As part of his Gene Week celebration over at Forbes, Matthew Herper has a provocative post titled "Why you can't have your $1000 genome". In this post I'll explain why, while Herper's pessimism is absolutely justified for genomes produced in a medical setting, I'm confident that I'll be obtaining my own near-$1000 genome in the not-too-distant future.
Matt's underlying argument is that while sequencing costs will continue to drop, obtaining a complete genome sequence that is sufficiently accurate for medical interpretation will require additional expenses (increased sequence coverage to ensure accuracy, all of the computation required to stitch the raw data into a useable form, and paying doctors to perform the interpretation) that will keep the cost of medical sequencing well above the arbimagical US$1,000 threshold. Instead, Herper argues, we will likely see medical-grade genomes stay above $10,000, or at least above the $2,000 currently forked out for MRI scans.
There's certainly some depressing truth here. I believe Herper is right that if you intend to access your genome sequence via a traditional medical route, it will certainly cost more than $1000 for the foreseeable future - if indeed you can get access to it at all, which is by no means guaranteed. The costs of clinical sequencing will include even more overheads than Herper notes in his short post: for instance, even as the accuracy of high-throughput sequencing technology improves, there will still be a need for variants with major medical impact to be independently validated in clinical labs, and custom assays don't come cheap.
However, many of these extra costs of clinical sequencing will be further inflated by regulatory demands (at least some of which will be arbitrary and pointless), and many will only apply if you obtain your genome through the medical system. Individuals with the motivation to seek alternative routes will be able to obtain a perfectly serviceable genome sequence at a substantially lower price: they'll have to be cautious in how they interpret the results, of course (although, importantly, this is also true of a medical test), but it will be possible to obtain substantial and potentially extremely useful information from your own genome without having to pass through the clinical toll-booths.
The key obstacle will be the development of cheap (or free), intuitive tools for annotating large-scale genetic information. Purchasing the sequencing itself will be trivial: even if the FDA succeeds in crushing innovation in direct-to-consumer genetic testing in the US, there will be plenty of companies abroad (especially in East Asia) willing to convert a mailed saliva sample into an assembled genome sequence. What the individual needs to do with that sequence is to (1) validate that the sequence they receive is in fact their own genome; (2) extract medically useful variants; (3) confirm that these variants are real; and (4) figure out how that information should be used to make health and lifestyle decisions.
Only one of these steps (the final one) will require direct consultation with the medical profession. The first will require comparing the sequence with independent genetic data (such as a genome scan from a company like 23andMe) to check that the two match the same individual (i.e. you), and also to provide an indicator of the global quality of the sequence. The second step is currently extremely challenging, but we can expect tremendous innovation in genome interpretation software and databases of functional variants over the next few years that will gradually simplify and improve this process. The third step will require sending another DNA sample to a company that does affordable, custom assays of a small number of genetic regions of interest using an independent technology. And the final step will involve discussing the results with everyone who might be able to tell you something useful about them, including your family and your doctor.
None of this is simple, but it will become easier with time. As the retail costs of sequencing drops, a substantial niche will develop for innovators providing affordable, intuitive, accurate interpretation tools (embryonic versions already exist: see, for instance, Promethease or Enlis Genomics). Open-source academic software built for large-scale sequencing projects will be adapted for use by non-specialists. The increasing availability of large-scale computing power (for instance, via Amazon EC2), coupled with this intuitive software, will make even compute-intensive analyses available to the educated, motivated lay-person. (Incidentally, tracking and fostering the development of these tools is one of the motivations behind the Genomes Unzipped project - and you'll hear more about our plans in this area in 2011).
Done carefully, there's no reason why a DIY genome couldn't be every bit as useful (or indeed as useless, in many cases) as one obtained through the doctor-as-gatekeeper route. As Dan Vorhaus argued after last year's sample mix-up at 23andMe, it is likely that clever DIY genomicists will be better at picking up certain kinds of errors (such as sample swaps) than clinical labs would. In terms of accuracy, while retail genomes may not reach the same quality standards as those generated by clinical labs, increased competition and innovation in the direct-to-consumer space will mean they're unlikely to lag too far behind - and judicious use of independent validation of important variants would in most cases raise the reliability to a level is equivalent to, or even higher than, a medical-grade test. Of course, for the very small number of genetic variants per genome that might require urgent, serious action - such as BRCA1 breast cancer-associated mutations - individuals can always fork out for a clinical test.
What proportion of people will take this DIY route? This isn't for everyone. Those wealthy enough to blithely fork out $10,000 for a medical genome interpretation, or sufficiently unwell to be able to convince their insurance company or public health system to pay for it, will by and large simply take the expensive medical route. Of the remainder, relatively few people will be sufficiently motivated to develop the background knowledge required to make sense of their genome, even if the analysis software is relatively intuitive. But for the non-trivial fraction of the population who want to know about their genomes, but don't want to pay the inflated costs associated with medical-grade sequencing - and I know this is a category that many readers of Genetic Future fall into - this will be an attractive and feasible option.
In addition, there will be advantages to the DIY approach beyond the lower cost. People who actively engage in the process of constructing useful information from raw sequence data - regardless of how intuitive the software is for doing it - will automatically learn important lessons about the nature of genetics (just as anyone who has given more than a casual glance at their own 23andMe profile has automatically learnt something important about the probabilistic nature of genetic risk factors for common diseases). They will also have opportunities to ask and answer fascinating questions that would be irrelevant in a purely medical consultation about your genome: for instance, what does your genetic information tell you about your ancestry?
They'll be able to ask these questions because they will own the data. How easy do you think it will be to obtain your raw genome sequence from your doctor to use to satisfy your own curiosity? How many forms and disclaimers will you need to sign? How many times will you need to listen to someone tell you that the data files are just too large, that the formats are inaccessible to lay-people, that your request is extremely unusual and will need to be considered for months by a hospital committee in the name of "health data privacy"? Anyone who has ever tried to get access to their own medical records will know how tedious and shrouded in unnecessary mystery this process can be; imagine how much larger the obstacles will loom when the system has the additional excuse of large, complex file formats to throw in your path.
Importantly, your genome is just one contributor to your present and future health. DIY genomics will, I hope, be part of a larger ongoing trend towards individuals taking greater personal responsibility for tracking and maintaining their own wellness - a task, incidentally, which modern healthcare systems are spectacularly ill-equipped to perform, something that seems unlikely to change substantively in the near future. As Western populations age, this broader shift of responsibility will be essential for healthcare systems to survive.
But I digress. My point here is simply this: Herper is perfectly correct that the overheads imposed (for a mixture of valid and arbitrary reasons) by medical-grade testing will ensure that clinical genomes remain expensive. But for those of us willing to learn the skills required to go outside the system, the $1000 genome is rapidly approaching. We just need to be ready to make the most of what it contains - and to reap the benefits of accessing that information as an active, engaged participant rather than a passive recipient.