Genetic Inference

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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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.

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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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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Yesteray was the first full day of the 2011 International Congress on Human Genetics in Montréal. This is the largest gathering of human geneticists in history, with over 7000 of us here to see over 350 talks by presentors from over 25 countries, along with thousands of posters. Exciting times all round.

As always, I aim to report on this blog at least one thing that I found interesting for every day of the conference. Also as always, I will be tweeting the odd thing of interest from my twitter feed @lukejostins, and you can get more in-depth coverage on the hashtag #ICHG2011.

This year I am also giving a talk. In fact I am giving one of the closing talks of the conference! (to put an overly positive spin on the graveyard slot). I’ll be talking at 3.15pm on Saturday in the Statistical Genetics IV session (room 517BC), so if anyone is interested in seeing a little something on disease risk prediction in families, come along!

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The second to last day of Biology of Genomes is now over, and instead of the usual late night set of talks, last night we were treated to a “lobster buffet”, followed by “all genome-nerd band” Ethidium Spill, lead by Francis Collins. As always, you can follow live coverage via twitter at #BG2011, and you can also read Matthew Herper’s thoughts at the Forbes blog.

The quality of all the talks remains very high, but today I am only going to write about two. What I liked about both of these talks was the link between recent human evolution, geography and phenotype-associated traits, despite being two very different methodologies.
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Biology of Genomes 2011 is keeping up the momentum, and the third day had some great talks, along with some sort-of-great burgers. The live coverage continues apace on the #BG2011 hashtag.

As a slightly different approach to the last two days, all the talks I am going to report on today are based on one concept. Suppose you have sequenced a new genome, and you want to get the best out of it. Maybe you want to find a Mendelian mutation or a large-effect risk factor, or just look at personal genome for overall assessment. Today’s Computational Genomics session was full of great ideas for what you can do to get the most out of your shiny new genome sequence. Continue reading →

The second day of Biology of Genomes has been and gone, and a brief wine-and-cheese interlude followed by talks to 11pm has ensured that everyone came away with a warm, if somewhat fuzzy, overview of the final session on Cancer and Functional Genomics.

Ewan Birney presented a deluge of information on ENCODE data with a host of interesting insights that I was entirely too jetlagged to take in at all, so will not attempt to discuss. However, there were a few interesting talks that I think I followed well enough to communicate.

As usual, you can follow live tweets from the conference at #bg2011. While poor WiFi performance has lead to somewhat patchy coverage of talks, most presentations have at least one person reporting on them.

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The first day of Biology of Genomes has now come and gone. The ambiguities about twitter and blog reporting have been resolved, and tweeting has started in earnest; you can follow live coverage of most of the talks on the #BG2011 hashtag.

The subject of the evening session was high- throughput genomics. There were a lot of cool talks, but two in particular got my excited, for reasons that I will explain at the end of the post. Both describe very elegant new sequencing-based techniques for studying gene regulation through transcription factor binding.

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As those of you who check this blog regularly (hi mum!) may know, I haven’t written anything since the American Society of Human Genetics conference at the end of last year. I tend to only really write posts here during conferences, when I try make daily blog posts about the talks I attend. In that vein, starting tomorrow is the Biology of Genomes meeting at Cold Spring Harbour; a major annual genomics meeting that marks the start of the conference cycle. I am here with fellow GNZer Daniel MacArthur, and hopefully both of us will get some content out, be it here, at Daniel’s Wired blog, at Genomes Unzipped, or on our respective twitter feeds.

The Biology of Genomes meeting can be somewhat difficult to navigate for a blogger and tweeter. There has been some controversy about the extent to which scientists can write about the conference via social media platforms, and I have no interest in pissing people off, so we will have to see what I can and cannot write about. I hope to put together posts about talks where the speakers specifically allow blogging coverage.

One thing I can write about is the laboritory itself. Me and Daniel are staying in a bizarrely picturesque little wood cabin in the woods on the Cold Spring Harbour Lab site:

CSHL is full of interesting wildlife, such like geese and swans, along with squirrels and a host of birds. As a European, one of the most exciting aspects is the presence of Eastern Chipmunks, which hang around in the woods around the cabins, looking cute but very slightly like they are planning something:

The contrast between my experiences this year and last is stark. This year, I have already had a good flight, a pretty wood cabin and an unexpected wine and cheese party and poster session with a group of honeybee scientists. Last year, I had an airway full of ash clouds, a dingy motel on a busy road, and a rickey old school bus with dodgy seatbelts and a tendency to violently launch you into the air at every bump. So all bodes well so far.

The cabi image is actually from Hugh Robertson’s website, and the chipmunk is from Wikipedia.