Data analysis methods for copy number discovery and interpretation

Copy number variation (CNV) is an important type of genetic variation that can give rise to a wide variety of phenotypic traits. Differences in copy number are thought to play major roles in processes that involve dosage sensitive genes, providing beneficial, deleterious or neutral modifications to individual phenotypes. Copy number analysis has long been a standard in clinical cytogenetic laboratories. Gene deletions and duplications can often be linked with genetic Syndromes such as: the 7q11.23 deletion of Williams-­‐Bueren Syndrome, the 22q11 deletion of DiGeorge syndrome and the 17q11.2 duplication of Potocki-­‐Lupski syndrome. Interestingly, copy number based genomic disorders often display reciprocal deletion / duplication syndromes, with the latter frequently exhibiting milder symptoms. Moreover, the study of chromosomal imbalances plays a key role in cancer research. The datasets used for the development of analysis methods during this project are generated as part of the cutting-­‐edge translational project, Deciphering Developmental Disorders (DDD). This project, the DDD, is the first of its kind and will directly apply state of the art technologies, in the form of ultra-­‐high resolution microarray and next generation sequencing (NGS), to real-­‐time genetic clinical practice. It is collaboration between the Wellcome Trust Sanger Institute (WTSI) and the National Health Service (NHS) involving the 24 regional genetic services across the UK and Ireland. Although the application of DNA microarrays for the detection of CNVs is well established, individual change point detection algorithms often display variable performances. The definition of an optimal set of parameters for achieving a certain level of performance is rarely straightforward, especially where data qualities vary ... [cont.].