It takes a lot of genes to wire the human brain. Billions of cells, of a myriad different types have to be specified, directed to migrate to the right position, organised in clusters or layers, and finally connected to their appropriate targets. When the genes that specify these neurodevelopmental processes are mutated, the result can be severe impairment in function, which can manifest as neurological or psychiatric disease.

How those kinds of neurodevelopmental defects actually lead to the emergence of particular pathological states – like psychosis or seizures or social withdrawal – is a mystery, however. Many researchers are trying to tackle this problem using mouse models – animals carrying mutations known to cause autism or schizophrenia in humans, for example. A recent study from my own lab (open access in PLoS One) adds to this effort by examining the consequences of mutation of an important neurodevelopmental gene and providing evidence that the mice end up in a state resembling psychosis. In this case, we start with a discovery in mice as an entry point to the underlying neurodevelopmental processes.

In just the past few years, over a hundred different mutations have been discovered that are believed to cause disorders like autism or schizophrenia. In many cases, particular mutations can actually predispose to many different disorders, having been linked in different patients to ADHD, epilepsy, mental retardation or intellectual disability, Tourette’s syndrome, depression, bipolar disorder and others. These clinical categories may thus represent more or less distinct endpoints that can arise from common neurodevelopmental origins.

For a condition like schizophrenia, the genetic overlap with other conditions does not invalidate the clinical category. There is still something distinctive about the symptoms of this disorder that needs to be explained. I have argued that schizophrenia can clearly be caused by single mutations in any of a very large number of different genes, many with roles in neurodevelopment. If that model is correct, then the big question is: how do these presumably diverse neurodevelopmental insults ultimately converge on that specific phenotype? It is, after all, a highly unusual condition. The positive symptoms of psychosis – hallucinations and delusions, for example – especially require an explanation. If we view the brain from an engineering perspective, then we can say that the system is not just not working well – it is failing in a particular and peculiar manner.

To try to address how this kind of state can arise we have been investigating a particular mouse – one with a mutation in a gene called Semaphorin-6A. This gene encodes a protein that spans the membranes of nerve cells, acting in some contexts as a signal to other cells and in other contexts as a receptor of information. It has been implicated in controlling cell migration, the guidance of growing axons, the specification of synaptic connectivity and other processes. It is deployed in many parts of the developing brain and required for proper development in the cerebral cortex, hippocampus, thalamus, cerebellum, retina, spinal cord, and probably other areas we don’t yet know about.

Despite widespread cellular disorganisation and miswiring in their brains, Sema6A mutant mice seem overtly pretty normal. They are quite healthy and fertile and a casual inspection would not pick them out as different from their littermates. However, more detailed investigation revealed electrophysiological and behavioural differences that piqued our interest.

Because these animals have a subtly malformed hippocampus, which looks superficially like the kind of neuropathology observed in many cases of temporal lobe epilepsy, we wanted to test if they had seizures. To do this we attached electrodes to their scalp and recorded their electroencephalogram (or EEG).This technique measures patterned electrical activity in the underlying parts of the brain and showed quite clearly that these animals do not have seizures.But it did show something else – a generally elevated amount of activity in these animals all the time.
What was particularly interesting about this is that the pattern of change (a specific increase in alpha frequency oscillations) was very similar to that reported in animals that are sensitised to amphetamine – a well-used model of psychosis in rodents. High doses of amphetamine can acutely induce psychosis in humans and a suite of behavioural responses in rodents. In addition, a regimen of repeated low doses of amphetamine over an extended time period can induce sensitisation to the effects of this drug in rodents, characterised by behavioural differences, like hyperlocomotion, as well as the EEG differences mentioned above. Amphetamine is believed to cause these effects by inducing increases in dopaminergic signaling, either chronically, or to acute stimuli.

This was of particular interest to us, as that kind of hyperdopaminergic state is thought to be a final common pathway underlying psychosis in humans. Alterations in dopamine signaling are observed in schizophrenia patients (using PET imaging) and also in all relevant animal models so far studied.

To explore possible further parallels to these effects in Sema6A mutants we examined their behaviour and found a very similar profile to many known animal models of psychosis, namely hyperlocomotion and a hyper-exploratory phenotype (in addition to various other phenotypes, like a defect in working memory). The positive symptoms of psychosis can be ameliorated in humans with a number of different antipsychotic drugs, which have in common a blocking action on dopamine receptors. Administering such drugs to the Sema6A mutants normalised both their activity levels and the EEG (at a dose that had no effect on wild-type animals).

These data are at least consistent with (though they by no means prove) the hypothesis that Sema6A mutants end up in a hyperdopaminergic state. But how do they end up in that state? There does not seem to be a direct effect on the development of the dopaminergic system – Sema6A is at least not required to direct these axons to their normal targets.

Our working hypothesis is that the changes to the dopaminergic system emerge over time, as a secondary response to the primary neurodevelopmental defects seen in these animals.

It is well documented that early alterations, for example to the hippocampus, can have cascading effects over subsequent activity-dependent development and maturation of brain circuits. In particular, it can alter the excitatory drive to the part of the midbrain where dopamine neurons are located, in turn altering dopaminergic tone in the forebrain. This can induce compensatory changes that ultimately, in this context, may prove maladaptive, pushing the system into a pathological state, which may be self-reinforcing.

For now, this is just a hypothesis and one that we (and many other researchers working on other models) are working to test. The important thing is that it provides a possible explanation for why so many different mutations can result in this strange phenotype, which manifests in humans as psychosis. If this emerges as a secondary response to a range of primary insults then that reactive process provides a common pathway of convergence on a final phenotype. Importantly, it also provides a possible point of early intervention – it may not be possible to “correct” early differences in brain wiring but it may be possible to prevent them causing transition to a state of florid psychopathology.

Rünker AE, O’Tuathaigh C, Dunleavy M, Morris DW, Little GE, Corvin AP, Gill M, Henshall DC, Waddington JL, & Mitchell KJ (2011). Mutation of Semaphorin-6A disrupts limbic and cortical connectivity and models neurodevelopmental psychopathology. PloS one, 6 (11) PMID: 22132072

Mitchell, K., Huang, Z., Moghaddam, B., & Sawa, A. (2011). Following the genes: a framework for animal modeling of psychiatric disorders BMC Biology, 9 (1) DOI: 10.1186/1741-7007-9-76

Mitchell, K. (2011). The genetics of neurodevelopmental disease Current Opinion in Neurobiology, 21 (1), 197-203 DOI: 10.1016/j.conb.2010.08.009

Howes, O., & Kapur, S. (2009). The Dopamine Hypothesis of Schizophrenia: Version III–The Final Common Pathway Schizophrenia Bulletin, 35 (3), 549-562 DOI: 10.1093/schbul/sbp006

There is a new paper in Nature, Social networks and cooperation in hunter-gatherers, which is very interesting. As Joe Henrich observes in his view piece the panel of figure 2 (see left) is probably the most important section.

The study focuses on the Hadza, a hunter-gatherer population of Tanzania. Their language seems to be an isolate, though there have been suggestions of a connection to Khoisan. Additionally the genetic evidences tells us that like the Bushmen and Pygmies the Hadza do descend from populations which are basal to other human lineages, and were likely resident in their homeland before the arrival of farmers. And it is critical to also note that the Hadza are probably uninterrupted hunter-gatherers in terms of the history of their lifestyle, as agriculture likely arrived in Tanzania on the order of two thousand years ago, and their genetic distinctiveness indicates a separation from groups like Bantus far deeper in time. When it comes to Paleolithic model populations the Hadza are relatively “uncontaminated.”

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The post below on teachers elicited some strange responses. Its ultimate aim was to show that teachers are not as dull as the average education major may imply to you. Instead many people were highly offended at the idea that physical education teachers may not be the sharpest tools in the shed due to their weak standardized test scores. On average. It turns out that the idea of average, and the reality of variation, is so novel that unless you elaborate in exquisite detail all the common sense qualifications, people feel the need to emphasize exceptions to the rule. For example, over at Fark:

Apparently what had happened was this: He played college football. He majored in math, minored in education. When he went to go get a job, he took it as a math teacher. When the football coach retired/quit, he took over. When funding for an advance computer class was offered, he said he could teach it after he got the certs – he easily got them within a month.

So the anecdote here is a math teacher who also coached. Obviously the primary issue happens to be physical education teachers who become math teachers! (it happened to me, and it happened to other readers apparently) In the course of double checking the previous post I found some more interesting GRE numbers. You remember the post where I analyzed and reported on GRE scores by intended graduate school concentration? It was a very popular post (for example, philosophy departments like it because it highlights that people who want to study philosophy have very strong GRE scores).

As it happens the table which I reported on is relatively coarse. ETS has a much more fine-grained set of results. Want to know how aspiring geneticists stack up against aspiring ecologists? Look no further! There are a lot of disciplines. I wanted to focus on the ones of interest to me, and I limited them to cases where the N was 100 or greater (though many of these have N’s in the thousands).

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The excellent site io9 has a piece up today which is a fascinating indicator of the nature of popular science publications as a lagging indicator. It is a re-post of a piece published last April, How Mitochondrial Eve connected all humanity and rewrote human evolution. In it you have an encapsulation of a particular period in our understanding of human natural history through evolutionary genetics. Notice for example the focus on maternally transmitted lineages, mtDNA and Y chromosomes. And the citations on genealogy date to the middle aughts. The science is mostly correct as far as it goes in the details (or at least it is defensible, last I checked there was still debate as to the validity of the molecular clocks used for Y chromosomal lineages), but it misses the big picture of how we’ve reframed our understanding of the human past over the last few years. The distance between 2011 and 2009 is far greater in this sense than between 2009 and 1999 (or even 2009 and 1989!). The io9 piece is a reflection of the era before the paradigmatic rupture.

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A regular issue that comes up on this weblog is that many of my posts are difficult to understand. I am aware of this. Unfortunately a problem is that there is a wide variation in fluency in genetics knowledge among the readership. To get a better sense I have created a survey with 60+ questions. It may seem like a lot, but the questions go fast because there are only three answers to each, and you should immediately know how to respond. I will likely use these responses to guide me in future “refresher” posts and the like. The questions range from relatively simple to moderately abstruse. That’s by design. Thanks.

Note: The survey will not show up in the RSS, so please click through!

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With DNA Testing, Suddenly They Are Family:

Several companies provide tests that can confirm whether adoptees are related to individuals they already know. Others cast a wider net by plugging DNA results into databases that contain tens of thousands of genetic samples, provided mostly by people searching for their ancestral roots. The tests detect genetic markers that reveal whether people share a common ancestor or relative.

Some experts on adoption and genetics have criticized ancestry and genealogy testing companies, saying they are, at times, connecting people whose genetic links are tenuous — in effect stretching the definition of a relative. Nevertheless, the growing popularity of the tests, combined with social media sites that connect people day to day, has given some adoptees a sense of family that feels tangible, intimate and immediate.

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You may not have noticed, but Google has been spiffing up its Data Explorer. Poking around you see nice illustrations of phenomena which you otherwise may just read about. For example, Argentina has been one of the classic illustrations in economic history of stagnation. To a great extent it peaked around 1900, and development has been erratic since then. This is clear when you see how much its neighbors and other Latin American nations have caught up:

This bar graph illustrates it better:

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Apparently the national media is reporting that scientific genealogy may result in leads to a cold case. The principle is simple: apparently Y chromosomal material was matched to public genealogy databases. From this the researcher concluded that the perpetrator is probably a male line descendant of Robert Fuller of Salem, Massachusetts. Contrary to the urban legends it does not seem that false paternity rates are much higher than ~1 percent in many societies (for example).

CeCe Moore and Blaine Bettinger have covered this story in detail, so I won’t go much further in this specific case. But as more and more people get typed and sequenced I suspect that genetic material is going to be more and more “actionable.” What long term effects will this have? Will criminals start taking precautions?

I haven’t posted one of these in a long time. My own assumption is that I know the core readership of this weblog through various means relating to comments (many of you connect your email addresses to Facebook, and usually I can do an IP trace if that’s not feasible). But I know many people do not comment, so this is an opportunity to “out” yourself and such (also, over the years there has been some talk about “networking” by readers who share common eclectic interests).

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I have seen references to this around the web, and don’t really know if I can believe this, because the details are so disturbing to consider. So I’ll pass it on, You can expect threats if you discuss Sharia:

My One Law for All Co-Spokesperson Anne Marie Waters was to speak at a meeting on Sharia Law and Human Rights at the University of London last night.

It was cancelled by the Queen Mary Atheism, Secularism and Humanism Society organisers after police had to be called in due to Islamist threats. One Islamist filmed everyone at the meeting and announced he would hunt down those who said anything negative about Islam’s prophet. Outside the hall, he threatened to kill anyone who defamed the prophet. Reference was made to the Jesus and Mo cartoon saga at UCL.

The University’s security guard – a real gem –arrived first only to blame the speaker and organisers rather than those issuing death threats. He said: ‘If you will have these discussions, what do you expect?’ Err, to speak without being threatened with death maybe?

A crazy British Muslim threatening to kill someone for defaming the prophet isn’t too surprising. ~3 percent of British Muslim university students think apostates should be killed. What is disturbing is that the establishment institutions are accepting this sort of disproportionate response as normal behavior. As in centuries past it is now the atheists who are by their nature offensive, and disturbing public order.

In the Netherlands the Dutch Muslim Party is going to contest for parliament. It already has some purchase in major cities with large Muslim minorities. Naturally one of its planks is to prosecute those who give offense to religion and religious people. Just jump to article 2.2. Welcome to multiculturalism!

In other news, an atheist has been charged with blasphemy in the world’s largest Muslim nation, where Islam is a moderate religion of peace. Dismay After Indonesian Atheist Charged With Blasphemy:

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