167 research outputs found
An Ancient Evolutionary Origin of Genes Associated with Human Genetic Diseases
Several thousand genes in the human genome have been linked to a heritable genetic disease. The majority of these appear to be nonessential genes (i.e., are not embryonically lethal when inactivated), and one could therefore speculate that they are late additions in the evolutionary lineage toward humans. Contrary to this expectation, we find that they are in fact significantly overrepresented among the genes that have emerged during the early evolution of the metazoa. Using a phylostratigraphic approach, we have studied the evolutionary emergence of such genes at 19 phylogenetic levels. The majority of disease genes was already present in the eukaryotic ancestor, and the second largest number has arisen around the time of evolution of multicellularity. Conversely, genes specific to the mammalian lineage are highly underrepresented. Hence, genes involved in genetic diseases are not simply a random subset of all genes in the genome but are biased toward ancient genes
Renormalization group scale-setting from the action - a road to modified gravity theories
The renormalization group (RG) corrected gravitational action in
Einstein-Hilbert and other truncations is considered. The running scale of the
renormalization group is treated as a scalar field at the level of the action
and determined in a scale-setting procedure recently introduced by Koch and
Ramirez for the Einstein-Hilbert truncation. The scale-setting procedure is
elaborated for other truncations of the gravitational action and applied to
several phenomenologically interesting cases. It is shown how the logarithmic
dependence of the Newton's coupling on the RG scale leads to exponentially
suppressed effective cosmological constant and how the scale-setting in
particular RG corrected gravitational theories yields the effective
modified gravity theories with negative powers of the Ricci scalar . The
scale-setting at the level of the action at the non-gaussian fixed point in
Einstein-Hilbert and more general truncations is shown to lead to universal
effective action quadratic in Ricci tensor.Comment: v1: 15 pages; v2: shortened to 10 pages, main results unchanged,
published in Class. Quant. Gra
ProteinHistorian: Tools for the Comparative Analysis of Eukaryote Protein Origin
The evolutionary history of a protein reflects the functional history of its ancestors. Recent phylogenetic studies identified distinct evolutionary signatures that characterize proteins involved in cancer, Mendelian disease, and different ontogenic stages. Despite the potential to yield insight into the cellular functions and interactions of proteins, such comparative phylogenetic analyses are rarely performed, because they require custom algorithms. We developed ProteinHistorian to make tools for performing analyses of protein origins widely available. Given a list of proteins of interest, ProteinHistorian estimates the phylogenetic age of each protein, quantifies enrichment for proteins of specific ages, and compares variation in protein age with other protein attributes. ProteinHistorian allows flexibility in the definition of protein age by including several algorithms for estimating ages from different databases of evolutionary relationships. We illustrate the use of ProteinHistorian with three example analyses. First, we demonstrate that proteins with high expression in human, compared to chimpanzee and rhesus macaque, are significantly younger than those with human-specific low expression. Next, we show that human proteins with annotated regulatory functions are significantly younger than proteins with catalytic functions. Finally, we compare protein length and age in many eukaryotic species and, as expected from previous studies, find a positive, though often weak, correlation between protein age and length. ProteinHistorian is available through a web server with an intuitive interface and as a set of command line tools; this allows biologists and bioinformaticians alike to integrate these approaches into their analysis pipelines. ProteinHistorian's modular, extensible design facilitates the integration of new datasets and algorithms. The ProteinHistorian web server, source code, and pre-computed ages for 32 eukaryotic genomes are freely available under the GNU public license at http://lighthouse.ucsf.edu/ProteinHistorian/
Phylostratigraphic tracking of cancer genes suggests a link to the emergence of multicellularity in metazoa
Background: Phylostratigraphy is a method used to correlate the evolutionary origin of founder genes (that is, functional founder protein domains) of gene families with particular macroevolutionary transitions. It is based on a model of genome evolution that suggests that the origin of complex phenotypic innovations will be accompanied by the emergence of such founder genes, the descendants of which can still be traced in extant organisms. The origin of multicellularity can be considered to be a macroevolutionary transition, for which new gene functions would have been required. Cancer should be tightly connected to multicellular life since it can be viewed as a malfunction of interaction between cells in a multicellular organism. A phylostratigraphic tracking of the origin of cancer genes should, therefore, also provide insights into the origin of multicellularity. Results: We find two strong peaks of the emergence of cancer related protein domains, one at the time of the origin of the first cell and the other around the time of the evolution of the multicellular metazoan organisms. These peaks correlate with two major classes of cancer genes, the 'caretakers', which are involved in general functions that support genome stability and the 'gatekeepers', which are involved in cellular signalling and growth processes. Interestingly, this phylogenetic succession mirrors the ontogenetic succession of tumour progression, where mutations in caretakers are thought to precede mutations in gatekeepers. Conclusions: A link between multicellularity and formation of cancer has often been predicted. However, this has not so far been explicitly tested. Although we find that a significant number of protein domains involved in cancer predate the origin of multicellularity, the second peak of cancer protein domain emergence is, indeed, connected to a phylogenetic level where multicellular animals have emerged. The fact that we can find a strong and consistent signal for this second peak in the phylostratigraphic map implies that a complex multi-level selection process has driven the transition to multicellularity
Hubble expansion and structure formation in the "running FLRW model" of the cosmic evolution
A new class of FLRW cosmological models with time-evolving fundamental
parameters should emerge naturally from a description of the expansion of the
universe based on the first principles of quantum field theory and string
theory. Within this general paradigm, one expects that both the gravitational
Newton's coupling, G, and the cosmological term, Lambda, should not be strictly
constant but appear rather as smooth functions of the Hubble rate. This
scenario ("running FLRW model") predicts, in a natural way, the existence of
dynamical dark energy without invoking the participation of extraneous scalar
fields. In this paper, we perform a detailed study of these models in the light
of the latest cosmological data, which serves to illustrate the
phenomenological viability of the new dark energy paradigm as a serious
alternative to the traditional scalar field approaches. By performing a joint
likelihood analysis of the recent SNIa data, the CMB shift parameter, and the
BAOs traced by the Sloan Digital Sky Survey, we put tight constraints on the
main cosmological parameters. Furthermore, we derive the theoretically
predicted dark-matter halo mass function and the corresponding redshift
distribution of cluster-size halos for the "running" models studied. Despite
the fact that these models closely reproduce the standard LCDM Hubble
expansion, their normalization of the perturbation's power-spectrum varies,
imposing, in many cases, a significantly different cluster-size halo redshift
distribution. This fact indicates that it should be relatively easy to
distinguish between the "running" models and the LCDM cosmology using realistic
future X-ray and Sunyaev-Zeldovich cluster surveys.Comment: Version published in JCAP 08 (2011) 007: 1+41 pages, 6 Figures, 1
Table. Typos corrected. Extended discussion on the computation of the
linearly extrapolated density threshold above which structures collapse in
time-varying vacuum models. One appendix, a few references and one figure
adde
Network of Cancer Genes: a web resource to analyze duplicability, orthology and network properties of cancer genes
The Network of Cancer Genes (NCG) collects and integrates data on 736 human genes that are mutated in various types of cancer. For each gene, NCG provides information on duplicability, orthology, evolutionary appearance and topological properties of the encoded protein in a comprehensive version of the human protein-protein interaction network. NCG also stores information on all primary interactors of cancer proteins, thus providing a complete overview of 5357 proteins that constitute direct and indirect determinants of human cancer. With the constant delivery of results from the mutational screenings of cancer genomes, NCG represents a versatile resource for retrieving detailed information on particular cancer genes, as well as for identifying common properties of precompiled lists of cancer genes. NCG is freely available at: http://bio.ifom-ieo-campus.it/ncg
Recommended from our members
Animals in a Bacterial World, A New Imperative for the Life Sciences
In the last two decades, the widespread application of genetic and genomic approaches has revealed a bacterial world astonishing in its ubiquity and diversity. This review examines how a growing knowledge of the vast range of animalโbacterial interactions, whether in shared ecosystems or intimate symbioses, is fundamentally altering our understanding of animal biology. Specifically, we highlight recent technological and intellectual advances that have changed our thinking about five questions: how have bacteria facilitated the origin and evolution of animals; how do animals and bacteria affect each otherโs genomes; how does normal animal development depend on bacterial partners; how is homeostasis maintained between animals and their symbionts; and how can ecological approaches deepen our understanding of the multiple levels of animalโbacterial interaction. As answers to these fundamental questions emerge, all biologists will be challenged to broaden their appreciation of these interactions and to include investigations of the relationships between and among bacteria and their animal partners as we seek a better understanding of the natural world.Earth and Planetary SciencesOrganismic and Evolutionary Biolog
Collection of Epithelial Cells from Rodent Mammary Gland Via Laser Capture Microdissection Yielding High-Quality RNA Suitable for Microarray Analysis
Laser capture microdissection (LCM) enables collection of cell populations highly enriched for specific cell types that have the potential of yielding critical information about physiological and pathophysiological processes. One use of cells collected by LCM is for gene expression profiling. Samples intended for transcript analyses should be of the highest quality possible. RNA degradation is an ever-present concern in molecular biological assays, and LCM is no exception. This paper identifies issues related to preparation, collection, and processing in a lipid-rich tissue, rodent mammary gland, in which the epithelial to stromal cell ratio is low and the stromal component is primarily adipocytes, a situation that presents numerous technical challenges for high-quality RNA isolation. Our goal was to improve the procedure so that a greater probe set present call rate would be obtained when isolated RNA was evaluated using Affymetrix microarrays. The results showed that the quality of RNA isolated from epithelial cells of both mammary gland and mammary adenocarcinomas was high with a probe set present call rate of 65% and a high signal-to-noise ratio
Structural View of a Non Pfam Singleton and Crystal Packing Analysis
Comparative genomic analysis has revealed that in each genome a large number of open reading frames have no homologues in other species. Such singleton genes have attracted the attention of biochemists and structural biologists as a potential untapped source of new folds. Cthe_2751 is a 15.8 kDa singleton from an anaerobic, hyperthermophile Clostridium thermocellum. To gain insights into the architecture of the protein and obtain clues about its function, we decided to solve the structure of Cthe_2751.The protein crystallized in 4 different space groups that diffracted X-rays to 2.37 ร
(P3(1)21), 2.17 ร
(P2(1)2(1)2(1)), 3.01 ร
(P4(1)22), and 2.03 ร
(C222(1)) resolution, respectively. Crystal packing analysis revealed that the 3-D packing of Cthe_2751 dimers in P4(1)22 and C222(1) is similar with only a rotational difference of 2.69ยฐ around the C axes. A new method developed to quantify the differences in packing of dimers in crystals from different space groups corroborated the findings of crystal packing analysis. Cthe_2751 is an all ฮฑ-helical protein with a central hydrophobic core providing thermal stability via ฯ:cation and ฯ: ฯ interactions. A ProFunc analysis retrieved a very low match with a splicing endonuclease, suggesting a role for the protein in the processing of nucleic acids.Non-Pfam singleton Cthe_2751 folds into a known all ฮฑ-helical fold. The structure has increased sequence coverage of non-Pfam proteins such that more protein sequences can be amenable to modelling. Our work on crystal packing analysis provides a new method to analyze dimers of the protein crystallized in different space groups. The utility of such an analysis can be expanded to oligomeric structures of other proteins, especially receptors and signaling molecules, many of which are known to function as oligomers
Cross-Sample Validation Provides Enhanced Proteome Coverage in Rat Vocal Fold Mucosa
The vocal fold mucosa is a biomechanically unique tissue comprised of a densely cellular epithelium, superficial to an extracellular matrix (ECM)-rich lamina propria. Such ECM-rich tissues are challenging to analyze using proteomic assays, primarily due to extensive crosslinking and glycosylation of the majority of high Mr ECM proteins. In this study, we implemented an LC-MS/MS-based strategy to characterize the rat vocal fold mucosa proteome. Our sample preparation protocol successfully solubilized both proteins and certain high Mr glycoconjugates and resulted in the identification of hundreds of mucosal proteins. A straightforward approach to the treatment of protein identifications attributed to single peptide hits allowed the retention of potentially important low abundance identifications (validated by a cross-sample match and de novo interpretation of relevant spectra) while still eliminating potentially spurious identifications (global single peptide hits with no cross-sample match). The resulting vocal fold mucosa proteome was characterized by a wide range of cellular and extracellular proteins spanning 12 functional categories
- โฆ