tigaR: integrative significance analysis of temporal differential gene expression induced by genomic abnormalities

Background

To determine which changes in the host cell genome are crucial for cervical carcinogenesis, a longitudinal in vitro model system of HPV-transformed keratinocytes was profiled in a genome-wide manner. Four cell lines affected with either HPV16 or HPV18 were assayed at 8 sequential time points for gene expression (mRNA) and gene copy number (DNA) using high-resolution microarrays. Available methods for temporal differential expression analysis are not designed for integrative genomic studies.

Results

Here, we present a method that allows for the identification of differential gene expression associated with DNA copy number changes over time. The temporal variation in gene expression is described by a generalized linear mixed model employing low-rank thin-plate splines. Model parameters are estimated with an empirical Bayes procedure, which exploits integrated nested Laplace approximation for fast computation. Iteratively, posteriors of hyperparameters and model parameters are estimated. The empirical Bayes procedure shrinks multiple dispersion-related parameters. Shrinkage leads to more stable estimates of the model parameters, better control of false positives and improvement of reproducibility. In addition, to make estimates of the DNA copy number more stable, model parameters are also estimated in a multivariate way using triplets of features, imposing a spatial prior for the copy number effect.

Conclusion

With the proposed method for analysis of time-course multilevel molecular data, more profound insight may be gained through the identification of temporal differential expression induced by DNA copy number abnormalities. In particular, in the analysis of an integrative oncogenomics study with a time-course set-up our method finds genes previously reported to be involved in cervical carcinogenesis. Furthermore, the proposed method yields improvements in sensitivity, specificity and reproducibility compared to existing methods. Finally, the proposed method is able to handle count (RNAseq) data from time course experiments as is shown on a real data set.

Electronic supplementary material

The online version of this article (doi:10.1186/1471-2105-15-327) contains supplementary material, which is available to authorized users.     

Non-native interactions play an effective role in protein folding dynamics

Systematic Monte Carlo simulations of simple lattice models show that the final stage of protein folding is an ordered process where native contacts get locked (i.e., the residues come into contact and remain in contact for the duration of the folding process) in a well‐defined order. The detailed study of the folding dynamics of protein‐like sequences designed as to exhibit different contact energy distributions, as well as different degrees of sequence optimization (i.e., participation of non‐native interactions in the folding process), reveals significant differences in the corresponding locking scenarios—the collection of native contacts and their average locking times, which are largely ascribable to the dynamics of non‐native contacts. Furthermore, strong evidence for a positive role played by non‐native contacts at an early folding stage was also found. Interestingly, for topologically simple target structures, a positive interplay between native and non‐native contacts is observed also toward the end of the folding process, suggesting that non‐native contacts may indeed affect the overall folding process. For target models exhibiting clear two‐state kinetics, the relation between the nucleation mechanism of folding and the locking scenario is investigated. Our results suggest that the stabilization of the folding transition state can be achieved through the establishment of a very small network of native contacts that are the first to lock during the folding process.     

Performance Enhancement of Polymer‐Free Carbon Nanotube Solar Cells via Transfer Matrix Modeling

Polymer‐free (6,5) single‐walled carbon nanotubes (SWCNTs) prepared using the gel permeation approach are integrated into SWCNT:C₆₀ solar cells. Evaporation‐driven self‐assembly is used to form large‐area SWCNT thin films from the surfactant‐stabilized aqueous suspensions. The thicknesses of various layers within the solar cell are optimized by theoretical modeling using transfer matrix calculations, where the distribution of the electric field within the stack is matched to light absorption by the SWCNTs through either their primary (S₁₁) or secondary (S₂₂) absorption peaks, or a combination thereof. The validity of the model is verified experimentally through a detailed parameter study and then used to develop SWCNT:C₆₀ solar cells with high open‐circuit voltage (0.44 V) as well as a cutting‐edge internal quantum efficiency of up to 86% through the nanotube S₁₁ transition, over an active area of 0.105 cm².     

Spatial distribution of Aphis glycines (Hemiptera: Aphididae): a summary of the suction trap network

The soybean aphid, Aphis glycines Matsumura (Hemiptera: Aphididae), is an economically important pest of soybean, Glycine max (L.) Merrill, in the United States. Phenological information of A. glycines is limited; specifically, little is known about factors guiding migrating aphids and potential impacts of long distance flights on local population dynamics. Increasing our understanding of A. glycines population dynamics may improve predictions of A. glycines outbreaks and improve management efforts. In 2005 a suction trap network was established in seven Midwest states to monitor the occurrence of alates. By 2006, this network expanded to 10 states and consisted of 42 traps. The goal of the STN was to monitor movement of A. glycines from their overwintering host Rhamnus spp. to soybean in spring, movement among soybean fields during summer, and emigration from soybean to Rhamnus in fall. The objective of this study was to infer movement patterns of A. glycines on a regional scale based on trap captures, and determine the suitability of certain statistical methods for future analyses. Overall, alates were not commonly collected in suction traps until June. The most alates were collected during a 3-wk period in the summer (late July to mid-August), followed by the fall, with a peak capture period during the last 2 wk of September. Alate captures were positively correlated with latitude, a pattern consistent with the distribution of Rhamnus in the United States, suggesting that more southern regions are infested by immigrants from the north.     

Factors influencing mate choice in Euschistus conspersus Uhler (Heteroptera: Pentatomidae)

The patterns of mating and possible factors influencing mate choice in the consperse stink bug, Euschistus conspersus Uhler, were studied in a series of laboratory experiments. Males were found to transfer a significant percentage of their body mass during the initial mating. Mating was also found to reduce male longevity by 37.8% but had no significant effect on female longevity or fecundity. There was no evidence of male or female choice based on weight of potential mating partners. There was assortative mating based on experience, however, with males mating preferentially with virgin females and females preferring mated males when given the choice. The implications of these findings within the mating dynamics of this aggregating species are discussed.     

Focusing on the genetics of hearing: you ain't heard nothin' yet

The complexity of genetic pathways for hearing is beginning to be amenable to unraveling by systematic functional genomic analysis. Genome-wide mutagenesis studies in the mouse are beginning to shed further light on the structure and regulation of the machinery of hearing.     

Mouse tumor biology database (MTB): enhancements and current status

The Mouse Tumor Biology Database (MTB) is a Web-based resource that provides access to information on tumor frequency and latency, genetics and pathology in genetically defined mice (transgenics, targeted mutations and inbred strains). MTB is designed to serve as an information resource for cancer genetics researchers who use the laboratory mouse as a model system for understanding human disease processes. Data in MTB are obtained from the primary scientific literature and direct submissions by the research community. MTB is accessible from the Mouse Genome Informatics Web site (http://www. informatics.jax.org). User support is available for MTB via Email at mgi-help@informatics.jax.org     

Ribosomal RNA secondary structure: compensatory mutations and implications for phylogenetic analysis

Using sequence data from the 28S ribosomal RNA (rRNA) genes of selected vertebrates, we investigated the effects that constraints imposed by secondary structure have on the phylogenetic analysis of rRNA sequence data. Our analysis indicates that characters from both base-pairing regions (stems) and non-base-pairing regions (loops) contain phylogenetic information, as judged by the level of support of the phylogenetic results compared with a well-established tree based on both morphological and molecular data. The best results (the greatest level of support of well-accepted nodes) were obtained when the complete data set was used. However, some previously supported nodes were resolved using either the stem or loop bases alone. Stem bases sustain a greater number of compensatory mutations than would be expected at random, but the number is < 40% of that expected under a hypothesis of perfect compensation to maintain secondary structure. Therefore, we suggest that in phylogenetic analyses, the weighting of stem characters be reduced by no more than 20%, relative to that of loop characters. In contrast to previous suggestions, we do not recommend weighting of stem positions by one-half, compared with that of loop positions, because this overcompensates for the constraints that selection imposes on the secondary structure of rRNA.