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Friday, August 27, 2010

Coloured hearing in Williams syndrome


The idea that our genes can affect many of the traits that define us as individuals, including our personality, intelligence, talents and interests is one that some people find hard to accept. That this is the case is very clearly and dramatically demonstrated, however, by a number of genetic conditions, which have characteristic profiles of psychological traits. Genetic effects include influences on perception, sometimes quite profound, and other times remarkably selective. A recent study suggests that differences in perception in two conditions, synaesthesia and Williams syndrome, may share some unexpected similarities.

Williams syndrome is a genomic disorder caused by deletion of a specific segment of chromosome 7. Due to the presence of a number of repeated sequences, this region is prone to errors during replication that can result in deletion of the intervening stretch of the chromosome, which contains approximately 28 genes. The disorder is characterised by typical facial morphology, heart defects and a remarkably consistent profile of cognitive and personality traits. These include mild intellectual disability, with relative strength in language and extreme deficits in visuospatial abilities (including being able to perceive the relationships of objects in 3D space and to construct and mentally manipulate 3D representations). Williams patients are also highly social – often to the point of being over-friendly – empathetic and very talkative. This behaviour may belie a high level of anxiety, however.

One of the most remarkable features of Williams syndrome is the strong attraction of patients for music. Many show a strong interest in music from an early age and greater emotional responses to music. They are also more likely to play a musical instrument, some using music to reduce anxiety. A recent study from Elisabeth Dykens and colleagues adds a new twist to this story. They found in a neuroimaging experiment that in addition to activating the auditory cortex, music also stimulates visual activity and perceptions in Williams patients. In fact, this is not specific to music – non-musical sounds had the same or even stronger effects.

This is very reminiscent of what happens in a form of synaesthesia, called “coloured hearing”. In this condition, which is also heritable, sounds, sometimes specifically music or words, sometimes general sounds, are accompanied by a visual percept. These percepts are typically fairly simple – patches of colour, for example – and can be experienced out in the world or “in the mind’s eye”. (They are alternatively sometimes felt more as an “association” with a visual property, so that the sound of a trombone might be blue, while a piano might be green). Importantly, these visual percepts are both idiosyncratic and extremely consistent – middle C may evoke the image of a small purple cloud, a dog’s bark may set off yellow starbursts, etc.

Neuroimaging experiments in synaesthesia have also found activation of visual areas in response to sounds. Various models have been proposed to account for this, which I have discussed previously. They all involve cross-activation from auditory circuits to those that represent visual information. This may be mediated by extra physical connections in the brains of synaesthetes, presumably due to genetic effects on how the brain is wired during development. Alternatively, the wires could be there in everyone but just working differently in synaesthetes. It has so far been very difficult to distinguish between these possibilities.

The situation in Williams syndrome may be much more amenable to investigation. Unlike synaesthesia, we know what the genetic cause is in Williams syndrome. We know which genes are deleted and researchers are beginning to dissect which ones are associated with which symptoms. Some of these genes are known to function in nerve growth and guidance. It has also been demonstrated very clearly using diffusion tensor imaging that there are large differences in various circuits in the brains of Williams patients, including the presence of additional fibre bundles to or from the intraparietal sulcus, a region involved in visuospatial construction. It will be very interesting to determine whether similar extra connections can be detected between auditory and visual areas.

It is important to recognise, however, some crucial differences between the auditory-visual effects observed in Williams syndrome and in synaesthesia. The visual percepts reported in Williams syndrome are far more complex than those reported in synaesthesia. The former reportedly involve objects and scenes, more like a dreamscape than a simple blob of colour. They also lack the consistency which is one of the defining characteristics of synaesthesia. There may thus be more than one way to end up with coloured hearing.

Whatever the cause in these conditions, they both highlight the fact that genetic differences can have profound effects on how people perceive the world.

Thornton-Wells, T., Cannistraci, C., Anderson, A., Kim, C., Eapen, M., Gore, J., Blake, R., & Dykens, E. (2010). Auditory Attraction: Activation of Visual Cortex by Music and Sound in Williams Syndrome American Journal on Intellectual and Developmental Disabilities, 115 (2) DOI: 10.1352/1944-7588-115.172

Marenco, S., Siuta, M., Kippenhan, J., Grodofsky, S., Chang, W., Kohn, P., Mervis, C., Morris, C., Weinberger, D., Meyer-Lindenberg, A., Pierpaoli, C., & Berman, K. (2007). Genetic contributions to white matter architecture revealed by diffusion tensor imaging in Williams syndrome Proceedings of the National Academy of Sciences, 104 (38), 15117-15122 DOI: 10.1073/pnas.0704311104

Friday, August 20, 2010

When to blame your parents, and for what


Studies linking some aspect of parental behaviour with some trait in their offspring are depressingly common in the sociological literature. Though these studies typically only report a correlation between parental behaviour and whatever the trait is in the offspring, the implication, and often the explicit conclusion, is that one causes the other. These kinds of stories get huge play in the popular press (and in the blogosphere), where the conclusion of a causative relationship is rarely challenged. For example, the finding that children who grow up with more books in the house are more successful academically is taken as evidence that simply having books around makes kids smarter.

This kind of thinking illustrates a common and fundamental flaw in interpreting sociological or epidemiological findings – correlation does not imply causation. Red hair and freckles are highly correlated but one does not cause the other. Both are caused by something else (a mutation in a gene controlling pigmentation). It seems a simple enough distinction but it is astonishing how pervasive this mistake is, even among academics supposedly trained in statistical methodology.

In the case of books, the conclusion that having them around is the causative factor on academic success is simply not warranted by the findings. The data from this kind of study design do not pertain to that question. The books could simply be an indicator of the real cause (like freckles). It seems quite possible that the underlying link is between the IQ of the parents (or some other cognitive trait predicting both academic success and bookishness – curiosity, open-mindedness, interest in more abstract topics) and that of their children. (It is well established that such traits are quite heritable).

I am not claiming that that actually is the explanation – just that it is a highly plausible one that must be considered. In fact, the study design does not permit this conclusion to be drawn either, and that illustrates one of the major problems in dissecting the possible effects of nature and nurture. It is hugely difficult to separate confounding genetic effects on behaviour of both parents and offspring from the effects of the behaviours themselves. Adoption studies – especially of identical twins reared apart – do provide one way to dissociate genetic effects from those of the family environment. These have consistently found large effects of shared genes and very little effect of family environment on a wide range of behavioural traits.

A far more tricky task is to dissociate the effects of parental behaviour prior to birth on the future behaviour of their offspring – adoption studies obviously cannot accomplish that. However, researchers in Cardiff, led by Anita Thapar, have come up with a clever and powerful new study design which does the trick. They have made use of the growing frequency of in vitro fertilisation to examine the effects of smoking during pregnancy. It is well known that smoking during pregnancy is associated with low birth weight and a number of other health issues. It is also associated with higher rates of antisocial behaviour in the offspring. Do these correlations really reflect the effects of smoking itself or could smoking be an indicator of a distinct underlying cause?

The IVF study design, which looked at records of 779 children, allowed these factors to be dissociated by splitting the mothers into two groups – those who were biologically related to their offspring and those who had used donor eggs and thus were unrelated to their offspring. These two groups were then examined for a correlation between the smoking behaviour of the mother during pregnancy and the birth weight and a measure of antisocial behaviour of their offspring. The findings were remarkably clear – smoking was associated with lower birth weight regardless of genetic relatedness. This effect is congruent with results from experimental animal studies on the effects of nicotine, cigarette smoke or carbon monoxide on birth weight and there are a variety of biological mechanisms postulated to explain the effect. So, all the evidence is consistent with this being a genuine effect of prenatal smoking per se.

But a very different picture was observed with respect to antisocial behaviour. High rates of antisocial behaviour were observed only in those mothers who smoked during pregnancy and who were related to their offspring. So, prenatal smoking itself does not seem to influence antisocial behaviour – it is more likely an indicator of some underlying genetic effect on behaviour of both the mother and the offspring. (See here for more on this).

So, smoking while pregnant is bad, mkay, for lots of reasons, but it will not make your child antisocial. And I would never argue against having books around, but articles proclaiming “Want smart kids? Here’s what to do” are uncritically promulgating an unfounded conclusion (also known as “talking shite”).


Evans, M., Kelley, J., Sikora, J., & Treiman, D. (2010). Family scholarly culture and educational success: Books and schooling in 27 nations Research in Social Stratification and Mobility, 28 (2), 171-197 DOI: 10.1016/j.rssm.2010.01.002

Rice, F., Harold, G., Boivin, J., Hay, D., van den Bree, M., & Thapar, A. (2009). Disentangling prenatal and inherited influences in humans with an experimental design Proceedings of the National Academy of Sciences, 106 (7), 2464-2467 DOI: 10.1073/pnas.0808798106

Friday, August 13, 2010

Defining developmental disorders through genetics


To many people, the term “autism” suggests a specific disorder – one with characteristic and recognizable symptoms, presumably reflecting the same underlying cause.  In fact, no such disorder exists.  Autism refers to a variable spectrum of symptoms – including deficits in social interaction, impaired communication (especially a delay in developing language), narrow, restricted interests and stereotyped behaviours.  Any one child who is diagnosed with autism may show only some of these symptoms.  There is a wide range of IQ in autism, including very high levels seen in what has been known as Asperger’s syndrome, but the average is about 70.  There is also a high incidence of epilepsy (around 10%).

Psychiatrists have long recognized this variability and use the term “autism spectrum disorder” to encompass the entire range.  Until recently, with a couple of exceptions, they have not had the means to distinguish different subtypes of autism based on their underlying cause.  One of these exceptions, which has been known for some time, is the gene responsible for Fragile X syndrome.  Routine screening for Fragile X mutations allows pediatric psychiatrists to define up to 5% of autism referrals as arising from this cause.  We now know that the symptoms of autism can be caused by a mutation in any of a large number of different genes (or by mutations which affect several adjacent genes on a chromosome). 

Screening for the latter type of mutation – deletions or duplications of several genes, collectively called copy number variants – is already being proposed as a routine step of clinical genetic testing in patients presenting with symptoms of autism.  These mutations are easy to detect but will probably be responsible for no more than 10% of cases.  Point mutations – changes to a single base of DNA – are likely to account for the rest.  Fortunately, it is now possible to sequence the entire genome, or at least the entire “exome” – the part of the genome that codes for proteins – in an individual for about 3,000 dollars and in under a week.  A far cry from the 3 billion dollars and ten years it took to sequence the first human genome! 

This approach has already been used to identify mutations in genes on the X chromosome in autism or schizophrenia cases but can now be extended to the entire genome.  It will not always be obvious which mutation is causative in any individual, and we should expect a good deal of complexity due to combinations of mutations, but it should at least be possible to identify a primarily responsible mutation in a large proportion of cases. 

The obvious question then is whether mutations in different genes are associated with distinct profiles of symptoms.  By grouping together patients with mutations in the same locus, it may be possible to recognise specific profiles of symptoms that are otherwise obscured by variability among carriers and phenotypic overlap with other patients.  This approach has been used very successfully in diagnosing cases of mental retardation, intellectual disability or other forms of developmental delay based on genetic lesion and has led to the identification and clinical characterisation of many new, distinct neurodevelopmental syndromes.

The first study to attempt this in autism spectrum disorder has been published recently by Bruining and colleagues.  They looked at cases of autism due to Klinefelter syndrome (caused by an extra X chromosome in males: XXY), deletion in a region of chromosome 22 (22q11) or a group with unknown causes.  By analyzing the profile of a list of clinical symptoms across these groups they were able to distinguish the Klinefelter and 22q11 cases from each other and from the cases with unknown etiology.  There is still a lot of variability in each type and substantial overlap between them in “clinical symptom space”, but the carriers of specific mutations are significantly more similar in profile to each other than to the general cases. 

This knowledge is tremendously useful in several ways.  First, it becomes possible to make clinical predictions about an individual’s prognosis, by comparison with other carriers of the same mutation.  Second, it allows prediction of genetic risk to relatives – this can be hugely important to parents of an autistic child who are considering having additional children.  Third, identification of the mutated gene is the first step to elucidating the underlying defect at a neurobiological level.  Ultimately, this may suggest routes to therapies which are rationally designed and personalised. 

The promise of new therapeutics is illustrated by progress in understanding the biology underlying Fragile X syndrome.  The fragile X gene encodes a protein, FMR1, which functions in nerve terminals to hold a set of RNA molecules in a state where they are ready to be translated into protein when the synapse is active.  The new proteins are needed when a synapse has to be strengthened after use (a core mechanism of learning).  Another protein, a glutamate channel called mGluR1, performs the opposing function – when activated it signals for these mRNAs to be translated.  If the FMR1 protein is mutated then the RNA molecules get translated too early.  This effect can be counter-balanced by turning down the activity of the mGluR1 protein.  Remarkably, this results in very significant amelioration of the “symptoms” of FMR1 deletion in a mouse model of Fragile X syndrome.  These results are so impressive that drugs to block mGluR proteins are now in small-scale clinical trials of human Fragile X patients. 

This example illustrates how discovery of the responsible gene and elucidation of its functions at a molecular level can suggest highly specific ways to correct or compensate for the effect of the mutation, specifically in those patients with that lesion.  We can expect this kind of approach to be similarly successful in discriminating patients with other disorders such as schizophrenia or epilepsy into genetically distinct subgroups.  This promises to radically transform how patients with these diverse symptoms are diagnosed and treated – no longer lumped together into categories of questionable validity and usefulness, but based on their individual genetic profile. 

 

Shen, Y., Dies, K., Holm, I., Bridgemohan, C., Sobeih, M., Caronna, E., Miller, K., Frazier, J., Silverstein, I., Picker, J., Weissman, L., Raffalli, P., Jeste, S., Demmer, L., Peters, H., Brewster, S., Kowalczyk, S., Rosen-Sheidley, B., McGowan, C., Duda, A., Lincoln, S., Lowe, K., Schonwald, A., Robbins, M., Hisama, F., Wolff, R., Becker, R., Nasir, R., Urion, D., Milunsky, J., Rappaport, L., Gusella, J., Walsh, C., Wu, B., Miller, D., & , . (2010). Clinical Genetic Testing for Patients With Autism Spectrum Disorders PEDIATRICS, 125 (4) DOI: 10.1542/peds.2009-1684

Piton, A., Gauthier, J., Hamdan, F., Lafrenière, R., Yang, Y., Henrion, E., Laurent, S., Noreau, A., Thibodeau, P., Karemera, L., Spiegelman, D., Kuku, F., Duguay, J., Destroismaisons, L., Jolivet, P., Côté, M., Lachapelle, K., Diallo, O., Raymond, A., Marineau, C., Champagne, N., Xiong, L., Gaspar, C., Rivière, J., Tarabeux, J., Cossette, P., Krebs, M., Rapoport, J., Addington, A., DeLisi, L., Mottron, L., Joober, R., Fombonne, E., Drapeau, P., & Rouleau, G. (2010). Systematic resequencing of X-chromosome synaptic genes in autism spectrum disorder and schizophrenia Molecular Psychiatry DOI: 10.1038/mp.2010.54

Bruining H, de Sonneville L, Swaab H, de Jonge M, Kas M, van Engeland H, & Vorstman J (2010). Dissecting the clinical heterogeneity of autism spectrum disorders through defined genotypes. PloS one, 5 (5) PMID: 20526357

Monday, August 9, 2010

Migrating neurons clear their path


Most neurons in the brain are not born in their final position – they are generated by cell division in one part of the brain and have to migrate, sometimes over long distances, along complicated routes, to finally arrive at their pre-specified destination.  This process entails an incredibly complex and dynamic set of genetic instructions and interactions between different cell types. 

A prime example is the migration of interneurons to the cerebral cortex – these inhibitory neurons make up one half of a balancing act that controls all cognitive functions in the cortex, but, unlike the excitatory neurons of the cortex, they are born in a completely different part of the brain (what will become the striatum).  Many researchers have been trying to understand how these neurons find their way specifically to the cortex.  A number of genes have been found which encode guidance cues which can attract or repel the migrating neurons and which mark out their correct pathway.  These cues are sensed by the receptor proteins expressed on the surface of the migrating neurons.  This basic mechanism has been at the core of most models of neuronal cell migration. 

A new paper adds a surprising new twist to this story, one that may be especially important for the migration of neurons generated in the adult brain.  One of the major sites of generation of new neurons in adults is called the sub-ventricular zone (SVZ), where an actively dividing population of neural stem cells persists in adults.  New neurons born here are destined to repopulate the olfactory bulbs – structures at the very front of the brain which receive information from odorant receptor neurons – where there is a high rate of turnover of neurons (in contrast to most of the brain). 

The migration of these new neurons from the SVZ occurs along a very discrete route called the rostral migratory stream (RMS).  One challenge for the migration of these neurons is that the mature cellular structures in the adult brain present a physical and molecular barrier to their movement.  This is a similar problem faced by nerve fibres trying to regenerate in the adult spinal cord or brain – as the nervous system matures, glial cells (a type of non-neuronal cell that outnumber neurons by about 10:1) begin to form an environment which actively restricts the movement of cells and the growth of new axons.  This makes some sense as a mechanism to keep everything in place once the complicated manoeuvres of neural development have been completed.  

The migrating neurons in the RMS thus have some hostile terrain to cross.  It now turns out that they accomplish this by turning the tables on the cells in their environment.  Rather than simply responding to attractive or repulsive cues that they encounter, they actively secrete a repulsive molecule themselves, which helps to clear out glial cells from their path.  These star-shaped glial cells, called astrocytes, then form a tunnel through which the migrating cells are free to pass.  If the migrating neurons do not make the repulsive protein, called Slit-1, or the astrocytes do not express the receptors for this protein (Robo-1 and -2), then the neurons cannot clear this pathway and many fail to reach their destination. 

This mechanism is a nice example of a reversal of a prominent paradigm – of course, these neurons are still themselves guided by other cues in their environment, but this adds a new and unexpected twist to the story.  More importantly, perhaps, it could have general implications as a mechanism to encourage the migration of new neurons or of damaged nerve fibres in the adult nervous system.  If such neurons can be encouraged to express a path-clearing molecule like Slit-1, their chances of successful navigation or regrowth may be greatly enhanced.  

 

Kaneko N, Marín O, Koike M, Hirota Y, Uchiyama Y, Wu JY, Lu Q, Tessier-Lavigne M, Alvarez-Buylla A, Okano H, Rubenstein JL, & Sawamoto K (2010). New Neurons Clear the Path of Astrocytic Processes for Their Rapid Migration in the Adult Brain. Neuron, 67 (2), 213-223 PMID: 20670830

 

 

 

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