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Haiyuan Yu

Publications and source records attributed to Haiyuan Yu.

26 records · Page 2Linked to original sources

Analyzing cellular biochemistry in terms of molecular networks.

One way to understand cells and circumscribe the function of proteins is through molecular networks. These networks take a variety of forms including webs of protein-protein interactions, regulatory circuits linking transcription factors and targets, and complex pathways of metabolic reactions. We first survey experimental techniques for mapping networks (e.g., the yeast two-hybrid screens). We then turn our attention to computational approaches for predicting networks from individual protein features, such as correlating gene expression levels or analyzing sequence coevolution. All the experimental techniques and individual predictions suffer from noise and systematic biases. These problems can be overcome to some degree through statistical integration of different experimental datasets and predictive features (e.g., within a Bayesian formalism). Next, we discuss approaches for characterizing the topology of networks, such as finding hubs and analyzing subnetworks in terms of common motifs. Finally, we close with perspectives on how network analysis represents a preliminary step toward a systems approach for modeling cells.

Biochemical Phenomena↗

Relationship between gene co-expression and probe localization on microarray slides.

BACKGROUND: Microarray technology allows simultaneous measurement of thousands of genes in a single experiment. This is a potentially useful tool for evaluating co-expression of genes and extraction of useful functional and chromosomal structural information about genes. RESULTS: In this work we studied the association between the co-expression of genes, their location on the chromosome and their location on the microarray slides by analyzing a number of eukaryotic expression datasets, derived from the S. cerevisiae, C. elegans, and D. melanogaster. We find that in several different yeast microarray experiments the distribution of the number of gene pairs with correlated expression profiles as a function of chromosomal spacing is peaked at short separations and has two superimposed periodicities. The longer periodicity has a spacing of 22 genes (approximately 42 Kb), and the shorter periodicity is 2 genes (approximately 4 Kb). CONCLUSION: The relative positioning of DNA probes on microarray slides and source plates introduces subtle but significant correlations between pairs of genes. Careful consideration of this spatial artifact is important for analysis of microarray expression data. It is particularly relevant to recent microarray analyses that suggest that co-expressed genes cluster along chromosomes or are spaced by multiples of a fixed number of genes along the chromosome.

Animals↗

A genome-wide analysis of blue-light regulation of Arabidopsis transcription factor gene expression during seedling development.

A microarray based on PCR amplicons of 1864 confirmed and predicted Arabidopsis transcription factor genes was produced and used to profile the global expression pattern in seedlings, specifically their light regulation. We detected expression of 1371 and 1241 genes in white-light- and dark-grown 6-d-old seedlings, respectively. Together they account for 84% of the transcription factor genes examined. This array was further used to study the kinetics of transcription factor gene expression change of dark-grown seedlings in response to blue light and the role of specific photoreceptors in this blue-light regulation. The expression of about 20% of those transcription factor genes are responsive to blue-light exposure, with 249 and 115 genes up or down-regulated, respectively. A large portion of blue-light-responsive transcription factor genes exhibited very rapid expression changes in response to blue light, earlier than the bulk of blue-light-regulated genes. This result suggests the involvement of transcription cascades in blue-light control of genome expression. Comparative analysis of the expression profiles of wild type and various photoreceptor mutants demonstrated that during early seedling development cryptochromes are the major photoreceptors for blue-light control of transcription factor gene expression, whereas phytochrome A and phototropins play rather limited roles.

Arabidopsis↗

A Bayesian networks approach for predicting protein-protein interactions from genomic data.

We have developed an approach using Bayesian networks to predict protein-protein interactions genome-wide in yeast. Our method naturally weights and combines into reliable predictions genomic features only weakly associated with interaction (e.g., messenger RNAcoexpression, coessentiality, and colocalization). In addition to de novo predictions, it can integrate often noisy, experimental interaction data sets. We observe that at given levels of sensitivity, our predictions are more accurate than the existing high-throughput experimental data sets. We validate our predictions with TAP (tandem affinity purification) tagging experiments. Our analysis, which gives a comprehensive view of yeast interactions, is available at genecensus.org/intint.

Bayes Theorem↗

Prediction of regulatory networks: genome-wide identification of transcription factor targets from gene expression data.

MOTIVATION: Defining regulatory networks, linking transcription factors (TFs) to their targets, is a central problem in post-genomic biology. One might imagine one could readily determine these networks through inspection of gene expression data. However, the relationship between the expression timecourse of a transcription factor and its target is not obvious (e.g. simple correlation over the timecourse), and current analysis methods, such as hierarchical clustering, have not been very successful in deciphering them. RESULTS: Here we introduce an approach based on support vector machines (SVMs) to predict the targets of a transcription factor by identifying subtle relationships between their expression profiles. In particular, we used SVMs to predict the regulatory targets for 36 transcription factors in the Saccharomyces cerevisiae genome based on the microarray expression data from many different physiological conditions. We trained and tested our SVM on a data set constructed to include a significant number of both positive and negative examples, directly addressing data imbalance issues. This was non-trivial given that most of the known experimental information is only for positives. Overall, we found that 63% of our TF-target relationships were confirmed through cross-validation. We further assessed the performance of our regulatory network identifications by comparing them with the results from two recent genome-wide ChIP-chip experiments. Overall, we find the agreement between our results and these experiments is comparable to the agreement (albeit low) between the two experiments. We find that this network has a delocalized structure with respect to chromosomal positioning, with a given transcription factor having targets spread fairly uniformly across the genome. AVAILABILITY: The overall network of the relationships is available on the web at http://bioinfo.mbb.yale.edu/expression/echipchip

Algorithms↗

Genomic analysis of gene expression relationships in transcriptional regulatory networks.

From merging several data sources, we created an extensive map of the transcriptional regulatory network in Saccharomyces cerevisiae, comprising 7419 interactions connecting 180 transcription factors (TFs) with their target genes. We integrated this network with gene-expression data, relating the expression profiles of TFs and target genes. We found that genes targeted by the same TF tend to be co-expressed, with the degree of co-expression increasing if genes share more than one TF. Moreover, shared targets of a TF tend to have similar cellular functions. By contrast, the expression relationships between the TFs and their targets are much more complicated, often exhibiting time-shifted or inverted behavior. Further information is available at http://bioinfo.mbb.yale.edu/regulation/TIG/

Gene Expression Regulation↗

Normal mode analysis of macromolecular motions in a database framework: developing mode concentration as a useful classifying statistic.

We investigated protein motions using normal modes within a database framework, determining on a large sample the degree to which normal modes anticipate the direction of the observed motion and were useful for motions classification. As a starting point for our analysis, we identified a large number of examples of protein flexibility from a comprehensive set of structural alignments of the proteins in the PDB. Each example consisted of a pair of proteins that were considerably different in structure given their sequence similarity. On each pair, we performed geometric comparisons and adiabatic-mapping interpolations in a high-throughput pipeline, arriving at a final list of 3,814 putative motions and standardized statistics for each. We then computed the normal modes of each motion in this list, determining the linear combination of modes that best approximated the direction of the observed motion. We integrated our new motions and normal mode calculations in the Macromolecular Motions Database, through a new ranking interface at http://molmovdb.org. Based on the normal mode calculations and the interpolations, we identified a new statistic, mode concentration, related to the mathematical concept of information content, which describes the degree to which the direction of the observed motion can be summarized by a few modes. Using this statistic, we were able to determine the fraction of the 3,814 motions where one could anticipate the direction of the actual motion from only a few modes. We also investigated mode concentration in comparison to related statistics on combinations of normal modes and correlated it with quantities characterizing protein flexibility (e.g., maximum backbone displacement or number of mobile atoms). Finally, we evaluated the ability of mode concentration to automatically classify motions into a variety of simple categories (e.g., whether or not they are "fragment-like"), in comparison to motion statistics. This involved the application of decision trees and feature selection (particular machine-learning techniques) to training and testing sets derived from merging the "list" of motions with manually classified ones.

Databases, Protein↗