Profiling gene expression in brain structures at various spatial and temporal scales is essential to understanding how genes regulate the development of brain structures. The Allen Developing Mouse Brain Atlas provides high-resolution 3-D in situ hybridization (ISH) gene expression patterns in multiple developing stages of the mouse brain. Currently, the ISH images are annotated with anatomical terms manually. In this paper, we propose a computational approach to annotate gene expression pattern images in the mouse brain at various structural levels over the course of development.

Traditional clustering and feature selection methods consider the data matrix as static. However, the data matrices evolve smoothly over time in many applications. A simple approach to learn from these time-evolving data matrices is to analyze them separately. Such strategy ignores the time-dependent nature of the underlying data. In this paper, we propose two formulations for evolutionary co-clustering and feature selection based on the fused Lasso regularization. The evolutionary co-clustering formulation is able to identify smoothly varying hidden block structures embedded into the matrices along the temporal dimension. Our formulation is very flexible and allows for imposing smoothness constraints over only one dimension of the data matrices. The evolutionary feature selection formulation can uncover shared features in clustering from time-evolving data matrices. We show that the optimization problems involved are non-convex, non-smooth and non-separable. To compute the solutions efficiently, we develop a two-step procedure that optimizes the objective function iteratively. We evaluate the proposed formulations using the Allen Developing Mouse Brain Atlas data. Results show that our formulations consistently outperform prior methods.

Differential gene expression patterns in cells of the mammalian brain result in the morphological, connectional, and functional diversity of cells. A wide variety of studies have shown that certain genes are expressed only in specific cell-types. Analysis of cell-type-specific gene expression patterns can provide insights into the relationship between genes, connectivity, brain regions, and cell-types. However, automated methods for identifying cell-type-specific genes are lacking to date.

Background: Multicellular organisms consist of cells of many different types that are established during development. Each type of cell is characterized by the unique combination of expressed gene products as a result of spatiotemporal gene regulation. Currently, a fundamental challenge in regulatory biology is to elucidate the gene expression controls that generate the complex body plans during development. Recent advances in high-throughput biotechnologies have generated spatiotemporal expression patterns for thousands of genes in the model organism fruit fly Drosophila melanogaster. Existing qualitative methods enhanced by a quantitative analysis based on computational tools we present in this paper would provide promising ways for addressing key scientific questions. Results: We develop a set of computational methods and open source tools for identifying co-expressed embryonic domains and the associated genes simultaneously. To map the expression patterns of many genes into the same coordinate space and account for the embryonic shape variations, we develop a mesh generation method to deform a meshed generic ellipse to each individual embryo. We then develop a co-clustering formulation to cluster the genes and the mesh elements, thereby identifying co-expressed embryonic domains and the associated genes simultaneously. Experimental results indicate that the gene and mesh co-clusters can be correlated to key developmental events during the stages of embryogenesis we study. The open source software tool has been made available at http://compbio.cs.odu.edu/fly/. Conclusions: Our mesh generation and machine learning methods and tools improve upon the flexibility, ease-of-use and accuracy of existing methods.

The mammalian brain contains cells of a large variety of types. The phenotypic properties of cells of different types are largely the results of distinct gene expression patterns. Therefore, it is of critical importance to characterize the gene expression patterns in the mammalian brain. The Allen Developing Mouse Brain Atlas provides spatiotemporal in situ hybridization gene expression data across multiple stages of mouse brain development. It provides a framework to explore spatiotemporal regulation of gene expression during development. We employ a graph approximation formulation to cocluster the genes and the brain voxels simultaneously for each time point. We show that this formulation can be expressed as a probabilistic latent semantic analysis (PLSA) model, thereby allowing us to use the expectation-maximization algorithm for PLSA to estimate the coclustering parameters. To provide a quantitative comparison with prior methods, we evaluate the coclustering method on a set of standard synthetic data sets. Results indicate that our method consistently outperforms prior methods. We apply our method to cocluster the Allen Developing Mouse Brain Atlas data. Results indicate that our clustering of voxels is more consistent with classical neuroanatomy than those of prior methods. Our analysis also yields sets of genes that are co-expressed in a subset of the brain voxels.