III: Small: Computational Infrastructure for the Identification of Copy Number Variations from SNP Microarrays

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It was recently discovered that copy number variations (CNVs) in human genome are quite common, and have important implications on phenotype. Currently, the primary platforms for large-scale detection and characterization of CNVs are SNP (single nucleotide polymorphism) microarrays. The current state-of-the-art in computational identification of CNVs from microarray data relies mostly on model-based approaches (e.g., Hidden Markov Models). However, such methods require extensive training data, which may not be always available. Furthermore, since these methods use common CNVs to train their models, they are not as successful in identifying rare CNVs, which are believed to make up a substantial proportion of all CNVs in the human population. The objective of this project is to develop optimization based algorithms and software for the identification and genotyping of CNVs, with a view to enabling fast and accurate identification of different types of CNVs (rare and common), without the requirement of training data.The proposed framework develops a novel computational approach by explicitly formulating CNV identification as a series of optimization problems that incorporate multiple factors, including sensitivity to noise, rarity/commonality of CNVs, genotypic specificity, and parsimony. This formulation enables development of efficient algorithms that treat identification of rare and common CNVs as different problems with different objective functions. Availability of the resulting software to the community will enable more efficient and accurate identification of CNVs in large samples, facilitating advances in understanding the role of CNVs in a range of complex phenotypes, including HIV, autism, schizophrenia, mental retardation, and many others. Furthermore, the computational innovations introduced by this project are likely to find applications in next generation sequencing.