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BIOLOGICAL SCIENCES / GENETICS
Systematic prediction and validation of breakpoints associated with copy-number variants in the human genome

Jan O. Korbel^*,,, Alexander Eckehart Urban^,¶, Fabian Grubert, Jiang Du^||, Thomas E. Royce^*, Peter Starr^*, Guoneng Zhong^*, Beverly S. Emanuel^**, Sherman M. Weissman, Michael Snyder^¶,, and Mark B. Gerstein^*,||,

Departments of *Molecular Biophysics and Biochemistry and Genetics, Yale University School of Medicine, New Haven, CT 06520; European Molecular Biology Laboratory, 69117 Heidelberg, Germany; Departments of ^¶Molecular, Cellular, and Developmental Biology and ^||Computer Science, Yale University, New Haven, CT 06520; and **Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104

Communicated by Francis H. Ruddle, Yale University, New Haven, CT, April 30, 2007 (received for review January 11, 2007)

Copy-number variants (CNVs) are an abundant form of genetic variation in humans. However, approaches for determining exact CNV breakpoint sequences (physical deletion or duplication boundaries) across individuals, crucial for associating genotype to phenotype, have been lacking so far, and the vast majority of CNVs have been reported with approximate genomic coordinates only. Here, we report an approach, called BreakPtr, for fine-mapping CNVs (available from http://breakptr.gersteinlab.org). We statistically integrate both sequence characteristics and data from high-resolution comparative genome hybridization experiments in a discrete-valued, bivariate hidden Markov model. Incorporation of nucleotide-sequence information allows us to take into account the fact that recently duplicated sequences (e.g., segmental duplications) often coincide with breakpoints. In anticipation of an upcoming increase in CNV data, we developed an iterative, "active" approach to initially scoring with a preliminary model, performing targeted validations, retraining the model, and then rescoring, and a flexible parameterization system that intuitively collapses from a full model of 2,503 parameters to a core one of only 10. Using our approach, we accurately mapped >400 breakpoints on chromosome 22 and a region of chromosome 11, refining the boundaries of many previously approximately mapped CNVs. Four predicted breakpoints flanked known disease-associated deletions. We validated an additional four predicted CNV breakpoints by sequencing. Overall, our results suggest a predictive resolution of 300bp. This level of resolution enables more precise correlations between CNVs and across individuals than previously possible, allowing the study of CNV population frequencies. Further, it enabled us to demonstrate a clear Mendelian pattern of inheritance for one of the CNVs.

copy number polymorphism | human genome variation | structural variants

The authors declare no conflict of interest.

Data deposition: Microarray data have been deposited in the Gene Expression Omnibus repository (accession no. GSE6010).

This article contains supporting information online at www.pnas.org/cgi/content/full/0703834104/DC1.

To whom correspondence may be addressed. E-mail: jan.korbel{at}yale.edu, michael.snyder{at}yale.edu, or mark.gerstein{at}yale.edu

© 2007 by The National Academy of Sciences of the USA

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