and biology to address specific questions about the structural properties and dynamical mechanisms of model systems. MD earned a great success in genome research, as it proved to be beneficial in sorting pathogenic from neutral genomic mutations. Considering their computational requirements, simulations are commonly performed on HPC computing devices, which are generally expensive and hard to administer. However, variables like the software tool used for modeling and simulation or the size of the molecule under investigation might make one hardware type or configuration more advantageous than another or even make the commodity hardware definitely suitable for MD studies. This work aims to shed lights on this aspect
Empowering precision medicine through high performance computing clusters
The role of High Performance Computing (HPC) in Medicine is greatly increase in these last years,
moving from basic research to the clinics. With the advent of Next Generation Sequencing (NGS)
technologies, diverse areas of human health have been investigated through different omics
techniques. The extensive use of these NGS platforms to high throughput profile human health
issues in a cost-efficient manner, is generating huge amount of sequencing data pushing
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bioinformatic research in the big-data field. Speed, accuracy and reproducibility of massively
sequencing analysis have allowed to transfer molecular biology knowledge into precision medicine.
Furthermore, Molecular Dynamics (MD) earned a great importance in aiding genome research.
Sequencing studies of cancer have allowed to detect and characterize mutated genes that drive
tumorigenesis. As a complementary approach, from a biophysical perspective, MD simulations,
executed on HPC architectures, have permitted to investigate the role played by pathological
mutations on the molecular mechanism of activation
Complex Systems Science: Dreams of Universality, Reality of Interdisciplinarity
Using a large database (~ 215 000 records) of relevant articles, we
empirically study the "complex systems" field and its claims to find universal
principles applying to systems in general. The study of references shared by
the papers allows us to obtain a global point of view on the structure of this
highly interdisciplinary field. We show that its overall coherence does not
arise from a universal theory but instead from computational techniques and
fruitful adaptations of the idea of self-organization to specific systems. We
also find that communication between different disciplines goes through
specific "trading zones", ie sub-communities that create an interface around
specific tools (a DNA microchip) or concepts (a network).Comment: Journal of the American Society for Information Science and
Technology (2012) 10.1002/asi.2264
Ribosome traffic on mRNAs maps to gene ontology : genome-wide quantification of translation initiation rates and polysome size regulation
Peer reviewedPublisher PD
Joint scaling laws in functional and evolutionary categories in prokaryotic genomes
We propose and study a class-expansion/innovation/loss model of genome
evolution taking into account biological roles of genes and their constituent
domains. In our model numbers of genes in different functional categories are
coupled to each other. For example, an increase in the number of metabolic
enzymes in a genome is usually accompanied by addition of new transcription
factors regulating these enzymes. Such coupling can be thought of as a
proportional "recipe" for genome composition of the type "a spoonful of sugar
for each egg yolk". The model jointly reproduces two known empirical laws: the
distribution of family sizes and the nonlinear scaling of the number of genes
in certain functional categories (e.g. transcription factors) with genome size.
In addition, it allows us to derive a novel relation between the exponents
characterising these two scaling laws, establishing a direct quantitative
connection between evolutionary and functional categories. It predicts that
functional categories that grow faster-than-linearly with genome size to be
characterised by flatter-than-average family size distributions. This relation
is confirmed by our bioinformatics analysis of prokaryotic genomes. This proves
that the joint quantitative trends of functional and evolutionary classes can
be understood in terms of evolutionary growth with proportional recipes.Comment: 39 pages, 21 figure
Association of a homozygous GCK missense mutation with mild diabetes
Background: Homozygous inactivating GCK mutations have been repeatedly reported to cause severe hyperglycemia, presenting as permanent neonatal diabetes mellitus (PNDM). Conversely, only two cases of GCK homozygous mutations causing mild hyperglycemia have been so far described. We here report a novel GCK mutation (c.1116G>C, p.E372D), in a family with one homozygous member showing mild hyperglycemia. Methods: GCK mutational screening was carried out by Sanger sequencing. Computational analyses to investigate pathogenicity and molecular dynamics (MD) were performed for GCK-E372D and for previously described homozygous mutations associated with mild (n = 2) or severe (n = 1) hyperglycemia, used as references. Results: Of four mildly hyperglycemic family-members, three were heterozygous and one, diagnosed in the adulthood, was homozygous for GCK-E372D. Two nondiabetic family members carried no mutations. Fasting glucose (p = 0.016) and HbA1c (p = 0.035) correlated with the number of mutated alleles (0â2). In-silico predicted pathogenicity was not correlated with the four mutationsâ severity. At MD, GCK-E372D conferred protein structure flexibility intermediate between mild and severe GCK mutations. Conclusions: We present the third case of homozygous GCK mutations associated with mild hyperglycemia, rather than PNDM. Our in-silico analyses support previous evidences suggesting that protein stability plays a role in determining clinical severity of GCK mutations
Family-specific scaling laws in bacterial genomes
Among several quantitative invariants found in evolutionary genomics, one of
the most striking is the scaling of the overall abundance of proteins, or
protein domains, sharing a specific functional annotation across genomes of
given size. The size of these functional categories change, on average, as
power-laws in the total number of protein-coding genes. Here, we show that such
regularities are not restricted to the overall behavior of high-level
functional categories, but also exist systematically at the level of single
evolutionary families of protein domains. Specifically, the number of proteins
within each family follows family-specific scaling laws with genome size.
Functionally similar sets of families tend to follow similar scaling laws, but
this is not always the case. To understand this systematically, we provide a
comprehensive classification of families based on their scaling properties.
Additionally, we develop a quantitative score for the heterogeneity of the
scaling of families belonging to a given category or predefined group. Under
the common reasonable assumption that selection is driven solely or mainly by
biological function, these findings point to fine-tuned and interdependent
functional roles of specific protein domains, beyond our current functional
annotations. This analysis provides a deeper view on the links between
evolutionary expansion of protein families and the functional constraints
shaping the gene repertoire of bacterial genomes.Comment: 41 pages, 16 figure
Reduction of dynamical biochemical reaction networks in computational biology
Biochemical networks are used in computational biology, to model the static
and dynamical details of systems involved in cell signaling, metabolism, and
regulation of gene expression. Parametric and structural uncertainty, as well
as combinatorial explosion are strong obstacles against analyzing the dynamics
of large models of this type. Multi-scaleness is another property of these
networks, that can be used to get past some of these obstacles. Networks with
many well separated time scales, can be reduced to simpler networks, in a way
that depends only on the orders of magnitude and not on the exact values of the
kinetic parameters. The main idea used for such robust simplifications of
networks is the concept of dominance among model elements, allowing
hierarchical organization of these elements according to their effects on the
network dynamics. This concept finds a natural formulation in tropical
geometry. We revisit, in the light of these new ideas, the main approaches to
model reduction of reaction networks, such as quasi-steady state and
quasi-equilibrium approximations, and provide practical recipes for model
reduction of linear and nonlinear networks. We also discuss the application of
model reduction to backward pruning machine learning techniques
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