Not long ago, it was discovered that individuals may differ in copy numbers of their genes, meaning that a segment of DNA may have more or less copies than usual in an individual's chromosome. Recent research suggests that these variations are associated with many diseases including Autism and Schizophrenia. Copy number variation (CNV) in somatic cells also underly various cancers. Copy numbers are usually identified using SNP microarrays, however, short-read sequence data is emerging as an important resource for characterizing structural variation in human genome. As an interdisciplinary group of researchers at Case Western Reserve University, we develop algorithms for fast and accurate identification of rare and de novo CNVs, as well as copy number polymorphisms (CNPs) and other forms of genomic variation (e.g., loss of heterozygosity) from these two data sources. We further extend these algorithms to identify small indels with applications to error correction in next generation sequencing, fine tuning of the alignment of short reads to the reference human genome, and characterization of tissue heterogeneity. With a view to enabling personalized genomics applications, we apply these algorithms to the identification of copy number variants, as well as single nucleotide polymorphisms, genes, genetic interactions, pathways, and networks that are associated with complex diseases.

Software

• LOQUM: A logistic regression based algorithm for recalibrating the mapping quality of short-read sequence alignments.


• SEAL: A comprehensive short read sequencing simulation and alignment tool evaluation suite implemented in Java.


• COKGEN: An R package for optimization-based identification of rare and de novo copy number variants from SNP microarray data.

Publications

• M. Ruffalo, M. Koyuturk, S. Ray, and T. LaFramboise. Accurate estimation of short read mapping quality for next generation genome sequencing, Bioinformatics Suppl. on 11th European Conference on Computational Biology (ECCB), in press.


• S. Erten, M. Ayati, Y. Liu, M. R. Chance, and M. Koyuturk. Algorithms for detecting complementary SNPs within a region of interest that are associated with diseases, 3rd ACM Conf. Bioinformatics, Computational Biology and Biomedicine (ACM-BCB'12), in press.


• Y. Liu, S. Maxwell, T. Feng, X. Zhu, R. C. Elston, M. Koyuturk, and M. R. Chance. Gene, pathway and network frameworks to identify epistatic interactions of single nucleotide polymorphisms derived from GWAS data. BMC Systems Biology, in press.


• G. Bebek, M. Koyuturk, N. D. Price, and M. R. Chance. Network biology methods integrating biological data for translational scie\ nce, Briefings in Bioinformatics, 13(4): 446-459, 2012.


• G. Nickel, J. Barnholtz-Sloan, M. P. Gould, S. McMahon, A. Cohen, M. D. Adams, K. Guda, A. E. Sloan, and T. LaFramboise. Characterizing mutational heterogeneity in a glioblastoma patient with double recurrence. PLoS One, 7(4): e35262, 2012.


• Y.Liu, M. Koyuturk, J. Barnholtz-Sloan, and M. R. Chance. Gene interaction enrichment and network analysis to identtfy dysregulated pathways in cancer, BMC Systems Biology, 6:65, 2012.


• M. Ruffalo, T. LaFramboise, and M. Koyuturk. Comparative analysis of algorithms for next generation sequencing read alignment. Bioinformatics, 27(20): 2790-2796, 2011.


• K. Wilkins and T. LaFramboise. Losing balance: Hardy-Weinberg disequilibrium as a marker for recurrent loss-of-heterozygosity in cancer. Human Molecular Genetics, 20(24):4831-4839, 2011.


• G. Yavas, M. Koyuturk, and T. LaFramboise. Optimization algorithms for identification and genotyping of copy number polymorphisms in human populations. 5th IAPR Int'l Conf. on Pattern Recognition in Bioinformatics (PRIB'10), 74-85, 2010.


• G. Yavas, M. Koyuturk, M. Ozsoyoglu, M. P. Gould, and T. LaFramboise. COKGEN: A software for the identification of rare copy number variation from SNP microarrays. Pacific Symposium on Biocomputing (PSB'10), 371-382, 2010.


• G. Yavas, M. Koyuturk, M. Ozsoyoglu, M. P. Gould, and T. LaFramboise. An optimization framework for unsupervised identification of rare copy number variation from SNP array data. Genome Biology, 10:R119, 2009.

People

	Katie Wilkins Undergraduate Student, Computer Science/Biochemistry (Now Ph.D. student at Cornell University)
	Matthew Ruffalo Ph.D. Student, Computer Science
	Daniel Savel Ph.D. Student, Computer Science
	Marzieh Ayati Ph.D. Student, Computer Science
	Gokhan Yavas Ph.D. Student, Computer Science (Now post-doctoral fellow at Case Comprehensive Cancer Center)
	Thomas LaFramboise Associate Professor, Genetics & Genome Sciences
	Mehmet Koyuturk Associate Professor, Electrical Engineering & Computer Science

Acknowledgments

This project is supported by National Science Foundation Award IIS-0916102.