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There’s been a fascinating back-and-forth going on in the genome blogosphere about the pre-publication of the Applied BioSystems (i.e., Life Technologies) whole-genome sequence of a Yoruba, the seventh published whole human genome (is this still correct?), although the Yoruba one was done twice. At MassGenomics last month, Dan Koboldt took the paper’s authors to task for not offering a comparison to Illumina’s earlier sequence of the exact same genome. ABI’s Kevin McKernan responded in the comments. Meanwhile, in a guest post at Genetic Future yesterday, Luke Jostins suggested that ABI’s paper was not entirely cricket (links by me):

What follows is idle speculation, and thus (hopefully) not slander. My guess is that SOLiD is attempting to reposition itself as the Low Coverage Sequencing Company. They have still failed to topple Illumina as the market leader, and I expect that they think if enough people start thinking of SOLiD as “the guys who did a good quality 18X genome”, all the people who found the low coverage 1000 Genomes Project work sexy will start looking to SOLiD. But to do this, they had to fudge a few things: get the coverage down by cutting out lots of reads, obfuscate the low quality of heterozygous calls, and give an overenthusiastic estimate of how cheap their technology is.

Ouch. And I thought the direct-to-consumer genomics debate was rough.

I love this [via Genomeweb]:

In a sign that genome-mapping is becoming increasingly common, a company called Knome plans to offer its personal gene-sequencing service to the highest bidder in an eBay auction set to begin on Friday and continue for 10 days. The company plans to opening the bidding at $68,000.

Daniel has his usual cogent breakdown, explaining why patience is a virtue.

Anyway, um, while you’re waiting for the genome bidding war to commence, perhaps I can interest you in something else that is considerably less expensive and easier to interpret?

In the current New England Journal of Medicine, David Goldstein wrote:

If common variants are responsible for most genetic components of type 2 diabetes, height, and similar traits, then genetics will provide relatively little guidance about the biology of these conditions, because most genes are “height genes” or “type 2 diabetes genes.”

In response, a friend of mine emailed and asked:

“What I find difficult to accept is that [Goldstein] has ongoing [genome-wide association] studies, so does he not believe in his own work?”

My response: I can’t speak for David, but having just read his commentary, I think he would say that if you’re going to do GWAS, the disease itself should probably not be the phenotype under study, because we’ve done those studies and so far they’ve produced a failry shitty ROI, at least by conventional definitions of clinical relevance. You’ll have more luck studying endophenotypes, e.g., drug response, brain structure as measured by MRI, a decline in working in memory, etc.

In an accompanying commentary, Joel Hirschhorn wrote:

I believe that the skeptics’ arguments either misconstrue the primary goal of genomewide association studies or are contradicted by their findings. The main goal of these studies is not prediction of individual risk but rather discovery of biologic pathways underlying polygenic diseases and traits. It is already clear that the genes being identified expose relevant biology.

Hmm. Yes of course we’ve learned a lot of biology, but isn’t this moving the goal posts a little bit? In the grants we write, do we not extol the clinical relevance of our work and the enormous promise it holds for diagnostics, therapeutics and–gasp!–actual cures for the diseases that ravage our species? Or do we modestly say, “Each discovery of a biologically relevant locus is a potential first step in a translational journey?” If we acknowledge that 100 years elapsed between the elucidation of the chemical makeup of cholesterol and the development of statins, does that make it okay? Given that 45 years have passed since the recognition that human response to anticoagulant drugs is genetically mediated and we STILL can’t agree about whether pharmacogenetic testing is a good idea, do we just shrug and say, “It is what it is?”

As I’ve said here before by way of disclosure, David Goldstein is a friend and colleague. Even if I don’t always agree with him (and I think he’s wrong when he offers the usual broad indictment of the personal genomics companies), I admire his willingness to — as Richard Preston said of Craig Venter — fart in church.

In the end I’ve had about enough of this debate. It is as if we are arguing over the merits of the compact disc when we all know its days are numbered. Within two years, I imagine that most everyone doing molecular human genetics and genomics of any kind will be sequencing whole genomes.

Whether anyone will understand the data is another matter…

I spend many of my waking hours thinking about DNA. Not hydrogen bonds, histones and angstroms per se, but genes and genomes, SNPs, third-generation sequencing, gene patents, genetic testing, privacy, redaction, etc. Consequently, I sometimes get jaded. I take nucleic acids for granted; I think of them as a useful but quotidian aspect of life on earth.

And then I open the newspaper and read this:

Investigators said they are also looking for video accounts of the plane’s brief flight. They have split into teams and invited outside specialists, including some from the Department of Agriculture, who will help analyze the reports about birds. Ms. Higgins said that the engines’ internal parts will generally yield enough DNA to allow investigators to identify not only whether there were birds, but “down to precisely the exact type of bird,” said Ms. Higgins.

What would you do with $5000? Buy a used car? Fight a war for one second? Put it in the stock market? Bwahahahahahaha.

How about your own full diploid genome sequence at 40x coverage? The $5000 genome is here–or it will be in six months:

Mr. Reid said Complete Genomics hoped to perform 1,000 human genome sequences next year and 20,000 in 2010, with a goal of completing a million by 2013. That assumes the company can raise the money and find partners to build 10 sequencing centers at a cost of $50 million each. It also assumes there will be enough demand.

To put that in perspective, the number of human genomes sequenced to date by all parties combined is, at most, in the double digits. Knome, for instance, says it is on track to have 20 customers by the end of this year.

Volume, of course, could further drive down prices. “If we’ve got a million genomes sequenced by 2013,” Mr. Reid said, “it’s going to be very hard for anyone to compete with us.”

Not to get all hyperbolic, but this is quite simply, as my boss says, a game-changer.  It is Moore’s law run amok. “Church’s Law” anyone?

Can you spot the real scientist? (photo by Bob Cook-Deegan)

I was walking through Tower City, the teeming mall in downtown Cleveland, regretting not calling friends I used to know when I lived there, when I spied, sitting alone at the food court with a New York Times, one of the giants of genome history, Maynard Freaking Olson, in town to give a brilliant plenary address. As is my wont, I shamelessly pulled up a chair and started interviewing him. I mentioned the PGP and his eyes lit up. We talked about personal genomics, why he thinks it’s all so much “Freudian genetics,” ELSI, race, changing fields, George Church, health care, liberal politics, the disappointments of GWAS, Jim Watson, and on and on.

I was wrong: George Church is unique in many ways, but he is not the only hardcore genome sequencer who actually takes a real interest in the societal implications of his work. Thank you, Maynard!

Expression Analysis takes delivery of the first Heliscope just before the start of our state-wide month-long holiday.

I’m a few days late on this (what else is new), but ABI has sequenced a Yoruba for $60,000 at 12x coverage–that’s 36 gigabases for those of you scoring at home. As usual, it was the X chromosomes doing the heavy lifting:

The sequence files are subdivided according to the SOLiD instrument in Beverly, Mass., that initially produced the sequence. McKernan’s group names each of its instruments after a famous female scientist. The instruments contributing to this project were named Amelia, Barb, Clara, Florence, Joan and Liz.

Up Heliscope…

Helicos BioSciences announced today (5 March 2008) that it has shipped its first machine. If, as the company says, this bad boy can churn out an entire human genome at 10x coverage in eight weeks for $72,000, then the next-gen market — and personal genomics in particular — just got a whole lot more interesting.

For me (and it’s all about me, right?), one of the highlights of the Marco Island meeting beyond the amazing mango cheesecake was seeing an actual Polonator (note the human telomere sequence flowing out of it). Why should you care? Well, this is a DNA sequencing machine whose descendants will presumably yield 100,000 genomes (or at least exomes), including mine and perhaps yours. Even more interesting than the technology itself is the fact that the Polonator is open source:

The system’s operating software is fully documented and freely available for public download, as are the protocols and reagent sets. All aspects of the system are fully programmable, with parameters and sequences accessible and modifiable by its users to improve and extend the instrument. In addition, all subsystems are highly modular and easily upgraded and/or retrofitted; as a result, we fully anticipate that the instrument will evolve and improve over time. We expect a worldwide user community to develop and flourish, advancing both the design and the operational specifics of the platform, from which all users in turn will benefit.

The reactions to the open-source model from other next-gen types at the meeting ranged from unbridled enthusiasm (”a great idea”) to deep skepticism (”Who will support it?”) to bemusement/amusement (”sounds like another cute George Church concept–I have no idea if it will work”).

Jonathan Eisen has more on the Polonator as well as lots of other great stuff on Marco Island. He was also seen sporting a tee shirt that read “What Would Jesus Sequence?” An appropriate query, perhaps, in  the wake of Evolution Sunday.