Weisenfeld, Neil I.Yin, ShuangyeSharpe, TedLau, BayoHegarty, RyanHolmes, LaurieSogoloff, BrianTabbaa, DianaWilliams, LouiseRuss, CarstenNusbaum, ChadLander, EricMacCallum, IainJaffe, David B.2015-07-132014Weisenfeld, N. I., S. Yin, T. Sharpe, B. Lau, R. Hegarty, L. Holmes, B. Sogoloff, et al. 2014. “Comprehensive variation discovery in single human genomes.” Nature genetics 46 (12): 1350-1355. doi:10.1038/ng.3121. http://dx.doi.org/10.1038/ng.3121.1061-4036http://nrs.harvard.edu/urn-3:HUL.InstRepos:17295794Complete knowledge of the genetic variation in individual human genomes is a crucial foundation for understanding the etiology of disease. Genetic variation is typically characterized by sequencing individual genomes and comparing reads to a reference. Existing methods do an excellent job of detecting variants in approximately 90% of the human genome, however calling variants in the remaining 10% of the genome (largely low-complexity sequence and segmental duplications) is challenging. To improve variant calling, we developed a new algorithm, DISCOVAR, and examined its performance on improved, low-cost sequence data. Using a newly created reference set of variants from finished sequence of 103 randomly chosen Fosmids, we find that some standard variant call sets miss up to 25% of variants. We show that the combination of new methods and improved data increases sensitivity several-fold, with the greatest impact in challenging regions of the human genome.en-USJournal Article2015-07-1310.1038/ng.3121