"The paradox of systems that are generally robust is that they may be quite vulnerable to large variation in a specific subset of components. Why specific types of genes are in this set, while others can be completely deleted without effect, is the big question." I believe it's less "components" than "parameters" one should be looking at. The parameters against whose variation the system will be least robust, are those that represent trade-offs between competing modes or subsystems that are, individually, highly complex and self-reinforcing under particular conditions. To use an analogy from political systems, the majority of bad policy arises from excessive influence by one or more special interest groups. In and of themselves, each of these interest groups serves a function helpful to the overall well-being of the population, but what is good for each of these groups is not always best for the whole. So, back in the world of biology, the key parameters (e.g. expression levels) to suspect for disease should be those that vary bimodally with the global state of the organism, or that act as markers for the relative growth rate or activity of a particular sub-system of the organism. If an enzyme concentration or activity has high predictive value for, as an example, distinguishing an energy-replete/fed state from an energy-deficient/starved state, or distinguishing a childhood state from an adult state, or even a state of child-rearing vs. having no children, etc., then it's a good candidate. This is because if a perturbation pushes the system toward one extreme, the robustness of THAT state will tend to AMPLIFY rather than dampen the change. Ironically, it's thus the parameters that participate in the most fundamental adaptive changes, that would be most vulnerable to causing MALadaptation. Thus it may be seen as a biological form of the fluctuation-dissipation theorem: http://en.wikipedia.org/wiki/Fluctuation-dissipation_theorem

@ Mark Houston: I think you are seeking a different kind of "why" than the majority of the people who do these genetic studies. If there are cases where a rare mutation in a gene occurs along with a phenotype of autism (or schizophrenia, or ADHD) multiple times, then it doesn't seem that far off to conjecture that this mutation was necessary for the phenotype, in those individuals. Whether it's sufficient is up for debate--that may be where environmental effects come in. This is all a very phenomenological type of "why"--when piece X breaks, phenotype Y can result. This single-gene causality sheds little light, however, on why it makes sense that the system breaks in certain characteristic ways rather than others. This is even more true when it is seen that the same mutations can show up in multiple different disorders. While it may be a small step to suggest that had gene X not mutated, uncommon phenotype Y would probably be absent, a model that can robustly predict whether phenotype Y or Z occurs based solely on knowledge of a few mutations X1, X2, etc. is much more difficult. Even more so, if you try to predict the manifestation of a spectrum disorder, i.e. whether the autism will involve speech difficulty or hyperlexia, for instance--and these are the things that really have meaning for what special accommodations or interventions are necessary. Things like growth patterns and resource trade-offs are much more likely to capture the failure modes as a whole. Biological systems clearly seem to malfunction in a very different way from human machines. If a brake fluid line is ruptured in a car, it will not cause the steering to become more accurate. The most adaptive we can get with designs is to incorporate redundancy, which delays the consequences of progressive malfunction. Probably the most fascinating characteristic of biological systems, in my opinion, is their ability to "get by with what they have". Yes, there are things like congenital blindness and deafness where there is simple absence of a trait, but more often there are both extreme losses of function and gains of function in the same disorder. It is probably more apt to think of an organism like an ecosystem where loss of one species causes die-offs of some species and overgrowths of others. True understanding of biological phenotypes will only come about by understanding the interconnectedness of this "ecosystem", which is much farther off than "lacking X correlates with end result Y".

I don't think it's that outlandish to suppose that disease states are extremes of rather continuous variables, with some "threshold" leading to disease. Although, for instance, type 2 diabetes may be labeled an "all or nothing" trait, there surely are healthy people with different efficiency of blood sugar regulation, i.e. if you feed them all the same amount of sugar, the immediate rise in blood glucose level may be damped to a different extent in different individuals, doesn't that seem reasonable? For psychological traits even more so: for instance autism is clearly a spectrum disorder, ranging from mere impairment of perceiving social nuances to the complete absence of speech and awareness of others--and sociability shows great variance even in supposedly "normal" people. Depression is even "worse", in that tolerance of stressors greatly differs between people, with some bouncing back like springs and some staying gloomy for weeks. In fact, I'd be apt to postulate a combined internal-external feedback model for depression, where the "sum" of the ability of the neural network and one's life circumstances to recover from loss must fall below some threshold before setbacks become self-perpetuating enough to cause clinical depression. Furthermore, many disease phenotypes involve trade-offs. For instance, obesity involves the trade-off between famine tolerance and present bodily health, autism involves the trade-off between cooperation/integration with a group and the pursuit of novel strategies the group may have overlooked, ADHD involves the balance of rejecting extraneous information and remaining aware of shifting environments, etc. Thus, I'd say that many disease states involve selection of the wrong strategy at the wrong time, or the pursuit of one strategy to the total exclusion of others.

"What I am arguing against is the assumption that the genetics of a trait like sociability, for example, is the same as the genetics of a symptom like social withdrawal. There can be a normal distribution of a trait and deviations from that distribution that are caused by different mechanisms. I argue that you need some major insult to get a serious phenotype – not just an accumulation of very small variants, because the system has to deal with that kind of variation all the time." This seems to imply that in each pathway, there is complete segregation of the components into those that produce qualitative vs. quantitative behavior. Imagine an enzyme where a particular mutation causes a complete loss of function--i.e. the enzyme fails to catalyze the reaction at all, or so little that the improvement over the uncatalyzed reaction has no physiological relevance. Then it seems logical that other mutations of the same enzyme, even possibly at the same amino acid position, may have milder effects on function, giving less extreme phenotypes that still seem "normal", just perturbed. And this view doesn't even take into account that qualitative changes in behavior need not necessarily arise from complete absence of any one component or interaction, even if they often do. Often, a combination of parameters will determine whether, e.g., a negative feedback is strong enough to keep a system stable. Besides, haven't you, or others, argued on this blog that rare variants also contribute substantially to "normal" phenotypes, i.e. things like personality types that are not considered diseases?

The idea of overpruning seems rather odd considering that the "broader psychosis phenotype" includes the tendency to make looser and more abundant associations between words, concepts, etc. I remember actually on GNXP there was a study mentioned where the relatives of those with schizophrenia came up with more associations to a word--like if they saw "apple", average people might think of "oranges", "pie", and "tree", while the schizophrenia relatives were more likely to think of words like "moonlight" or "fishing" that have no obvious literal connection. Unless it's maybe the interneurons responsible for lateral inhibition that are pruned. I remember once reading about someone making a mathematical model of 5HT2 agonist-induced visual hallucinations (like, LSD spirals dude). The key there was increased gain in the neurons, making the circuit less "overdamped" and the boundaries between adjacent cells "leaky". This allowed for macroscopic standing or traveling waves to emerge in a 2-D layer of the visual cortex. Similar waves are observed in migraines, as far as I'm aware, which can produce hallucinatory experiences as well.

And of course, it may also be that "simple" and "complex" hallucinations (i.e., swirling lines vs. the recognizable image of a person or the sound of the person's voice) have a completely different etiology, though it appears that stimulating the same receptors can trigger both.

Yes I agree that the associations in schizophrenia are more like exaggerations of normal processing than in, for example, synesthesia. In that it's not connection of *truly* arbitrary things, more like "leaps". For example, the "apple" to "fishing" may go like "apple"--> "apple trees" --> "Grandpa's farm in the summer" --> "fishing at the lake", but perceived all at once like a reflex, while a normal person's thought train would only go where attention explicitly wills it. I've listened to/read the "word salad" of some schizophrenics before, and each individual grouping of words somewhat makes sense, it is only when you try to understand it as a whole that it becomes gibberish.

What is the route of administration? A peptide hormone like that will not be orally bioavailable, and even when injected IV I doubt much of it gets across the blood-brain barrier. Maybe it's something like the DDAVP nasal spray (http://www.rxlist.com/cgi/generic/ddavp-spray.htm), which differs by only a few amino acids, but even then I don't know how good the brain penetration would be. That's even ignoring the fact that any peptide neuromodulator will have proteases waiting to cut it up as soon as it gets near the synapse. 
 
Even if all the delivery issues could be sorted out, I somehow suspect that some of the variability in social behavior may be due not to the hormone itself, but due to its receptors. We already know about the DRD4 receptor having an effect on personality. Also, if I remember rightly, there was some study on voles that linked mating patterns to the expression pattern of one of the ADH receptors. If something similar is going on in some people, then adding hormone will not change the regional specificity of activation, only amplify the magnitude.  
 
If it works for some people, great, but I wouldn't bet on it.

"I wonder which group selects for higher digit ratios in males." 
 
That's an interesting question.  
 
On a semi-related note, I would be interested in seeing an attempted correction for amount and type of visuospatial processing involved in the three niches. This could very well be a confounding factor. 
 
For instance, in the task with the gloves, hand, and scarf, the gloves and hand are related not only by a functional resemblance, but by a morphological (shape) similarity as well. Also, in the task with the square and line, the relative task corresponds to seeing the same hypothetical object at different viewing distances, i.e. a common spatial transformation, yet absolute lengths of lines in a visual field are not a useful cue in most 3-D environments.  
 
Interestingly, given the tasks shown in the paper, I probably would have shown a preference for the "holistic" style in all three tasks--even the one with the flowers where the "independent" unidimensional rule was favored to varying degrees in all societies (Note, however that this would have changed if I had learned that the stem shape was especially predictive of something). This is despite the fact that I am very individualistic and frankly awful at perceiving context in social situations.  
 
I think the reason is that categories "for their own sake" are a kind of verbal construct that depends on a certain reference point or convention, whereas perceptual similarity is more of a visual property. When I say "for their own sake", I mean categories that do not correspond to any overall structural or functional properties. For instance, "reptiles" corresponds to a group of animals with similar overall morphological and physiological characteristics (cold-blooded, skin often covered with some type of scales, etc.), whereas "animals with a long tail" does not. When looked at in this sense, the distinction almost seems to say the opposite of what the authors think--shouldn't societies that emphasize conformity be MORE attentive to seemingly arbitrary dividing lines and rules?

I find that the internet actually helps me make connections between different things, because I can let my brain control the information, rather than the other way around. If you are reading a book, and you think of an idea that happens to be beyond the scope of what is described in the book, you have to put it down and go look for another source, which takes time and breaks your concentration. With the net, if a seemingly inspired idea comes to you, you can check the facts in a matter of seconds, and in doing so probably get more information than you ever wanted to know about the subject.  
 
When reading, you see a subject as the author wanted you to see it, which is not always conducive to finding new ways of looking at things. I'm sure we all know, or have known, students who seem to understand how to solve problems as long as they are from the same textbook from which they studied, but seem lost when they are asked to solve a problem that doesn't look like any of the examples in the book. This is on top of the fact that in many fields, a great deal of what is written in books is either obsolete or just plain wrong by the time you get around to reading about it. 
 
One place where the internet is not so useful is in getting a background for a subject. If I want to know the general overview of, say, a particular metabolic pathway, I will still go to a book first. If you are just starting to build a mental map of a subject, reading websites will tend to flood your brain with too much noise, before the filters are in place to make sense of it.

That paper is rather interesting, but only a small step in the right direction. This quote  
 
"With this first structure we can start to build models of binding sites and hopefully in the future design more effective pharmaceuticals for a wide range of medical conditions.? 
 
is nothing but hype at this point--anything even approaching the resolution necessary for drug design is going to need a resolution at least 6 times better than the current one. This will require a completely different technique, like x-ray diffraction or NMR, that will in turn bring a whole new set of challenges. For now, models based on existing high-resolution structures of other ion channels are almost certainly of more use--including for the purpose of rationalizing the effect of mutations in the sequence.

I find the first sentence rather funny: 
 
"Mental Retardation (MR), one type of psychosis, is mainly characterized by the feeblemindedness and inadequate social adaptation ability." 
 
This sentence reads as if it were simultaneously un-influenced by both proper English and political correctness. I don't think mental retardation is actually considered a psychosis, and when was the last time you saw the word "feeblemindedness" in any sort of academic writing?

Many of you may be interested to hear that MC4 is also involved in another, quite unrelated function. This was discovered when some men taking melanotan-II, a highly potent skin-tanning agent that activates MC4R in addition to other melanocortin receptors, developed an "interesting" side effect.

For a second I though you meant this Carlos Bustamante: 
 
http://mcb.berkeley.edu/faculty/BMB/bustamantec.html 
 
He isn't exactly working on population genetics (I took a class from him once).

Wow, nice explanation! I actually felt like I understood that, without even having to read the paper.

You all should read this because it's so funny. I found it as a link off of one of the posts in the Just Science feed, and it's to a CD sold by Amazon: 
 
http://www.amazon.com/gp/product/B000N97NCG?&camp=212361&creative=384005&linkCode=wpc&tag=daysofhsien-20 
 
From the site: 
 
According to Angel Ariel, all life follows a divine blueprint that we have labeled DNA. Science has discovered the first two physical strands of the DNA blueprint. It has been discovered to be the double helix building block of all life. There are five other double helix pairs in the DNA system. The six pairs of strands are called the 12-strand spiritual DNA. In the 12-strand system, the first pair is physical and the other five pairs of strands are non-physical energy imprints in the human energy field. This audio CD explains the roles that these six pairs of DNA double-helix strands have in our lives. The 12-Strand DNA activation workshop is a 1 hour audio program that not only contains the lecture give by Stevan Thayer, but also contains the activation energy. Anyone listening to this tape will receive the 12-Strand DNA energy activation. Recorded in 2000. 
 
I wonder what the "activation energy" is for--to separate the DNA strands?

Now he's making weak arguments for his brand of "libertarian transhumanist." 
 
What's wrong with libertarian transhumanism? It happens to come closest, of any philosophy I've heard, to my own view of technology. I don't think you have to discount the reality of global warming to believe in humans' right to enhance their bodies' functioning with technology.

"the Untied States" 
 
It seems that someone could come up with a joke based on this typo about how the states interact with each other, or how other countries view the U.S. 
 
Sorry about the silly comment, I just thought it was kind of funny.

Now a non-ethical comment: 
 
Does anyone else find it odd how in the child pictures the two somehow look switched? Except for the hair, Elyse at age 11 looks to me more like Paula as an adult, and vice versa.

I must admit I don't get Seth Lloyd's equation, though the general form reminds me a little of some of the stuff we have done in my fluid mechanics class lately (not that there really is any relationship). 
 
LOL at Drew Endy's--by the way, I have spoken to him in person, and I have to say his analogies are as entertaining as that little drawing suggests. 
 
As for Mahzarin R. Banaji, what does it mean for the first premise to cease to hold? It does not hold absolutely in the current sense, does she mean that nobody will make that association?