GenRate: A Generative Model that Reveals Novel Transcripts in Genome-Tiling Microarray Data

Genome-wide microarray designs containing millions to hundreds of millions of probes are available for a variety of mammals, including mouse and human. These genome tiling arrays can potentially lead to significant advances in science and medicine, e.g., by indicating new genes and alternative primary and secondary transcripts. While bottom-up pattern matching techniques (e.g., hierarchical clustering) can be used to find gene structures in microarray data, we believe the many interacting hidden variables and complex noise patterns more naturally lead to an analysis based on generative models. We describe a generative model of tiling data and show how the sum-product algorithm can be used to infer hybridization noise, probe sensitivity, new transcripts, and alternative transcripts. The method, called GenRate, maximizes a global scoring function that enables multiple transcripts to compete for ownership of putative probes. We apply GenRate to a new exon tiling dataset from mouse chromosome 4 and show that it makes significantly more predictions than a previously described hierarchical clustering method at the same false positive rate. GenRate correctly predicts many known genes and also predicts new gene structures. As new problems arise, additional hidden variables can be incorporated into the model in a principled fashion, so we believe that GenRate will prove to be a useful tool in the new era of genome-wide tiling microarray analysis.