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arXiv2019

Genetic Code: Four-Codon and Non-Four-Codon Degeneracy

In this work it is shown that 20 canonical amino acids (AAs) within genetic code appear to be a whole system with strict distinction in Genetic Code Table (GCT) into some different quantums: 20, 23, 61 amino acid molecules. These molecules distinction is followed by specific balanced atom number and/or nucleon number distinctions within those molecules. In this second version two appendices are added; also a new version of Periodic system of numbers, whose first verson is given in arXiv:1107.1998 [q-bio.OT].

q-bio.BM↗

arXiv2008

Tellipsoid: Exploiting inter-gene correlation for improved detection of differential gene expression

Motivation: Algorithms for differential analysis of microarray data are vital to modern biomedical research. Their accuracy strongly depends on effective treatment of inter-gene correlation. Correlation is ordinarily accounted for in terms of its effect on significance cut-offs. In this paper it is shown that correlation can, in fact, be exploited {to share information across tests}, which, in turn, can increase statistical power. Results: Vastly and demonstrably improved differential analysis approaches are the result of combining identifiability (the fact that in most microarray data sets, a large proportion of genes can be identified a priori as non-differential) with optimization criteria that incorporate correlation. As a special case, we develop a method which builds upon the widely used two-sample t-statistic based approach and uses the Mahalanobis distance as an optimality criterion. Results on the prostate cancer data of Singh et al. (2002) suggest that the proposed method outperforms all published approaches in terms of statistical power. Availability: The proposed algorithm is implemented in MATLAB and in R. The software, called Tellipsoid, and relevant data sets are available at http://www.egr.msu.edu/~desaikey

stat.ME↗

arXiv2008

Zinc adaptation and resistance to cadmium toxicity in mammalian cells. Molecular insight by proteomic analysis

To identify proteins involved in cellular adaptive responses to zinc, a comparative proteome analysis between a previously developed high zinc- and cadmium- resistant human epithelial cell line (HZR) and the parental HeLa cells has been carried out. Differentially produced proteins included co-chaperones, proteins associated with oxido-reductase activities, and ubiquitin. Biochemical pathways to which these proteins belong were probed for their involvement in the resistance of both cell lines against cadmium toxicity. Among endoplasmic reticulum stressors, thapsigargin sensitized HZR cells, but not HeLa cells, to cadmium toxicity more acutely than tunicamycin, implying that these cells heavily relied on proper intracellular calcium distribution. The similar sensitivity of both HeLa and HZR cells to inhibitors of the proteasome, such as MG-132 or lactacystin, excluded improved proteasome activity as a mechanism associated with zinc adaptation of HZR cells. The enzyme 4-hydroxyphenylpyruvate dioxygenase was overproduced in HZR cells as compared to HeLa cells. It transforms 4-hydroxyphenylpyruvate to homogentisate in the second step of tyrosine catabolism. Inhibition of 4-hydroxyphenylpyruvate dioxygenase decreased the resistance of HZR cells against cadmium, but not that of HeLa cells, suggesting that adaptation to zinc overload and increased 4-hydroxyphenylpyruvate removal are linked in HZR cells

q-bio.GN↗

arXiv2008

Interchromatidal central ridge and transversal symmetry in early metaphasic human chromosome one

The topographic structure of Giemsa banded (G-banded) early metaphase human chromosomes adsorbed on glass was analyzed by atomic force microscope using amplitude modulation mode [AM-AFM]. Longitudinal height measurements for early metaphasic human chromosomes showed a central ridge that was further characterized by transversal height measurements. The heterochromatic regions displayed a high level of transversal symmetry, while the euchromatic ones presented several peaks across the transversal height measurements. We suggest that this central ridge and symmetry patterns point out a transitional arrangement of the early metaphase chromosome and support evidence for interchromatidal interactions prior to disjunction.

q-bio.GN↗

arXiv2008

Chance and necessity in chromosomal gene distributions

By analyzing the spacing of genes on chromosomes, we find that transcriptional and RNA-processing regulatory sequences outside coding regions leave footprints on the distribution of intergenic distances. Using analogies between genes on chromosomes and one-dimensional gases, we constructed a statistical null model. We have used this to estimate typical upstream and downstream regulatory sequence sizes in various species. Deviations from this model reveal bi-directional transcriptional regulatory regions in S. cerevisiae and bi-directional terminators in E. coli.

q-bio.GN↗

arXiv2008

Understanding Distal Transcriptional Regulation from Sequence Motif, Network Inference and Interactome Perspectives

Gene regulation in higher eukaryotes involves a complex interplay between the gene proximal promoter and distal genomic elements (such as enhancers) which work in concert to drive spatio-temporal expression. The experimental characterization of gene regulatory elements is a very complex and resource-intensive process. One of the major goals in computational biology is the \textit{in-silico} annotation of previously uncharacterized elements using results from the subset of known, annotated, regulatory elements. The computational annotation of these hitherto uncharacterized regions would require an identification of features that have good predictive value for regulatory behavior. In this work, we study transcriptional regulation as a problem in heterogeneous data integration, across sequence, expression and interactome level attributes. Using the example of the \textit{Gata2} gene and its recently discovered urogenital enhancers \cite{Khandekar2004} as a case study, we examine the predictive value of various high throughput functional genomic assays in characterizing these enhancers and their regulatory role. Observing results from the application of modern statistical learning methodologies for each of these data modalities, we propose a set of attributes that are most discriminatory in the localization and behavior of these enhancers.

q-bio.GN↗

arXiv2008

Matrix genetics, part 2: the degeneracy of the genetic code and the octave algebra with two quasi-real units (the genetic octave Yin-Yang-algebra)

Algebraic properties of the genetic code are analyzed. The investigations of the genetic code on the basis of matrix approaches ("matrix genetics") are described. The degeneracy of the vertebrate mitochondria genetic code is reflected in the black-and-white mosaic of the (8*8)-matrix of 64 triplets, 20 amino acids and stop-signals. This mosaic genetic matrix is connected with the matrix form of presentation of the special 8-dimensional Yin-Yang-algebra and of its particular 4-dimensional case. The special algorithm, which is based on features of genetic molecules, exists to transform the mosaic genomatrix into the matrices of these algebras. Two new numeric systems are defined by these 8-dimensional and 4-dimensional algebras: genetic Yin-Yang-octaves and genetic tetrions. Their comparison with quaternions by Hamilton is presented. Elements of new "genovector calculation" and ideas of "genetic mechanics" are discussed. These algebras are considered as models of the genetic code and as its possible pre-code basis. They are related with binary oppositions of the Yin-Yang type and they give new opportunities to investigate evolution of the genetic code. The revealed fact of the relation between the genetic code and these genetic algebras is discussed in connection with the idea by Pythagoras: "All things are numbers". Simultaneously these genetic algebras can be utilized as the algebras of genetic operators in biological organisms. The described results are related with the problem of algebraization of bioinformatics. They take attention to the question: what is life from the viewpoint of algebra?

q-bio.QM↗

arXiv2008

The effect of the SOS response on the mean fitness of unicellular populations: A quasispecies approach

This paper develops a quasispecies model that incorporates the SOS response. We consider a unicellular, asexually replicating population of organisms, whose genomes consist of a single, double-stranded DNA molecule, i.e. one chromosome. We assume that repair of post-replication mismatched base-pairs occurs with probability $ λ$, and that the SOS response is triggered when the total number of mismatched base-pairs exceeds $ l_S $. We further assume that the per-mismatch SOS elimination rate is characterized by a first-order rate constant $ κ_{SOS} $. For a single fitness peak landscape where the master genome can sustain up to $ l $ mismatches and remain viable, this model is analytically solvable in the limit of infinite sequence length. The results, which are confirmed by stochastic simulations, indicate that the SOS response does indeed confer a fitness advantage to a population, provided that it is only activated when DNA damage is so extensive that a cell will die if it does not attempt to repair its DNA.

q-bio.PE↗

arXiv2008

An efficient strategy to characterize alleles and complex haplotypes using DNA-markers

We consider the problem of detecting and estimating the strength of association between a trait of interest and alleles or haplotypes in a small genomic region (e.g. a gene or a gene complex), when no direct information on that region is available but the values of neighbouring DNA-markers are at hand. We argue that the effects of the non-observable haplotypes of the genomic regions can and should be represented by factors representing disjoint groups of marker-alleles. A theoretical argument based on a hypothetical phylogenetic tree supports this general claim. The techniques described allow to identify and to infer the number of detectable haplotypes in the genomic region that are associated with a trait. The methods proposed use an exhaustive combinatorial search coupled with the maximization of a version of the likelihood function penalized for the number of parameters. This procedure can easily be implemented with standard statistical methods for a moderate number of marker-alleles.

stat.AP↗

arXiv2008

A Fast and Flexible Method for the Segmentation of aCGH Data

Motivation: Array Comparative Genomic Hybridization (aCGH) is used to scan the entire genome for variations in DNA copy number. A central task in the analysis of aCGH data is the segmentation into groups of probes sharing the same DNA copy number. Some well known segmentation methods suffer from very long running times, preventing interactive data analysis. Results: We suggest a new segmentation method based on wavelet decomposition and thresholding, which detects significant breakpoints in the data. Our algorithm is over 1,000 times faster than leading approaches, with similar performance. Another key advantage of the proposed method is its simplicity and flexibility. Due to its intuitive structure it can be easily generalized to incorporate several types of side information. Here we consider two extensions which include side information indicating the reliability of each measurement, and compensating for a changing variability in the measurement noise. The resulting algorithm outperforms existing methods, both in terms of speed and performance, when applied on real high density CGH data. Availability: Implementation is available under software tab at: http://www.ee.technion.ac.il/Sites/People/YoninaEldar/ Contact: yonina@ee.technion.ac.il

q-bio.QM↗

arXiv2008

Network Structure and Dynamics, and Emergence of Robustness by Stabilizing Selection in an Artificial Genome

Genetic regulation is a key component in development, but a clear understanding of the structure and dynamics of genetic networks is not yet at hand. In this work we investigate these properties within an artificial genome model originally introduced by Reil. We analyze statistical properties of randomly generated genomes both on the sequence- and network level, and show that this model correctly predicts the frequency of genes in genomes as found in experimental data. Using an evolutionary algorithm based on stabilizing selection for a phenotype, we show that robustness against single base mutations, as well as against random changes in initial network states that mimic stochastic fluctuations in environmental conditions, can emerge in parallel. Evolved genomes exhibit characteristic patterns on both sequence and network level.

q-bio.MN↗

arXiv2011

On the Law of Directionality of Genome Evolution

The problem of the directionality of genome evolution is studied from the information-theoretic view. We propose that the function-coding information quantity of a genome always grows in the course of evolution through sequence duplication, expansion of code, and gene transfer between genomes. The function-coding information quantity of a genome consists of two parts, p-coding information quantity which encodes functional protein and n-coding information quantity which encodes other functional elements except amino acid sequence. The relation of the proposed law to the thermodynamic laws is indicated. The evolutionary trends of DNA sequences revealed by bioinformatics are investigated which afford further evidences on the evolutionary law. It is argued that the directionality of genome evolution comes from species competition adaptive to environment. An expression on the evolutionary rate of genome is proposed that the rate is a function of Darwin temperature (describing species competition) and fitness slope (describing adaptive landscape). Finally, the problem of directly experimental test on the evolutionary directionality is discussed briefly.

q-bio.GN↗

arXiv2008

An algebraic hypothesis about the primeval genetic code

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, G, A, U, C}, where the letter D represents one or more hypothetical bases with unspecific pairing. We hypothesized that the high degeneration of a primeval genetic code with five bases and the gradual origin and improvements of a primitive DNA repair system could make possible the transition from the ancient to the modern genetic code. Our results suggest that the Watson-Crick base pairing 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 later. 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.

q-bio.GN↗

arXiv2008

A limiting rule for the variability of coding sequence length in microbial genomes

The mean length and the variability of coding sequences for 48 genomes of bacteria and archaea were analyzed. It was found that the plotted data can be described by an angular area. This suggests the followings: a) The variability of a genome increases as the mean length increases; b) There is an upper and a lower limit for variability for a given mean length; c) Extrapolation of the upper and lower limits to lower mean values converges to a single point which might be assimilated to a primordial cell. The whole picture is reminding of a process which starts from a single cell and evolves into more and more species which, in turn, show more and more variability.

q-bio.GN↗

arXiv2008

Elucidation of differential response networks from toxicogenomics data

We describe a novel approach to the analysis of toxicogenomics data and elucidation of biological networks affected by drug treatments. In this method approximately 15,000 linear pathway modules were generated from manually assembled pathway maps from MetaCore (GeneGo, Inc.). Microarray expression data from livers of rat exposed to phenobarbital, mestranol and tamoxifen were mapped onto these modules. Using different analytical techniques we have identified sets of "differential" pathways featuring highly correlated expression among multiple repeats of the same treatment while showing strong anti-correlation across different treatments. Network modules distinguishing chemical treatments were re-assembled based on these pathways. Unlike traditional statistical and clustering procedures in expression profiling, our method takes into account both network connectivity and gene expression in the course of the analysis. We demonstrate that it enables identification of important cellular mechanisms involved in drug response that would have been missed by the analysis based on individual gene expression profiles.

q-bio.MN↗

arXiv2008

Extrinsic and intrinsic nucleosome positioning signals

In eukaryotic genomes, nucleosomes function to compact DNA and to regulate access to it both by simple physical occlusion and by providing the substrate for numerous covalent epigenetic tags. While nucleosome positions in vitro are determined by sequence alone, in vivo competition with other DNA-binding factors and action of chromatin remodeling enzymes play a role that needs to be quantified. We developed a biophysical model for the sequence dependence of DNA bending energies, and validated it against a collection of in vitro free energies of nucleosome formation and a nucleosome crystal structure; we also successfully designed both strong and poor histone binding sequences ab initio. For in vivo data from S.cerevisiae, the strongest positioning signal came from the competition with other factors. Based on sequence alone, our model predicts that functional transcription factor binding sites have a tendency to be covered by nucleosomes, but are uncovered in vivo because functional sites cluster within a single nucleosome footprint, making transcription factors bind cooperatively. Similarly a weak enhancement of nucleosome binding in the TATA region for naked DNA becomes a strong depletion when the TATA-binding protein is included, in quantitative agreement with experiment. Predictions at specific loci were also greatly enhanced by including competing factors. Our physically grounded model distinguishes multiple ways in which genomic sequence can influence nucleosome positions and thus provides an alternative explanation for several important experimental findings.

q-bio.GN↗

arXiv2008

Microbial genome as a fluctuating system: Distribution and correlation of coding sequence lengths

The length of coding sequence series in microbial genomes were regarded as a fluctuating system and characterized by the methods of statistical physics. The distribution and the correlatin properties of 50 genomes including bacteria and several archaea were investigated. The distribution was investigated by rank-size analysis (Zipf's law. We found that coding sequence lengths series do not obey Zipf's law contrary to natural languages. The distribution was found to be more closely to an exponential distribution. The correlation appeared to be similar to natural languages. Segmentation analysis of the series showed to be short range memory systems.

q-bio.GN↗

arXiv2008

Matrix genetics, part 3: the evolution of the genetic code from the viewpoint of the genetic octave Yin-Yang-algebra

The set of known dialects of the genetic code (GC) is analyzed from the viewpoint of the genetic octave Yin-Yang-algebra. This algebra was described in the previous author's publications. The algebra was discovered on the basis of structural features of the GC in the matrix form of its presentation ("matrix genetics"). The octave Yin-Yang-algebra is considered as the pre-code or as the model of the GC. From the viewpoint of this algebraic model, for example, the sets of 20 amino acids and of 64 triplets consist of sub-sets of "male", "female" and "androgynous" molecules, etc. This algebra permits to reveal hidden peculiarities of the structure and evolution of the GC and to propose the conception of "sexual" relationships among genetic molecules. The first results of the analysis of the GC systems from such algebraic viewpoint say about the close connection between evolution of the GC and this algebra. They include 8 evolutionary rules of the dialects of the GC. The evolution of the GC is appeared as the struggle between male and female beginnings. The hypothesis about new biophysical factor of "sexual" interactions among genetic molecules is put forward. The matrix forms of presentation of elements of the genetic octave Yin-Yang-algebra are connected with Hadamard matrices by means of the simple U-algorithm. Hadamard matrices play a significant role in the theory of quantum computers, in particular. It gives new opportunities for possible understanding the GC systems as quantum computer systems. Revealed algebraic properties of the GC permit to put forward the problem of algebraization of bioinformatics on the basis of the algebras of the GC. Our investigation is connected with the question: what is life from the viewpoint of algebra? The algebraic version of the origin of the GC is discussed.

q-bio.GN↗