Is a personal genome sequence worth $350,000?

This little USB drive represents the current pinnacle of luxury personal genomics. It's the product of Knome (pronounced "know me"), a Cambridge, MA-based biotech start-up fronted by genomics pioneer George Church (recently profiled in Wired). In return for $350,000, Knome's customers receive a shiny 8 Gb drive containing their entire genome sequence (or rather, a hefty fraction of it), along with specialised browser software for viewing it.

$350,000 is a hell of a lot of money to fork over for a few gigabytes of data. So, how much of a return will these customers be getting on their substantial investment?

What you get for your $350,000
A recent article in Technology Review outlines what a Knome customer can expect to receive for their generous outlay. Generating the genome sequence itself (which is done through a collaboration with the Beijing Genomics Institute) is just the beginning; the resulting data are then pored over by a team of informaticians and clinicians to mine out the useful details:

The first things the analysts look for are small variations that are found frequently in the broader population and have been linked to increased risk for myriad diseases. They then look for other types of genetic changes--including DNA deletions or duplications--linked to specific diseases. Lastly, they scan the genome for novel variations, changes that have not yet been spotted in the limited amount of human DNA that has been sequenced to date. The effects of such changes are uncertain, but the scientists try to predict them by considering the structure of the resulting proteins.

Customers receive their data at a "mini symposium dedicated to the recipient's genome, where scientists explain the results, the process behind them, and their limitations" - basically a genetics conference with themselves as the only subject.

It's hard to know how many uber-wealthy genetics geeks out there have both the cash and the desire to sample Knome's product, although Technology Review reports that the company handed over its first complete sequence to a customer last month, and aims to sequence at least 20 genomes this year.

A marginal return
Obtaining a complete genome sequence is certainly a massive technological leap beyond the offerings of the current crop of "budget" personal genomics companies, like 23andMe and deCODEme. These companies charge around $1000 for a chip-based analysis of up to a million sites of common variation scattered throughout your DNA, while Knome aims to provide the sequence of all three billion bases in your genome. In dollar-per-byte terms, Knome's customers are paying around 350 times more but receiving almost 3,000 times the information.

That starts to make Knome sound like a pretty good deal, at least for those of you with a spare $350,000. However, it's worth bearing in mind that the seemingly paltry one million or so sites targeted by deCODEme et al. are not a random sample of the genome, but have been selected to be as informative as possible about patterns of common variation at other sites. The chips used by deCODEme, for instance, directly examine around 0.3% of the genome but provide surprisingly accurate information about more than 80% of common variation, due to the magic of linkage disequilibrium - put simply, variants close to one another on a chromosome tend to be inherited together, so by examining one variant in a region you can indirectly obtain information about many other nearby sites.

In addition, the million or so variants targeted by the "budget" companies are the ones that researchers know the most about, since the chips these companies use were also the backbone technology for recent genome-wide association studies of common diseases. Virtually all of the over 200 genetic variants recently associated with diseases like diabetes and rheumatoid arthritis are already covered by 23andMe's chip; you don't need a complete genome sequence to see if you have them or not.

In fact, the major advantage of whole genome sequencing is that it provides information on rare variants - changes in your genome that you share with fewer than 1% of the general population - that are almost completely invisible to chip-based assays. Because natural selection tends to hold seriously nasty variants at low frequency, rare variants are enriched for changes that are likely to have a negative impact on health. That means that a complete genome sequence will find many interesting variants that would be missed by a 23andMe-style scan; the problem is that rare disease-causing variants are also very poorly characterised by current studies, both because they are poorly tagged by chips, and because their low frequency makes it hard to find enough carriers to study.

That means that right now obtaining a complete catalogue of the rare variants in your genome is not a great deal of use for most people: we could probably confidently assign disease-causing status to perhaps a dozen or so mutations (most of which would only cause disease in your children if you had the bad luck to mate with someone carrying mutations in the same gene), and tentatively tag a few hundred or so as likely candidates. The majority of the monsters in your genome, on the other hand, would remain hidden in the noise - especially those lurking in the vast non-coding areas of the genome in which function is currently almost impossible to decipher.

So the major advantage of whole-genome sequencing is largely defused by our lack of knowledge about how the genome operates. In other words, compared to chip-based personal genomics companies a full genome sequence provides a hefty dose of extra genetic information in absolute terms, but the immediate return in terms of useful, medically relevant information is likely to be pretty small.

The race is on
Of course, this doesn't mean that whole genome sequencing will always be a waste of money. The cost of DNA sequencing has plummeted over the last few years due to the advent of "next-generation" sequencing technology, with three competing platforms currently battling to stake out a share of the lucrative medical sequencing market. At the same time, large-scale genetic association studies and advances in other fields of biomedical science are rapidly increasing researchers' ability to assign function to genetic variants, thus boosting the value of a personal genome sequence. The stylised graph below gives you a rough idea of the dynamics here:

Basically, we're currently at a stage where costs are dropping much faster than the rate at which the value of genetic information is increasing - in other words, you and I will be able to afford a genome sequence long before science will be able to tell us much about what it really means. However, the beauty of a finished genome sequence is that (unlike 23andMe-style chips, which are constantly being replaced by higher-resolution models) it never becomes obsolete. Once you have your entire sequence sitting on your hard drive you can simply sit back and wait for new associations and techniques for assigning function, which will soon be appearing at an exponentially increasing rate as technology improves.

It will be a while before any company will be able to offer an "entire" genome sequence in the literal sense - there are still many regions of the human genome (mainly large, repetitive areas close to the centres and ends of chromosomes) that can't be fully sequenced with any existing technology. For this reason, Knome's customers are probably only getting reliable sequence information for somewhere between 85 and 90% of their entire genome. In addition, the "short read" nature of current high-throughput sequencing methods means that they will likely be missing information on large structural variations (insertions, deletions and other rearrangements of large chunks of genetic material). We have a long way to go before a personal genome sequence can be regarded as truly "finished".

Nonetheless, the desire to have as much of your sequence as possible, ready to cross-check against new genetic discoveries, is presumably one of the rationales driving customers to Knome. Millionaire Dan Stoicescu, Knome's first publicly named customer, was described in an article in the NY Times back in March as intending to "check discoveries about genetic disease risk against his genome sequence daily, like a stock portfolio." (Mind you, given that he could likely buy the same service for a thousand dollars or so in a few years' time for the same informational return, this is a curious investment - I can only assume he followed different logic when making his millions).

Of course, there are other justifications for being an early adopter: for instance, Stoicescu also views his extravagant purchase as "a kind of sponsorship" helping to fund improvements in sequencing technology and genome analysis. There's some genuine truth to that. In the same way that wealthy early adopters created markets for later-commodified gadgets like laptops and mobile phones, the lessons learnt from Knome's first few affluent customers will pave the way for cheap personal genome sequences for the rest of us.

How much is a genome worth?
It depends on who you are, and why you want it. For someone suffering from a rare genetic disease with an unknown mutation, that sequence could make a huge difference - potentially allowing a more accurate prognosis, genetic counselling, and pre-natal diagnosis to prevent passing on the disease to children. For the rest of us the benefits are currently pretty small, and will likely remain so for the next few years; and by the time the average health benefits of having a genome sequence become non-trivial, the sequence itself will likely be cheaper than many standard diagnostic tests. At that point the decision is straightforward and personal genomics will become mundane.

For those of us with a strong interest in human genetics the critical point is likely to be reached substantially earlier. I certainly can't afford Stoicescu's lavish price, but I'd fork over a few thousand bucks to take a peek inside my DNA. I'm under no illusions about the likely meagre health outcomes, but if there are any obvious and unpleasant surprises in there I want to know. There are also the non-medical bonuses, like being able to put myself on the genetic map - even if I know roughly where I'm likely to end up, it would still be damn cool.

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