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The A-to-T SNP rs7794745 in the CNTNAP2 gene was found to be associated with increased risk of autism (see Arking et al., 2008).  Specifically, the TT genotype, found in about 15% of individuals, increases these folks’ risk by about 1.2-1.7-fold.  Sure enough, when I checked my 23andMe profile, I found that I’m one of these TT risk-bearing individuals.  Interesting, although not alarming since me and my kids are beyond the age where one typically worries about autism.  Still, one can wonder if such a risk factor might have exerted some influence on the development of my brain?

The recent paper by Tan et al., “Normal variation in fronto-occipital circuitry and cerebellar structure with an autism-associated polymorphism of CNTNAP2” [doi:10.1016/j.neuroimage.2010.02.018 ] suggests there may be subtle, but still profound influences of the TT genotype on brain development in healthy individuals.  According to the authors, “homozygotes for the risk allele showed significant reductions in grey and white matter volume and fractional anisotropy in several regions that have already been implicated in ASD, including the cerebellum, fusiform gyrus, occipital and frontal cortices. Male homozygotes for the risk alleles showed greater reductions in grey matter in the right frontal pole and in FA in the right rostral fronto-occipital fasciculus compared to their female counterparts who showed greater reductions in FA of the anterior thalamic radiation.”

The FA (fractional anisotropy – a measurement of white-matter or myelination) results are consistent with a role of CNTNAP2 in the establishment of synaptic contacts and other cell-cell contacts especially at Nodes of Ranvier – which are critical for proper function of white-matter tracts that support rapid, long-range neural transmission.  Indeed, more severe mutations in CNTNAP2  have been associated with cortical dysplasia and focal epilepsy (Strauss et al., 2006).

Subtle changes perhaps influencing long-range information flow in my brain – wow!

More on CNTNAP2 … its evolutionary history and role in language development.

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Walter Dean Myers, an author of The Young Landlords and many other classic coming of age novels once remarked, “The special place of the young adult novel should be in its ability to address the needs of the reader to understand his or her relationships with the world, with each other, and with adults.”  Indeed, the wonderful elaborations of psychosocial development that occur during the teenage years makes for a vivid and tumultuous time – worthy of many a book – especially those like Myers’ that so help adolescents to cope.  During this time, a child’s brain and body is supplanted by adult systems, which, from a physiological point of view, place the adolescent’s mind and body at the mercy of thousands of shifting biochemical processes.  Such a notion of the shifting sands of adolescence were brought to mind while reading a research article focused on one – just one single example – of biochemical change.

The paper entitled, “Cortico-striatal synaptic defects and OCD-like behaviors in SAPAP3 mutant mice” [doi: 10.1038/nature06104] points out that mice who lack the function of the post-synaptic density scaffolding protein encoded by the SAPAP3 gene display excessive grooming and other behaviors reminiscent of obsessive compulsive disorder – a condition that frequently emerges during adolescence.  One of the main findings of the paper is that a normal developmental shift of NR2B –> NR2A subunits of the NMDA receptor does NOT seem to occur – rendering the SAPAP3 mutant mice with an immature form of NMDA receptor.  The authors suggest that this may be the underlying reason for the aberrant behavior, and were able to normalize the mutant mice by re-introducing SAPAP3 protein via a lentiviral-mediated expression vector placed in the striatum.

Gosh.  This NR2B –> NR2A shift is just one example – one grain – in the shifting biochemical sands of development.  Just one of thousands.  How did my brain ever make it through?

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Just a pointer to onetime University of Edinburgh Professor C.H. Waddington’s 1972 Gifford Lecture on framing the genes vs. environment debate of human behavior.  Although Waddington is famous for his work on population genetics and evolutionary change over time, several of his concepts are experiencing some resurgence in the neuroimaging and psychological development literatures these days.

One term, CHREOD, combines the Greek word for “determined” or “necessary” and the word for “pathway.” It describes a system that returns to a steady trajectory in contrast to homeostasis which describes a system which returns to a steady state.  Recent reviews on the development of brain structure have suggested that the “trajectory” (the actual term “chreod” hasn’t survived) as opposed to any specific time point is the essential phenotype to use for understanding how genes relate to psychological development.  Another term, CANALIZATION, refers to the ability of a population to produce the same phenotype regardless of variability in its environment or genotype.  A recent neonatal twin study found that the heritability of grey matter in neonatal humans was rather low.  However it seems to then rise until young adulthood – as genetic programs presumably kick-in – and then decline again.  Articles by neurobiologist Jay N. Giedd and colleagues have suggested that this may reflect Waddington’s idea of canalization.  The relative influence of genes vs. environment may change over time in ways that perhaps buffer against mutations and/or environmental insults to ensure the stability and robustness of functions and processes that are both appropriate for survival and necessary for future development.  Another Waddington term, EPIGENETIC LANDSCAPE, refers to the limitations on how much influence genes and environment can have on the development of a given cell or structure.  Certainly the environment can alter the differentiation, migration, connectivity, etc. of neurons by only so much.  Likewise, most genetic mutations have effects that are constrained or compensated for by the larger system as well.

Its amazing to me how well these evolutionary genetic concepts capture the issues at the nexus of of genetics and cognitive development.  From his lecture, it is clear that Waddington was not unaware of this.  Amazing to see a conceptual roadmap laid out so long ago.  Digging the book cover art as well!

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Day 191 - Stick it Out

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Like “Joe the Plumber” (whose real name is Samuel), CNTNAP2 (whose real name is CASPR2) has achieved a bit of fame lately.  While recently appearing almost everywhere (here, here, here) except FOX News, CNTNAP2 (not Joe the Plumber) is apparently a transcriptional target of the infamous FOXP2 “language gene” – so says Sonja C. Vernes & colleagues [doi: 10.1056/NEJMoa0802828] who precipitated DNA-protein complexes using anti-FOXP2 antibodies from a cell line transiently expressing FOXP2. The team later evaluated measures of expressive and receptive language abilities and nonsense-word repetition and found that a series of snps – most significantly rs17236239 – were associated with performance of children from a consortium of families at risk for language impairment.  This adds to several previous reports of CNTNAP2 and risk for autism, a disorder where language ability is severely impaired.

So what’s all the fuss ? How can something so insignificant (rs17236239 not Joe the Plumber) stir up so much trouble ?  Well, as reported in a previous post, the expression of CNTNAP2 in the developing superior temporal cortex may be a relevant clue since this brain region is activated by language tasks.  Also, this gene encodes a rather massive protein which (as reported by Coman et al.,) seems to participate in the establishment of myelination and “nodes” that permit rapid neural transmission and long-range coordination across neural structures in the brain. Interestingly, this gene shows evidence for recent positive selection in humans (as posted on here and here) although the newly derived G-allele at rs17236239 seems to be the allele that is causing the language difficulties.  My own 23andMe profile shows a middling A/G here which makes it slightly hard to recall and repeat “Samuel Wurzelbacher”.

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