Complete Genomics and ISB Team Up for Huge Whole Genome Study

The era of genetic studies based on whole genome sequencing is definitely upon us. According to a recent press release, Complete Genomics will provide the Institute for Systems Biology with 100 (nearly) whole genome sequences to researchHuntington’s disease – a degenerative brain condition which affects nearly 1 in 10,000 people in the US.

This will be the largest genetic association study of its kind ever. While the genetic causes for Huntington’s are well understood, the study will focus on the unknown “disease modifiers” – genes that cause the variation in severity in patients. If successful, the ISB study will also boost Complete Genomics’ reputation for sequencing.There are many ways to associate genes with diseases.

Companies like 23andMe regularly use SNPs (single nucleotide polymorphisms) to identify individuals with high risks for certain conditions. The ISB study, however, will examine nearly all of the genome – looking at SNPs, and sequences of DNA that cannot be analyzed with today’s SNP technology. As whole genome sequencing becomes cheaper (CG is at $20k and dropping) more and more research institutes will be able to follow in ISB’s footsteps and find important discoveries in the less well known stretches of your DNA.

That’s going to lead to a better understanding of the associations between illness and genetics and ultimately provide you with improved healthcare.Of course, the study isn’t remarkable simply for using whole genome sequences, it’s the number of those genomes that’s impressive. 100 genomes (probably around $20k each) is a substantial research investment. ISB is taking advantage of the patient pool size by looking at volunteers with severe forms of Huntington’s, members that exhibit a family history of the disease, unaffected family members, and control groups.

This is the first large sequence study that CG will attempt with their newly expanded facilities. It also puts them squarely on the path to achieving their goal of sequencing 10,000 genomes by the end of 2010. By expanding the range of DNA analysis to outside the standard set of SNPs, CG and other whole genome sequence companies are allowing geneticists to really examine the exome (protein coding sections) and regulatory portions of DNA. As CG, Illumina, and others make whole genome sequencing more affordable, these associated scientific advantages will become even more desirable. That’s going to mean big business growth in the next few years. Hopefully it will also mean big successes in medicine as well.

November 5th, 2009 by Aaron Saenz

Get Your Entire Genome From Complete Genomics For $5000

It’s getting progressively cheaper to sequence your entire genome. Earlier in June, Illuminaannounced it would provide sequencing for close to $50k, half of their original price. Not to be outdone, Complete Genomics just released on Monday that it had gathered $45 million dollars in funding. The Silicon Valley based company is planning to use that money to further develop their streamline sequencing operations so that they can offer a complete genome for just $5000 by next year. CG’s goal is to finish 10,000 sequences by years end 2010. Even though that’s later than we had hoped, it’s still a whole lot of DNA and at the cheapest price for a whole genome seen so far. The question is, can they really pull it off?

We’ve been looking for a company, any company really, to break the $1000 price mark for a complete genome sequencing sometime in the next few years. That’s about the point where retail sales of the service will explode. With their exponentially decreasing price tag, Complete Genomics might be on that path. However, we know of at least one company that is trying to reach that goal by the end of this year. Stay tuned for that story in the next few weeks.

If you’ve never heard of Complete Genomics, read our first and second story to catch up. Basically they use a common form of short read sequencing and throw in a ton of computer power to sequence a human genome. Interest in personal genomics is escalating as genetic links to diseases are discovered. 23andMe already offers some testing for such diseases and is hoping to gather samples for further clinical trials. By providing the entire genome for perusal on the cheap, CG could make it economically feasible to expand that research into many more illnesses. Already, we’ve shown you how some facilities are erroneously promising to predict a child’s aptitudebased on genetic sampling. Perhaps with the cheap sequencing CG could provide, scientific research will match pace with the growing demand for such testing.

Daniel MacArthur of Genetic Future was able to pry CG head Cliff Reid to provide some details in how they hope to achieve their goals. First, Reid disclosed that the test won’t be offered directly to consumers, but rather through retail providers such as Knome and 23andMe. That means the price you or I will see could be considerably higher than $5k. Whatever the retail price, Reid promises 120 billion base pairs sequenced, 98% of the genome, with just one error in 10,000. That’s considerably better stats than what CG offered in February (92% of genome, about one error in 1,000).

Between now and year’s end 2009, Complete Genomics will focus on its dozens of customers currently in the line up. These include the Broad Institute out of MIT and Harvard which announced it was purchasing at least 5 genomes from CG in March. The Broad Institute reportedly paid $20k for each of their genomes which might be taken as the current baseline price for CG customers. If so, that’s a factor of four that the company has to make up between now and next year.

But scaling is no problem for genome sequencing. Remember that it took 15 years to sequence the first human genome, but the next 6 were done in 24 months. Now we’re talking about doing thousands a year. That’s just nuts and one of the amazing parts about sequencing that I love. Exponential growth is sexy science. And it’s supposed to be one of CG’s strengths. They just finished their first genome in the summer of 2008, and are now on schedule to finish 100 by the end of 2009. Current estimates of finishing 1000 by mid 2010, and 9000 more by the end of that year fit within the exponential growth curve. As MacArthur points out, most of these sequencing services will likely be purchased by researchers in genomic and cancer studies. So the demand is also there.

How can CG scale so quickly? By remaining inflexible but efficient. Their process doesn’t rely on making huge improvements in sequencing technology. Or finding a new sequencing technique. It comes down to streamlining the process. Stick to one task, human genome sequencing, miniaturize whenever possible, fewer reagents means lower costs, and build build build. You can bet a huge portion of that $45 million is going to expanding their facilities in Mountain View.

Who provides the cheap genomes is probably less important than the change it will create. While scientific research will undoubtedly benefit first, the public at large will likely become a dominant consumer. Genetic information is on the journey to becoming one of the most important sets of data someone can know about themselves, with insights into disease, aptitudes, and longevity. Give us the chance for cheap access to that info and you’ll never run out of customers. Just a little while longer, it’s bound to happen.

Whole-Genome Sequencing: Any Useful Data?

ClinSeq is a pilot project to investigate the use of whole-genome sequencing as a tool for clinical research. By piloting the acquisition of large amounts of DNA sequence data from individual human subjects, we are fostering the development of hypothesis-generating approaches for performing research in genomic medicine, including the exploration of issues related to the genetic architecture of disease, implementation of genomic technology, informed consent, disclosure of genetic information, and archiving, analyzing, and displaying sequence data.

In the initial phase of ClinSeq, we are enrolling roughly 1,000 participants; the evaluation of each includes obtaining a detailed family and medical history as well as a clinical evaluation. The participants are being consented broadly for research on many traits and for whole-genome sequencing. Initially, Sanger-based sequencing of 300-400 genes thought to be relevant to atherosclerosis is being performed, with the resulting data analyzed for rare, high-penetrance variants associated with specific clinical traits.

He also mentioned the 1000$ genome project and the unofficial estimation is that now it’s possible to sequence a person’s genome for under 5000$ and the 1000$ aim can become a reality at the end of this year.

Breakthrough: Should you customize your drugs to your DNA?

Here's a shocker: Due to differences in DNA, up to 60% of the most common drugs are associated with adverse reactions. This includes medication used to treat common conditions like hypertension, heart failure, depression, high cholesterol, and asthma.

Hence the hope being pinned on "pharmacogenetics," a field of medicine that promises to improve health care by allowing doctors to customize medical treatment to suit a person's unique genetic signature. Though experts predict that it could be decades before personalized medicine becomes the norm, research is moving ahead: Last fall, for instance, researchers at Duke University reported that people with a specific genetic variant saw less reduction in LDL, or "bad" cholesterol, when taking statins.

But for some drugs, the future is now. A genetic test recently approved by the FDA should help doctors determine the optimal dose of warfarin (sold as Coumadin), a blood thinner used by 1 million Americans. Determining the right dose is crucial: Too much may result in an increased risk of excessive bleeding, while too little may cause a potentially fatal blood clot. By one estimate, using DNA analysis to prescribe warfarin would prevent about 17,000 strokes and 85,000 serious bleeding incidents.

A small but growing number of doctors and hospitals are also using genetic testing to tailor treatment for these medicines:

• Tamoxifen DNA testing identifies the 8% of women with genetic variants that keep them from metabolizing the breast cancer drug, rendering it ineffective.
  
• Painkillers like codeine Up to 8% of whites and 2% of Asians and African Americans are poor metabolizers of these drugs and won't get relief from them; for the 1% of "ultrarapid metabolizers," risks include respiratory problems.
  
• Antidepressants and antipsychotics Some of these drugs are metabolized by the CYP2D6 and CYP2C19 genes. In 2005, the FDA approved a test that looks for these gene variations, and now companies sell consumer versions. But experts advise against using the at-home tests without having your doctor interpret the results, notes Julie Johnson, PharmD, professor of pharmacy and medicine at the University of Florida. The reason: These genes are involved in the metabolization of 25% of all prescription drugs, including several where they're very important. If you misinterpret the results of an at-home test (and mistakenly think you don't have the gene), you might avoid taking one or more drugs you really need.

Knome offers sequencing of all of your protein-coding genes for $24,500

Personal genomics is a rapidly evolving game, with a clear end goal in sight: offering consumers an accurate, affordable and complete genome sequence, and providing them with tools to dig out the useful nuggets of information contained therein. That goal remains out of reach, and while DNA sequencing technology continues to mature companies in the personal genomics space are offering products at various points on the trade-off curve between information content and cost.

At the low-information/low-cost end, companies such as 23andMe and deCODEme offer cheap (sub-$1000) genome scans looking at between 500,000 and a million sites of common variation throughout the genome. These provide insight into a small fraction of your genome, but include the variants we know the most about (due to the recent explosion of genome-wide association studies, which look for common genetic variants associated with complex disease risk).

Meanwhile, at the other end of the spectrum we have the boutique service offered byKnome - sequencing of the entire human genome, or at least the 85-90% of it that can be reached with current short-read technologies, for the princely sum of close to $100,000. It's difficult to justify this cost given the interpretable information currently obtainable from a genome sequence, but a full genome sequence does offer the possibility of getting insight into rare, severe disease-causing variants lurking in your genome that are largely invisible to genome scans.

Now Knome has launched a new product that provides a substantial chunk of the information value of a whole genome sequence at a quarter of the cost, by focusing exclusively on the 2-3% of the genome that codes for proteins: unlike low-priced SNP-based genotyping, which captures genetic changes known as common variants by taking a sample of less than 0.05% of the genome, comprehensive gene sequencing captures the entire coding region of an individual's genes, collectively known as the exome, enabling the detection of rare variants - mutations that many scientists believe account for the majority of the genetic burden of disease.

That last claim is pretty optimistic - it's now clear from genome-wide association studies that the majority of the common variants associated with common diseases are actually found outside protein-coding regions. However, it's also true that more rare, severe disease-causing mutations do tend to cluster within and around protein-coding regions. 

Perhaps more importantly, there is a sound pragmatic reason for focusing on this fraction of the genome: it's simply much easier to interpret a mutation in a protein-coding region than outside it. Right now, our dismal ability to predict the functional impact of variants in non-coding regions means that sequencing the majority of the genome falling outside protein-coding genes actually adds very little in terms of health prediction. For the moment, combining a cheap genome scan (to pick up genome-wide patterns of common variation) with exome sequencing (to detect any rare, clearly pathogenic mutations) would give you pretty much everything you'd be likely to get from a whole genome sequence.

Knome plans to offer the service for $24,500 for individuals, or $19,500 per person for couples and families. That's still well and truly in the boutique price range - but you should see this as yet another waypoint on the road towards affordable, complete genome sequencing.

preparing doctors for the genomic tsunami

Mark Henderson has a great piece in the Times exploring the impact of personal genomics on the practice of medicine.

The basic theme should be familiar to anyone who has been following the emergence of the personal genomics industry: doctors are currently almost completely unprepared for the onslaught of genetic information they are about to experience. Here's the situation: at present, genetic training focuses on Mendelian diseases - rare mutations in single genes, which usually have severe effects. People who inherit the Huntington's mutation, for example, will invariably develop the fatal brain disorder, while 80 per cent of women who have a mutated BRCA1 gene will contract breast cancer.

This focus is perfectly understandable. Doctors need to understand and recognise these disorders, even if they will see few cases. Until recently, too, Mendelian conditions were the only ones for which genetic roots had been properly established. A knowledge of these rare diseases, however, is not going to be much help when patients start to visit their GPs waving printouts from genome scans like the one I took.

The genome scans Henderson describes are analyses of hundreds of thousands of common genetic variants scattered throughout the genome, currently offered by companies such as 23andMe, deCODEme and Navigenics (Henderson had his own genome scan performed by deCODEme). Over the last three years around 400 of these common variants have been convincingly associated with almost 80 common diseases and complex traits - everything from eye colour to prostate cancer - but each variant typically has a very small effect on disease risk, usually increasing it by 10-70% above baseline risk. That means that the results of a modern genome scan are very different to the clear-cut diagnostic genetic tests that clinicians are most familiar with: instead of telling a patient that they will almost certainly contract a serious, rare disease, clinicians are faced with a series of fuzzy probabilities: a lifetime risk of type 2 diabetes of 27% compared to the population average of 22%, for example. 

The task of sorting clinically relevant information from statistical noise is daunting even for experts - let alone for GPs, lacking any training in modern genomics, who might have a 10 or 15 minute consultation to reassure a bewildered patient. In such cases the temptation must be strong to simply shrug their shoulders, tell the patient that the whole lot is garbage, and get back to the business of treating patients with actual diseases.

Yet to do so would be a grave mistake. Even current genome scans can yield clinically valuable data regarding the risk of some diseases, such as Alzheimer's, or the risk of adverse reactions to drugs like warfarin. But it's also crucial to note that current genome scans represent just our first feeble steps into the world of predictive health genetics: in less than five years large-scale DNA sequencing will be cheap enough for whole-genome sequencing to become routine, and during that time our understanding of the genetic basis of common diseases will continue to grow exponentially. If individual doctors - and the medical establishment as a whole - fail to adapt quickly to the approaching genomic era then patients will miss out on the substantial benefits of genomic medicine.

The only possible solution is intensive clinician education: both incorporating genomic knowledge deeply into medical degrees, and offering continuing education to practising doctors. Of course it's hard to teach about a field that is developing so rapidly, and Henderson notes that course material will need to be broad and flexible: 

Personal genomics is in its infancy, and with new discoveries emerging all the time, we cannot yet know the detail of what tomorrow's doctors will need to know. They do not need to learn about every variant that has been linked to a disease risk or drug response: that knowledge remains incomplete, and it can always be looked up. What they do require, however, is an appreciation of how genetic discoveries are likely to become integrated into medical practice, and basic skills to make the most of them. In other words, doctors won't need to memorise the fact that the T version of variant rs7903146 is associated with type 2 diabetes; but they will need to know the difference between a SNP and a CNV, or between a genome scan and a genome sequence. They will need to become familiar with the terminology and interpretation of probabilistic genetic risk estimates and with the use of available online resources.

There is genuine urgency here. Right now it is a simple fact that 23andMe explains the implications of a genome scan far more accurately than the vast majority of clinicians ever could, a fact that makes many of the lamentations of the medical establishment about the dangers of direct-to-consumer genomics (at least at the high end of the market, i.e. 23andMe and deCODEme) seem rather absurd. If clinicians want to re-establish their centrality in the era of genomic medicine they have a lot of catching up to do - and they need to do it fast.