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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Image via Wikipedia The evolution of language sometimes seems like a sort of jewel in the evolutionary crown of homo sapiens. Evidence of positive selection in the verbal dyspraxia FOXP2 gene, is often discussed with amazement and a reverential tone befitting this special evolutionary achievement. Enter the humble zebra finch – who’s songs and language articulation could teach Sinatra a thing or two. Haesler and colleagues use short-hairpin RNAs to interfere with the zebra finch homolog of FOXP2 in a brain area known as ‘area x’ (functionally equivalent to the human striatum) where the gene is upregulated during the late summer when males must belt out their best version of Strangers in the Night to woo the females. In their paper, “Incomplete and Inaccurate Vocal Imitation after Knockdown of FoxP2 in Songbird Basal Ganglia Nucleus Area X“, (DOI) the research team finds that young zebra finches with lower expression of FOXP2 have difficulty learning new songs and are less able to articulate specific sounds and lyrical blurbs. These difficulties are much like the difficulties experienced by human children who carry mutations in FOXP2.
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- Image by pfv. via Flickr
The acquisition of language in humans remains a complex and fascinating mystery from both a neuro- and evolutionary-biological perspective. Attempts to identify genetic regulators of neural processes that are involved in language acquisition have the potential to shed light, not only on the natural history of homo sapiens, but also, to help understand the complex neurodevelopmental disorder, Autism, often associated with profound language impairments. So, it is very exciting to read, “Genome-wide analyses of human perisylvian cerebral cortical patterning” by Abrahams et al., (DOI) who examined human gene expression in frontal vs. superior temporal cortex at a developmental period where neurogenesis and neuronal migration are particularly active. The authors went looking for differential gene expression during a critical developmental time point and in a critical brain region – since the superior temporal cortex is an area that is reliably activated by linguistic tasks as well as social cognition tasks. According to the article, a total of 345 differentially expressed genes were identified, with 61 enriched and 284 down-regulated in superior temporal cortex across two microarray platforms, with 13 genes identified by both microarray array platforms. One of the genes identified is LDB1, a regulator of the asymmetrically expressed LIM domain-only 4 (LMO4) a known mediator of calcium-dependent transcription in cortical neurons and known to regulate thalamocortical connectivity. Another gene, CNTNAP2, a member of the neurexin transmembrane superfamily of proteins that mediate cellular interactions in the nervous system has been previously associated with autism. Both of these genes seem to have important developmental roles and should provide access to the fine-scale wiring that occurs during the development of neural networks involved in language.
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Posted in ASPM, MCPH1, tagged evolution, language on November 21, 2007|
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Comparisons of human genome variation within and across closely related species have great potential to reveal ways in which the brain and mind of modern humans may or may not have differed from our hominid ancestors. Such comparisons have recently revealed a great many genomic targets of natural selection, some of which are expressed in the developing brain, and, hence, might provide clues to the mental life of our ancestors. Variation in two such candidates ASPM (rs964201) and MCPH1 (rs2442496) arose approximately 50,000 years ago and show strong positive selection in the lineage leading to humans. What do these genes and common variants do ? Do they affect language acquisition ? Social behavior ? Intelligence ? Any type of process that might smack of something uniquely ‘human’ ? In their paper [DOI], “Investigation of MCPH1 G37995C and ASPM A44871G polymorphisms and brain size in a healthy cohort“, Dobson-Stone et al., used structural MRI to determine whether differences in whole brain volume or grey matter volume might relate to either or both of these variants. Although no evidence was found that relate these common variants (rare mutations can cause microcephaly) their methodological approach seems like a fantastic strategy for gaining insights into our human origins.
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Image by wallyg via Flickr Can you say this 5 times quickly, “secreted sushi containing SRPX2 as a source of sylvian seizures seems like a spandrel” ? Well, if you can, you might say thanks to your FOXP2 gene (much ado recently), but of course its important to say thanks to so many other co-evolutionary substitutions. A recent article by Royer et al. (doi:10.1186/1471-2156-8-72) examines the recent evolution of the SRPX2 gene and found an R75K change that marks a human-primate split and also occurs in an important functional loop of the first sushi domain of SRPX2 (one that carries a mutation that is responsible for sylvian seizures involving oral and speech dyspraxia). Although they did not find evidence for positive selection, its easy to suspect that Lysine-75 plays an important supporting role in our tongue-twisting skills.
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