Integration of relational and hierarchical network information for protein function prediction

BACKGROUND:In the current climate of high-throughput computational biology, the inference of a protein's function from related measurements, such as protein-protein interaction relations, has become a canonical task. Most existing technologies pursue this task as a classification problem, on a term-by-term basis, for each term in a database, such as the Gene Ontology (GO) database, a popular rigorous vocabulary for biological functions. However, ontology structures are essentially hierarchies, with certain top to bottom annotation rules which protein function predictions should in principle follow. Currently, the most common approach to imposing these hierarchical constraints on network-based classifiers is through the use of transitive closure to predictions.RESULTS:We propose a probabilistic framework to integrate information in relational data, in the form of a protein-protein interaction network, and a hierarchically structured database of terms, in the form of the GO database, for the purpose of protein function prediction. At the heart of our framework is a factorization of local neighborhood information in the protein-protein interaction network across successive ancestral terms in the GO hierarchy. We introduce a classifier within this framework, with computationally efficient implementation, that produces GO-term predictions that naturally obey a hierarchical 'true-path' consistency from root to leaves, without the need for further post-processing.CONCLUSION:A cross-validation study, using data from the yeast Saccharomyces cerevisiae, shows our method offers substantial improvements over both standard 'guilt-by-association' (i.e., Nearest-Neighbor) and more refined Markov random field methods, whether in their original form or when post-processed to artificially impose 'true-path' consistency. Further analysis of the results indicates that these improvements are associated with increased predictive capabilities (i.e., increased positive predictive value), and that this increase is consistent uniformly with GO-term depth. Additional in silico validation on a collection of new annotations recently added to GO confirms the advantages suggested by the cross-validation study. Taken as a whole, our results show that a hierarchical approach to network-based protein function prediction, that exploits the ontological structure of protein annotation databases in a principled manner, can offer substantial advantages over the successive application of 'flat' network-based methods.

"Not Without My Ancestors": A Christological Case Study of the Shona Ancestor Cult of Zimbabwe

The issue of ancestors has been controversial since the first encounters of Christianity with Shona religion. It remains a major theological problem that needs to be addressed within the mainline churches of Zimbabwe today. Instead of ignoring or dismissing the ancestor cult, which deeply influences the socio-political, religious, and economic lives of the Shona, churches in Zimbabwe should initiate a Christology that is based on it. Such a Christology would engage the critical day-to-day issues that make the Shona turn to their ancestors. Among these concerns are daily protection from misfortune, maintaining good health and increasing longevity, successful rainy seasons and food security, and responsible governance characterized by economic and political stability. Since the mid-16th century arrival of Jesuit missionaries in the Mutapa Kingdom, the Church has realized that many African Christians resorted to their ancestors in times of crisis. Although both Catholic and Protestant missionaries from the 1700s through the early 1900s fiercely attacked Shona traditional beliefs as superstitious and equated ancestors with evil spirits, the cult did not die. Social institutions, such as schools and hospitals provided by missionaries, failed to eliminate ancestral beliefs. Even in the 21st century, many Zimbabweans consult their ancestors. The Shona message to the church remains "Not without My Ancestors." This dissertation examines the significance of the ancestors to the Shona, and how selected denominations and new religious movements have interpreted and accommodated ancestral practices. Taking the missiological goal of "self-theologizing" as the framework, this dissertation proposes a "tripartite Christology" of "Jesus the Family Ancestor", "Jesus the Tribal Ancestor," and "Jesus the National Ancestor," which is based on the Shona "tripartite ancestrology." Familiar ecclesiological and liturgical language, idioms, and symbols are used to contribute to the wider Shona understanding of Jesus as the ancestor par excellence, in whom physical and spiritual needs-including those the ordinary ancestors fail to meet-are fulfilled.