Multi-platform discovery of haplotype-resolved structural variation in human genomes

Chaisson, M. J. P.; Sanders, A. D.; Zhao, X.; Malhotra, A.; Porubsky, D.; Rausch, T.; Gardner, E. J.; Rodriguez, O.; Guo, L.; Collins, R. L.; Fan, X.; Wen, J.; Handsaker, R. E.; Fairley, S.; Kronenberg, Z. N.; Kong, X.; Hormozdiari, F.; Lee, D.; Wenger, A. M.; Hastie, A.; Antaki, D.; Audano, P.; Brand, H.; Cantsilieris, S.; Cao, H.; Cerveira, E.; Chen, C.; Chen, X.; Chin, C.-S.; Chong, Z.; Chuang, N. T.; Church, D. M.; Clarke, L.; Farrell, A.; Flores, J.; Galeev, T.; David, G.; Gujral, M.; Guryev, V.; Haynes-Heaton, W.; Korlach, J.; Kumar, S.; Kwon, J. Y.; Lee, J. E.; Lee, J.; Lee, W.-P.; Lee,

doi:10.1101/193144

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bioRxiv · 10.1101/193144

Multi-platform discovery of haplotype-resolved structural variation in human genomes

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Abstract

The incomplete identification of structural variants (SVs) from whole-genome sequencing data limits studies of human genetic diversity and disease association. Here, we apply a suite of long-read, short-read, and strand-specific sequencing technologies, optical mapping, and variant discovery algorithms to comprehensively analyze three human parent-child trios to define the full spectrum of human genetic variation in a haplotype-resolved manner. We identify 818,054 indel variants (<50 bp) and 27,622 SVs ([≥]50 bp) per human genome. We also discover 156 inversions per genome--most of which previously escaped detection. Fifty-eight of the inversions we discovered intersect with the critical regions of recurrent microdeletion and microduplication syndromes. Taken together, our SV callsets represent a sevenfold increase in SV detection compared to most standard high-throughput sequencing studies, including those from the 1000 Genomes Project. The method and the dataset serve as a gold standard for the scientific community and we make specific recommendations for maximizing structural variation sensitivity for future large-scale genome sequencing studies.

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Chaisson, M. J. P., Sanders, A. D., Zhao, X., Malhotra, A., Porubsky, D., Rausch, T., Gardner, E. J., Rodriguez, O., Guo, L., Collins, R. L., Fan, X., Wen, J., Handsaker, R. E., Fairley, S., Kronenberg, Z. N., Kong, X., Hormozdiari, F., Lee, D., Wenger, A. M., Hastie, A., Antaki, D., Audano, P., Brand, H., Cantsilieris, S., Cao, H., Cerveira, E., Chen, C., Chen, X., Chin, C.-S., Chong, Z., Chuang, N. T., Church, D. M., Clarke, L., Farrell, A., Flores, J., Galeev, T., David, G., Gujral, M., Guryev, V., Haynes-Heaton, W., Korlach, J., Kumar, S., Kwon, J. Y., Lee, J. E., Lee, J., Lee, W.-P., Lee,. 2017-09-23. Multi-platform discovery of haplotype-resolved structural variation in human genomes. https://doi.org/10.1101/193144

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