This paper from the Kellis lab is a great demostration of how functional genomic studies should be in the post hight throughput sequencing era.
They took on a classic GWAS example, obesity, which has a fairly high genetic component, up to 80% heritability. A 47kb region spanning the first and second intron of the FTO gene is strongly associated with the genetic variation of body-mass index (BMI). Subsequent KO studies in animal models revealed a direct functional link between the FTO protein and control of thermogenesis, energy expenditure and regulation of body weight.
Then you wanna ask yourself: WTH are we still doing, when FTO sure looks like the culprit for obesity? Because none of the associated variants could explain the disregulation of FTO expression. In other words, there’s a missing link between the genotype and phenotype, which puts the whole idea of FTO being causal into question.
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Today was all systems neuroscience, an area that I don’t quite get. And because of this lack of understanding, research in this field usually falls into two categories to me: questions too simple to study, and questions too lofty to grasp. But still, I found most of the talks interesting and well-presented. Topics range from visual reflex, motor coordination and learning, to reward and decision making.
The one talk that I really like is a functional imaging study of conditioned fear memory from the Schnitzer lab. The presentation was too fast to absorb every bits of detail and the computation is little too difficult for me, but the gist of it is that they managed to perform calcium imaging in an ensemble of neurons in lateral amygdala, an area critically important for the formation, storage and retrieval of fear memory, during a typical conditioned fear memory paradigm. The take home is that during training sessions, the populational activity pattern of neurons responsive to the conditioned stimulus (CS) becomes more similar to the neurons responsive to the unconditioned stimulus (US); and this similarity becomes even higher during the consolidation period after the training. What’s more interesting is that after memory extinction, the similarity between the CS and US neurons is lost, but the activity pattern of the CS neurons do not reverse back to their naive state before training, rather they adopt a totally different state, which suggests that extinction is perhaps not a simple erasure of the established memory but is an active mechanism driving the cells into a new circuit.

It was a busy day packed with all sorts of exciting science and personality.
Totally didn’t sleep well last night. Luckily the meeting started with works from Kolodkin and Engle labs that I’m quite familiar with. So that was a easy wake up transition for me.
A ton of circuit studies today. Aggression from Anderson, taste perception from Zuker, salt appetite from Palmiter, olfactory memory from Bargmann, and memory from Tonegawa. Not too many new stuff. No new technique. But still, good to hear them presenting in person.
The highlight of day, in my opinion, is work presented by Chris Chang at Berkeley on metal, particularly copper, as signaling molecules in the nervous system. There’re regions in the brain that are highly enriched in copper and they’ve devised imaging and other methods to visualize copper in real time and in response to different stimuli. Pharmacological perturbation of copper transport affects various aspects of normal neuronal function besides its crucial role as a redox center in metabolism. That opens up a lot of interesting directions. Copper is the new Calcium, in a way, if you have the right tools.
Had somewhat in-depth discussion with Walsh, Ecker and Axel. They seemed to have high praise about my work and be enthusiastic about a possible future. Pretty sure now that I’m going to line up an interview with Walsh. There’s a lot new initiatives and huge projects that get me really itchy and hooked up, and I could see, easily, a 10, 15 years of outlook stemmed from these projects.