Tag Archive for 'personal genomics'

Learning more from your 23andMe results with Imputation

PeterAndEliana This is a guest post by Peter Cheng and Eliana Hechter from the University of California, Berkeley.

Suppose that you’ve had your DNA genotyped by 23andMe or some other DTC genetic testing company. Then an article shows up in your morning newspaper or journal (like this one) and suddenly there’s an additional variant you want to know about. You check your raw genotypes file to see if the variant is present on the chip, but it isn’t! So what next? [Note: the most recent 23andMe chip does include this variant, although older versions of their chip do not.]

Genotype imputation is a process used for predicting, or “imputing”, genotypes that are not assayed by a genotyping chip. The process compares the genotyped data from a chip (e.g. your 23andMe results) with a reference panel of genomes (supplied by big genome projects like the 1000 Genomes or HapMap projects) in order to make predictions about variants that aren’t on the chip. If you want a technical review of imputation (and the program IMPUTE in particular), we recommend Marchini & Howie’s 2010 Nature Reviews Genetics article. However, the following figure provides an intuitive understanding of the process.

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Response to “Exaggerations and errors in the promotion of genetic ancestry testing”


Following the Genomes Unzipped post entitled “Exaggerations and errors in the promotion of genetic ancestry testing”, we received a request to reply from Jim Wilson. Jim Wilson is the chief scientist of BritainsDNA. He is not the one who gave the BBC interview that prompted the Genomes Unzipped post but he is a key contributor to the science behind BritainsDNA. We are keen to tell both sides of this story and this post is an opportunity for BritainsDNA to state their arguments and motivation. -VP

I saw Vincent Plagnol’s post here on Genomes Unzipped about the promotion of genetic ancestry testing and felt compelled to respond. While I did not give the interview that was the subject of the post, I am the chief scientist at BritainsDNA and I feel that the post was biased in presenting only one side of the story and thus misrepresenting the situation. Perhaps I can offer another perspective for readers.

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Dozens of new IBD genes, but can they predict disease?

Out in Nature this week is a paper by three Genomes Unzipped authors reporting 71 new genetic associations with inflammatory bowel disease (IBD). This breaks the record for the largest number of associations for any common disease, and includes many new and interesting biological insights that you should all go and read about in the paper itself (pay-to-access I’m afraid) or on the Sanger Institute’s website.

One thing that we did not discuss in the paper was genetic prediction of IBD (i.e. using the risk variants we have discovered to predict who will or will not develop the disease). In this post I want to outline some of the situations in which we have considered using genetic risk prediction of IBD, and discuss whether any of them would actually work in practice.

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Society and the personal genome

Victory! Those of us involved in genomics research spend a lot of time thinking about how scientific and technological developments might influence personal genomics. For instance, does the falling cost of sequencing mean that medically useful personal genomics will likely be based on sequence rather than genotype data? (Yes.)

At the Sanger Institute we’ve recently launched (along with our friends at EBI) a project to look more deeply at a question which is less often on the lips of genomics boffins: “How does genomics affect as us people, both individually and in communities?” Because of the obvious resonance with Genomes Unzipped it should come as no surprise that many of us (including myself, Daniel and Luke) have been intimately involved in this initiative.

The actual line-up of events has been diverse, and a lot of fun. We’ve had two excellent debates, including one between Ewan Birney and Paul Flicek (pictured) on the value, or lack thereof, of celebrity genomes (covered in more detail here). A poet, Fiona Sampson, spent some time on campus and we’ve commissioned a book of poetry from her. This one raised some eyebrows, but I have to say that talking to her has given me some brand new ways of thinking about my own work. We’re also working on a more interactive project in the hope of making personal genomics a bit more personal. Stay tuned.

Identical twins usually do not die from the same thing

Over at Nature News, Erika Check Hayden has a post about a recent Science Translational Medicine paper by Bert Vogelstein and colleages looking at the potential predictive power of genetics. The take-home message from the study (or at least the message that has been taken home by, e.g., this NYT article) is that DNA does not perfectly determine which disease or diseases you may get in the future. This take home message is true, and to me relatively obvious (in the same way that smoking doesn’t perfectly determine lung cancer, or body weight and dietary health doesn’t perfectly determine diabetes status).

A lot of researchers have had a pretty negative reaction to this paper (see Erika’s storify of the twitter coverage). There are lots of legitimate criticism (see Erika’s post for details), but to be honest I suspect that a lot of this is a mixture of indignation and sour grapes that this paper, a not particularly original or particularly well done attempt to answer a question that many other people have answered before, got so much press (including a feature in the NYT). A very large number of people have tried to quantify the potential predictive power of genetics for a number of years – why was there no news feature for me and Jeff, or David Clayton, or Naomi Wray and Peter Visccher, or any of the other large number of stat-gen folks who have been doing exactly these studies for years. ANGER RISING and so forth.

But of course, the reason is relatively obvious. Continue reading ‘Identical twins usually do not die from the same thing’

Making sequencing simpler with nanopores

The Advances in Genome Biology and Technology (AGBT) conference, one of the main go-to destinations for those who get excited by DNA sequencing technology, is currently going down in Florida. Sadly, no-one from GNZ could make it this year, but we are keeping up with the various announcements about new genomics tech as best we can. One that caught our attention was the announcement of a brand new sequencing machine from a company that has previously kept very quiet about its technology.

Oxford Nanopore, who we have written about before, today announced two new sequencing machines to come out this year. The announcement has caused quite a buzz amoungst, well, everyone. Nature, New Scientist, GenomeWeb, BioIT World and Forbes all have reported on it, and bloggers Nick Loman and Keith Robison have also had a chance to talk to some of the Oxford Nanopore peeps about their new toys.

A lot of the interest has come from the (very cool) MinION, a tiny, disposable USB-key sequencer (shown in the picture above) that can sequence about a billion base pairs of DNA, and cost around $500-$900 each. The applications of this are endless – the ability to pick up a bit of biological matter, mix it with a few chemicals, and read whatever DNA is in it, could help with diagnostics, epidemiology, ecology, forensics. It is also (though not quite) the price where hobbyists could consider having a play; perhaps in a few years plug-and-play DIY genetics could be a possibility.

Less immediately striking, but still just as interesting, is the GridION sequencing machine. This is the work-horse of the nanopore sequencing world, made for reading lots of DNA, and scaling up to massive sequencing centers. Obviously, many scientists are going to be very interested in many of the features (notably, the ability to read very long pieces of DNA, a trick that has previously been more-or-less impossible to do reliably). However, what will this announcement mean for those of us who are interested in personal genomics?

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Direct-to-consumer genetic test results in a clinical setting: a case report

Dr Neeta Tailor is an anaesthetist working at the Royal Gwent Hospital in Wales. Dr Tailor recently treated a friend of Genomes Unzipped members (referred to here as Patient X) who required emergency surgery following some unusual and fairly horrible complications (believe me, I’ve seen the photos!) from wisdom tooth removal. The remarkable thing about this case: prior to surgery the patient volunteered information about her potential drug responses based on her 23andMe profile, including variation in one gene that could have had a profound effect on her response to a standard muscle relaxant. Dr Tailor kindly agreed to write up her experience in this guest post.

For those interested in the genetic details: Patient X’s 23andMe results suggest she is heterozygous for the rs1799807 SNP, which induces an aspartate to glycine change in the BCHE gene and is associated with a substantially prolonged apnea (loss of breathing) following administration of succinylcholine. This is one of three separate mutations in the BCHE gene tested by 23andMe. Although in this case the clinicians had already decided independently to avoid the use of succinylcholine, it’s intriguing to think about how rapidly this type of information could become useful to clinicians – and what steps will need to be taken to ensure DTC genetic testing results are trustworthy enough to justify their consideration in this kind of emergency setting. [DM]

Anaesthesia is classically described as the pharmacologically induced triad of amnesia (memory loss), analgesia (pain reduction) and the loss of muscle reflexes. Patients usually come across anaesthetists during their pre-operative anaesthetic assessment; we are the ones telling you that our job is to pop you off to sleep, although it is usually more complicated than that!

The patient described below works in the world of genetics and invited me to describe her case in order to illustrate how pharmacogenomics and person specific genetic characteristics may affect the choice of general anaesthesia.

A 37 year old woman (Patient X) was booked onto the emergency theatre list on a Sunday morning. The planned operation was incision and drainage of an infected haematoma in the cheek, an unusual complication which had developed quickly over 48 hours following the extraction of a wisdom tooth by her own dentist. By the time she was admitted to hospital, she had extensive facial swelling, not just of her gum, but also the whole of the left side of her face from her forehead to her neck. In addition, she had reduced jaw movement, as well as limited mouth opening of less than one finger breadth. She was also feeling quite unwell having vomited during the night and her blood tests showed raised markers of infection. She was in pain requiring several different types of analgesia.

This presentation in itself poses some difficulty. One of our jobs as anaesthetists involves administering drugs to cause unconsciousness which subsequently requires maintenance of a patent airway using either a mask, an airway device that sits above the vocal cords, or by a tube in the trachea. We usually then maintain unconsciousness using an inhaled volatile anaesthetic via the chosen device.

During this operation we knew we were going to need to share the airway with our maxillo-facial surgery colleagues performing the procedure. To ensure the optimal outcome for all (an anaesthetised patient for us and access to the mouth for the maxfax team), a tube in the trachea was the most ideal option. However, to get to the trachea, we have to get in the mouth and get a good view of the vocal cords and this is where the potential problem could arise.
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A case study in personal genomics

I have no strong family history of any disease, despite having 7 blood aunts and uncles and countless cousins. So when I sent my spit off to 23andMe at the start of the Genomes Unzipped project, I was expecting something very similar to Caroline’s experience: a 5% increase in risk here, a 2% decrease in risk there, nothing that would really tell my anything about my health.

However, this was not my experience. Along with a pretty interesting Y haplogroup, I also had three unexpected and potentially worrying health results. I am a cystic fibrosis carrier, a hemochromatosis compound heterozygote, and have a strongly elevated risk of age-related macular degeneration. This cocktail of genetic disease certainly was not what I came to the test expecting!

After some thinking, I decided to take my test results to my GP, and see if there was any advice or testing he would recommend. In the end, my GP referred me to a clinical geneticist, which started a cascade of appointments which in turn led to a number of important changes in how I treat my own health.

What was most interesting is how the whole experience got me thinking about my health as something I am in charge of. I have since made a number of important life-style changes, some of them directly related to my genotyping results, some more generally to improve my overall health.

The point of this post is just to go through some of the experiences, what I have learned about specific conditions, and what changes I have made to my life since. In some sense, I feel like my experience is a case-study in what good outcomes can come from personal genomics, both for specific conditions, and more generally for how genetic data can change your own approach to your health.

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Cracking non-coding variation, carrying cystic fibrosis, and more Alzheimer’s prediction

Daniel and Luke attended the Biology of Genomes conference at Cold Spring Harbour last week. The talks did not have a huge amount of direct relevance to personal genomics, but did show some real quantum leaps in understanding the function of the non-coding DNA that makes up most of our genomes. Understanding mutations that lie outside of coding DNA is largely a prerequisite for transitioning to whole-genome sequencing for personal genomics, as most of the variation that drives genetic differences between people appears to lie there. As we’ve said before, one of the powerful aspects of sequencing is that it allows you to get at the aspects of your DNA that are unique to you, but that is only really useful (and a lot cooler) if we know what this unique variation does. Biology of Genomes showed us that that dream is closer now than it has ever been before.

For a (somewhat technical) account of some of the conference talks, you can read Luke’s blog posts over at Genetic Inference (along with a signficiantly less technical post about chipmunks and wood cabins), and Matthew Herper has a lay-friendly post on his Forbes blog. As has become standard, Twitter was an important way of disseminating knowledge live during talks, and Keith Bradnam and EpiExperts wrote about this aspect. [LJ]

Since GNZ started, Luke has actually been holding back writing about his many and varied genomics woes, and his resulting quest for bodily health, mostly for lack of time. However, one part of this has leaked out somewhat: he has recently given an interview to fellow blogger Elaine Westwick about being one of the two cystic fibrosis carriers in Genomes Unzipped. Read the interview at Elaine’s blog The Stuff of Life. [LJ]

On a similar subject to our recent post about calculating Alzheimer’s risk, over at Genomics Law Report Dan has written a detailed post about the regulatory challenges ahead for both direct-to-consumer and clinical tests for Alzheimer’s. [LJ]

Last chance to submit comments to the FDA about DTC genetics

Today is the last day to submit comments to the FDA about the future of regulation of direct-to-consumer genetic testing, and, by extension, the future of personal genomics. I would strongly urge anyone reading this blog to submit a comment; the FDA needs to hear the full diversity of opinions and facts on this subject to make an informed decision.

Have you or your family taken a DTC genetic test, and can explain your experiences, either positive or negative? Are you a scientist working on human genetics and have thoughts about the scientific merits of the tests? Are you a clinician, and have insights into how individual’s having direct access to their own genetic information will effect your practice? Are you an ethicist, social scientist or public health professional with opinions about the rights of individuals to access their genetic data, or the impacts such access will have on society or public health? Write a hundred words or so and submit them to the FDA.

You can submit comments via this form; remember, today is the last day before comments close. You can see the comments that have already been submitted here.

For more coverage on this round of comments, see posts by Dan, Daniel and Razib. You may also like to reread our consensus statement about the FDA’s recent investigations.

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