Systematic prediction and validation of breakpoints associated with copy-number variants in the human genome. Export

@article{citeulike:1822389, abstract = {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 approximately 300 bp. 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.}, author = {Korbel, J. O. and Urban, A. E. and Grubert, F. and Du, J. and Royce, T. E. and Starr, P. and Zhong, G. and Emanuel, B. S. and Weissman, S. M. and Snyder, M. and Gerstein, M. B.}, citeulike-article-id = {1822389}, citeulike-linkout-0 = {http://dx.doi.org/10.1073/pnas.0703834104}, citeulike-linkout-1 = {http://www.pnas.org/cgi/content/abstract/104/24/10110}, citeulike-linkout-2 = {http://view.ncbi.nlm.nih.gov/pubmed/17551006}, citeulike-linkout-3 = {http://www.hubmed.org/display.cgi?uids=17551006}, day = {12}, doi = {10.1073/pnas.0703834104}, issn = {0027-8424}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, keywords = {breakpoints, cnv, genome, hmm, human}, month = {June}, number = {24}, pages = {10110--10115}, posted-at = {2008-10-08 14:58:45}, priority = {2}, title = {Systematic prediction and validation of breakpoints associated with copy-number variants in the human genome.}, url = {http://dx.doi.org/10.1073/pnas.0703834104}, volume = {104}, year = {2007} }

TY - JOUR ID - citeulike:1822389 L3 - citeulike-article-id:1822389 N2 - 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 approximately 300 bp. 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. IS - 24 JF - Proceedings of the National Academy of Sciences of the United States of America SN - 0027-8424 EP - 10115 TI - Systematic prediction and validation of breakpoints associated with copy-number variants in the human genome. VL - 104 SP - 10110 KW - breakpoints KW - cnv KW - genome KW - hmm KW - human AU - Korbel, JO AU - Urban, AE AU - Grubert, F AU - Du, J AU - Royce, TE AU - Starr, P AU - Zhong, G AU - Emanuel, BS AU - Weissman, SM AU - Snyder, M AU - Gerstein, MB PY - 2007/06/12/ UR - http://dx.doi.org/10.1073/pnas.0703834104 ER -