Thanks for visiting my blog - I have now moved to a new location at Nature Networks. Url: - Please come visit my blog there.

Monday, June 15, 2009

Another day, another result...

I had the urge to just sit down and type out a long rant, but then common sense kicked in and I realized that no one is really interested in yet another graduate student's rant about their project not working. However, it only took a few minutes for me to figure out why it's relevant to the general world - something that's (unfortunately) missing from most grad student projects.

If you follow along with Daniel McArthur's blog, Genetic Future, you may have caught the announcement that Illumina is getting into the personal genome sequencing game. While I can't admit that I was surprised by the news, I will have to admit that I am somewhat skeptical about how it's going to play out.

If your business is using arrays, then you'll have an easy time sorting through the relevance of the known "useful" changes to the genome - there are only a couple hundred or thousand that are relevant at the moment, and several hundred thousand more that might be relevant in the near future. However, when you're sequencing a whole genome, interpretation becomes a lot more difficult.

Since my graduate project is really the analysis of transcriptome sequencing (a subset of genome sequencing), I know firsthand the frustration involved. Indeed, my project was originally focused on identifying changes to the genome common to several cancer cell lines. Unfortunately, this is what brought on my need to rant: there is vastly more going on in the genome than small sequence changes.

We tend to believe blindly what we were taught as the "central paradigm of molecular biology". Genes are copied to mRNA, mRNA is translated to proteins, and the protein goes off to do it's work. However, cells are infinitely more complex than that. Genes can be inactivated by small changes, can be chopped up and spliced together to become inactivated or even deregulated, interference can be run by distally modified sequences, gene splicing can be completely co-opted by inactivating genes we barely even understand yet and desperately over-expressed proteins can be marked for deletion by over-activating garbage collection systems so that they don't have a chance to get where they were needed in the first place. And here we are, looking for single nucleotide variations, which make up a VERY small portion of the information in a Cell.

I don't have the solution, yet, but whatever we do in the future, it's not going to involve $48,000 genome re-sequencing. That information on it's own is pretty useless - we'll have to study expression (WTSS or RNA-Seq, so figure another $30,000), changes to epigenetics (of which there are many histone marks, so figure 30 x $10,000) and even dna methylation (I don't begin to know what this process costs.)

So, yes, while I'm happy to see genome re-sequencing move beyond the confines of array based SNP testing, I'm pretty confident that this isn't the big step forward it might seem. The early adopters might enjoy having a pretty piece of paper that tells them something unique about their DNA, and I don't begrudge it. (In fact, I'd love to have my DNA sequenced, just for the sheer entertainment value.) Still, I don't think we're seeing a revolution in personal genomics - not quite yet. Various experiments have shown we're on the cusp of a major change, but this isn't the tipping point: we're still going to have to wait for real insight into the use of this information.

When Illumina offers a nice toolkit that allows you to get all of the SNVs, changes in expression and full ChIP-Seq analysis - and maybe even a few mutant transcription factor ChIP-Seq experiments thrown in - and all for $48,000, then we'll have a truly revolutionary system.

In the meantime, I think I'll hold out on buying my genome sequence. $48,000 would buy me a couple more weeks in Tahiti, which would currently offer me a LOT more peace of mind. (=

And on that note, I'd better get back to doing the things I do.... new FindPeaks tag, anyone?

Labels: , , , ,


Anonymous tc said...

Right on target. I figure they're going to need about 10-15 more years of solid discoveries before they're worth anything close to $48K.

June 15, 2009 11:46:00 PM PDT  
Blogger morin.ryan said...

Firstly, I agree that genome sequencing is not the be-all and end-all. However, one burning question: on which tissue(s) would you do all these experiments? A gene expression and epigenetic profile is going to be different in different cell types and tissues. If you are looking for an epigenetic signature of disease, it is most likely going to be in specific tissues in which that disease originates (unless there are systemic biomarkers). The genome is the only thing that (except for somatic changes) is effectively the same in all your cells.


June 16, 2009 8:01:00 AM PDT  
Blogger Anthony Fejes said...

Hi Ryan,

I think your comment really underscores my point: the genome is really the only thing in common between all of your cells, but how much use is having that sequence, when all of your cells are off doing their own thing and using the genomic "template" information differently? Simply having a genome sequence (regardless of the cost) is insufficient to gain real insight into how things operate anywhere in the human body.

At any rate, my point with the transcriptome and ChIP-seq is simply to illustrate how woefully inadequate Genome sequencing is as a lifestyle changing guide - which seeme to be how Illumina, 23andMe and the rest of the companies are promoting it. Figuring out which tissues to sequence is something that would only make sense in terms of diagnostics (as you've pointed out), and is something I felt was outside the scope of this particular post.(=

June 16, 2009 9:11:00 AM PDT  

Post a Comment

<< Home