Molecular Biology

Each human has approximately 50-280 frameshifting indels, yet their implications are unknown. We created SIFT Indel, a prediction method for frameshifting indels which has 84% accuracy. The percentage of human frameshifting indels predicted to be gene-damaging is negatively correlated with allele frequency. We also show that although the first frameshifting indel in a gene causes loss of function, there is a tendency for the second frameshifting indel to compensate and restore protein function. SIFT Indel is available at http://siftdna.org/www/SIFT_indels2.html

Background: Ethnic differences in human DNA methylation have been shown for a number of CpG sites, but the genome-wide patterns and extent of these differences are largely unknown. In addition, whether the genetic control of polymorphic DNA methylation is population-specific has not been investigated. Results: Here we measure DNA methylation near the transcription start sites of over 14,000 genes in 180 cell lines derived from one African and one European population. We find population-specific patterns of DNA methylation at over a third of all genes. Furthermore, although the methylation at over a thousand CpG sites is heritable, these heritabilities also differ between populations, suggesting extensive divergence in the genetic control of DNA methylation. In support of this, genetic mapping of DNA methylation reveals that most of the population-specificity can be explained by divergence in allele-frequencies between populations, and that there is little overlap in genetic associations between populations. These population-specific genetic associations are supported by the patterns of DNA methylation in several hundred brain samples, suggesting that they hold in vivo and across tissues. Conclusions: These results suggest that DNA methylation is highly divergent between populations, and that this divergence may be due in large part to a combination of differences in allele frequencies and complex epistasis or gene x environment interactions.

Background: The study of typical morphological variations using quantitative, morphometric descriptors has always interested biologists in general. However, unusual examples of form, such as abnormalities are often encountered in biomedical sciences. Despite the long history of morphometrics, the means to identify and quantify such unusual form differences remains limited. Methods: A theoretical concept, called dysmorphometrics, is introduced augmenting current geometric morphometrics with a focus on identifying and modelling form abnormalities. Dysmorphometrics applies the paradigm of detecting form differences as outliers compared to an appropriate norm. To achieve this, the likelihood formulation of landmark superimpositions is extended with outlier processes explicitly introducing a latent variable coding for abnormalities. A tractable solution to this augmented superimposition problem is obtained using Expectation-Maximization. The topography of detected abnormalities is encoded in a dysmorphogram. Results: We demonstrate the use of dysmorphometrics to measure abrupt changes in time, asymmetry and discordancy in a set of human faces presenting with facial abnormalities. Conclusion: The results clearly illustrate the unique power to reveal unusual form differences given only normative data with clear applications in both biomedical practice and research.

In this paper, a new mathematical model is developed to represent the interaction between healthy and cancer cells in the human body, focusing on the role of environmental factors and quality of life in the progression of cancer. We have investigated the dynamic effects of inputs on cancer growth, and provide an explanation of how cancer has variable behavior patterns throughout the lives of different patients. The behavior of the system with input and its trajectory patterns are investigated using trajectory patterns and stability analysis. The analysis suggests that a proper treatment method should change the dynamics of the cancer instead of only reducing the population of cancer cells and treatment burden.

Background: Generally, utility based decision making models focus on experimental outcomes. In this paper we propose a utility model based on molecular diffusion to simulate the choice behavior of Drosophila larvae exposed to different light conditions. Methods: In this paper, light/dark choice-based Drosophila larval phototaxis is analyzed with our molecular diffusion based model. An ISCEM algorithm is developed to estimate the model parameters. Results: By applying this behavioral utility model to light intensity and phototaxis data, we show that this model fits the experimental data very well. Conclusions: Our model provides new insights into decision making mechanisms in general. From an engineering viewpoint, we propose that the model could be applied to a wider range of decision making practices.

Background: Cancer arises when within a single cell multiple malfunctions of control systems occur, which are,broadly, the system that promote cell growth and the system that protect against erratic growth. Additionalsystems within the cell must be corrupted so that a cancer cell, to form a mass of any real size, producessubstances that promote the growth of new blood vessels. Multiple mutations are required before a normal cellcan become a cancer cell by corruption of multiple growth-promoting systems. Methods: We develop a simple mathematical model to describe the solid cancer growth dynamics inducingangiogenesis in the absence of cancer controlling mechanisms. Results: The initial conditions supplied to the dynamical system consist of a perturbation in form of pulse: Theorigin of cancer cells from normal cells of an organ of human body. Thresholds of interacting parameters wereobtained from the steady states analysis. The existence of two equilibrium points determine the strongdependency of dynamical trajectories on the initial conditions. The thresholds can be used to control cancer. Conclusions: Cancer can be settled in an organ if the following combination matches: better fitness of cancercells, decrease in the effciency of the repairing systems, increase in the capacity of sprouting from existingvascularization, and higher capacity of mounting up new vascularization. However, we show that cancer is rarelyinduced in organs (or tissues) displaying an efficient (numerically and functionally) reparative or regenerativemechanism.

Background: As many invertebrate species have multipotent cells that undergo cell growth and differentiation during regeneration and budding, many unique and interesting homeostatic factors are expected to exist in those animals. However, our understanding of such factors and global mechanisms remains very poor. Single zooids of the tunicate, Polyandrocarpa misakiensis, can give off as many as 40 buds during the life span. Bud development proceeds by means of transdifferentiation of very limited number of cells and tissues. TC14-3 is one of several different but closely related polypeptides isolated from P. misakiensis. It acts as a cytostatic factor that regulates proliferation, adhesion, and differentiation of multipotent cells, although the molecular mechanism remains uncertain. The Polycomb group (PcG) genes are involved in epigenetic control of genomic activity in mammals. In invertebrates except Drosophila, PcG and histone methylation have not been studied so extensively, and genome-wide gene regulation is poorly understood. Results: When Phe65 of TC14-3 was mutated to an acidic amino acid, the resultant mutant protein failed to dimerize. The replacement of Thr69 with Arg69 made dimers unstable. When Glu106 was changed to Gly106, the resultant mutant protein completely lost Ca2+ binding. All these mutant proteins lacked cytostatic activity, indicating the requirement of protein dimerization and calcium for the activity. Polyandrocarpa Eed, a component of PcG, is highly expressed during budding, like TC14-3. When wild-type and mutant TC14-3s were applied in vivo and in vitro to Polyandrocarpa cells, only wild-type TC14-3 could induce Eed without affecting histone methyltransferase gene expression. Eed-expressing cells underwent trimethylation of histone H3 lysine27. PmEed knockdown by RNA interference rescued cultured cells from the growth-inhibitory effects of TC14-3. Conclusion: These results show that in P. misakiensis, the cytostatic activity of TC14-3 is mediated by PmEed and resultant histone modification, and that the gene expression requires both the protein dimerization and Ca2+-binding of TC14-3. This system consisting of a humoral factor, PcG, and histone methylation would contribute to the homeostatic regulation of cell growth and terminal differentiation of invertebrate multipotent cells.

The International Crocodilian Genomes Working Group (ICGWG) will sequence and assemble the American alligator (Alligator mississippiensis), saltwater crocodile (Crocodylus porosus) and Indian gharial (Gavialis gangeticus) genomes. The status of these projects and our planned analyses are described.

Background: Expression quantitative trait loci (eQTLs) are likely to play an important role in the genetics of complex traits; however their functional basis remains poorly understood. Using the HapMap lymphoblastoid cell lines, we combine 1000 Genomes genotypes and an extensive catalogue of human functional elements to investigate the biological mechanisms that eQTLs perturb. Results: We use a Bayesian hierarchical model to estimate the enrichment of eQTLs in a wide variety of regulatory annotations. We find that ~40% of eQTLs occur in open chromatin, and that they are particularly enriched in transcription factor binding sites, suggesting that many directly impact protein-DNA interactions. Analysis of core promoter regions shows that eQTLs also frequently disrupt some known core promoter motifs but, surprisingly, are not enriched in other well-known motifs such as the TATA box. We also show that information from regulatory annotations alone, when weighted by the hierarchical model, can provide a meaningful ranking of the SNPs that are most likely to drive gene expression variation. Conclusions: Our study demonstrates how regulatory annotation and the association signal derived from eQTL-mapping can be combined into a single framework. We used this approach to further our understanding of the biology that drives human gene expression variation, and of the putatively causal SNPs that underlie it.

Reconstructed models of metabolic networks are widely used for studying metabolism in various organisms. Many different reconstructions of the same organism often exist concurrently, forcing researchers to choose one of them at the exclusion of the others. We describe MetaMerge, an algorithm for semi-automatically reconciling a pair of existing metabolic network reconstructions into a single metabolic network model. We use MetaMerge to combine two published metabolic networks for Mycobacterium tuberculosis into a single network which allows many reactions that could not be active in the individual models to become active, and predicts essential genes with a higher positive predictive value.

We present Uberon, an integrated cross-species ontology consisting of over 6500 classes representing a variety of anatomical entities, organized according to traditional anatomical classification criteria. The ontology represents structures in a species-neutral way and includes extensive associations to existing species-centric anatomical ontologies, allowing integration of model organism and human data. Uberon provides a necessary bridge between anatomical structures in different taxa for cross-species inference. It uses novel methods for representing taxonomic variation, and has proved to be essential for translational phenotype analyses. Uberon is available at http://obo.svn.sourceforge.net/viewvc/obo/uberon/releases/2011-09-25/

We propose a method for predicting splice graphs that enhances curated gene models using evidence from RNA-Seq and EST alignments. Results obtained using RNA-Seq experiments in Arabidopsis thaliana show that predictions made by our SpliceGrapher method are more consistent with current gene models than predictions made by TAU and Cufflinks. Furthermore, analysis of plant and human data indicates that the machine learning approach used by SpliceGrapher is useful for discriminating between real and spurious splice sites, and can improve the reliability of detection of alternative splicing. SpliceGrapher is available for download at http://SpliceGrapher.sf.net.

{no abstract}

Mosaic amplification of receptor tyrosine kinases in glioblastoma suggests that tumor cells with different progression driver mutations may coevolve rather than compete during clonal evolution.

A report of the Wellcome Trust Functional Genomics and Systems Biology Conference, Hinxton, UK, 29 November to 1 December 2011.

A report on the Plant Genomes and Biotechnology: From Genes to Networks meeting, held at Cold Spring Harbor Laboratory, 30 November to 3 December 2011.

Using a device termed the 'morbidostat', a recent study sheds new light on the determinism of genetic and phenotypic trajectories leading to high antibiotic resistance.

An elegant, genome-wide approach to define the precise DNA sequences bound by transcription factors has been developed by Rhee and Pugh.

An elegant, genome-wide approach to define the precise DNA sequences bound by transcription factors has been developed by Rhee and Pugh.

Background: Although it is agreed that a major polyploidy event, gamma, occurred within the eudicots, the phylogenetic placement of the event remains unclear. Results: To determine when this polyploidization occurred relative to speciation events in angiosperm history, we employed a phylogenomic approach to investigate the timing of gene set duplications located on syntenic gamma blocks. 769 putative gene families were populated with large sets of homologs obtained from public transcriptomes of basal angiosperms, magnoliids, asterids, and more than 91.8 gigabases of new Next-Generation transcriptome sequences of non-grass monocots and basal eudicots. The overwhelming majority (95%) of well-resolved gamma duplications was placed before the separation of rosids and asterids and after the split of monocots and eudicots, providing strong evidence that the gamma polyploidy event occurred early in eudicot evolution. Further, the majority of gene duplications was placed after the divergence of the Ranunculales and core eudicots, indicating that the gamma appears to be restricted to core eudicots. Molecular dating estimates indicate that the duplication events were intensely concentrated around 117 million years ago. Conclusions: The rapid radiation of core eudicot lineages that gave rise to nearly 75% of angiosperm species appears to have occurred coincidentally or shortly following the gamma triplication event. Reconciliation of gene trees with a species phylogeny can elucidate the timing of major events in genome evolution, even when genome sequences are only available for a subset of species represented in the gene trees. Comprehensive transcriptome datasets are valuable complements to genome sequences for high-resolution phylogenomic analysis.