Missing value imputation for epistatic MAPs

<p>Abstract</p> <p>Background</p> <p>Epistatic miniarray profiling (E-MAPs) is a high-throughput approach capable of quantifying aggravating or alleviating genetic interactions between gene pairs. The datasets resulting from E-MAP experiments typically take the form of a symmetric pairwise matrix of interaction scores. These datasets have a significant number of missing values - up to 35% - that can reduce the effectiveness of some data analysis techniques and prevent the use of others. An effective method for imputing interactions would therefore increase the types of possible analysis, as well as increase the potential to identify novel functional interactions between gene pairs. Several methods have been developed to handle missing values in microarray data, but it is unclear how applicable these methods are to E-MAP data because of their pairwise nature and the significantly larger number of missing values. Here we evaluate four alternative imputation strategies, three local (Nearest neighbor-based) and one global (PCA-based), that have been modified to work with symmetric pairwise data.</p> <p>Results</p> <p>We identify different categories for the missing data based on their underlying cause, and show that values from the largest category can be imputed effectively. We compare local and global imputation approaches across a variety of distinct E-MAP datasets, showing that both are competitive and preferable to filling in with zeros. In addition we show that these methods are effective in an E-MAP from a different species, suggesting that pairwise imputation techniques will be increasingly useful as analogous epistasis mapping techniques are developed in different species. We show that strongly alleviating interactions are significantly more difficult to predict than strongly aggravating interactions. Finally we show that imputed interactions, generated using nearest neighbor methods, are enriched for annotations in the same manner as measured interactions. Therefore our method potentially expands the number of mapped epistatic interactions. In addition we make implementations of our algorithms available for use by other researchers.</p> <p>Conclusions</p> <p>We address the problem of missing value imputation for E-MAPs, and suggest the use of symmetric nearest neighbor based approaches as they offer consistently accurate imputations across multiple datasets in a tractable manner.</p

Protein Complexes are Central in the Yeast Genetic Landscape

If perturbing two genes together has a stronger or weaker effect than expected, they are said to genetically interact. Genetic interactions are important because they help map gene function, and functionally related genes have similar genetic interaction patterns. Mapping quantitative (positive and negative) genetic interactions on a global scale has recently become possible. This data clearly shows groups of genes connected by predominantly positive or negative interactions, termed monochromatic groups. These groups often correspond to functional modules, like biological processes or complexes, or connections between modules. However it is not yet known how these patterns globally relate to known functional modules. Here we systematically study the monochromatic nature of known biological processes using the largest quantitative genetic interaction data set available, which includes fitness measurements for ∼5.4 million gene pairs in the yeast Saccharomyces cerevisiae. We find that only 10% of biological processes, as defined by Gene Ontology annotations, and less than 1% of inter-process connections are monochromatic. Further, we show that protein complexes are responsible for a surprisingly large fraction of these patterns. This suggests that complexes play a central role in shaping the monochromatic landscape of biological processes. Altogether this work shows that both positive and negative monochromatic patterns are found in known biological processes and in their connections and that protein complexes play an important role in these patterns. The monochromatic processes, complexes and connections we find chart a hierarchical and modular map of sensitive and redundant biological systems in the yeast cell that will be useful for gene function prediction and comparison across phenotypes and organisms. Furthermore the analysis methods we develop are applicable to other species for which genetic interactions will progressively become more available

“Guilt by Association” Is the Exception Rather Than the Rule in Gene Networks

Gene networks are commonly interpreted as encoding functional information in their connections. An extensively validated principle called guilt by association states that genes which are associated or interacting are more likely to share function. Guilt by association provides the central top-down principle for analyzing gene networks in functional terms or assessing their quality in encoding functional information. In this work, we show that functional information within gene networks is typically concentrated in only a very few interactions whose properties cannot be reliably related to the rest of the network. In effect, the apparent encoding of function within networks has been largely driven by outliers whose behaviour cannot even be generalized to individual genes, let alone to the network at large. While experimentalist-driven analysis of interactions may use prior expert knowledge to focus on the small fraction of critically important data, large-scale computational analyses have typically assumed that high-performance cross-validation in a network is due to a generalizable encoding of function. Because we find that gene function is not systemically encoded in networks, but dependent on specific and critical interactions, we conclude it is necessary to focus on the details of how networks encode function and what information computational analyses use to extract functional meaning. We explore a number of consequences of this and find that network structure itself provides clues as to which connections are critical and that systemic properties, such as scale-free-like behaviour, do not map onto the functional connectivity within networks

The Impact of Multifunctional Genes on "Guilt by Association" Analysis

Many previous studies have shown that by using variants of “guilt-by-association”, gene function predictions can be made with very high statistical confidence. In these studies, it is assumed that the “associations” in the data (e.g., protein interaction partners) of a gene are necessary in establishing “guilt”. In this paper we show that multifunctionality, rather than association, is a primary driver of gene function prediction. We first show that knowledge of the degree of multifunctionality alone can produce astonishingly strong performance when used as a predictor of gene function. We then demonstrate how multifunctionality is encoded in gene interaction data (such as protein interactions and coexpression networks) and how this can feed forward into gene function prediction algorithms. We find that high-quality gene function predictions can be made using data that possesses no information on which gene interacts with which. By examining a wide range of networks from mouse, human and yeast, as well as multiple prediction methods and evaluation metrics, we provide evidence that this problem is pervasive and does not reflect the failings of any particular algorithm or data type. We propose computational controls that can be used to provide more meaningful control when estimating gene function prediction performance. We suggest that this source of bias due to multifunctionality is important to control for, with widespread implications for the interpretation of genomics studies

Transcriptome-based Gene Networks for Systems-level Analysis of Plant Gene Functions

Present day genomic technologies are evolving at an unprecedented rate, allowing interrogation of cellular activities with increasing breadth and depth. However, we know very little about how the genome functions and what the identified genes do. The lack of functional annotations of genes greatly limits the post-analytical interpretation of new high throughput genomic datasets. For plant biologists, the problem is much severe. Less than 50% of all the identified genes in the model plant Arabidopsis thaliana, and only about 20% of all genes in the crop model Oryza sativa have some aspects of their functions assigned. Therefore, there is an urgent need to develop innovative methods to predict and expand on the currently available functional annotations of plant genes. With open-access catching the ‘pulse’ of modern day molecular research, an integration of the copious amount of transcriptome datasets allows rapid prediction of gene functions in specific biological contexts, which provide added evidence over traditional homology-based functional inference. The main goal of this dissertation was to develop data analysis strategies and tools broadly applicable in systems biology research. Two user friendly interactive web applications are presented: The Rice Regulatory Network (RRN) captures an abiotic-stress conditioned gene regulatory network designed to facilitate the identification of transcription factor targets during induction of various environmental stresses. The Arabidopsis Seed Active Network (SANe) is a transcriptional regulatory network that encapsulates various aspects of seed formation, including embryogenesis, endosperm development and seed-coat formation. Further, an edge-set enrichment analysis algorithm is proposed that uses network density as a parameter to estimate the gain or loss in correlation of pathways between two conditionally independent coexpression networks

Directional adposition use in English, Swedish and Finnish

Directional adpositions such as to the left of describe where a Figure is in relation to a Ground. English and Swedish directional adpositions refer to the location of a Figure in relation to a Ground, whether both are static or in motion. In contrast, the Finnish directional adpositions edellä (in front of) and jäljessä (behind) solely describe the location of a moving Figure in relation to a moving Ground (Nikanne, 2003). When using directional adpositions, a frame of reference must be assumed for interpreting the meaning of directional adpositions. For example, the meaning of to the left of in English can be based on a relative (speaker or listener based) reference frame or an intrinsic (object based) reference frame (Levinson, 1996). When a Figure and a Ground are both in motion, it is possible for a Figure to be described as being behind or in front of the Ground, even if neither have intrinsic features. As shown by Walker (in preparation), there are good reasons to assume that in the latter case a motion based reference frame is involved. This means that if Finnish speakers would use edellä (in front of) and jäljessä (behind) more frequently in situations where both the Figure and Ground are in motion, a difference in reference frame use between Finnish on one hand and English and Swedish on the other could be expected. We asked native English, Swedish and Finnish speakers’ to select adpositions from a language specific list to describe the location of a Figure relative to a Ground when both were shown to be moving on a computer screen. We were interested in any differences between Finnish, English and Swedish speakers. All languages showed a predominant use of directional spatial adpositions referring to the lexical concepts TO THE LEFT OF, TO THE RIGHT OF, ABOVE and BELOW. There were no differences between the languages in directional adpositions use or reference frame use, including reference frame use based on motion. We conclude that despite differences in the grammars of the languages involved, and potential differences in reference frame system use, the three languages investigated encode Figure location in relation to Ground location in a similar way when both are in motion. Levinson, S. C. (1996). Frames of reference and Molyneux’s question: Crosslingiuistic evidence. In P. Bloom, M.A. Peterson, L. Nadel & M.F. Garrett (Eds.) Language and Space (pp.109-170). Massachusetts: MIT Press. Nikanne, U. (2003). How Finnish postpositions see the axis system. In E. van der Zee & J. Slack (Eds.), Representing direction in language and space. Oxford, UK: Oxford University Press. Walker, C. (in preparation). Motion encoding in language, the use of spatial locatives in a motion context. Unpublished doctoral dissertation, University of Lincoln, Lincoln. United Kingdo