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arXiv2008

The Alternative Choice of Constitutive Exons throughout Evolution

Alternative cassette exons are known to originate from two processes exonization of intronic sequences and exon shuffling. Herein, we suggest an additional mechanism by which constitutively spliced exons become alternative cassette exons during evolution. We compiled a dataset of orthologous exons from human and mouse that are constitutively spliced in one species but alternatively spliced in the other. Examination of these exons suggests that the common ancestors were constitutively spliced. We show that relaxation of the 59 splice site during evolution is one of the molecular mechanisms by which exons shift from constitutive to alternative splicing. This shift is associated with the fixation of exonic splicing regulatory sequences (ESRs) that are essential for exon definition and control the inclusion level only after the transition to alternative splicing. The effect of each ESR on splicing and the combinatorial effects between two ESRs are conserved from fish to human. Our results uncover an evolutionary pathway that increases transcriptome diversity by shifting exons from constitutive to alternative splicing

q-bio.GN↗

arXiv2008

Intronic Alus Influence Alternative Splicing

Examination of the human transcriptome reveals higher levels of RNA editing than in any other organism tested to date. This is indicative of extensive double-stranded RNA (dsRNA) formation within the human transcriptome. Most of the editing sites are located in the primate-specific retrotransposed element called Alu. A large fraction of Alus are found in intronic sequences, implying extensive Alu-Alu dsRNA formation in mRNA precursors. Yet, the effect of these intronic Alus on splicing of the flanking exons is largely unknown. Here, we show that more Alus flank alternatively spliced exons than constitutively spliced ones; this is especially notable for those exons that have changed their mode of splicing from constitutive to alternative during human evolution. This implies that Alu insertions may change the mode of splicing of the flanking exons. Indeed, we demonstrate experimentally that two Alu elements that were inserted into an intron in opposite orientation undergo base-pairing, as evident by RNA editing, and affect the splicing patterns of a downstream exon, shifting it from constitutive to alternative. Our results indicate the importance of intronic Alus in influencing the splicing of flanking exons, further emphasizing the role of Alus in shaping of the human transcriptome

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arXiv2008

Combining chromosomal arm status and significantly aberrant genomic locations reveals new cancer subtypes

Many types of tumors exhibit chromosomal losses or gains, as well as local amplifications and deletions. Within any given tumor type, sample specific amplifications and deletionsare also observed. Typically, a region that is aberrant in more tumors,or whose copy number change is stronger, would be considered as a more promising candidate to be biologically relevant to cancer. We sought for an intuitive method to define such aberrations and prioritize them. We define V, the volume associated with an aberration, as the product of three factors: a. fraction of patients with the aberration, b. the aberrations length and c. its amplitude. Our algorithm compares the values of V derived from real data to a null distribution obtained by permutations, and yields the statistical significance, p value, of the measured value of V. We detected genetic locations that were significantly aberrant and combined them with chromosomal arm status to create a succint fingerprint of the tumor genome. This genomic fingerprint is used to visualize the tumors, highlighting events that are co ocurring or mutually exclusive. We allpy the method on three different public array CGH datasets of Medulloblastoma and Neuroblastoma, and demonstrate its ability to detect chromosomal regions that were known to be altered in the tested cancer types, as well as to suggest new genomic locations to be tested. We identified a potential new subtype of Medulloblastoma, which is analogous to Neuroblastoma type 1.

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arXiv2009

Fundamentally different strategies for transcriptional regulation are revealed by information-theoretical analysis of binding motifs

To regulate a particular gene, a transcription factor (TF) needs to bind a specific genome location. How is this genome address specified amid the presence of ~10^6-10^9 decoy sites? Our analysis of 319 known TF binding motifs clearly demonstrates that prokaryotes and eukaryotes use strikingly different strategies to target TFs to specific genome locations; eukaryotic TFs exhibit widespread nonfunctional binding and require clustering of sites in regulatory regions for specificity.

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arXiv2008

The Dynamic Replicon: adapting to a changing cellular environment

Eukaryotic cells are often exposed to fluctuations in growth conditions as well as endogenous and exogenous stress-related agents. In addition, during development global patterns of gene transcription change dramatically, and these changes are associated with altered patterns of DNA replication. In metazoan embryos, for example, transcription is repressed globally and any sequence in the genome can serve as a site for the start of DNA synthesis. As transcription is activated and a G1 phase imposed, the pattern of replication adapts to these changes by restricting the sites where DNA synthesis begins. Recent evidence indicates that each unit of replication, or replicon, is specified by two or more potential replication origins, but only one is selected to initiate replication of the replicon. How the cell distinguishes between potential origins, and how it selects a given origin of replication remain unclear. This raises important questions concerning the nature and definition of the eukaryotic replicon. In the following we will review emerging evidence concerning the mechanisms involved in regulating replication origins during both the normal and perturbed eukaryotic cell cycle.

q-bio.GN↗

arXiv2008

Measuring Fit of Sequence Data to Phylogenetic Model: Gain of Power using Marginal Tests

Testing fit of data to model is fundamentally important to any science, but publications in the field of phylogenetics rarely do this. Such analyses discard fundamental aspects of science as prescribed by Karl Popper. Indeed, not without cause, Popper (1978) once argued that evolutionary biology was unscientific as its hypotheses were untestable. Here we trace developments in assessing fit from Penny et al. (1982) to the present. We compare the general log-likelihood ratio (the G or G2 statistic) statistic between the evolutionary tree model and the multinomial model with that of marginalized tests applied to an alignment (using placental mammal coding sequence data). It is seen that the most general test does not reject the fit of data to model (p~0.5), but the marginalized tests do. Tests on pair-wise frequency (F) matrices, strongly (p < 0.001) reject the most general phylogenetic (GTR) models commonly in use. It is also clear (p < 0.01) that the sequences are not stationary in their nucleotide composition. Deviations from stationarity and homogeneity seem to be unevenly distributed amongst taxa; not necessarily those expected from examining other regions of the genome. By marginalizing the 4t patterns of the i.i.d. model to observed and expected parsimony counts, that is, from constant sites, to singletons, to parsimony informative characters of a minimum possible length, then the likelihood ratio test regains power, and it too rejects the evolutionary model with p << 0.001. Given such behavior over relatively recent evolutionary time, readers in general should maintain a healthy skepticism of results, as the scale of the systematic errors in published analyses may really be far larger than the analytical methods (e.g., bootstrap) report.

q-bio.PE↗

arXiv2008

Fit of Fossils and Mammalian Molecular Trees: Dating Inconsistencies Revisited

Divergence time estimation requires the reconciliation of two major sources of data. These are fossil and/or biogeographic evidence that give estimates of the absolute age of nodes (ancestors) and molecular estimates that give us estimates of the relative ages of nodes in a molecular evolutionary tree. Both forms of data are often best characterized as yielding continuous probability distributions on nodes. Here, the distributions modeling older fossil calibrations within the tree of placental (eutherian) mammals are reconsidered. In particular the Horse/Rhino, Human/Tarsier, Whale/ Hippo, Rabbit/Pika and Rodentia calibrations are reexamined and adjusted. Inferring the relative ages of nodes in a phylogeny also requires the assumption of a model of evolutionary rate change across the tree. Here nine models of evolutionary rate change, are combined with various continuous distributions modeling fossil calibrations. Fit of model is measured both relative to a normalized fit, which assumes that all models fit well in the absence of multiple fossil calibrations, and also by the linearity of their residuals. The normalized fit used attempts to track twice the log likelihood difference from the best expected model. The results suggest there is a very large difference in the age of the root proposed by calibrations in Supraprimates (informally Euarchontoglires) versus Laurasiatheria. Combining both sets of calibrations results in the penalty function vastly increasing in all cases. These issues remain irrespective of the model used or whether the newer calibrations are used.

q-bio.PE↗

arXiv2009

Darwinian purifying selection versus complementing strategy in Monte Carlo simulations

Intragenomic recombination (crossover) is a very important evolutionary mechanism. The crossover events are not evenly distributed along the natural chromosomes. Monte Carlo simulations revealed that frequency of recombinations decides about the strategy of chromosomes' and genomes' evolution. In large panmictic populations, under high recombination rate the Darwinian purifying selection operates keeping the fraction of defective genes at the relatively low level. In small populations and under low recombination rate the strategy of complementing haplotypes seems to be more advantageous. Switching between the two strategies has a character of phase transition - it depends on inbreeding coefficient and crossover rate. The critical recombination rate depends also on the size of chromosome. It is also possible, that in one genome some chromosomes could be under complementing while some other under purifying selection. Such situation stabilizes genome evolution and reproduction strategy. It seems that this phenomenon can be responsible for the positive correlation between kinship and fecundity, recently found in the Islander population. When large population is forced to enter the complementing strategy, the phenomenon of sympatric speciation is observed.

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arXiv2009

Evolution of the Age Structured Populations and Demography

We describe the simulation method of modelling the population evolution using Monte Carlo based on the Penna model. Individuals in the populations are represented by their diploid genomes. Genes expressed after the minimum reproduction age are under a weaker selection pressure and accumulate more mutations than those expressed before the minimum reproduction age. The generated gradient of defective genes determines the ageing of individuals and age-structured populations are very similar to the natural, sexually reproducing populations. The genetic structure of a population depends on the way how the random death affects the population. The improvement of the medical care and healthier life styles are responsible for the increasing of the life expectancy of humans during the last century. Introducing a noise into the relations between the genotype, phenotype, and environment, it is possible to simulate some other effects, like the role of immunological systems and a mother care. One of the most interesting results was the evolution of sex chromosomes. Placing the male sex determinants on one chromosome of a pair of sex chromosomes is enough to condemn it for shrinking if the population is panmictic (random-mating is assumed). If males are indispensable for taking care of their offspring and have to be faithful to their females, the male sex chromosome does not shrink.

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arXiv2009

To Understand Nature - Computer Modelling between Genetics and Evolution

We have presented the basic knowledge on the structure of molecules coding the genetic information, mechanisms of transfer of this information from DNA to proteins and phenomena connected with replication of DNA. In particular, we have described the differences of mutational pressure connected with replication of the leading and lagging DNA strands. We have shown how the asymmetric replication of DNA affects the structure of genomes, positions of genes, their function and amino acid composition. Results of Monte Carlo simulations of evolution of protein coding sequences have shown a specific role of genetic code in minimizing the effect of nucleotide substitutions on the amino acid composition of proteins. The results of simulations were compared with the results of analyses of genomic and proteomic data bases. This chapter is considered as an introduction to further chapters where chromosomes with genes represented by nucleotide sequences were replaced by bitstrings with single bits representing genes.

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arXiv2009

The role of cooperative binding on noise expression

The origin of stochastic fluctuations in gene expression has received considerable attention recently. Fluctuations in gene expression are particularly pronounced in cellular systems because of the small copy number of species undergoing transitions between discrete chemical states and the small size of biological compartments. In this paper, we propose a stochastic model for gene expression regulation including several binding sites, considering elementary reactions only. The model is used to investigate the role of cooperativity on the intrinsic fluctuations of gene expression, by means of master equation formalism. We found that the Hill coefficient and the level of noise increases as the interaction energy between activators increases. Additionally, we show that the model allows to distinguish between two cooperative binding mechanisms.

q-bio.SC↗

arXiv2009

Sample-Align-D: A High Performance Multiple Sequence Alignment System using Phylogenetic Sampling and Domain Decomposition

Multiple Sequence Alignment (MSA) is one of the most computationally intensive tasks in Computational Biology. Existing best known solutions for multiple sequence alignment take several hours (in some cases days) of computation time to align, for example, 2000 homologous sequences of average length 300. Inspired by the Sample Sort approach in parallel processing, in this paper we propose a highly scalable multiprocessor solution for the MSA problem in phylogenetically diverse sequences. Our method employs an intelligent scheme to partition the set of sequences into smaller subsets using kmer count based similarity index, referred to as k-mer rank. Each subset is then independently aligned in parallel using any sequential approach. Further fine tuning of the local alignments is achieved using constraints derived from a global ancestor of the entire set. The proposed Sample-Align-D Algorithm has been implemented on a cluster of workstations using MPI message passing library. The accuracy of the proposed solution has been tested on standard benchmarks such as PREFAB. The accuracy of the alignment produced by our methods is comparable to that of well known sequential MSA techniques. We were able to align 2000 randomly selected sequences from the Methanosarcina acetivorans genome in less than 10 minutes using Sample-Align-D on a 16 node cluster, compared to over 23 hours on sequential MUSCLE system running on a single cluster node.

cs.DC↗

arXiv2009

An Overview of Multiple Sequence Alignment Systems

An overview of current multiple alignment systems to date are described.The useful algorithms, the procedures adopted and their limitations are presented.We also present the quality of the alignments obtained and in which cases(kind of alignments, kind of sequences etc) the particular systems are useful.

cs.DS↗

arXiv2009

Pyro-Align: Sample-Align based Multiple Alignment system for Pyrosequencing Reads of Large Number

Pyro-Align is a multiple alignment program specifically designed for pyrosequencing reads of huge number. Multiple sequence alignment is shown to be NP-hard and heuristics are designed for approximate solutions. Multiple sequence alignment of pyrosequenceing reads is complex mainly because of 2 factors. One being the huge number of reads, making the use of traditional heuristics,that scale very poorly for large number, unsuitable. The second reason is that the alignment cannot be performed arbitrarily, because the position of the reads with respect to the original genome is important and has to be taken into account.In this report we present a short description of the multiple alignment system for pyrosequencing reads.

cs.DS↗

arXiv2009

Multiple Sequence Alignment System for Pyrosequencing Reads

Pyrosequencing is among the emerging sequencing techniques, capable of generating upto 100,000 overlapping reads in a single run. This technique is much faster and cheaper than the existing state of the art sequencing technique such as Sanger. However, the reads generated by pyrosequencing are short in size and contain numerous errors. Furthermore, each read has a specific position in the reference genome. In order to use these reads for any subsequent analysis, the reads must be aligned . Existing multiple sequence alignment methods cannot be used as they do not take into account the specific positions of the sequences with respect to the genome, and are highly inefficient for large number of sequences. Therefore, the common practice has been to use either simple pairwise alignment despite its poor accuracy for error prone pyroreads, or use computationally expensive techniques based on sequential gap propagation. In this paper, we develop a computationally efficient method based on domain decomposition, referred to as pyro-align, to align such large number of reads. The proposed alignment algorithm accurately aligns the erroneous reads in a short period of time, which is orders of magnitude faster than any existing method. The accuracy of the alignment is confirmed from the consensus obtained from the multiple alignments.

q-bio.GN↗

arXiv2009

MicroRNA Interaction network in human: implications of clustered microRNA in biological pathways and genetic diseases

A novel group of small non-coding RNA, known as microRNA (miRNA) is predicted to regulate as high as 90% of the coding genes in human. The diversity and abundance of miRNA targets offer an enormous level of combinatorial possibilities and suggest that miRNAs and their targets form a complex regulatory network. In the present study, we analyzed 711 miRNAs and their 34, 525 predicted targets in the miRBase database which generate a complex bipartite network having numerous numbers of genes forming the hub. Genes at the hub (total 9877) are significantly over represented in genes with specific molecular functions, biological processes and biological pathways as revealed from the analysis using PANTHER. We further construct a miRNA co-target network by linking every pair of miRNAs which co-target at least one gene. The weight of the link, which is taken to be the number of co-targets of the pair of miRNAs vary widely, and we could erase several links while keeping the relevant features of the network intact. The largest connected sub-graph, thus obtained, contains 479 miRNAs. More than 75% of the miRNAs deregulated in 15 different diseases collected from published data are found to be in this largest sub graph. We further analyze this sub-graph to obtain 70 small clusters containing total 330 miRNAs of 479. We identified the biological pathways where the co-targeted genes in the clusters are significantly over- represented in comparison to that obtained with that are not co-targeted by the miRNAs in the cluster. Using published data, we identified that specific clusters of miRNAs are associated with specific diseases by altering particular pathways. We propose that instead of single miRNA, clusters of miRNA that co-targets the genes are important for the regulation of miRNA in diseases.

q-bio.GN↗

arXiv2009

Mathematical Framework for Phylogenetic Birth-And-Death Models

A phylogenetic birth-and-death model is a probabilistic graphical model for a so-called phylogenetic profile, i.e., the size distribution for a homolog gene family at the terminal nodes of a phylogeny. Profile datasets are used in bioinformatics analyses for the inference of evolutionary trees, and of functional associations between gene families, as well as for the quantification of various processes guiding genome evolution. Here we describe the mathematical formalism for phylogenetic birth-and-death models. We also present an algorithm for computing the likelihood in a gain-loss-duplication model.

q-bio.PE↗

arXiv2009

p-Adic numbers in bioinformatics: from genetic code to PAM-matrix

In this paper we denonstrate that the use of the system of 2-adic numbers provides a new insight to some problems of genetics, in particular, generacy of the genetic code and the structure of the PAM matrix in bioinformatics. The 2-adic distance is an ultrametric and applications of ultrametrics in bioinformatics are not surprising. However, by using the 2-adic numbers we match ultrametric with a number theoretic structure. In this way we find new applications of an ultrametric which differ from known up to now in bioinformatics. We obtain the following results. We show that the PAM matrix A allows the expansion into the sum of the two matrices A=A^{(2)}+A^{(\infty)}, where the matrix A^{(2)} is 2-adically regular (i.e. matrix elements of this matrix are close to locally constant with respect to the discussed earlier by the authors 2-adic parametrization of the genetic code), and the matrix A^{(\infty)} is sparse. We discuss the structure of the matrix A^{(\infty)} in relation to the side chain properties of the corresponding amino acids.

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