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arXiv2009

A Unified Theory on Construction and Evolution of the Genetic Code

A quantitative theory on the construction and the evolution of the genetic code is proposed. Through introducing the concept of mutational deterioration (MD) and developing a theoretical formalism on MD minimization we have proved: 1, the redundancy distribution of codons in the genetic code obeys MD minimization principle; 2, the hydrophilic-hydrophobic distribution of amino acids on the code table is global MD (GMD) minimal; 3, the standard genetic code can be deduced from the adaptive minimization of GMD; 4, the variants of the standard genetic code can be explained quantitatively by use of GMD formalism and the general trend of the evolution is GMD non-increasing which reflects the selection on the code. We have demonstrated that the redundancy distribution of codons and the hydrophobic-hydrophilic (H-P) distribution of amino acids are robust in the code relative to the mutational parameter, and indicated that the GMD can be looked as a non-fitness function on the adaptive landscape. Finally, an important aspect on the symmetry of the code construction, the Yin-Yang duality is investigated. The Yin-Yang duality among codons affords a sound basis for understanding the H-P structure in the genetic code.

q-bio.OT↗
arXiv2009

Exceptional error minimization in putative primordial genetic codes

We investigated the error-minimization properties of putative primordial codes that consisted of 16 supercodons, with the third base being completely redundant, using a previously derived cost function and the error minimization percentage as the measure of a code's robustness to mistranslation. It is shown that, when the 16-supercodon table is populated with 10 putative primordial amino acids, inferred from the results of abiotic synthesis experiments and other evidence independent of the code evolution, and with minimal assumptions used to assign the remaining supercodons, the resulting 2-letter codes are nearly optimal in terms of the error minimization level. The results of the computational experiments with putative primordial genetic codes that contained only two meaningful letters in all codons and encoded 10 to 16 amino acids indicate that such codes are likely to have been nearly optimal with respect to the minimization of translation errors. This near-optimality could be the outcome of extensive early selection during the co-evolution of the code with the primordial, error-prone translation system, or a result of a unique, accidental event. Under this hypothesis, the subsequent expansion of the code resulted in a decrease of the error minimization level that became sustainable owing to the evolution of a high-fidelity translation system.

q-bio.GN↗
arXiv2009

Emergent Network Structure, evolvable Robustness and non-linear Effects of Point Mutations in an Artificial Genome Model

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 paper we investigate these properties within an artificial genome model originally introduced by Reil (1999). 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 dynamical robustness against single base mutations, as well as against random changes in initial states of regulatory dynamics that mimic stochastic fluctuations in environmental conditions, can emerge in parallel. Point mutations at the sequence level have strongly non-linear effects on network wiring, including as well structurally neutral mutations and simultaneous rewiring of multiple connections, which occasionally lead to strong reorganization of the attractor landscape and metastability of evolutionary dynamics. Evolved genomes exhibit characteristic patterns on both sequence and network level.

q-bio.MN↗
arXiv2009

Modeling of the genetic switch of bacteriophage TP901-1: A heteromer of CI and MOR ensures robust bistability

The lytic-lysogenic switch of the temperate lactococcal phage TP901-1 is fundamentally different from that of phage lambda. In phage TP901-1, the lytic promoter PL is repressed by CI whereas repression of the lysogenic promoter PR requires the presence of both of the antagonistic regulator proteins, MOR and CI. We model the central part of the switch and compare the two cases for PR repression: the one where the two regulators interact only on the DNA, and the other where the two regulators form a heteromer complex in the cytoplasm prior to DNA binding. The models are analyzed for bistability, and the predicted promoter repression folds are compared to experimental data. We conclude that the experimental data are best reproduced the latter case, where a heteromer complex forms in solution. We further find that CI sequestration by the formation of MOR:CI complexes in cytoplasm makes the genetic switch robust.

q-bio.MN↗
arXiv2009

Rare-Allele Detection Using Compressed Se(que)nsing

Detection of rare variants by resequencing is important for the identification of individuals carrying disease variants. Rapid sequencing by new technologies enables low-cost resequencing of target regions, although it is still prohibitive to test more than a few individuals. In order to improve cost trade-offs, it has recently been suggested to apply pooling designs which enable the detection of carriers of rare alleles in groups of individuals. However, this was shown to hold only for a relatively low number of individuals in a pool, and requires the design of pooling schemes for particular cases. We propose a novel pooling design, based on a compressed sensing approach, which is both general, simple and efficient. We model the experimental procedure and show via computer simulations that it enables the recovery of rare allele carriers out of larger groups than were possible before, especially in situations where high coverage is obtained for each individual. Our approach can also be combined with barcoding techniques to enhance performance and provide a feasible solution based on current resequencing costs. For example, when targeting a small enough genomic region (~100 base-pairs) and using only ~10 sequencing lanes and ~10 distinct barcodes, one can recover the identity of 4 rare allele carriers out of a population of over 4000 individuals.

q-bio.GN↗
arXiv2009

Parameter Estimation in multiple-hidden i.i.d. models from biological multiple alignment

In this work we deal with parameter estimation in a latent variable model, namely the multiple-hidden i.i.d. model, which is derived from multiple alignment algorithms. We first provide a rigorous formalism for the homology structure of k sequences related by a star-shaped phylogenetic tree in the context of multiple alignment based on indel evolution models. We discuss possible definitions of likelihoods and compare them to the criterion used in multiple alignment algorithms. Existence of two different Information divergence rates is established and a divergence property is shown under additional assumptions. This would yield consistency for the parameter in parametrization schemes for which the divergence property holds. We finally extend the definition of the multiple-hidden i.i.d. model and the results obtained to the case in which the sequences are related by an arbitrary phylogenetic tree. Simulations illustrate different cases which are not covered by our results.

stat.AP↗
arXiv2012

Efficient algorithms for training the parameters of hidden Markov models using stochastic expectation maximization EM training and Viterbi training

Background: Hidden Markov models are widely employed by numerous bioinformatics programs used today. Applications range widely from comparative gene prediction to time-series analyses of micro-array data. The parameters of the underlying models need to be adjusted for specific data sets, for example the genome of a particular species, in order to maximize the prediction accuracy. Computationally efficient algorithms for parameter training are thus key to maximizing the usability of a wide range of bioinformatics applications. Results: We introduce two computationally efficient training algorithms, one for Viterbi training and one for stochastic expectation maximization (EM) training, which render the memory requirements independent of the sequence length. Unlike the existing algorithms for Viterbi and stochastic EM training which require a two-step procedure, our two new algorithms require only one step and scan the input sequence in only one direction. We also implement these two new algorithms and the already published linear-memory algorithm for EM training into the hidden Markov model compiler HMM-Converter and examine their respective practical merits for three small example models. Conclusions: Bioinformatics applications employing hidden Markov models can use the two algorithms in order to make Viterbi training and stochastic EM training more computationally efficient. Using these algorithms, parameter training can thus be attempted for more complex models and longer training sequences. The two new algorithms have the added advantage of being easier to implement than the corresponding default algorithms for Viterbi training and stochastic EM training.

q-bio.QM↗
arXiv2009

Characterising the D2 statistic: word matches in biological sequences

Word matches are often used in sequence comparison methods, either as a measure of sequence similarity or in the first search steps of algorithms such as BLAST or BLAT. The D2 statistic is the number of matches of words of k letters between two sequences. Recent advances have been made in the characterisation of this statistic and in the approximation of its distribution. Here, these results are extended to the case of approximate word matches. We compute the exact value of the variance of the D2 statistic for the case of a uniform letter distribution, and introduce a method to provide accurate approximations of the variance in the remaining cases. This enables the distribution of D2 to be approximated for typical situations arising in biological research. We apply these results to the identification of cis-regulatory modules, and show that this method detects such sequences with a high accuracy. The ability to approximate the distribution of D2 for both exact and approximate word matches will enable the use of this statistic in a more precise manner for sequence comparison, database searches, and identification of transcription factor binding sites.

q-bio.QM↗
arXiv2010

Some mathematical refinements concerning error minimization in the genetic code

The genetic code has been shown to be very error robust compared to randomly selected codes, but to be significantly less error robust than a certain code found by a heuristic algorithm. We formulate this optimisation problem as a Quadratic Assignment Problem and thus verify that the code found by the heuristic is the global optimum. We also argue that it is strongly misleading to compare the genetic code only with codes sampled from the fixed block model, because the real code space is orders of magnitude larger. We thus enlarge the space from which random codes can be sampled from approximately 2.433 x 10^18 codes to approximately 5.908 x 10^45 codes. We do this by leaving the fixed block model, and using the wobble rules to formulate the characteristics acceptable for a genetic code. By relaxing more constraints three larger spaces are also constructed. Using a modified error function, the genetic code is found to be more error robust compared to a background of randomly generated codes with increasing space size. We point out that these results do not necessarily imply that the code was optimized during evolution for error minimization, but that other mechanisms could explain this error robustness.

q-bio.QM↗
arXiv2009

Data Management for High-Throughput Genomics

Today's sequencing technology allows sequencing an individual genome within a few weeks for a fraction of the costs of the original Human Genome project. Genomics labs are faced with dozens of TB of data per week that have to be automatically processed and made available to scientists for further analysis. This paper explores the potential and the limitations of using relational database systems as the data processing platform for high-throughput genomics. In particular, we are interested in the storage management for high-throughput sequence data and in leveraging SQL and user-defined functions for data analysis inside a database system. We give an overview of a database design for high-throughput genomics, how we used a SQL Server database in some unconventional ways to prototype this scenario, and we will discuss some initial findings about the scalability and performance of such a more database-centric approach.

cs.DB↗
arXiv2009

A Simpler Explanation to BAK1 Gene Variation in Aortic and Blood Tissues

The explanation is that in aortic tissue (both diseased and nondiseased) a BAK1 pseudogene is expressed; while in the matching blood samples the actual BAK1 gene is expressed. This explanation was reached after we realized that BAK1 has two edited copies in human genome. These copies are probably BAK1 pseudogenes. One copy belongs to chromosome 11 (NG_005599.3) and the other to chromosome 20 (NC_000850.5). The first copy has frameshifts which means that probably it does not express any functional protein; by other hand, the chromosome 20 copy has no frameshifts and what is more important contains all the reported polymorphisms.

q-bio.GN↗
arXiv2009

Local stability and evolution of the genetic code

The standard genetic code is known to be robust to translation errors and point mutations. We studied how small modifications of the standard code affect its robustness. The robustness was assessed in terms of a proper stability function, the negative variations of which correspond to a more robust code. The fraction of more robust codes obtained under small modifications appeared to be unexpectedly high, ranged from 0.1 to 0.4 depending on the choice of stability function and code modifications, yet significantly lower than the corresponding fraction in the random codes (about a half). In this sense the standard code ought to be considered distinctly non-random in accordance with previous observations. The distribution of the negative variations of stability function revealed very abrupt drop beyond one standard deviation, much sharper than for Gaussian distribution or for the random codes with the same number of codons in the sets coding for amino acids or stop-codons. This behavior holds for both the standard code as a whole and its binary NRN-NYN, NWN-NSN, and NMN-NKN blocks. Previously, it has been proved that such binary block structure is necessary for the robustness of a code and is inherent to the standard genetic code. The modifications of the standard code corresponding to more robust coding may be related to the different variants of the code. These effects may also contribute to the rates of replacements of amino acids. The observed features demonstrate the joint impact of random factors and natural selection during evolution of the genetic code.

q-bio.QM↗
arXiv2009

On the clustering of rare codons and its effect on translation

The presence of clusters of rare codons is known to negatively impact the efficiency and accuracy of protein production. In this paper, we demonstrate a statistical method of identifying such clusters in the coding sequence of a gene. Using E. coli as our model organism, we show that genes having denser clusters tend to have lower protein yields.

q-bio.GN↗
arXiv2009

The hypothesis that coelacanth is the closest living relative of tetrapods 3 was rejected based on three genome-scale approaches

Since its discovery of the living fossil in 1938, the coelacanth (Latimeria chalumnae) has generally been considered to be the closest living relative of the land vertebrates, and this is still the prevailing opinion in most general biology textbooks. However, the origin of tetrapods has been the subject of intense debate for decades. The three principal hypothesis (lungfish-tetrapod, coelacanth-tetrapod, or lungfish-coelacanth sister group) have been proposed. We used the maximum gene-support tree approach to analyze 43 nuclear genes encoding amino acid residues, and compared the results of concatenation and majority-rule tree approaches. The results inferred with three common phylogenetic methods and three genome-scale approaches consistently rejected the hypothesis that the coelacanth is the closest living relative of tetrapods.

q-bio.PE↗
arXiv2009

GeneSupport Maximum Gene-Support Tree Approach to Species Phylogeny Inference

Summary: GeneSupport implements a genome-scale algorithm: Maximum Gene-Support Tree to estimate species tree from gene trees based on multilocus sequences. It provides a new option for multiple genes to infer species tree. It is incorporated into popular phylogentic program: PHYLIP package with the same usage and user interface. It is suitable for phylogenetic methods such as maximum parsimony, maximum likelihood, Baysian and neighbour-joining, which is used to reconstruct single gene trees firstly with a variety of phylogenetic inference programs.

q-bio.GN↗
arXiv2009

Mechanics and Dynamics of X-Chromosome Pairing at X Inactivation

At the onset of X Chromosomes Inactivation, the vital process whereby female mammal cells equalize X products with respect to males, the X chromosomes are colocalized along their Xic (X-Inactivation Center) regions. The mechanism inducing recognition and pairing of the X's remains, though, elusive. Starting from recent discoveries on the molecular factors and on the DNA sequences (the so-called ``pairing sites'') involved, we dissect the mechanical basis of Xic colocalization by using a Statistical Physics model. We show that soluble DNA specific binding molecules, as those experimentally identified, can be indeed sufficient to induce the spontaneous colocalization of the homologous chromosomes, but only when their concentration, or chemical affinity, rises above a threshold value, as a consequence of a thermodynamic phase transition. We derive the likelihood of pairing and its probability distribution. Chromosome dynamics has two stages: an initial independent Brownian diffusion followed, after a characteristic time scale, by recognition and pairing. Finally, we investigate the effects of DNA deletion/insertions in the region of pairing sites and compare model predictions to available experimental data.

q-bio.GN↗
arXiv2009

Combining predictors of natively unfolded proteins to detect a twilight zone between order and disorder in generic datasets

Natively unfolded proteins lack a well defined three dimensional structure but have important biological functions, suggesting a re-assignment of the structure-function paradigm. Many proteins have amino acidic compositions compatible both with the folded and unfolded status, and belong to a twilight zone between order and disorder. This makes difficult a dichotomic classification of protein sequences into folded and natively unfolded ones. In this methodological paper dichotomic folding indexes are considered: hydrophobicity-charge, mean packing, mean pairwise energy, Poodle-W and a new global index, that is called here gVSL2, based on the local disorder predictor VSL2. The performance of these indexes is evaluated on different datasets. Poodle-W, gVSL2 and mean pairwise energy have good performance and stability in all the datasets considered and are combined into a strictly unanimous combination score SSU, that leaves proteins unclassified when the consensus of all combined indexes is not reached. The unclassified proteins: i) belong to an overlap region in the vector space of amino acidic compositions occupied by both folded and unfolded proteins; ii) are composed by approximately the same number of order-promoting and disorder-promoting amino acids; iii) have a mean flexibility intermediate between that of folded and that of unfolded proteins. These proteins reasonably have physical properties intermediate between those of folded and those of natively unfolded proteins and their structural properties and evolutionary history are worth to be investigated.

q-bio.BM↗