25,833 research outputs found
Phylogenetic Analysis of Cell Types using Histone Modifications
In cell differentiation, a cell of a less specialized type becomes one of a
more specialized type, even though all cells have the same genome.
Transcription factors and epigenetic marks like histone modifications can play
a significant role in the differentiation process. In this paper, we present a
simple analysis of cell types and differentiation paths using phylogenetic
inference based on ChIP-Seq histone modification data. We propose new data
representation techniques and new distance measures for ChIP-Seq data and use
these together with standard phylogenetic inference methods to build
biologically meaningful trees that indicate how diverse types of cells are
related. We demonstrate our approach on H3K4me3 and H3K27me3 data for 37 and 13
types of cells respectively, using the dataset to explore various issues
surrounding replicate data, variability between cells of the same type, and
robustness. The promising results we obtain point the way to a new approach to
the study of cell differentiation.Comment: Peer-reviewed and presented as part of the 13th Workshop on
Algorithms in Bioinformatics (WABI2013
Predicting Genetic Regulatory Response Using Classification
We present a novel classification-based method for learning to predict gene
regulatory response. Our approach is motivated by the hypothesis that in simple
organisms such as Saccharomyces cerevisiae, we can learn a decision rule for
predicting whether a gene is up- or down-regulated in a particular experiment
based on (1) the presence of binding site subsequences (``motifs'') in the
gene's regulatory region and (2) the expression levels of regulators such as
transcription factors in the experiment (``parents''). Thus our learning task
integrates two qualitatively different data sources: genome-wide cDNA
microarray data across multiple perturbation and mutant experiments along with
motif profile data from regulatory sequences. We convert the regression task of
predicting real-valued gene expression measurement to a classification task of
predicting +1 and -1 labels, corresponding to up- and down-regulation beyond
the levels of biological and measurement noise in microarray measurements. The
learning algorithm employed is boosting with a margin-based generalization of
decision trees, alternating decision trees. This large-margin classifier is
sufficiently flexible to allow complex logical functions, yet sufficiently
simple to give insight into the combinatorial mechanisms of gene regulation. We
observe encouraging prediction accuracy on experiments based on the Gasch S.
cerevisiae dataset, and we show that we can accurately predict up- and
down-regulation on held-out experiments. Our method thus provides predictive
hypotheses, suggests biological experiments, and provides interpretable insight
into the structure of genetic regulatory networks.Comment: 8 pages, 4 figures, presented at Twelfth International Conference on
Intelligent Systems for Molecular Biology (ISMB 2004), supplemental website:
http://www.cs.columbia.edu/compbio/geneclas
Variable selection for BART: An application to gene regulation
We consider the task of discovering gene regulatory networks, which are
defined as sets of genes and the corresponding transcription factors which
regulate their expression levels. This can be viewed as a variable selection
problem, potentially with high dimensionality. Variable selection is especially
challenging in high-dimensional settings, where it is difficult to detect
subtle individual effects and interactions between predictors. Bayesian
Additive Regression Trees [BART, Ann. Appl. Stat. 4 (2010) 266-298] provides a
novel nonparametric alternative to parametric regression approaches, such as
the lasso or stepwise regression, especially when the number of relevant
predictors is sparse relative to the total number of available predictors and
the fundamental relationships are nonlinear. We develop a principled
permutation-based inferential approach for determining when the effect of a
selected predictor is likely to be real. Going further, we adapt the BART
procedure to incorporate informed prior information about variable importance.
We present simulations demonstrating that our method compares favorably to
existing parametric and nonparametric procedures in a variety of data settings.
To demonstrate the potential of our approach in a biological context, we apply
it to the task of inferring the gene regulatory network in yeast (Saccharomyces
cerevisiae). We find that our BART-based procedure is best able to recover the
subset of covariates with the largest signal compared to other variable
selection methods. The methods developed in this work are readily available in
the R package bartMachine.Comment: Published in at http://dx.doi.org/10.1214/14-AOAS755 the Annals of
Applied Statistics (http://www.imstat.org/aoas/) by the Institute of
Mathematical Statistics (http://www.imstat.org
Antigenic diversity is generated by distinct evolutionary mechanisms in African trypanosome species
Antigenic variation enables pathogens to avoid the host immune response by continual switching of surface proteins. The protozoan blood parasite Trypanosoma brucei causes human African trypanosomiasis ("sleeping sickness") across sub-Saharan Africa and is a model system for antigenic variation, surviving by periodically replacing a monolayer of variant surface glycoproteins (VSG) that covers its cell surface. We compared the genome of Trypanosoma brucei with two closely related parasites Trypanosoma congolense and Trypanosoma vivax, to reveal how the variant antigen repertoire has evolved and how it might affect contemporary antigenic diversity. We reconstruct VSG diversification showing that Trypanosoma congolense uses variant antigens derived from multiple ancestral VSG lineages, whereas in Trypanosoma brucei VSG have recent origins, and ancestral gene lineages have been repeatedly co-opted to novel functions. These historical differences are reflected in fundamental differences between species in the scale and mechanism of recombination. Using phylogenetic incompatibility as a metric for genetic exchange, we show that the frequency of recombination is comparable between Trypanosoma congolense and Trypanosoma brucei but is much lower in Trypanosoma vivax. Furthermore, in showing that the C-terminal domain of Trypanosoma brucei VSG plays a crucial role in facilitating exchange, we reveal substantial species differences in the mechanism of VSG diversification. Our results demonstrate how past VSG evolution indirectly determines the ability of contemporary parasites to generate novel variant antigens through recombination and suggest that the current model for antigenic variation in Trypanosoma brucei is only one means by which these parasites maintain chronic infections
Phylogeny of Prokaryotes and Chloroplasts Revealed by a Simple Composition Approach on All Protein Sequences from Complete Genomes Without Sequence Alignment
The complete genomes of living organisms have provided much information on their phylogenetic relationships. Similarly, the complete genomes of chloroplasts have helped to resolve the evolution of this organelle in photosynthetic eukaryotes. In this paper we propose an alternative method of phylogenetic analysis using compositional statistics for all protein sequences from complete genomes. This new method is conceptually simpler than and computationally as fast as the one proposed by Qi et al. (2004b) and Chu et al. (2004). The same data sets used in Qi et al. (2004b) and Chu et al. (2004) are analyzed using the new method. Our distance-based phylogenic tree of the 109 prokaryotes and eukaryotes agrees with the biologists tree of life based on 16S rRNA comparison in a predominant majority of basic branching and most lower taxa. Our phylogenetic analysis also shows that the chloroplast genomes are separated to two major clades corresponding to chlorophytes s.l. and rhodophytes s.l. The interrelationships among the chloroplasts are largely in agreement with the current understanding on chloroplast evolution
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