With the virtual completion of the human DNA sequence research attention has shifted to issues including the resolution of the genetic composition, evolutionary history, and health impact of portions of the human genome which have proven difficult to sequence due to their duplicative and dynamic nature. The proposed research aims to address these problems through the development of algorithms and software tools for discovery, resolution and evolutionary analysis of genomic duplications and other genome-wide segmental rearrangements. The ultimate goal is to help understand mechanisms for and the sources of genetic disposition to genome-wide structural rearrangements. Some of these structural rearrangements are known to cause dosage imbalance of developmentally important genes during recombination events; as a result, genomic diseases, including several birth defects as well as a number of adult diseases occur at a rate of $~1$ in every $1000$ births. The premise of this research is that understanding the mechanisms under such segmental rearrangements may help improve methods for diagnosis, treatment and prevention of these genetic disorders.
The basic research components of the proposal are (1) identification of all chromosomal segments that are duplicated along the genome, (2) understanding the complex evolutionary relationships between these interesting segments through novel phylogenetic analysis algorithms for a single genome sequence, and (3) identification of the duplication order via known or derived properties of duplication mechanisms, and (4) development of similarity measures between genome sequences that involve not only point mutations but structural rearrangements, particularly duplications. The short-term education goal of the proposal is to establish the algorithmic and the fundamental software development component of an interdisciplinary bioinformatics program at CWRU, that will provide means of awarding M.S. and Ph.D. degrees within existing departmental degree-granting programs. The long-term goal is to establish a free-standing graduate program in computational genomics, offering a wide-range of introductory and advanced level courses in bioinformatics. To this end the investigator has developed and taught a new introductory graduate course on algorithmic issues in bioinformatics, with the involvement of students from both the Computer Science program and the School of Medicine at CWRU. Funds from this proposal will be used to enhance this activity through the development of a new advanced level graduate course in computational genomics for in-depth training on individualized research topics, as well as an intensive summer research and training program for graduate and undergraduate students.
