
When sequencing makes genotyping obsolete (soon) - cinquemb
http://www.unz.com/gnxp/when-sequencing-makes-genotyping-obsolete-soon/
======
adenadel
The author makes the comparison between the cost of 23andme's genotyping
arrays and the cost of whole genome sequencing (WGS), but the comparison with
whole exome sequencing (WES) is probably more appropriate. For the unfamiliar,
exome sequencing specifically sequences the exons (which are the components of
genes). I'm not sure how many SNPs 23andme genotypes outside of exomes. Since
the exome is 1-2% of the whole genome. You can imagine the savings when doing
WES vs WGS (although the prep for WES is more costly). WES can be done for
under $300 at this point (I'm not sure of the actual price point on the latest
Illumina systems, but my guess is it's lower than this).

~~~
coetzeesg
Anything that is interrogating risk for complex disease must look outside of
exons. Most genome wide association study (GWAS) index SNPs, in diseases such
as cancer[1], autoimmune disorders and psychiatric disorders, fall in introns
of genes and the large intergenic regions. This means that it's hard to
pinpoint the gene that is being effected, and if you're only looking at the
exons of genes, you're missing almost the whole picture of inherited risk.

[1] from my paper in 2012:
[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3467035/figure/g...](http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3467035/figure/gks542-F1/)

~~~
adenadel
I agree with you completely, but comparing from a consumer standpoint the
exome gives you a lot more information than the SNP chips for a potentially
similar consumer price point.

~~~
coetzeesg
That's fair, but if you don't already present with a disease, I don't know how
much WES can tell you. At least with a SNP chip, and the correct analysis, you
can start speculating about what may happen down the road.

~~~
adenadel
I agree completely. The nice thing about the exome is that the knowledge is
more extensible than the SNP chip. If we discover new variants within the
exome you won't need to be genotyped a second time. That logic probably argues
more for WGS though. It is also the problem with WGS and WES. You get a ton of
variants of unknown significance that the patient/customer will be curious
about but be able to obtain no answers.

------
_of
The terminology is not accurate. Sequencing can be a form of genotyping. What
the title refers to is that sequencing makes array-based genotyping obsolete.

~~~
a_bonobo
Yes - with Sequence-based Genotyping or RADSeq you use sequencing machines for
genotyping

The upsides of using genomic or RAD reads compared to array-based is that you
don't need to make an array first, and sequencing reads is still more
expensive than using an array; but with an array you get a more complete set
of called genotypes, and you don't get problems with any eventual bad-quality
read library.

Nevertheless, at some point we'll drop array-based genotypings.

------
gabeiscoding
They are correct in calling out Illumina's de-facto monopoly rents they are
extracting on the market, but sadly I don't share their wildly optimistic view
that we are eminent for technological disruption that will re-start the price
plummeting of whole genome sequencing.

Nanopores are no where near the throughput and accuracy of Illumina's
sequencing by synthesis tech, and if there is a pathway to challenge
Illumina's position, it will be extremely complex, iterative and _long_.

Meanwhile Illumina is amassing a billion dollar war chest and is adding its
own complex and iterative improvements to its platform (two-color detection,
longer and longer reads, higher cluster density), maintaining its market lead.

As much as the analogy to microprocessor manufacturing and Moore's law is
alluring, the messy stuff of biology and single molecule chemical manipulation
and sensor detection is unlikely to obediently follow the same innovation
curve.

~~~
waiquoo
I've got something for nanopore sequencing coming out in the next few month.
Stay tuned.

~~~
adenadel
Do you use a different nanopore than α-hemolysin or MspA?

~~~
waiquoo
solid-state

~~~
cinquemb
Read some of your works, if its related, sounds pretty cool! Would love to
hear more.

------
Camillo
I think the real differentiator for a company in this field would be to let
you pay full price for your genome, but with the guarantee that they will not
retain any copies of it once you have received it.

~~~
adenadel
Almost all sequencing centers will not hold your data much longer than a few
months (and won't put it to any use in that time). The storage requirements
are just too high for them to put them on tape and archive them long term.
Companies like 23andme are obviously a different story.

EDIT: I'm talking about sequencing core labs that do sequencing as a service.
They also have no need to keep the data because they don't necessarily have
any metadata about the samples that they are sequencing.

~~~
VikingCoder
"The storage requirements are just too high" Yeah? Can you elaborate on how
big we're talking here?

~~~
adenadel
100GB per person for the raw data from 30X WGS

~~~
cinquemb
So right now, one can buy 5 TB hard-rive for about $130 (lets ignore bulk
buying because I have no knowledge of such).

If you theoretically could get 30 Million people at 30X WGS, that would be
about 3M terabytes (600k drives) and you would need at least $78M, which seems
a bit expensive, but it seems feasible if you were planning on capitalizing
for at least a order of magnitude more, no?

~~~
tetron
Buying those 600,000 drives is probably only 10% of your costs, you need to
run a data center if you want to actually use that data.

Also analysis pipelines generate intermediate results that are also large, and
data is stored with 2x or 3x redundancy. So that 100GB might be more like
300GB once you factor in robust storage and bioinformatics.

~~~
cinquemb
Still, multiply that by 3, then 1.5 for the overhead… that's still about 5
months of QE :P

A post doc at who worked at ATLAS came to visit our lab a couple weeks a go,
and just listening to the workflow they have for the events coming off the
detectors… and all the BS they have to deal with working in academia… yeah…
I'll take that money, erect a CSP system up in Spain and ask them to come do
this with me, just to start off with a fun side project :P

