Genetic Future

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.

Read the comments on this post...

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:

Read the rest of this post... | Read the comments on this post...

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:

Read the rest of this post... | Read the comments on this post...

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.

Subscribe to Genetic Future

Follow Daniel on Twitter

Read the comments on this post...

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:

Read the rest of this post... | Read the comments on this post...

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.

Read the rest of this post... | Read the comments on this post...

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.

Subscribe to Genetic Future.

Follow Daniel on Twitter

Read the comments on this post...

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.

Subscribe to Genetic Future.

Follow Daniel on Twitter

Read the comments on this post...

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).

Subscribe to Genetic Future.

Follow Daniel on Twitter

Read the comments on this post...

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:

Read the rest of this post... | Read the comments on this post...

New players in sequencing debut at AGBT

Sun, 28 Feb 2010 11:00:00 -0500

The main theme of this year's Advances in Genome Biology and Technology meeting should come as no surprise to regular readers: sequencing. Generating as many bases of DNA sequence as quickly, cheaply and accurately as possible is the goal of the moment, and the number of companies jostling to achieve that goal is growing rapidly.

The meeting saw impressive performances from established players in the field, especially Illumina: their new HiSeq 2000 instrument seems to have dug in as the platform of choice for generating vast amounts of high-quality short-read data. Life Technologies seem to be slowly abandoning the research genomics market (already dominated by Illumina) with their SOLiD platform, focusing instead on capturing the clinical sequencing market; they showed some impressive accuracy improvements for their technology.

As I mentioned in my previous post, PacBio largely underwhelmed the audience with their theatrical unveiling of a massive box with quite limited applications, although we'll have to wait and see how much its specifications improve over the next couple of years. Meanwhile, Complete Genomics gave an understated but seriously impressive series of presentations on their human genome sequencing service; I'll have more on them in a day or two.

Anyway, in this post I want to focus on the two brand new platforms announced in the emerging technologies session on the last day of the conference: the newcomer Ion Torrent, and Life Technologies' futuristic quantum dot technology.

Read the rest of this post... | Read the comments on this post...

Pacific Biosciences introduces new third-generation sequencing instrument at AGBT

Fri, 26 Feb 2010 17:15:00 -0500

Stephen Turner from Pacific Biosciences gave a dramatic presentation this afternoon launching PacBio's new third-generation sequencing instrument. The room was packed for the seminar, with a palpable buzz, and Turner's presentation was preceded by a theatrical introduction from PacBio CEO Hugh Martin.

The crescendo of Turner's presentation was the unveiling of a video showing the new (and enormous) PacBio instrument, which has been tucked away in a room here at AGBT and revealed to a trickle of VIPs (including Bio-IT World's Kevin Davies) - if that's the kind of thing you're into, PacBio has just released a high-resolution photo of the machine online (see thumbnail left).

The presentation was overall impressive, but light on numbers - and in question time Turner was almost comically evasive on the issue of error rates (more on this below). No doubt Luke Jostins will have some more technical details online soon, but here are my initial thoughts:

Read the rest of this post... | Read the comments on this post...

Belated news from AGBT

Fri, 26 Feb 2010 13:45:00 -0500

I've been remiss in blogging from the Advances in Genome Biology and Technology meeting here in Marco Island, Florida, primarily due to some panic-stricken last-minute changes to the slides for my own presentation last night.

Fortunately the conference has been extremely well-covered by others: Sanger colleague Luke Jostins has blog posts up summarising day 1 and day 2 of the meeting; Dan Koboldt from MassGenomics has his first impressions and a review of the cancer genomics session; and Anthony Fejes is continuing the tradition of publishing extensive notes on every talk he attends.

There have been some great presentations outlining both developments in genomic technology (read: next-generation sequencing) and applications of those technologies to biomedical research. A major highlight for me has been a number of presentations on exome sequencing (capturing and sequencing all of the protein-coding regions of the genome), especially Debbie Nickerson's impressive outline of her group's work using this technology to hunt down mutations underlying rare, severe Mendelian diseases, and her plans to apply the technology to over 7,000 samples over the next year to explore the genetic origins of more complex traits.

Exome sequencing is the technology of the moment because it provides access to the best-characterised functional regions of the genome at a substantially lower cost than whole-genome sequencing. However, it is not without its drawbacks: capture methods are still far from perfect, resulting in uneven coverage across the genome and resulting difficulties for downstream analysis, and of course the approach will miss any variants found outside coding regions.

Several speakers discussed cost-benefit analyses comparing exome sequencing with whole-genome sequencing; it's clear that this is a technology with a very limited lifespan (perhaps as little as twelve months) before sequencing costs drop to the point that whole-genome analysis is more cost-effective.

As always, much of the most interesting material at this meeting has been found outside the sessions, in the buzz and hype surrounding the increasingly crowded field of next-generation sequencing.

Read the rest of this post... | Read the comments on this post...

Complete Genomics announces 500 genomes in the pipeline

Mon, 22 Feb 2010 15:45:00 -0500

I'll be at the Advances in Genome Biology and Technology meeting in Marco Island, Florida for the next week, soaking up sun and genomics, keeping my eye out for the anticipated major announcements from sequencing companies and researchers, and quietly panicking about my presentation on Thursday. You'll hear more about the meeting from me and the other bloggers there - Luke Jostins, David Dooling, Dan Koboldt and Anthony Fejes - over the next week.

It's amazing to think that it was at the same meeting in 2009 - just one year ago - that Complete Genomics emerged dramatically from stealth mode, announcing results from its first human genome sequence. The company has had a fairly impressive year since: despite delays in obtaining funding due to the economic situation the company successfully pulled in $45 million last August to fund the construction of its new sequencing facility, and published a Science paper on analysis of their first three genomes.

Now, on the eve of the meeting, the company has announced that it has orders booked for 500 more complete genome sequences. The press release also notes that the company successfully churned out a total of 50 sequences in 2009 for more than 10 customers.

These are impressive numbers for a company whose technology and business model - a unique "genome factory" approach in which its technology is deployed only in its own custom-built facilities rather than sold to genome facilities - were regarded with profound skepticism by many researchers in the AGBT audience last year. Will the company be able to meet its stated target of 10,000 genomes (oops, I mean 5,000 genomes) this year? We'll see.

Anyway, I'm looking forward to seeing what else the company has to say in the presentation by its CSO Rade Drmanac on Saturday.

Subscribe to Genetic Future.

Follow Daniel on Twitter

Read the comments on this post...

The place to be on April 27th: the Genomes Environments Traits (GET) Conference

Thu, 18 Feb 2010 11:30:00 -0500

The Genomes Environments Traits conference in Boston is without a doubt the place to be on April 27th for anyone interested in personal genomics: the conference has managed to attract nearly every human being in the world who has had their complete genome sequenced (excluding, of course, anonymous participants in the 1000 Genomes Project and various cancer studies), as well as an impressive list of luminaries from the field.

Wired describes the meeting as "The First and Last Meeting of Everyone with a Fully Sequenced Genome", and while that's a little hyperbolic (the twice-sequenced anonymous Nigerian NA18507, for instance, will be notable in his absence!), this will indeed be a unique opportunity to hear about the experience of obtaining a full picture of one's genetic material right at the very beginning of the genomic revolution.

Tickets are $999, but proceeds go to the Personal Genome Project, a worthy cause. Attendance is limited to 200 participants, and I suspect you'd need to book pretty quickly to be assured a slot.

Unfortunately I won't be able to attend myself, but I'll be keeping a jealous eye on the Twitter buzz and watching out for the promised webcasts.

Here's more about the conference from the press release:

Read the rest of this post... | Read the comments on this post...