A comparative analysis of exome resequencing and genome resequencing

Human exome resequencing has attained widespread popularity with the success of commercially available exome capture kits that utilize a solution-based workflow, thus freeing users from having to handle arrays and investing in the equipment necessary for array processing. We have rigorously evaluated the coverage capabilities of exome capture against that of whole genome resequencing. Our investigation of two solution capture platforms revealed they were both quite capable of capturing their intended targets, but their realistic coverage of the exome was limited by the actual target they were designed for, the CCDS rather than the more comprehensive RefSeq. The exome kits were able to cover up to about 48% of RefSeq, whereas the whole genome data we studied were capable of covering about 98% of RefSeq. We evaluated the kinetics of exome coverage provided by solution capture, which revealed differences in efficiency and uniformity between the two platforms we studied, and neither platform was able to match the more optimal uniformity we observed for whole genome data from the 1000 Genomes Project. These factors directly influence the amount of raw sequence data required to obtain significant exome coverage. We analyzed the genotyping accuracy and sensitivity of exome capture and detected >99.35% accuracy and <0.67% false positive rate based on HapMap 3 data and >99.9968% accuracy and <0.28% false positive rate based on whole genome data. The consistently high accuracy and sensitivity of exome capture confirmed that target capture is appropriate for genotyping given that the target of interest is adequately covered.