Anthropology.net

The current issue of the Journal of Neurodevelopmental Disorders has published an open access paper announcing the discovery of a new candidate gene linked to language, KIAA0319. The paper is titled, “Convergent genetic linkage and associations to language, speech and reading measures in families of probands with Specific Language Impairment.”

The gene sits on short arm of Chromosome 6. Through linkage analysis, it was found to be associated with variability in language abilities in a study of children with Specific Language Impairment (SLI) and their family members, as well as with variability in speech and reading abilities. Specific alleles were confirmed with association analysis.

“A total of 322 participants, including 86 probands, 134 siblings, and 102 parents and other relatives were tested from an ongoing longitudinal study of Specific Language Impairment… The significant results cluster in the 5’ region of KIAA0319… In particular, we replicate the associated alleles for rs4504469 (allele C); rs761100 (allele G); rs6935076 (allele T) and rs3756821 (allele A).”

It should be noted that KIAA0319 was already linked to dyslexia in previous studies. But, in this paper, the pleiotropic effects of KIAA0318 alleles on language ability, speech impairments, and text comprehension were correlated.

Rice, M., Smith, S., & Gayán, J. (2009). Convergent genetic linkage and associations to language, speech and reading measures in families of probands with Specific Language Impairment Journal of Neurodevelopmental Disorders DOI: 10.1007/s11689-009-9031-x

FOXP2 is one of my favorite genes. I studied it extensively while getting my Master’s degree and wrote about it several times on Anthropology.net. For those that do not know much about it, I’ll quickly introduce it. FOXP2 is a transcription factor gene, which means it controls the expression and regulation of many other genes. It is significant in that it is implicated in human language.

I caught news of a new study on FOXP2 today while reading Nicholas Wade’s article in the New York Times about a hot-off-the-press Max Planck study published in Cell on FOXP2. The study comes from Svante Pääbo‘s lab, who created a strain of transgenic mice with the human FOXP2 variant and noted that these mutant mice made whistles that had a slightly lower pitch than ones with the wild-type FOXP2 gene.

The study has been published as an open access paper under the title, “A Humanized Version of Foxp2 Affects Cortico-Basal Ganglia Circuits in Mice.” There are more findings tucked inside the paper that indicate the impact of the human FOXP2. Aside from the changes in dopamine levels, the most interesting one is the increased axonal and dendritic length of medium spiny neurons in the basal ganglia by 80% when compared to FOXP2^wt. These neurons coordinate the movement and timing of multiple organ systems. Check out the differences for yourself:

Foxp2(hum) Increases the Length of Dendritic Trees

The authors hypothesize on the meaning behind this change in these neurons,

“Currently, one can only speculate about the role these effects may have played during human evolution. However, since patients that carry one nonfunctional FOXP2 allele show impairments in the timing and sequencing of orofacial movements (Alcock etal., 2000,Watkins etal., 2002a), one possibility is that the amino acid substitutions in FOXP2 contributed to an increased fine-tuning of motor control necessary for articulation, i.e., the unique human capacity to learn and coordinate the muscle movements in lungs, larynx, tongue and lips that are necessary for speech (Lieberman, 2006). We are confident that concerted studies of mice, humans and other primates will eventually clarify if this is the case.”

What’s also curious is that the mutant FOXP2 mice don’t seem to have any other effects on other organs, despite the fact that FOXP2 is pretty much ubiquitously expressed all over. It seems like the only manifestations of a human variant showed up in the neuron length and dopamine levels of the brain and ultimately vocalization behaviors. This is an excellent paper which investigates the functional differences of FOXP2, and I recommend you downloading a copy and reading it for yourself.

Today’s issue of Nature has a brief essay on the role of language in cultural evolution. The authors touch up on a lot basics, such as anatomical localization of brain activity related to language and tool making, FOXP2, and how language has helped humans pass on cultural information more effectively than any other form of communication. Overall, it is a well written review that I want to pass on.

Related, Erin from the Spitton, shared news of the identification of a new language related SNP on the gene CNTNAP2. The paper which reports this is titled, “A Functional Genetic Link between Distinct Developmental Language Disorders,” and was published in the New England Journal of Medicine. I believe it is open access, I got to the full text with no problem. The authors hypothesized that neural pathways downstream of FOXP2 can also affect language impairment.

To identify possible downstream candidates that might be involved in typical SLI, the authors transfected a human brain cancer cell line (SH-SY5Y) to continually express FOXP2. FOXP2 is a transcription factor, meaning it is a controller of the expression of other genes. If it is mutated, it can’t regulate its targets properly and leads to different, sometimes mutant, phenotype. The used a type of test called the chromatin immunoprecipitation (ChIP) assay which identifies how and often where proteins, like the FOXP2 transcription factor, bind to specific regions of the genome. This is done by using specific antibodies that recognize a specific protein or a specific modification of a protein, in this situation anti-FOXP2 antibodies.

The ChIP assay showed that the FOXP2 transcription factor binds to a particular, novel region of interest, the first intron of gene CNTNAP2. When transcribed and translated, CNTNAP2 normally encodes for the protein CASPR2 — a protein that is localized and understood to function in the nodes of Ranvier on myelinated neurons. Of further interest, CNTNAP2 is expressed in the human cerebral cortex, specifically the orbital gyrus and superior frontal anlage, spanning the inferior and middle frontal gyri — all regions know to related to language cognition.

To make sure that FOXP2 was for sure targeting this region, and wasn’t mislead due to any conformational changes that came from the antibody it was complexed with, the authors did some PCR and sequencing and saw that this region of interest, intron 1, does have matching known consensus, binding sequence for FOXP2. They did some other tests that shows that this sequence is highly specific to FOXP2… all of which suggests that this site on CNTNAP2 is definitively a binding site for FOXP2 (CAAATT).

The authors next varied the amount of FOXP2 expression and tried to see if it affects the ultimate expression of CNTNAP2. They were able to show there is a correlation — CNTNAP2 transcript levels were lowest where there are higher levels of FOXP2, suggesting that FOXP2 down regulates CNTNAP2. We haven’t know about FOXP2-CNTNAP2 interactions before, because FOXP2-bound fragment of CNTNAP2 is outside of the classically defined regulatory regions that promoter based microarrays identify… So identifying this pathway is very commendable.

With this downstream candidate gene isolated the authors moved to see how polymorphisms in CNTNAP2 manifest language phenotypes. Their population sample was made up from children from 184 different families where at least one child had a specific language impairment (SLI). The children had wildtype FOXP2, but children who carried the guanine nucleotide at rs17236239 SNP on CNTNAP2 had worse scores on a test that measures their ability to reproduce nonsense words like “brufid” and “contramponist.”

Now don’t get me wrong, this SNP, rs17236239, ain’t on intron 1 — where FOXP2 binds. FOXP2 was used as bait to fish out what gene bites to it. When CNTNAP2 was figured out to be a new novel target of FOXP2, the authors tried to see if CNTNAP2 variations also affect language. And they do. What’s also of interest is that other SNPs in the same regaion that rs17236239 is found also have CNTNAP2 as been linked to delayed speech in children with autism.

I’m really impressed with this paper. It’s a gem. Well written and straight forward. I don’t regularly read papers of such caliber, to be honest… So I really appreciate when I do. The new language related gene is also very important as we begin to piece together the complex network of genes and proteins, anatomy and behaviors that have allowed us to have language and use it.

Eörs Szathmáry, Szabolcs Számadó (2008). Being Human: Language: a social history of words Nature, 456 (7218), 40-41 DOI: 10.1038/456040a

S. C. Vernes, D. F. Newbury, B. S. Abrahams, L. Winchester, J. Nicod, M. Groszer, M. Alarcon, P. L. Oliver, K. E. Davies, D. H. Geschwind, A. P. Monaco, S. E. Fisher (2008). A Functional Genetic Link between Distinct Developmental Language Disorders New England Journal of Medicine DOI: 10.1056/NEJMoa0802828

One of my favorite papers from last year was the investigation of FOXP2 allele in Neandertals. It seems like it was one of your favorite papers too, that post gets a lot of hits still! That being said, I think we’ll all appreciate a brand new paper (in works) on this specific topic. It was caught first by Dienekes, and then Razib.

The authors behind the new paper, “The Timing of Selection at the Human FOXP2 Gene,” don’t accept that the FOXP2 allele modern humans and Neandertals carry coulda originated over 300,000 years ago — in a shared common ancestor of both species. Instead, they wonder if the sequence similarity observed is attributed to low rates of gene flow between modern humans and Neandertals, or even contamination.

The issue of contamination was raised last year, at the same time by Sung Kim and Jeffrey Wall, but on a much larger scale… Sung Kim and Jeffrey Wall had beef with quality of the 1 million base pair sequence of Neandertals.

The authors of this new paper,

“collect additional data and introduce a modeling framework to estimate levels of modern human contamination of the Neandertal samples. We find that, depending on the assumptions, additional control experiments may be needed to rule out contamination at FOXP2.”

I don’t have advance access to the manuscript, but from what I can read in the abstract, I know I’ll appreciate it a lot. Why? Well, I’ve personally been doing a lot of research on FOXP2 and know how conserved it is. There are very few differences in the sequence of FOXP2 alleles from chimps and humans, so there maybe even fewer differences in the sequence of FOXP2 alleles of other hominins to humans. The ways Neandertal fossils are collected, even in the most sterile conditions, could introduce modern human DNA that will alter conclusions and the fact that the authors of this new paper hone in on that, is something I look forward to reading.

FOXP2 is thought to be a language gene. It is highly conserved in most mammals but in humans there are two unique mutations in the protein caused by nucleotide substitutions at positions 911 and 977 of exon 7. It is thought to be a language gene because humans who have one FOXP2 copy have speech impediments and deficiencies in orofacial movement.

Now with all the progress in sequencing the genome of Neandertals, it seems like some anthropologists and biologists from Max Planck and institutions in France and Spain got curious about finding out the whether or not Neandertals have the same two mutuations as modern humans do in their FOXP2 gene.

Their work has been published today, in Current Biology under the following title, “The Derived FOXP2 Variant of Modern Humans Was Shared with Neandertals.” Thanks to one of our readers, Hugo, who sent me this paper I’ve had a chance to read this outstanding paper. Now, if you’ve been keeping track of the Neandertal genome project, I know what you’re thinking, “What about the inconsistencies with Neandertal sequences!?!”

Well the authors, Johannes Krause and team, were very careful about this from the beginning. They made sure the two bones from El Sidrón cave in Asturias were extracted under sterile condition. They also amplified the FOXP2 gene using Neandertal specific primers. That was done so that little to no modern human genes shoulda been targeted for amplification.

After a whole lot of cycles, sequencing, and alignment, the team found out that the Neandertals carried FOXP2 that was identical to that of present-day humans in the only two positions that differ between human and chimpanzee. Speicifcally, at position 911 on exon 7 of the Neandertal FOXP2, threonine is swapped for aspartic acid just like humans and also at position 977 of the Neandertal FOXP2, arginine replaces serine… just like in humans. Sending the samples to other lab to reproduce the experiments yielded the same results.

While the authors are a bit cautious, saying that the whole genome of the Neandertal will provide much more resolution in comparing FOXP2 genes, I do want to point out that this new finding messes up the results of Pääbo, who showed that the mutations in FOXP2 in modern humans were very recent, maybe less than 200,000 years ago in 2002. The authors kinda sorta challenge Pääbo’s conclusion,

“Leaving out the unlikely scenario of gene flow [between the two lineages], this establishes that these changes were present in the common ancestor of modern humans and Neandertals. The date of the emergence of these genetic changes therefore must be older than that estimated with only extant human diversity data, thus demonstrating the utility of direct evidence from Neandertal DNA sequences for understanding recent modern human evolution.”

So the common ancestor of Neandertals had this unique allele of FOXP2. Does that mean they had language capabilities? Does this mean Neandertals had language capabilities… I’d sure hope so because at this point in human evolution, erectines like Neandertals and their culture were widespread. Their ability to communicate in some higher form or another was crucial for their ubiquity in Europe and Asia.