Mark Gerstein, PhD, is Albert L Williams Professor of Biomedical Informatics and professor of molecular biophysics and biochemistry, and of computer science at the Yale School of Medicine in New Haven, Connecticut. He is also codirector of the Yale Program in Computational Biology & Bioinformatics.
Dr Gerstein spoke with Cancer Therapy Advisor about the diagnostic use of whole-genome compared with whole-exome next-generation sequencing to search for gene mutations that are thought to contribute to the risk of cancer and other diseases.1-3
Cancer Therapy Advisor (CTA): What is the difference between whole-exome sequencing (WES) and whole-genome sequencing (WGS)?
Dr Gerstein: WGS sequences a patient’s entire genome. You get the DNA and shred it up into fragments and put it into a sequencing machine. Those reads then get mapped back to the reference genome and you look at places where the reads match or where there might be differences, to identify gene variants — single nucleotide polymorphisms [SNPs], single-base mutations, insertions, deletions etc.
In exome sequencing, it’s a very similar process. But it only sequences the exome — the protein-coding regions of the genome. Canonically, people think of it as only 1% to 2% of the genome. That is where people think most of the action is in certain contexts; if you have certain somatic mutations in cancer, people think it’s more important to look directly at the protein-coding part of the genome.
Whole-exome sequencing is the same process but there’s an extra step of using a capturing reagent to preferentially bind to and capture the exome regions of the genome.
It’s not 100%, but that means most reads are now from exomic regions, and so for much less cost, we can get high coverage of the exome. And one can sequence more samples at lower cost. That’s the idea.
CTA: So, an underlying assumption for WES is that the disease-relevant parts of the genome are found in the exomic regions. But there are clinically relevant roles of noncoding regions of the genome, as well, right? Is that one advantage of WGS?
Dr Gerstein: Right. There are a lot of things going on there in noncoding regions. Essentially all of the regulatory architecture for regulating genes is there, and variants in those regions can lead to disease.