November 20, 2008
Category: disease genetics
At Gene Expression, p-ter points to two studies in this week's New England Journal of Medicine examining the predictive value of known genetic markers for type 2 diabetes.
Both studies find the additional predictive power of the genetic markers beyond traditional predictors (like age, sex, family history, body-mass index, fasting glucose levels, systolic blood pressure, high-density lipoprotein cholesterol levels, and serum triglyceride levels) to be extremely small, to the point of complete clinical insignificance. Thus while massive genome-wide association studies for T2D have been informative in terms of uncovering the molecular pathways underlying the disease, they haven't yet yielded much of value in terms of individual risk prediction.
As p-ter notes, this result is quite unsurprising given the small fraction of the overall risk variance explained by these markers, but it's still important to quantitate the extent of the disappointment...
One small ray of hope: one of the articles notes that "[t]he discriminative power of genetic risk factors improved with an increasing duration of follow-up, whereas that of clinical risk factors decreased". In other words, genetic information increases in value relative to clinical predictors when there is a long time lag between testing and disease onset - again unsurprising given that clinical variables change over time while genetic risk factors are fixed, but still important to bear in mind. This suggests that genetic information will be most valuable to clinicians for predicting the risk of adult-onset diseases in children, or predicting the risk of late-onset diseases in adults.
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Posted by Daniel MacArthur at 12:15 PM • 1 Comments
Category: personal genomics
Pharmacogenomics Reporter (subscription required) describes an intriguing twist in the ongoing struggle between the nascent personal genomics industry and regulatory bodies: apparently the FDA is exploring the possibility of collaborating with consumer genomics providers to track adverse drug reactions:
Lawrence Lesko, director of FDA's Office of Clinical Pharmacology, said the agency has already begun preliminary discussions with some undisclosed personal genomics firms "to evaluate the feasibility" of forging such alliances.
In marketing ancestry and disease-predisposition genetic testing services directly to consumers, personal genomics companies are building large electronic databases of clinical and genomic information that the FDA believes can be useful in tracking adverse drug reactions in a post-marketing setting.
The major advantage of the databases accumulated by personal genomics providers, of course, is that you can immediately look for common genetic variants associated with variation in the risk for any newly identified adverse response:
Read on »
Posted by Daniel MacArthur at 6:40 AM • 6 Comments
November 19, 2008
Category:
A
Nature News article describes the growing availability of technology that allows the screening of human embryos for hundreds of different genetic disorders prior to implantation.
The technology is based on the same type of chips used by personal genomics companies like 23andMe, but the chips used for embryo screening would initially be used to target known rare disease-causing mutations or large chromosomal abnormalities rather than performing a genome-wide scan for common variants (in the article, a screening company director describes the targeted diseases as "nasty, early-onset and ethically uncomplicated"). Such testing is generally accepted by Western society, as witnessed by the
extremely high rate of termination of trisomy 21 embryos.
However, the article also notes that there's currently nothing to stop companies from including variants on the chips that provide information about adult-onset diseases like diabetes or Alzheimers - indeed, in the UK there have already been embryos screened for breast cancer risk variants. This type of screening currently raises some serious ethical eyebrows, but perhaps not for long: the article argues that "as the technology advances, consumer demand is likely to overwhelm societal ethical qualms" - and I'd tend to agree, in general.
However, before we get too carried away by visions of a Gattaca-style future, it's worth noting a couple of serious obstacles in the path of widespread adoption of the use of this technology to screen for common disease genes.
Read on »
Posted by Daniel MacArthur at 6:49 PM • 3 Comments
November 18, 2008
Category:
A Nature News article discusses the ongoing 1000 Genomes Project, an international effort planning to sequence 1,200-1,500 human genomes. The discussion springs from project co-chair David Altshuler's update at last week's American Society of Human Genetics meeting on the progress of the project (in brief: 3.8 terabases down, 996.2 terabases to go).
The article provides a generally positive overview of the project's historical context, goals and progress. The one contrary note comes from Duke University's David Goldstein, who has previously publicly expressed skepticism regarding the value of much of the data currently emerging from genome-wide association studies looking for common variants underlying common disease risk. Goldstein is also wary about over-stating the importance of the 1000 Genomes data:
Read on »
Posted by Daniel MacArthur at 11:18 AM • 0 Comments
November 15, 2008
Category: genetic ancestry testing
Blaine Bettinger at the Genetic Genealogist has an extensive and thoughtful critique of the American Society of Human Genetics' recently released statement on genetic ancestry testing (pdf). (You can read about the Society's statement at GenomeWeb News and Science Now; 23andMe also comments from the point of view of a company engaged in ancestry testing.)
If you have comments on the issues surrounding genetic ancestry testing I'd encourage you to add them to Blaine's post.
Posted by Daniel MacArthur at 9:41 AM • 0 Comments
November 14, 2008
Category: 1000 genomes project • whole-genome sequencing
Last week I posted on the publication of three papers in Nature describing whole-genome sequencing using next-generation technology: one African genome, one Asian genome, and two genomes from a female cancer patient (one from her cancer cells and one from healthy skin tissue). At the end of that post I noted that the era of the single-genome publication is drawing to a close as the age of population genomics commences.
Today GenomeWeb News reports from the American Society of Human Genetics meeting on the biggest current foray into the field of population genomics: the 1000 Genomes Project. The project aims to sequence somewhere between 1,200 and 1,500 whole genomes at low coverage (sequencing each base an average of 2 to 4 times), providing a powerful catalogue of human genetic variation extending down into the variants below 1% in frequency.
At ASHG, David Altshuler announced the near-completion of three pilot projects for the 1KG project and the generation thus far of 3.8 terabases (that's 3.8 million million bases) of sequence data. Over the last two months, according to GenomeWeb News, "the team deposited as much data each week as was present in GenBank when the effort began". That's a mind-boggling amount of data, and an indicator of the staggering volumes of data still to come: in 2009 the project is expected to generate about 250 times that volume of sequence.
The hard part of human genomics - linking sequence variation to disease risk and other traits - is still to come, but the 1KG project (as Brendan Maher calls it) will pave the way for these difficult experiments, both by creating a map of human genetic variation and by driving the development of the tools required for large-scale human genome sequencing. Exciting times...
Posted by Daniel MacArthur at 2:18 PM • 0 Comments
November 11, 2008
Category: personal genomics
Reports in Australian papers
the Age and
the Brisbane Times note the impending arrival of a newcomer to the personal genomics scene:
Lumigenix, a home-grown offering cooked up by Sydney entrepreneur Romain Bonjean.
The new arrival will face several major obstacles to establishing itself in the market. Firstly, 23andMe has been offering its well-established and well-publicised service in Australia since October 3rd (announced on Twitter). There's no obvious home-ground advantage for an industry where the service requires only a postal address and an internet connection, so Lumigenix will have to compete on an even playing field - and that's a tough ask against an outfit as slick, professional and experienced as 23andMe. (At AU$700 = US$470, the Lumigenix test will be slightly more expensive than 23andMe's US$399 offering.)
But perhaps more importantly, the regulatory environment in Australia is fairly forbidding for direct-to-consumer (DTC) genetic testing, especially compared to the relatively open US situation. Both articles note ominously that the Australian government actually looks set to institute a complete ban on DTC genetic testing in the not-too-distant future:
The federal bureaucracy is preparing laws for late next year -- or possibly the year after -- that will prohibit access to home use and direct-to-consumer genetic tests. The Therapeutic Goods Administration has government approval to proceed, and draft legislation is on the way.
The central argument is that any "in vitro diagnostic device" -- which includes a website designed to interpret your DNA -- that is used to diagnose a disease or test for susceptibility to disease must be in a clinical setting to ensure high-quality health care.
Both articles also quote Professor Ron Trent from Sydney University laying down the traditional line on DTC genetic testing:
"They are right, it is the future of medicine -- but it's got to be used appropriately," he says. "These companies are allowing medical professionals to be bypassed. It's all very well for them to advise you to get genetic counselling (afterwards), but the (test) results have very important repercussions for your health and the health of your children, brothers and sisters. DNA tests must be accompanied by the appropriate advice from a health professional." [my emphasis]
Neither article mentions that Trent chairs a high-level committee advising the Australian government on human genetics. If this is the sort of opinion the government is hearing from its expert advisers, that doesn't bode well for personal genomics companies looking to provide unfettered access for customers to their own genetic data.
Fortunately the article in The Age also presents an opposing viewpoint, from respected geneticist and notable contrarian Bob Williamson:
He believes the medical establishment is too uptight about giving people unfettered access to their genetic codes. "In the long run, honest information empowers people to make the right choices, while ignorance disempowers people," he says.
[...]
"Doctors underestimate the extent to which people are able to understand complex concepts when applied to their own health and their own lives," he says. "Many people are used to dealing with probabilities when it comes to breast cancer or lung cancer, which are partly genetic and partly environmental. You don't need it explained by a medical professional on every occasion."
Needless to say I find Williamson's argument more convincing than Trent's. My position is that allowing people free access to information about themselves should always be the default position, unless there is strong evidence to show that doing so will result in harm. At this stage there are no compelling data demonstrating that personal genomic data is likely to cause serious harm to customers, so it's premature for regulators to shut access to the industry down.
By all means governments should introduce minimal standards to help filter out amateurish DTC genetic testing outfits (like, say, Gene Essence); but a complete ban on DTC genetic testing would be an outrageous, paternalistic and unjustified violation of the freedom of consumers to access their own genetic information.
As for Lumigenix, it remains to be seen whether this venture will succeed in the face of rigorous competition, over-zealous regulation, and an economic slowdown that will likely seriously punish sales of "luxury" goods like genome scans - but I'd say the odds aren't good.
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Posted by Daniel MacArthur at 9:22 AM • 1 Comments
November 10, 2008
Category: genome-wide scans for selection
Note: I'm introducing Do It Yourself as a new and hopefully semi-regular section on Genetic Future. The aim is to provide readers with instructions on how to access online resources for sequence analysis - an activity traditionally restricted to researchers, but one that will no doubt become more common as more and more people begin to access and interpret their own genetic data.
In this post I'll introduce the brand new HGDP Selection Browser, a tool for exploring traces of recent positive selection in the human genome produced by researchers at the University of Chicago.
Introduction: the traces of positive selection in the human genome
Over the last 50-100,000 years the human species has successfully spread from its African homeland to colonise nearly every corner of the globe, including environments ranging from desert to tundra. Adaptation to these diverse environments, along with major dietary changes, rapid population growth and exposure to a range of novel infectious diseases, has left its mark on the human genome. Essentially, all of us carry a molecular record of our ancestors' adaptation - and with the recent growth of databases of human genetic variation, we can actually determine (albeit imperfectly) which genes played a role in this process.
Genetic variants that offer a benefit to the individuals who carry them - such that they have, on average, more surviving offspring than non-carriers - will tend to increase in frequency in a population through positive natural selection. This relatively rapid increase in frequency has a substantial impact on the region of the genome immediately around the selected variant, resulting in what's known as a "selective sweep": a local reduction in genetic diversity, and an elevation of long-range linkage disequilibrium.
(You can think of these signatures as being a consequence of a selected variant being younger (on average) than a neutral region at the same frequency, due to its rapid increase in frequency. The low genetic diversity and high linkage disequilibrium result from the fact that there hasn't been much time for mutation and recombination, respectively, to act on the section of the genome closely linked to the selected variant.)
If the selection is restricted to just one or a few populations (due to a specific environmental pressure, or simply a lack of the beneficial variant in other populations) there will also be an increase in population differentiation in the region; in other words, in this portion of the genome, human populations will tend to look more different to one another than they do in other areas.
These classic signatures of a selective sweep have been used to hunt for genes subject to recent positive selection in humans by many groups, taking advantage of genetic variation data from the HapMap project and various other sources. The results of these analyses have been used to argue that recent human evolution has been characterised by pervasive, often population-specific positive selection, presumably resulting from the adaptation of modern humans to diverse, novel environments outside of Africa.
What's been lacking in most of these studies is analysis of a broad range of human populations - most attempts, by necessity, have been restricted to the European, East Asian and West African populations samples by the HapMap project. That's changed now with the arrival earlier in the year of data on 650,000 genetic markers (SNPs) in 938 individuals from over 50 populations, using DNA samples from the Human Genome Diversity Panel.
These genome-wide data have now been analysed for various signatures of recent selection by a team at the University of Chicago - and while the publication isn't out yet, the team has generously made their data available through a nifty online browser. It's worth noting that the same group previously produced the Haplotter browser, which allows you to examine signatures of selection in the four HapMap populations (for an introduction to Haplotter and other online resources, see the So you want to be a population geneticist? post on GNXP).
Using the HGDP Selection Browser
If you want to see if your favourite gene shows a signature of population-specific positive selection, here's how the browser works:
Read on »
Posted by Daniel MacArthur at 8:18 AM • 7 Comments
November 7, 2008
Category: personal genomics
deCODE CEO Kari Stefansson on the recent award of Time magazine's "Invention of the Year" to personal genomics competitor 23andMe:
Despite the fact that we launched our test first - so we basically invented this, and also 23andMe is using a substantial number of sequence variants that we discovered. So we feel flattered by the fact that our test was selected as the invention of the year by Time magazine. We are amused by the fact that they decided to ascribe the invention to 23andMe, probably because its founder is associated with the rich and famous.
From an article in Bio-IT World on deCODE's growing financial woes. Here's the company's stock price over the last twelve months:
I genuinely hope that deCODE manages to climb out of this particular financial pit - the loss of this company would put a major dent in the diversity of the personal genomics sector (effectively granting 23andMe a monopoly, at least temporarily) and would also be a blow to human genetics research in general. If you're unaware of just how much of the recent boom in large-scale human genetics has been due to deCODE, try a
PubMed search for "stefansson k".
Posted by Daniel MacArthur at 12:44 PM • 8 Comments
November 5, 2008
Category: personal genomics
In addition to the African and Asian genome studies I discussed in my last post, Nature's latest issue is completely dominated by the topic of personal genomics.
Erika Check Hayden has a nice piece on methods to squeeze the most out of your own personal genomic data, including a profile of the Promethease analysis tool developed by SNPedia's Mike Cariaso and Greg Lennon, which allows personal genomics customers to match their own genetic data against the SNPedia database.
Hayden also gives me my first ever mention in Nature - unfortunately, it's in the context of the unflattering comments I made about the preliminary sequence data released recently by the Personal Genome Project. While I stand by those comments (and I see that PGP leader George Church agrees with them), I do want to note that my criticism was directed purely at the quality of some early-release data, and not at the project as a whole - which I regard as an extremely important step towards the development of personalised medicine, both from a social and a scientific viewpoint. (I should also emphasise that I was expressing my own opinion and in no sense representing the views of my employer, the Wellcome Trust Sanger Institute).
Moving on, Nature also has a fascinating and timely article on the case of the missing heritability - the puzzle of why current genome-wide association studies, despite their well-publicised successes, have failed to uncover the vast majority of heritable disease risk. It's good to see this issue begin to get some serious attention: I've been noting this for a while (see why do genome-wide scans fail?), and David Goldstein raised it in the NY Times back in September, but the vast majority of coverage has focused (perhaps understandably) on the successes of the approach. The article describes several of the places where the missing genetic risk may be hiding, and the challenges of tracking it down - I'll be writing about approaches to tackle a few of these darker regions of the genome (particularly rare variants and copy number variation) over the next month or so.
There's are also articles on the issues of consent in the genome age, and on the troublesome question of what sort of regulation needs to be put in place for the personal genomics industry. These are well worth a read, although I find myself both confused and rather irritated by the latter piece - I guess there's something about the phrase "society should not succumb to fantasies about 'empowered' individuals making free, informed choices in an unregulated genomic marketplace" that just rubs me the wrong way...
Anyway, that's enough rambling from me - go read them for yourself!
Posted by Daniel MacArthur at 8:42 PM • 0 Comments
