ASHG2012: Who does family studies?

The American Society of Human Genetics’ annual meeting has now kicked off in San Francisco. The usual terrifyingly large conference center, dizzying collection of stalls and posters as far as the eye can see are all very much in evidence, as is the migrating herds of human geneticists wondering the landscape looking for food in the perpetually busy local restaurants.

The first session I attended was given the perplexing title of “Yes Virginia, Family Studies Really Are Useful for Complex Traits in the Next-Generation Sequencing Era”. The session was in honour of the 80th birthday of statistical geneticist Robert Elston, whose development of the Elston-Stewart algorithm in the 1970s kickstarted the field of parametric linkage. It covered the use of next-generation sequencing family studies in the discovery of the hypothesised rare risk variants that everyone hopes to find. This isn’t really a new topic, and I last wrote about it at ASHG 2010, but it had a very different feel to two years ago.

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Some updates

A few updates about blogging and my career, for everyone who reads this blog to keep up with my news (hey mum!).

The big paper

Out this week in Nature is our new big paper on the genetics of inflammatory bowel disease. We genotyped over 75 thousand individuals and discovered 71 new loci and god am I sick of writing this sentence. In what may seem like slightly desperate behaviour, I have posted four different bits of writing on four different websites (five if you include this post) following up on this paper. You can read my general thoughts on the Sanger Institute website, what I think this publication means for the biology of IBD on the International IBD Genetics Consortium’s website, what I think these loci do (or do not) mean for genetic risk prediction at Genomes Unzipped, and some thoughts on how we went about visualising the results on my team’s website.

In my defense this is the Big Paper from my PhD, and is probably the most significant marker of what I have managed to get done over the last four years, so I do have plenty of things to say on the subject!

My PhD and beyond

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BoG2012: Digging deeper into genomic regulation

Day three of the Biology of Genomes conference is complete. The ELSI session about “Public Genomic literacy for the public” was pretty interesting, and taught us that Americans actually know far more about science than most countries, despite being hobbled by bad high school science education and a preponderance of hostile religious beliefs, and the UK has pretty bad science literacy despite the fact that we once ruled the world. That’s all a bit beyond my pay grade so I won’t comment on it further. I have sort of lost track of the days, so this blog post is a mix of Wednesday and Thursday sessions, tied together by a pretty strong non-coding genome regulation theme. The presentations I am going to talk about came from “Computational Genomics” and “Functional And Cancer Genomics”.

Ewan Birney reported on results from the ENCODE project, a truly massive consortium project to look at the role of non-coding functional DNA. My take-home message was that a chunk of the genome significantly larger than the entire exome can be confidently said to be bound by a protein in at least one cell line. This includes bound transcription factor motifs and DNase1 footprints: these aren’t wooly definitions, and certainly miss out lots of important non-coding annotations. Ewan also presented evidence implying that we have only captured half of what we eventually could if we sequenced all human cell types. Overall, we can guess that for every base pair that codes for part of an exon, there will be another four base pairs responsible for binding proteins. A few other ENCODE talks dug deeper into the data, including one from Mark Gerstein about using transcription factor binding to construct gene networks. Interestingly, he showed that networks connected via distal regulation (i.e. regulation via proteins bound outside the promoter) are very different to those formed by proximal regulation.

As well as cataloging this variation, researchers are also getting better and better at figuring out the mechanisms of genome regulation, and there were quite a few talks that really dug down into the specific dynamics of the genome and its assorted bound products.

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BoG2012: Smart study design for non-human complex traits

The second day of the Biology of Genomes conference is complete. In the morning we had the Genetics of Complex Traits session, followed by the poster session and the always exciting “Wine and Cheese Party”.

As usual, there were a few talks in the first session describing large consortium analyses of human complex disease. For instance, I presented work (on behalf of the International IBD Genetics Consortium) on the Inflammatory Bowel Disease immunochip project. We have genotyped tens of thousands of cases from 15 different countries, and discovered a host of new common loci for IBD. I’ll be writing about this project on Genomes Unzipped soon. On the other end of the allele frequency spectrum, Mark McCarthy reported on some of the next-generation sequencing projects that are going on in Type 2 Diabetes; these have less samples (something like 7K cases in total), but generated high quality calls for a large number of rare variants. Mark reported on a few interesting hints of rare T2D associations, but his overall conclusion was that we will need tens of thousands of samples to be well powered to find rare variants that underlie common disease. We will need to go beyond just sequencing a few thousand samples, and start designing well-powered replication studies to follow up what we find.

But I wanted to talk about some more non-standard, and slightly cleverer studies of non-human phenotypes that I found interesting. Three speakers described pretty nifty studies that used the particular properties of non-human sequence data to do some well-powered sequencing experiments that wouldn’t be possible with humans.

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BoG12: Sequencing single cells

The Biology of Genomes conference officially kicked off last night. Twitter coverage was strong as usual, and you can get a pretty detailed impression of all the talks by reading the #BoG12 hashtag.

To cut straight to the chase, the first session (High Throughput Genomics and Genetics) included a total of four different talks on sequencing the genomes of single cells. A clear theme if ever there was one.

Two of these talks discussed creating personal genetic maps of recombination by directly sequencing single sperm cells. Adam Auton went first – his dataset was an example of a particularly tricky setup, including massive amplification biases and a whopping 75% of his samples showing evidence of contamination. Despite this, he showed that with the right QC and statistical model you can still get a good map that is very similar to existing maps, even given these problems. Stephen Quake presented a somewhat less difficult sperm sequencing study, which used a special microfluidic chip (previously used for chromosome separation) to separate out the sperm cells. Low coverage sequencing could produce a map that closely recapitulated existing maps, and higher coverage could be used to estimate rates of aneuploidy and de novo mutation.

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BoG2012: The long climb

Today is the first day of the 2012 Biology of Genomes conference at Cold Spring Harbor Laboratories in New York. This is a fun conference as it has talks from across the range of genome biology, moving from human disease genetics to evolutionary genetics to animal genetics to functional genetics. As usual, I will attempt to write a daily blog posts about what I find interesting that day. I will also be attempting (presenters and the small god of the wifi router willing) to tweet interesting tidbits from the talks – you can follow me at @lukejostins. More coverage can be read using the hashtag #BoG12.

I am lucky enough to be staying on site again this year, rather than having to endure the daily death-defying suspensionless bus ride from one of the satellite hotels. However, the cabin that I have been put in this year breaks my current record for the longest climb from lecture theater to front door:

Phantom heritability and additivity

Just out in prepublication at PNAS is a paper from Eric Lander’s lab, entitled, somewhat provocatively The mystery of missing heritability: Genetic interactions create phantom heritability. This suggests that certain types of gene-gene interactions (often called “epistasis”) could be causing us to overestimate the additive heritability of complex traits, and thus underestimate the proportion of heritability our genetic studies have explained, without being detectable by standard methods.

At its heart, this paper is a challenge to a common assumption used in statistic genetics: the assumption of additive genetic risk. This states that genetic risk factors act independently of each other, with each variant increasing genetic risk by the same amount regardless of what other risk factors are present*. Of course, this is clearly a spherical cow situation, we know that the cell is full of complex interactions of various sorts, and a mutation cannot help but be effected in some way by the rest of the genome. But mathematically the assumption simplifies much of the complexity of statistical genetics, and allows you to do a number of things that would be very hard otherwise. We generally think additivity is a good approximation; it doesn’t matter if it is slightly wrong, and we’d have picked up if it were very wrong.

Zuk et al’s claim is that it is possible that additivity is wrong, that did not pick it up, and that it really does matter. This blog post will discuss the specific arguments that Zuk et al make against additivity. Some of the broader implications of the research is discussed over at Genomes Unzipped, and in particular looking at what this does and doesn’t say about total (not additive) heritability.

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Students blogging the classical world

Everyone who reads blogs about biology know the number of grad students who write about their subject and their work. Obviously I’m massively in favour of this, both because it lets us reach a wider audience, and put across our own take on our fields.

A new group blog, res gerendae, came online at the end of last year, and is interesting for a few reasons. Firstly, it is written by Classics students (those who study Roman, Greek and other societies of the Classical antiquity), who aren’t really known for their blogging. Secondly, the blog is open to all the Classics grads of Cambridge University, potentially acting as a voice for all students of the Faculty of Classics.

So far you can read about graffiti then and now, the real location of Troy and a surprisingly technical reading of a postcard.

Lets hope other student bodies take inspiration from this, and do their bit to get students involve in writing about their field.

ICHG2011: The state of play in complex trait sequencing

The International Congress of Human Genetics is rapidly approaching its conclusion (namely, my talk today at 3.15pm in Room 517, be there or be, I dunno, hanging out in Montreal I guess).

For me, the hightlight of yesterday was (somewhat obviously) the Individual Resequencing for Complex Trait Genetics session. This was organised by Mark Daly and Ben Neale of Mass. Gens. Analytic and Translational Genetics Unit, and gathered together a number of the Big Men (all men, unfortunately) of disease association together to talk about the many and varied Next-Generation sequencing studies they have been working on. I’ve summarised some of what was said below.

As always, you can find more coverage of ICHG on twitter (@lukejostins for me, #ICHG2011 for aggregated coverage).

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ICHG2011: Debating the future of genome sequencing is medicine

Yesterday night at the International Congress on Human Genetics we had a debate, entitled “Current and Emerging Sequencing Technologies: Changing the Practice of Medical Genetics”. You can see the full list of participants here.

The debate was pretty lively, and in parts both enlivening and depressing. Below are a few points that I found interesting.

As always, you can find more coverage of ICHG on twitter (@lukejostins for me, #ICHG2011 for aggregated coverage).

Different perspectives

Joris Veltman described his exome sequencing of 500 individuals with intractable disease, and noted that there has been much success, and very little evidence of harm. Ségolène Aymé mentioned NIH targts that hope to see almost all genetic diseases diagnosed by 2020, and new treatments for rare diseases to be developed simultaneously. There seemed to be a solid consensus across the panel that sequencing should be rolled out as a standard tool in the diagnosis of genetic diseases, provided that the approach is a targeted one, restricted to finding the pathogenic mutation(s) causing the disease.

More controversial was the role of sequencing of healthy individuals, and the general return of data to patients or doctors for any reason other than directly diagnosing a genetic disease. Rade Drmanac, chief scientific officer of Complete Genomics, was obviously strongly in favour of everyone having their genome sequenced, and made it clear that Complete Genomics intends to start offering sequencing to doctors in the future. In his vision, genomes are sequenced at birth, and an initial analysis of immediately actionable results (e.g. potential genetic diseases) is passed to the doctor and patient, with further analyses being carried out if and when they are required.

Michael Hayden immediately dismissed this as hype. He pointed out how unable the US is to handle medical sequencing, with no good systems of reimbursement, a massive shortage of genetic councilors, and a general lack of training in the medical profession.While more positive in general, Louanne Hudgins also expressed worries about the lack of knowledge of genetics among doctors, with some truly scary examples of MDs failing to understanding even the most basic genetics.

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