The exome is only a small portion of the genome

Ricki Lewis (Genetic linkage blog) wrote a great guest post for Scientific American on what exome sequencing can’t do. It seems timely considering the explosion of interest in exome sequencing and exome arrays. Not so long ago most people I knew still talked about junk DNA, exome sequencing and exome arrays essentially allows users to ignore the junk to get on with real science. As Ricki points out exome analysis is a phenomenally useful tool but users need to understand what they can’t do to get the most from their studies.

Ricki listed 10 things exomes are not so good for, my list is a lot shorter at just 4.

1. Regulatory sequence is missing (although this is being added, e.g. Illumina).
2. Not all exons are included.
3. Structural variants (CNV, InDel, Inv, Trans, etc) are not easily assayed with current exome products.
4. No two exome products are the same.

Exome analysis has had a real impact, especially on Mendelian diseases that remain undiagnosed. However users need to remember they are only looking at a very small portion of the genome. Ricki puts it this way “the exome, including only exons, is to the genome what a Wikipedia entry about a book is to the actual book”.

I posted a month or so ago about choosing between exome-chip and exome-seq. The explosion in exome-chips has been an even bigger surprise then exome-seq. Illumina admitted that they had been overwhelmed with demand for their array products. It appeared to be pretty clear that exome-seq would take off as soon as the cost came down to something reasonable. However according to Illumina over 1M samples have now been run on exome chips!

Of course analysis of an exome is allowing studies to happen that would never get off the ground if whole genome sequencing were the only option. The cost and relative ease of analysis makes the technology accessible to almost anyone. As the methods and content improve over the next coupe of years this is going to get even easier.

The simplest thing for users to remember is that they are restricting analysis to a subset of the genome. This means that just because you don’t find a variant does not mean one is not lurking outside the exome; absence of evidence is not evidence of absence as statisticians would put it.

It is also helpful to remember that not all exomes are created equal. Commercial products are designed with a price and user in mind. Academic input is usually limited to a few groups and there are always other bits that could be added in. Illumina have done a great job including some of the regulome in their product but the commercial products are in a similar arms race to the one faced by microarray vendors a decade ago. Just because a product targets a bigger exome does not mean it is better for your study.

Exomes are well and truly here to stay. We'll probably see an exome journal soon enough as there is so much interest.