Genomes vs Exomes

Regular readers of my Substack will know that I am a noncoding genome enthusiast. I get excited every time I read about a new noncoding discovery, and I highlight such findings in the Substack post. However, as an industry scientist working on drug discovery, if I am asked to choose between whole exome sequencing (WES) and whole genome sequencing (WGS), my money would be on WES. My colleagues at Regeneron Genetics Center (RGC) feel the same.

RGC was one of the eight pharmaceutical companies that invested in the whole exome sequencing of 500,000 UK Biobank research participants. But when industry giants later joined hands to throw money on whole genome sequencing the full UK Biobank, RGC opted out. The leadership, which includes pioneers in human genetics, strongly felt that WES provides more bang for the buck than WGS. They even assigned a team to empirically make this case. The results of their study are now published in Nature Genetics. In the study, Gaynor et al. ask how many more genetic associations can be found by WGS compared to WES and arrive at a sobering answer: not that many.

The current standard in the field to perform genome-wide association study (GWAS) is by combining array genotyping with WES. The array genotyping measures a sparse set of variants (~500,000) distributed across the genome, which are then used to impute unmeasured variants (~10M to 15M) using linkage disequilibrium (LD) maps. This approach helps to confidently identify only common variants (minor allele frequency >1%) as imputation accuracy drops at lower allele frequencies due to poor LD. So, researchers go for sequencing technology to measure rare variants. WES helps find rare variants from the coding regions, which span around 1-2% of the genome. So, the combination of common variants across the genome and rare variants across the exome has been the work horse of the field so far. So, the extra information that WGS provides is rare variants from the noncoding genome. Since the noncoding genome comprise more than 98% of the genome, there has been understandably high expectations for potential genetic discoveries from noncoding rare variants. In their analysis, Gaynor et al. specifically evaluated the yield of new genetic signals from noncoding rare variants by making a head-to-head comparison between WES+IMP and WGS.