Tag Archive for 'sequencing'

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.

Guest post by Ben Neale: Evaluating the impact of de novo coding mutation in autism

[Dr. Neale is currently an Assistant in Genetics in the Analytic and Translational Genetics Unit at Massachusetts General Hospital and Harvard Medical School and an affiliate of the Broad Institute of Harvard and MIT. Dr. Neale's research centers on statistical genetics and how to apply those methods to complex traits, with a particular focus on childhood psychiatric illness such as autism and ADHD.]

Today, in Nature, three letters (1, 2, 3) were published on the role of de novo coding mutations in the development of autism. I am lead author on one of these manuscripts, working in collaboration with the ARRA Autism Consortium. In this post, I’ll describe the main findings of our work as they relate to autism and how we approached the interpretation of de novo mutations. In essence, de novo point mutation is likely relevant to autism in ~10% of cases, but a single de novo event is not likely to be sufficient to cause autism. Underscoring this is that fewer than half of the cases had an obviously functional point mutation in the exome. However, three genes, SCN2A, KATNAL2 and CHD8 have emerged as likely candidates for contributing to autism pathogenesis.

De novo is Latin for “from the beginning,” and when describing genetic variation or mutation means that the variant has spontaneously arisen and was not inherited from either parent. In autism, de novo copy number variants are among the earliest clearly identified genetic risk factors (see Sanders et al. and Pinto et al. for reviews). Given that these events are novel, natural selection has not acted on them, except for instances where the point mutation is lethal in early life. With next generation sequencing (NGS), we now have the opportunity to identify these events directly.

In this study we explored the impact of de novo mutations on autism by performing targeted sequencing of the protein-coding regions of the genome (known collectively as the exome, and comprising just 1.5% of the genome as a whole) in 175 mother-father-child trios in which the child was diagnosed as autistic. Having sequence from all three members of each family allowed us to find mutations that had arisen spontaneously in a patient’s genome, rather than being inherited from their parents.

We have made a pre-formatted version of our manuscript available here. In this post I just wanted to highlight some of the key lessons emerging from our study.
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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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Complete Genomics to sequence 1500 whole genomes for pre-term birth study

Genome sequencing provider Complete Genomics has announced a deal with the non-profit Inova Translational Medicine Institute, under which the company would sequence 1,500 complete human genomes to help explore the genetic basis of premature birth.

The Inova collaboration is one of many large-scale genome sequencing studies currently being planned and performed around the world. In some respects the study is actually quite a small one – only 250 “cases” (i.e. premature babies) are being sequenced, along with 250 normal-term control babies, which means the researchers will have low statistical power by the standards of modern genomics. However, sequencing this number of complete genomes to high depth is (as far as I know) unprecedented, and the inclusion of the parents of all of the children in the study will provide the team with the ability to do some very interesting analyses – for instance, looking at “de novo” mutations that arise in the babies but weren’t present in either parent, as well as exploring potential effects of the maternal genome. Maternal genetics are known to be important in determining the risk of premature birth: girls born prematurely have a higher risk of delivering a pre-term baby themselves (with twin studies suggesting between 15 and 40% of the risk is heritable), while paternal genes seem to have almost no effect.
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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]

Defining a complete genome, innovative sequencers, and the mess ahead for personalised medicine

The Archon X Prize for Genomics offers a $10 million prize to to the first team that can sequence 100 human genomes within 10 days or less at a total cost of $10,000, with strict criteria for accuracy and completeness. However, given that there aren’t currently any gold standard genomes that could be used to confirm that a team has met the Prize’s requirements, and the complexity of judging the winner is far greater than for any previous award from the X Prize Foundation. To help refine the validation process, the Prize Foundation has just announced a collaboration with Nature to crowd-source ideas, which can be submitted via comments on the current plan over at Nature Precedings. If you’re interested in helping to define the state of the art in human genome construction, head over and have your say. [DM]

This week MIT’s Technology Review released this year’s TR50, a list of the 50 most innovative companies. Biomedical companies make a good showing, with 8 in total. Excitingly, three of these companies have been chosen for innovations in DNA sequencing technology; Complete Genomics, for developing the service approach to sequencing human genomes, Life Technologies for aquiring the new Ion Torrent machine, and Pacific Biosciences for their single-molecule sequencing machines. [LJ]

Over at Forbes, Matthew Herper pointed out the announcement of an exciting new targeted drug for cystic fibrosis that showed greater than expected results in clinical trials, as well as the announcement by Life Technologies of an impending upgrade to their Ion Torrent sequencing platform (also comprehensively dissected by Keith Robison here and here). This all sounds like good news, but Herper warned in a separate post that the implications of recent developments in genomics and pharmaceuticals might be heading towards a chaotic impact:
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A decade of genomics, 60 new genomes, parenthood and sharing genetic data, and more on data return

To celebrate 10 years since the back-to-back publications of complete human genomes in Science and Nature, Science has published series of articles looking back at the last 10 years of genomics, and forward to the future. The article contains short essays from Francis Collins and Craig Venter, the former talking about some of the successes of medical sequencing (including giving a name and photograph to the exome-sequenced IBD patient I discussed a few weeks ago), and the latter discussing how far we still have to go before genomics can reach its potential. Baylor’s Richard Gibbs talks about how the large-scale technical discipline of genomics and the biological subject of genetics are starting to re-merge, after the Human Genome Project saw the two diverging, and there is an oddly inspiring comment from theologian Ronald Cole-Turning about how genomics is redefining our vision of humanity.

Of particular interest is an article by Eliot Marshall on why genomics hasn’t yet had a large effect on medical practice, and what needs to be done to allow the genomic revolution to trickle into medical care. He argues that scientists and doctors need to meet each other half way; scientists need to focus more on showing the direct clinical utility of genomics, whereas doctors need to be more ready to accept new technologies and discoveries, and adapt the way they practice medicine to make full use of them. [LJ]

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Cluster Sequencing with Oxford Nanopore’s GridION System

More on nanopore sequencing this week. I mentioned in my Genetic Future post that the UK sequencing company Oxford Nanopore is somewhat of a dark horse, and an agreement with Illumina has required complete silence about their potential DNA sequencing machines. However, this wasn’t strictly true; Illumina has signed an agreement for the exonuclease sequencing technology, and on that we aren’t likely to hear anything until it is ready.

However, Oxford Nanopore still can, and does, talk about other aspects of their technology. And today, they have released information on their website on the GridION platform, which will be used to run all their nanopore technology (including DNA sequencing and protein analysis). In effect, these are details about the sequencing machine, but with no new specifics about the sequencing process itself.

Here are a few first impressions.

Sequencing in Clusters

The machines are small and low-cost; I expect they will cost the same or less than an Ion Torrent machine. Like the Ion Torrent, MiSeq and GS Junior, the Nanopore machines should be suitable to sit on the bench of a small lab, running small projects and with small budgets and floorspace.

However, this isn’t the full story. Each individual machine is rocking the VCR-machine-circa-1992 look, and the reason for this becomes clear when you see many of them together. The boxes are designed to fit together in standard computing cluster racks, and Oxford Nanopore refer to each of the individual machines as “nodes”. The nodes connect together via a standard network, and can talk to each other, as well as reporting data in real time through the network to other computers. When joined together like this, one machine can be designated as the control node, and during sequencing many nodes can be assigned to sequence the same sample.

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HiSeq doubles its output, a next-gen sequencing primer, and return of genetic data to patients

Illumina CEO Jay Flatley announced that an upgrade to their HiSeq 2000 platform expected this spring will allow users to generate 600 gigabases of sequence (the equivalent of 5 high quality human genomes) per one-week run of the machine. This would essentially double the current throughput of the platform and propel Illumina even further ahead in the arms race of delivering vast quantities of low cost sequence data. [JCB]

Over at Golden Helix, Gabe Rudy has just completed a three-part series introducing readers to the promise and challenges of new DNA sequencing technologies, which is well worth a read for those just starting out in the analysis of next-gen sequence data or who have a more-than-casual interest in the current state of the field. [DM]

This month’s edition of Trends in Genetics includes a review article on the ethical issues raised by the feedback of individual genetic data to research participants by Bredenoord and colleagues. This has long been a subject of debate, but the recent increase in studies that assay a large number of genetic variants (such as genome-wide association studies and whole-genome sequencing studies) has brought this issue to the fore. There is currently no consensus on how to deal with this, and in my experience the approach favoured has varied both between projects and between the ethics committees that have assessed them.

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Sequencing DNA with Nanopores

As we have already mentioned, Daniel has recently moved his blog Genetic Future over to the Wired science blogging network. While Daniel is off flying around Europe introducing his newborn to mozzarella and skiing, I have written a guest post for Genetic Future entitled An Introduction to Nanopore Sequencing.

I have been meaning to write about nanopore sequencing for quite a while (if you don’t know what nanopore sequencing is at all, go read the post!). What prompted me to write this was a CGI video made by Oxford Nanopore that managed to sum up nicely some of the basic theory behind nanopore sequencing:

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