Genetic Future

Will the Myriad gene patent decision harm innovation in genomics?

Thu, 01 Apr 2010 10:00:00 -0500

My previous post on the Myriad gene patent decision has resulted in one of the most useful and enjoyable comment threads in the history of this blog.

The debate revolves around a single, central question: while it's clear that the loss of gene-based patent protection (should the current decision be upheld by the Supreme Court) will be beneficial for companies and academic labs seeking to develop multi-gene tests - extending up to whole-genome sequencing - will these benefits come at a disastrous cost to the field as a whole by eroding financial incentives for innovation?

This outcome is being waved around by various people (Nature News' piece on the patent decision is sub-titled "Court ruling may spell bad news for biotech industry"). However, several commenters in the thread make devastating arguments against this claim, and I'm being swayed towards the idea that the concerns about stifling of innovation are overblown.

Many thanks to Dan Vorhaus, Linda Avey, Keith Grimaldi, p-ter and others for their civil and constructive comments.

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Nature special issue on genomics

Thu, 01 Apr 2010 08:15:00 -0500

If you haven't already browsed through Nature's most recent edition, do so immediately - it's packed with juicy genomic goodness.

I particularly enjoyed the brief commentaries from Francis Collins and Craig Venter, both providing retrospectives on the last decade of human genomics and predictions for the future of the field, and the neat infographic illustrating the staggering change in sequencing capacity over the last ten years - but the whole issue is well worth reading.

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Common copy number variation doesn't explain much complex disease risk - but why not?

Thu, 01 Apr 2010 00:00:01 -0500

Wellcome Trust Case Control Consortium. (2010). Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls Nature, 464 (7289), 713-720 DOI: 10.1038/nature08979

The Wellcome Trust Case Control Consortium has just published the results of a massive survey of common, large DNA duplications and deletions (collectively termed copy number variation, or CNVs) in 16,000 patients suffering from complex diseases and 3,000 controls. The results come as no surprise, but are nonetheless disappointing: the study identified absolutely no novel CNVs associated with complex disease. Although three such variants were found to alter disease susceptibility, all three had been identified from previous studies.

The study's findings suggests that - despite their size - common CNVs play very little role in the etiology of common, complex diseases like rheumatoid arthritis and type 2 diabetes, and researchers will have to look elsewhere to uncover the notorious "missing heritability" for these diseases.

The result shouldn't come as a shock: the major conclusions of this study were presaged by a paper published in Nature late last year (and led by colleagues at the Sanger Institute). This earlier study, using far fewer samples, showed that most common CNVs are well "tagged" by nearby single nucleotide polymorphisms (SNPs), suggesting that any with substantial effects of common CNVs on disease risk would likely have been picked up by earlier SNP-based genome-wide association studies. It also showed that despite this tagging only a handful of common CNVs could be found that were correlated with known disease-associated SNPs.

The authors of the earlier paper thus concluded:

[...] CNV could only explain a small minority of the disease risk already accounted for existing GWAS studies, let alone the larger (for most diseases) bulk of 'missing' heritability that remains unaccounted for [...]

The new results from the WTCCC should thus really be viewed as extremely large-scale validation of a known negative result, confirming an already-suspected limited role for common CNVs in complex disease susceptibility.

So, no real surprises here. But still, an obvious question remains: why don't common CNVs play a major role in complex disease susceptibility?

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"Jaw-dropping" verdict against Myriad in BRCA patent case

Tue, 30 Mar 2010 05:58:33 -0500

One of the major potential stumbling blocks for the field of genome-based diagnostics - particularly as we begin to move into the whole-genome sequencing era - is the unresolved issue of gene patents.

Currently somewhere in the order of 20% of the protein-coding genes in the human genome are covered by some kind of patent protection. However, the legal status of gene patents remains contentious.

Yesterday's astonishing defeat of Myriad Genetics in an ACLU-led case before a United States District Court is unexpected, and potentially a positive outcome for companies seeking to offer large-scale genome-based diagnostics. The decision invalidates patents held by Myriad on the BRCA1 and BRCA2 genes, mutations in which are associated with increased risk of breast and ovarian cancers, and casts doubt on the validity of thousands of gene patents.

As you might expect, the place to go for expert coverage and analysis of the decision is Genomics Law Report. GLR has already posted some initial thoughts on the case from Dan Vorhaus, followed by a superb and thorough analysis by Dan and colleague John Conley.

The take-home message: this is a truly astonishing victory for critics of gene patents, but the full implications are yet to become clear. Myriad still has room for appeal, and the legal scope of the case is limited. Vorhaus and Conley argue that the decision should be viewed as just one part of a much larger battle:

In the broader policy debate surrounding gene and biotechnology patents, however, this decision is the latest, unmistakable shot across the bow of gene patent holders, particularly those such as Myriad Genetics that have developed businesses around patent-protected genetic tests supported by exclusive rights in underlying gene patents. As we wrote last summer, and as the SACGHS report pointed out in detail, there is a coming crisis at the intersection of multiplex genetic testing and whole-genome sequencing and biotechnology patents, particularly gene patents. This decision is sure to intensify the public policy discussion surrounding the appropriateness of gene patents, and ratchet up the media and public attention paid to the issue.

If the decision is upheld it seems likely to be a strong positive for companies like 23andMe and Counsyl, who offer multi-gene scans for genetic variants associated with diseases and other traits, as well as for academic diagnostic labs. It's also good news (at least in the short term) for those of us interested in affordable personal genomics. [Update: I've transiently deleted a confusing sentence here until I have enough time to actually write something coherent.]

For updates on the decision, keep an eye on Genomics Law Report and follow Dan Vorhaus on Twitter.

Added 30/03/10: See the comments below for more useful discussion, including comments by Dan Vorhaus, Keith Grimaldi and 23andMe co-founder Linda Avey.

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Further response to Camilla Long's ode to genetic ignorance

Tue, 23 Mar 2010 13:15:00 -0500

Earlier this month I wrote a post skewering a terrible opinion piece about personal genomics in the Sunday Times by Camilla Long. This was my conclusion:

If Long wishes to stay ignorant of her own genetic risks - just as she has managed to remain ignorant of the entire field of genetics, even while writing an op-ed piece about it - that should be her choice. But her criticism of others who choose to pursue a greater understanding of their own genetic risk is entirely, horrendously misplaced.

Dan Vorhaus from Genomics Law Report was equally disgusted by the piece. While we were unsuccessful in getting a formal response published as a letter in last weekend's Sunday Times [added 01/04/10: a heavily-edited version of our letter has now been published], we've now penned a combined rebuttal to Long's article as a post on the Times Online Science blog.

Thanks to the Times Online Science crew for kindly agreeing to host the article!

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Estimating the number of sequencers in the wild using a WWII formula

Fri, 19 Mar 2010 07:30:00 -0500

Nick Loman (of the University of Birmingham, and the Pathogens: Genes and Genomes blog) has a post updating us on his survey of second-generation sequencing machines around the world. Loman's results are also available in the format of a handy Google map (see left).

The take-home messages based on 669 machines in the database: Illumina continues to utterly dominate the second-gen market, with competing short-read platform SOLiD squabbling for scraps with Roche's 454. That's a pretty poor outcome for SOLiD, which has failed to gain traction in the market despite having the full force of Life Technologies' marketing machinery behind it.

Meanwhile, Nick has also hatched a fiendish plan to refine the estimate the number of second-gen sequencing machines in the wild, using an approach pioneered by British statisticians seeking to estimate German tank production during World War II.

The strategy is simple: by recording the serial numbers of sequencing machines and the date on which they were received, and making some assumptions (e.g. the serial numbers are in fact continuous), one can generate a probabilistic estimate of the rate at which machines are being distributed.

There are certainly a number of ways in which such estimates can prove inaccurate - but as Loman says, it's still worth doing the experiment. So if you're in charge of second-gen sequencers, add your serial numbers now.

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Francis Collins announces voluntary genetic test registry

Thu, 18 Mar 2010 13:00:00 -0500

Update: Dan Vorhaus has a brilliantly thorough post outlining the implications of the registry.

NIH Director Francis Collins has announced the creation of a voluntary registry for genetic testing services, with the details of each service being made fully available in a public database.

Much depends on the details, but if this database is done right it will be good news both for consumers and for reputable genetic testing companies. The press release states that one aim of the database is to "[e]ncourage providers of genetic tests to enhance transparency by publicly sharing information about the availability and utility of their tests" - thus providing consumers with an easier way to distinguish between accurate, useful genetic tests and contemptible bottom-feeders.

Here's the press release:

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Willful ignorance is not an effective argument against personal genomics

Sun, 14 Mar 2010 13:00:00 -0500

Camilla Long's appallingly bad op-ed piece about personal genomics in the Sunday Times is a true masterpiece of unsupported criticism, and an ode to willful ignorance.

I'd encourage readers to discover their own favourite errors and misconceptions (there are plenty to go around), but here are some of the more glaring flaws:

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On plausible alternative hypotheses

Thu, 11 Mar 2010 12:45:00 -0500

Nic Wade says something very strange in his most recent article on whole genome sequencing in reference to the outcomes of genome-wide association studies:

The results of this costly international exercise have been disappointing. About 2,000 sites on the human genome have been statistically linked with various diseases, but in many cases the sites are not inside working genes, suggesting there may be some conceptual flaw in the statistics.

Erm... or maybe many common variants affecting the risk of complex diseases simply aren't found in protein-coding regions? That's the (biologically entirely plausible) hypothesis that most complex disease geneticists are working under right now.

I'm guessing the statement is an oblique reference to the recent synthetic association paper from David Goldstein's group? If so, it's worth noting that the claims made in that paper are seriously contentious among others in the field.

I'm certainly not alone in my puzzlement here; in a comment on a previous post, p-ter also gives Wade's statement a hearty wtf.

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Celebrity genomics without the Y chromosome: Glenn Close has her genome sequenced

Thu, 11 Mar 2010 09:30:00 -0500

Zoe McDougall from Oxford Nanopore points me to a press release from Illumina announcing a new era of celebrity genomics:

Illumina, Inc. (NASDAQ:ILMN) today announced that it has sequenced the DNA of American actress Glenn Close, the first publicly named female to have her DNA sequenced to full coverage. The service was completed in Illumina's CLIA certified and CAP accredited laboratory utilizing Illumina's Genome Analyzer technology and following the established process shown at http://www.everygenome.com/. Ms. Close's DNA was sequenced to an average depth greater than 30 fold, providing information on SNP variation and allowing for the analysis of other structural characteristics of the genome such as insertions, deletions and rearrangements. Specifically, over 95% of the known genome was reported, including over 12 million genotype calls on previously documented SNPs. In addition, 379,000 SNPs previously not reported in any public database were found.

While there's nothing new about celebrity genomics, previous examples have largely been "scientific celebrities" (such as Jim Watson and Craig Venter) - so Close is the first genome with broader celebrity status, and also the first named individual without a Y chromosome to rack up her 6 billion base pairs. That's of negligible interest scientifically, but there's no doubt this will dramatically increase the public profile of whole genome sequencing.

(Added in edit: I've just been reminded by Misha Angrist that technically Close isn't the first named female to be sequenced - a press release back in May 2008 announced the sequencing of Dutch geneticist Marjolein Kriek, although we're yet to see an actual publication of those data and the quality of the sequence is unclear.)

Illumina launched its retail genome sequencing service (which requires a doctor's permission) back in June. It's not cheap - currently a whole genome will set you back a hefty $48,000 - but it's likely that prices will tumble this year as competition heats up from emerging sequencing provider Complete Genomics.

Complete doesn't offer sequencing direct to customers, but it will partner with personal genomics companies such as Knome to offer its product to high-end consumers. I have a longer article about Complete in the works, but it's worth noting that based on its recent analysis of four complete genomes it seems to have an error profile comparable with - or even better than - Illumina's technology.

Meanwhile, it looks like Illumina has bigger plans ahead for its own sequencing service:

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Disease hunting with whole genome sequences: the good news, and the bad news

Wed, 10 Mar 2010 17:00:00 -0500

Lupski, J.R., et al. (2010). Whole-genome sequencing in a patient with Charcot-Marie-Tooth neuropathy. New England Journal of Medicine advance online 10.1056/nejmoa0908094

Roach, J.C., & et al. (2010). Analysis of genetic inheritance in a family quartet by whole-genome sequencing. Science : 10.1126/science.1186802

Two new papers out today - the first ever studies to employ whole-genome sequencing for disease gene discovery - neatly illustrate both the promise and the challenges lying ahead both for clinical and personal genomics.

The first paper presents the final - and successful - outcome of geneticist James Lupski's attempt to track down the genetic basis of his own disease. Lupski suffers from a syndrome called Charcot-Marie-Tooth (CMT) disease, a neurological condition which results in muscle weakness and wasting. The paper describes the process of sifting through the thousands of potentially functional variants to eventually pin down the mutations responsible, which turn out to be in a gene that has been previously associated with CMT.

This study is a clear illustration of the power of whole-genome sequencing to cast light on a long-standing personal mystery (Lupski has been searching for his disease mutation for decades). However, Lupski was fortunate that his mutation fell within a gene that had already been demonstrated to be linked to CMT; as the second study shows, researchers hunting for entirely novel disease-causing genes face a more serious challenge.

The second paper describes a similar attempt to nail down the gene responsible for a severe disease, this time using whole genome sequencing performed by Complete Genomics on four members of a family: two siblings affected by a disease called postaxial acrofacial dysostosis (Miller syndrome), and their two unaffected parents.

Here the outcome is less unambiguously cheerful: this paper illustrates that even with complete genomes it can still be hard to pick apart the genetic origins of disease.

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State of sequencing technology in 2010

Wed, 10 Mar 2010 06:15:00 -0500

Dan Koboldt has a very nice recap of the various sequencing technologies presented at last week's Advances in Genome Biology and Technology meeting. I totally agree with his central point:

Something had been bothering me about the sequencing-company presentations this year, and I finally realized what it was. During AGBT 2009, every player was gunning to take over the world. This year it seems like every sequencing platform has a niche in mind.

The recent proliferation of sequencing technologies - each with their own characteristic profile of strengths and weaknesses - has been bewildering, especially given the excessive hype being sprayed around as companies seek to raise venture capital and drown out their competitors. However, I think Dan's right that the market is now openly segmenting as each platform seeks to find the applications that best fit its strength/weakness profile.

As one notable example, it's very clear now that the third-generation single molecule sequencing technology developed by Pacific Biosciences - originally touted as being a replacement for second-generation platforms - will be restricted to niche applications (rapid confirmation of variants discovered by another technology, and supplementing second-gen sequencing in the assembly of novel genomes) for the foreseeable future due to its low yield and high error rate.

Anyway, if you're interested in how the sequencing field is starting to play out, go and read Dan's post.

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Genetic ancestry testing: people who don't want to know

Mon, 08 Mar 2010 16:25:00 -0500

Dan Vorhaus pointed me to this review of the recent PBS series Faces of America. I haven't seen the series myself, but I found this segment of the review hilarious:

The element of the last PBS episode I found most intriguing was Gates' interview with novelist Louise Erdrich, who declined to have her DNA tested because her identity as a descendant of the Chippewa Native American tribe is so important to her. She said that she felt her tribe and family were what made her who she was. And, as she explained to Gates, she "didn't want to add any confusion to it."

Erdrich, in other words, didn't want cold, scientific facts to confuse her cherished notion of who she was, based on her assumed heritage.

It's easy to see how the routine availability of large-scale genetic testing is going to upset a lot of people.

Added in edit: I've clarified that I found the segment of the review amusing; I wasn't laughing so much at Erdrich's reluctance to get tested as at the reviewer's response to it.

In the comments, Fog also clarifies the context of Erdrich's remarks:

As for the section above, Louise Erdrich also added that she had spoken with her family members and they did not want her to find her genetic ancestry either. Gates then said something about how it's not just her own personal information to find out.

[...]

I just checked the video online (the entire series is on the PBS website) and she said she checked with her "extended family" and was told "it's not yours to give, Louise."

This comment from John Hawks (below) also makes an important point about the trade-off between individual choice and effects on broader communities:

If each person's decision were independent, that would be one thing. But what do these companies know about Chippewa ancestry? They know the genotypes of some other people who self-identify as Native American, and they'd like very much to add more self-reported people to their databanks so that they can improve their interpretive abilities. Fair enough.

But that means that every self-identified Chippewa who gives a sample helps to build the genetic picture of identity in that tribal unit. So that every person who contributes may help to *take away* the status of *other people* who self-identify and are genotyped in the *future*.

Individuals should be tested or not as they choose, my viewpoint is personal rights, not collective rights. But the effect of your test on the collective identity is a possibly negative externality of testing -- your genes help to identify others who share distant ancestry with you.

So long as people's identity and economic well-being hangs on the tenuous string of genetic clustering, angst will ensue.

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On finding folks you know: 23andMe reveals some unexpected cousins

Sun, 07 Mar 2010 16:45:00 -0500

A colleague just pointed me to an entry on Brad Templeton's blog where Templeton reveals some bizarre connections between people he has met as distant cousins via 23andMe's Relative Finder algorithm. Nothing too spooky, but a precursor of things to come if (as I hope and expect) 23andMe manages to ride out the current troubles besetting personal genomics and continue building its genetic database.

(H/T John).

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The end is nigh for 23andMe?

Thu, 04 Mar 2010 12:00:00 -0500

Over at Gene Expression, Razib suggests that trouble lies ahead for personal genomics company 23andMe. Although I'm generally a bit of a cheerleader for the Mountain View-based startup, I must admit the signs over the past year or so haven't been good: two rounds of lay-offs, the departure of co-founder Linda Avey, and the apparent deployment of $4M from a recent funding round to pay back a loan from fellow co-founder Anne Wojcicki.

Razib also notes some anonymous employee reviews of the company on GlassDoor suggesting poor morale among 23andMe workers; it's hard to make too much of these given their uncertain provenance, but one of them is well worth a read.

In an economic environment where the sorts of disposable cash required for people to invest in luxury goods like personal genomics is scarce, DTC genetic testing companies were always going to have to work hard to stay afloat - and the bankruptcy of 23andMe's competitor deCODE Genetics showed that this is no easy feat.

Razib also points to a recent entry on Avey's blog warning of an impending NY Times article by reporter Andrew Pollack that will apparently cast a very negative light on the personal genomics industry. Avey launches a pre-emptive strike on Pollack, describing his impending piece as "a desperate attempt to make some headlines" and noting a growing number of anti-personal genomics stories in the mainstream press:

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