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Brian Krueger, PhD
Columbia University Medical Center
New York NY USA

Brian Krueger is the owner, creator and coder of LabSpaces by night and Next Generation Sequencer by day. He is currently the Director of Genomic Analysis and Technical Operations for the Institute for Genomic Medicine at Columbia University Medical Center. In his blog you will find articles about technology, molecular biology, and editorial comments on the current state of science on the internet.

My posts are presented as opinion and commentary and do not represent the views of LabSpaces Productions, LLC, my employer, or my educational institution.

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Wednesday, January 15, 2014

Illumina, the world leader in short read DNA sequencing, made a series of very big announcements yesterday at the JPMorgan Healthcare Conference.  These developments have many sequencing labs around the world excited and worried all at the same time.  The excitement comes from the fact that it appears on the surface that Illumina has broken the $1000 genome* barrier – the worry comes from the realization that only a few of us can afford it.

While the $1000 genome* announcement is the current buzz in the sequencing world, Illumina also announced a new mid-range sequencer and more progress on the substantial upgrade to the HiSeq2000/2500 line

The new machine is called the NextSeq 500.  It appears to be in direct competition with Life’s Ion Proton system.  If the NextSeq delivers the speed and quality of a MiSeq/HiSeq, this certainly spells trouble for Ion Torrent as this new Illumina sequencer will be able to sequence 12 exomes or a single genome in approximately 30 hours.  The major drawback of the NextSeq is that the read lengths are only 150bp whereas the MiSeq and Ion Torrent systems can go beyond 300bp per read.  The Proton/PGM/MiSeq may still hold some ground in niche sequencing markets, but I imagine the NextSeq 500 will all but eliminate sales of Proton’s to hospital labs who were hoping to use the technology to do small scale local sequencing of patient samples.  Ion Torrent and the Proton have struggled to develop a reliable system with yields and quality that match those of the Illumina based systems.  Illumina also announced a price drop for the MiSeq whose direct competition is Ion Torrent's PGM.  Together these announcements are no doubt triggering a lot of soul searching over at Ion Torrent.

The upgrades to the HiSeq 2500, which were first announced at this year's ASHG conference, are significant because they cut the current high output run time from 11 days down to 6 days with an increase in sequencing yield from 600 gigabases to 1 terabase.  This comes from a number of improvements in the latest generation of HiSeqs including increasing cluster densities, use of a more powerful laser, faster imaging, improved chemistry (V4), and a new polymerase.  The other increase in yield over the current HiSeq workflow comes from an increase in cluster read lengths from 100bp to 125bp.  The read length of rapid mode has also been modified to allow for 150bp reads.  Current HiSeq 2000/2500 owners will be able to upgrade all of their systems to this new technology (given they bought their HiSeqs in the last year or so) by paying a $15,000 liscensing fee.

Of course the milestone announcement from Illumina was that they have broken the $1000 genome* barrier with their newest sequencing system called the HiSeq X.  This system is capable of generating 1.8 terabases of data in less than 3 days.  That’s enough sequencing to sequence 16 human genomes to 30x coverage.  To do this using a standard HiSeq 2000 in high output mode would require 3 machines and take 11 days (The X ten can do ~64 in that time).  The improvement Illumina has achieved here is staggering.  It will be interesting to see how this is possible but early information I have received is that even better optical hardware is being implemented along with a proprietary prep kit, TS Nano, and the fabled “patterned” flowcell.  The patterned flowcell is actually a cool development that’s been discussed for about a year now.  Currently sequencing clusters are generated randomly on the surface of the flowcell and this clustering is dependent on how much DNA is loaded to create the clusters.  If too much DNA is added to the flowcells, the clusters overlap and the system can’t interrogate the bases accurately resulting in cluster loss.  Illumina says that close to 30% of all clusters are lost in every run.  The patterned flowcell fixes this by only allowing clusters to be generated on pre-patterned spots/nanowells.  Supposedly you don’t have to worry about over clustering and we’ll be able to generate data from every cluster now, reclaiming that lost 30%!  The X system is configured to only perform whole genome sequencing.  Standard preparations for exome or RNA sequencing aren’t compatible at this time according to my sources at Illumina.   One huge drawback for current HiSeq owners is that there is no upgrade or trade in path to the X ten.  If you recently bought a cluster of HiSeqs, you're stuck with them.

 Not only did Illumina drastically improve sequencing efficiency but they claim that the reagent cost per genome will be $800 on the X ten system.  Current reagent costs for Illumina genome sequencing at academic institutions runs about $4000.  That’s a massive reduction in cost!  Illumina has left an extra $200 in the cost of their $1000 genome* to cover instrument depreciation (the cost of purchasing/replacing the system in the future), but these numbers are followed by a gigantic asterisk.  To get the $1000 genome* you first have to ignore covering the costs for overhead, analysis and data storage which can run anywhere from $500-5000 per genome depending on a variety of factors.  If this is CLIA certified work the costs for overhead will tip toward the high end.  Secondly, the X ten system is only sold as a 10 pack, at $10 million, so your average University sequencing lab will not be able to afford to purchase this system.  It’s only available to sequencing factories so while the Broad’s and the BGI’s of the world get to churn out $1000 genomes*, we’re all stuck with our $4500-10000 genomes.  I’m not quite sure this falls within the spirit of the $1000 genome which served as a benchmark for when sequencing had become cheap enough for the general public to have access to their genome.  While the $1000 genome is a huge milestone we’re not quite there yet. 

No doubt these latest developments from Illumina are exciting for the future of human genetics, but I imagine a lot of other mid-range sequencing labs are wondering why anyone would ever spend $4000 on genome sequencing locally if they could find the same exact product at one of these massive factories for a quarter the cost.  I'm guessing Illumina's play here is that they're doing a limited release to stoke demand and test the system in the field.  By aligning with places like the Broad, they know they'll have a system running somewhere with access to a huge amount of real world samples to do the QC/QA testing they likely can't do in house.  Otherwise, from my vantage point, it looks like they're giving a giant middle finger to small and mid-range sequencing labs.  Hopefully they let the rest of us schlubs have access to the tech once it's perfected and ready for primetime.
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*if you can afford to buy into and support the scale of a $10 million 10 sequencer setup.

Edit: The original posting said the HiSeq 2500 would be able to use the new patterened flowcells. That does not appear to be the case.  Only the new HiSeq X coupled with the TS Nano kit can utilize this new technology.

Further reading:

BioItWorld: What You Need to Know About Illumina's New Sequencers

Nature: Is the $1,000 genome for real?

GenEngNews: New Illumina Sequencer Enables $1,000 Genome

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