Machine-learning (ML) techniques have been widely applied to solve different problems in biology. However, biological data are large and complex, which often result in extremely intricate ML models. Frequently, these models may have a poor performance or may be computationally unfeasible. This study presents a set of novel computational methods and focuses on the application of genetic algorithms (GAs) for the simplification and optimization of ML models and their applications to biological problems. The dissertation addresses the following three challenges. The first is to develop a generalizable classification methodology able to systematically derive competitive models despite the complexity and nature of the data. Although several algorithms for the induction of classification models have been proposed, the algorithms are data dependent. Consequently, we developed OmniGA, a novel and generalizable framework that uses different classification models in a treeXlike decision structure, along with a parallel GA for the optimization of the OmniGA structure. Results show that OmniGA consistently outperformed existing commonly used classification models. The second challenge is the prediction of translation initiation sites (TIS) in plants genomic DNA. We performed a statistical analysis of the genomic DNA and proposed a new set of discriminant features for this problem. We developed a wrapper method based on GAs for selecting an optimal feature subset, which, in conjunction with a classification model, produced the most accurate framework for the recognition of TIS in plants. Finally, results demonstrate that despite the evolutionary distance between different plants, our approach successfully identified conserved genomic elements that may serve as the starting point for the development of a generic model for prediction of TIS in eukaryotic organisms. Finally, the third challenge is the accurate prediction of polyadenylation signals in human genomic DNA. To achieve this, we analyzed genomic DNA sequences for the 12 most frequent polyadenylation signal variants and proposed a new set of features that may contribute to the understanding of the polyadenylation process. We derived Omni-PolyA, a model, and tool based on OmniGA for the prediction of the polyadenylation signals. Results show that Omni-PolyA significantly reduced the average classification error rate compared to the state-of-the-art results.

Cleavage and polyadenylation of a precursor mRNA is important for transcription termination, mRNA stability, and regulation of gene expression. This process is directed by a multitude of protein factors and cis elements in the pre-mRNA sequence surrounding the cleavage and polyadenylation site. Importantly, the location of the cleavage and polyadenylation site helps define the 3’ untranslated region of a transcript, which is important for regulation by microRNAs and RNA binding proteins. Additionally, these sites have generally been poorly annotated. To identify 3’ ends, many techniques utilize an oligo-dT primer to construct deep sequencing libraries. However, this approach can lead to identification of artifactual polyadenylation sites due to internal priming in homopolymeric stretches of adenines. Previously, simple heuristic filters relying on the number of adenines in the genomic sequence downstream of a putative polyadenylation site have been used to remove these sites of internal priming. However, these simple filters may not remove all sites of internal priming and may also exclude true polyadenylation sites. Therefore, I developed a naïve Bayes classifier to identify putative sites from oligo-dT primed 3’ end deep sequencing as true or false/internally primed. Notably, this algorithm uses a combination of sequence elements to distinguish between true and false sites. Finally, the resulting algorithm is highly accurate in multiple model systems and facilitates identification of novel polyadenylation sites.