On In Our Time with Melvin Bragg the host often asks his guests to give him a “flavor” of the debate amongst scholars. I always feel that this is acceptable when they are talking about history (e.g., The Diet of Worms), but somewhat bristle at the presumption when it comes to science (e.g., Galaxies). I suppose that I feel that much of scientific work on an advanced level, when science become more than just natural philosophy, is beyond simple intelligibility via sampling a “flavor.” In other words, the necessary contigency of scientific debate makes is rather difficult to extract out a portion to impart the quality of the argument. In contrast history is a bundle of facts with little theoretical unity, so one can more easily capture via sampling the rough distribution of the debate. Agree or disagree?

See Aetiology for the details.

In 2004, a group based out of Bruce Lahn‘s lab published a paper arguing that nervous system genes had experienced accelerated evolution in primates, particularly on the human lineage. Their approach was based on the following observations: humans and macaques diverged about 20 million years ago, as did mice and rats. But the changes in brain morphology are strikingly different in the two taxa (see their figure on the left). So they compared the evolution of a set of genes expressed in the nervous system in rodents with the evolution of the same genes in primates. Their set of 200-some genes was chosen based on a number of criteria, including expression studies, literature searches, and the inclusion of genes mutated in known neurological diseases.

As a sort of control, they did the same analyses on a number of “housekeeping” genes– genes that perform important cellular processes, and thus are likely to be evolving under strong evolutionary constraint. Their results were consistent with their predictions– nervous system genes, in general, evolved faster in primates than in rodents, while housekeeping genes evolved at about the same rate in both taxa. They then further broke down their group of nervous system genes into those involved in neurodevelopment, those involved in physiology, and those that they couldn’t classify. Strikingly, it seemed that the difference between primates and rodents was most pronounced in neurodevelopmental genes. The group then nominated genes with particularly accelerated evolution in primates as candidates worthy of further study. 17 of these 24 are involved in regulating brain size or behavior, a particularly interesting finding. Of course, they then followed up on some of them.

It seems an odd time to attack this study as unjustified, but that’s exactly what a new paper attempts to do. They claim the Lahn paper has four major shortcomings; I present them here in bold, with my comments afterwards:

1. “First, they compared only 24 nervous system genes between human and chimpanzee–the most relevant species pair for studying evolution of the human brain”

It’s true the original paper is based on a human-macaque comparison (they then compare their 24 outliers with chimps), but they justify this as follows:

Recent discussions surrounding the genetic origin of humans have placed a great emphasis on human-chimpanzee comparative genomics. Undoubtedly, this approach has revealed-and will continue to reveal-genetic differences that might underlie the biological distinctions between these two sister species. Because of the exceedingly high degree of sequence identity between human and chimpanzee genomes, however, comparative studies often lack statistical power, and in many cases would overlook genetic differences that bear biological relevance. The issue of weak statistical power in human-chimpanzee sequence comparisons has been noted before (Shi et al., 2003) and is supported by our simulation studies showing that the average stochastic variance in Ks as a fraction of the true underlying mutation rate is about twice in human-chimpanzee comparison as it is in human-macaque comparison (our unpublished data). Relative to human-chimpanzee comparisons, our approach offers two important advantages. First, the use of a more distant primate species for comparison with humans provides the much needed statistical power for determining the evolutionary significance of sequence changes.

Further, while human-chimp comparisons are certainly valuable, it’s worth noting that we are extremely similar to chimps, and the evolutionary trends leading to modern humans are likely to have been present long before the human-chimpanzee divergence.

2. “Second, their list of nervous system genes was manually compiled and might thus be incomplete or biased”

The new paper claims to make an unbiased complilation of brain expressed genes and show that, in this compilation, there is no acceleration for nervous system genes. I don’t feel like I’m really in a position to judge this claim, except to note that, well, the “small, biased gene set” used by Lahn’s group contained a lot of genes that have later been confirmed to be under selection. There’s certainly a difference in goals between the two groups: Lahn’s group sought to identify candidates to follow up, thus they used specific hypotheses about which genes to include, while this group looks to comment on broad patterns in human evolution. That is, they want to say that many amino acid changes in many genes are not involved in human brain evolution. Lahn identified 24 of them; maybe that’s not enough to claim “a lot”, but it’s certainly an interesting set of genes to examine.

3. “Third, they used house-keeping genes as controls in some of the analyses, which seems inappropriate because tissue-specific genes and house-keeping genes are expected to have different evolutionary patterns”

Yes, tissue-specific genes and housekeeping genes are supposed to have different evolutionary patterns, in that houskeeping genes are supposed to be under more constraint. That is, indeed, the point of using them as a control.

4. “Fourth, a recent comparison between the dog and mouse genomes found that 18 nervous system genes that evolved faster in primates than in rodents also evolved faster in carnivores than in rodents, suggesting that the findings of Dorus et al. [the Lahn paper] might partially be due to rodent deceleration rather than primate acceleration”

I’m glad this point came last, because it’s particularly interesting. So the domestic dog has experienced an acceration of nervous system genes relative to rodents. The authors seems to think this implies a deceleration of evolution in rodents. The other possibility, of course, is that evolution was accelerated on the dog lineage as well as on the primate lineage. I don’t know too much about the ancestral species leading to dogs, but it’s worth noting that the domestic dog has been under intense artificial selection for behavioral traits in the last 100,000 years. So perhaps the molecular substrates underlying dog domestication and human domestication (because essentially, our recent evolution has been a “domestication”) are similar. I find this hypothesis much more enticing.

A reader emailed me asking about the genetics of hair color. Since I’ve discussed the topic before I simply pointed them to the query of the topic on my other blog. But, I thought it might be good to directly answer two specific questions:
Why do many people have much lighter hair during childhood?
The same reason that European babies are often with blue eyes or dark skinned babies are born with light skin, we get darker as we age (with the partial exception of females during puberty). The darkening of hair is simply a symptom of a general trend toward increased melanin as we age (or as women go through pregnancies). Proximately in an individual’s life history it probably has hormonal upstream causes, e.g., the increased level of testosterone vs. estrogen levels in females after menopause (and pregnancies), or the elevation testosterone in males after puberty. Our ancestral state was probably “pink,” but after we lost our fur humans developed dark skin (a “consensus sequence” is found among tropical peoples). Light skinned peoples are a response to the relaxation of this particular selection pressure, but the darkness is something that we develop (some of us more than others) over our lifetime as genes express proteins which lead to the phenotype.
Also discuss the dependency and independency between hair and eye color, and hair and skin color.

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Long article on face blindness in Wired.

The new Neuron has a bunch of good stuff in it. I don’t understand how they expect me to do lab work if they keep giving me all this good junk to read. I think the PI for this report was Tobias Bonhoeffer. It’s a short paper with just a few experiments but it has wide implications. The standard story is that activity related to memory storage should cause protein synthesis and those proteins are used to build the changes into synapses to make a lasting change in cellular response to input. Some papers recently have shown that protein degradation may be as important for long-term potentiation (the cellular model for memory) as protein synthesis. Besides the Bingol and Schuman paper linked above there is the example in drosophila of an activity-dependent degradation of the protein, armitage, which released CaMKII RNA from translational repression (Ashraf et al, 2006).

In the Bonhoeffer paper, they did the normal thing experiment where you block the longest lasting form of LTP (late-LTP) with a protein synthesis inhibitor. But then they also tried the same experiment with a protein degradation inhibitor in the solution as well. BooyaShocka! The late-LTP was back to normal levels. Activity must be degrading proteins that could’ve been used for synaptic plasticity. This is really odd. I don’t really know how to interpret it yet. A cluster of synapses could be sharing proteins and so very local degradation could increase specificity of a modification, just like you can add inhibition to a neural network to increase your signal to noise ratio, but when protein synthesis and degradation are both inhibited perhaps the synapses that need to be modified just borrow from their neighbors instead of making new proteins. The proteins that are degraded must be the same ones that are being synthesized as if the overall metabolic rate is increased rather than any specific synthesis. One wonders if there is any sort of local cellular metabolic stress state due to use of amino acids and ATP in these processes.

If this was the case then you could do an interesting “synaptic competition” experiment where you establish LTP in one input and then establish it in a second input under the influence of synthesis and degradation blockers, perhaps the second input would pull some of the material away from the first. This will take some time to digest. The need for protein synthesis was just on the verge of dogma in the field of synaptic plasticity. At the very least, we can expect a much more detailed study of the proteasome (the protein degradation machinery) at synapses in coming months/years.

John Wilkins has a good post on religion, I tend to agree with its general thrust though I might quibble with details. Not being gifted with much marginal time right now, a few quick thoughts:
1) I believe that institutional organized religion, e.g., Christianity, Islam, etc., can increase the magnitude of a social vector, but has little influence on its direction. For example in relation to slavery religion was a force for inflaming both abolitionist enthusiasm and justifying the holding of other humans in bondage. Religion doesn’t do good or evil, humans do, religion is simply a ‘virus of the mind’ which hitch-hikes and surfs on cultural waves.
2) There is a distinction between basal religion, psychological propensities toward supernatural belief, and formalized systematic “higher religions” which exist on top of the basal layer and channel sociological dynamics and psychological biases toward the perpetuation of their particular “meme-complexes” (i.e., higher religions are constrained toward being cognitively optimal).
Second, Chad has two posts on The God Delusion. In reality Chad was commenting on this review in The New York Times. I was also pointed to this thrashing of Dawkins’ book. A few points:

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Well, you know that The Complete Work of Charles Darwin Online is now live, right? But remember to give some love to the R.A. Fisher Digital Archive, where you can read his genetical and non-genetical papers. Also, keep an eye over at Abebooks for cheap copies of The Genetical Theory of Natural Selection. They’re all north of $65 US dollars right now (that’s like $2,000 Canadian right?), but I got my copy for $33, so just keep checking.

A recent paper in Neuron provides a note of caution when interpreting gene knockout studies, a hint of the impact RNAi technology has on a field of study, and some new tidbits about AMPA receptor trafficking. Previous studies has shown that overexpressing a protein called PSD-95 (post-synaptic density – 95 kDa) led to an increase in synaptic AMPA receptors. AMPA receptors are responsible for a major portion of the excitatory neurotransmission in the brain. They normally respond to pre-synaptic glutamate release by opening a pore through their center and allowing sodium into the cell, thereby depolarizing the post-synaptic neuron and increasing the probability that it will fire an action potential. Increases in synaptic AMPA receptor content are likely to explain the increased synaptic response observed in long-term potentiation (LTP). Since PSD-95 seems capable of modulating this factor it has attracted much interest.

PSD-95 is part of a larger family of proteins called PSD-MAGUKs that also includes PSD-93, SAP102, and SAP97. MAGUKs don’t seem to have a catalytic activity. Rather, they are likely to serve as scaffolding proteins, connecting one protein to another through multiple binding sites up and down the MAGUK sequence. All PSD-MAGUKs share similar binding domains but vary in the details. Part of the impetus for the present paper is that a transgenic mouse with targeted disruption of the portion of PSD-95 that ought to interact with AMPA receptors shows no signs of difficulty in synaptic transmission. Now, thanks to these authors, we have a mouse that lacks PSD-95 altogether and still no deficit in AMPA receptor delivery.

Long story short, PSD-93 is picking up the slack when PSD-95 is knocked out. It’s compensation. Redundancy and degeneracy are the rule rather than the exception in biological systems. This set of experiments makes it so clear that a knockout mouse is never what you expected you were making. There is no deficit in a PSD-93 knockout either. Only in the double knockout (mice lacking PSD-95 and PSD-93) do you get a significant decrease in AMPA receptor transmission, and in that case SAP-102 still pops up and does its damnedest to keep the synapses running on time.

The way all of this was discovered was through the use of more acute gene knockdown using short hairpin RNAs expressed via a viral vector. You can create a virus that will code for something that looks tasty to the RNA interference machinery like an shRNA and infect a slice of brain tissue with it. RNAi machinery will grab the shRNA, chop out a 22 base sequence from it, and go around translationally repressing or destroying any RNA that matches that sequence. So you can get gene specific knockdown quick enough in the adult preparation and not allow the neuron time to compensate by upregulating a redundant gene. As opposed to knocking out PSD-95 from day 1, shRNA targeted against PSD-95 drastically decreased excitatory synaptic transmission. The same goes for PSD-93. Knocking down SAP-102 with shRNAs in the PSD-93/PSD-95 double knockout almost completely eliminated any sign of synaptic AMPA receptors. One of the most interesting control experiments in the study was to use shRNA against a gene that was already knocked out (i.e. PSD-95-shRNA in the PSD-95-KO). This invariably produced no effect, showing that the shRNA manipulation was specific.

When SAP-102 isn’t rescuing PSD-93/95 double knockout mice from oblivion, it has a day job. It is normally expressed earlier in development (peaking at 10 days post-natal). There is a developmental switch in which MAGUKS are the prominent AMPA receptor traffickers, so after SAP-102 for a couple weeks, PSD-93/95 come on and take over synapse scaffolding duty. In normal mice, shRNA against SAP-102 only has an effect in the early developmental timepoint.

Also, in the normal mouse, PSD-95 shRNA doesn’t completely block AMPA receptor currents and neither does PSD-93 knockdown. This suggests that normal mice have a heterogeneous population of synapses, some of which utilize 93 and others that use 95. It would be interesting to know if there is any functional or localization difference between a 93 and a 95 synapse. While one of the major messages of this paper is that these proteins can compensate for each other seamlessly at least in the assays performed thus far, it seems unlikely that they will perform the exact same function in their natural setting.

One of the things I regret during my tenure blogging is that I started doing “10 questions” too late to get in touch with John Maynard Smith. If you haven’t, I highly recommend this interview by Robert Wright from a few years ago. Also, Smith wrote one of the more readable introductory texts on Evolutionary Genetics, as well as pioneering the use of game theory in evolutionary biology, introducing the concept of the ESS.