Whole-genome sequencing is more powerful than whole-exome sequencing for detecting exome variants

Whole-genome sequencing is more powerful than whole-exome sequencing for detecting exome variants
Aziz Belkadi, Alexandre Bolze, Yuval Itan, Quentin B Vincent, Alexander Antipenko, Bertrand Boisson, Jean-Laurent Casanova, Laurent Abel
doi: http://dx.doi.org/10.1101/010363
We compared whole-exome sequencing (WES) and whole-genome sequencing (WGS) for the detection of single-nucleotide variants (SNVs) in the exomes of six unrelated individuals. In the regions targeted by exome capture, the mean number of SNVs detected was 84,192 for WES and 84,968 for WGS. Only 96% of the variants were detected by both methods, with the same genotype identified for 99.2% of them. The distributions of coverage depth (CD), genotype quality (GQ), and minor read ratio (MRR) were much more homogeneous for WGS than for WES data. Most variants with discordant genotypes were filtered out when we used thresholds of CD≥8X, GQ≥20, and MRR≥0.2. However, a substantial number of coding variants were identified exclusively by WES (105 on average) or WGS (692). We Sanger sequenced a random selection of 170 of these exclusive variants, and estimated the mean number of false-positive coding variants per sample at 79 for WES and 36 for WGS. Importantly, the mean number of real coding variants identified by WGS and missed by WES (656) was much larger than the number of real coding variants identified by WES and missed by WGS (26). A substantial proportion of these exclusive variants (32%) were predicted to be damaging. In addition, about 380 genes were poorly covered (~27% of base pairs with CD<8X) by WES for all samples, including 49 genes underlying Mendelian disorders. We conclude that WGS is more powerful and reliable than WES for detecting potential disease-causing mutations in the exome.

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