Tracing origin of Human language using Humanized version of Foxp2 in Mice
Foxp2 gene was identified as gene involved in speech and language disorders, after studying an extended family referred to as KE. Over three generations of this family, about half the family members suffer from a number of problems, the most obvious of which is severe difficulty in speaking. The scientists could narrow down to Chromosome 7 by studying members of KE family ,but it was the comparison of the KE family data with that of another patient outside the family led them to discovery of Foxp2 gene. These findings of Lai et al; were published in Nature journal on October 4, 2001.
Background:
The Foxp2 gene encodes a transcription factor containing a polyglutamine tract and forkhead DNA-binding domain. Mutation in conserved DNA binding forkhead domain was responsible for extreme speech and language disorder condition in both KE family and unrelated patient. Foxp2 is not the only gene responsible for language development, but rather a component of a complex network of interacting proteins and genes. Foxp2 gene expresses in other tissues also apart from brain in early developing embryo and plays a vital role in various processes. There are different alternate splice forms of Foxp2 gene and major form is 715 amino acids long. This Foxp2 transcription factor is highly conserved in other species(even in animals which lack sophisticated speaking skills like humans) and a 100% conservation is observed when Foxp2 genes of chimpanzee, gorilla and rhesus monkey are compared. The mouse FOXP2 differs in just one amino acid from these three species. However Human Foxp2 show two additional changes in amino acids when compared to chimpanzee, gorilla and only three out of 715 amino acids differ between Mice and humans. So, in 75 million years since the divergence of mouse and chimpanzee lineages only one change has occurred in Foxp2 and in the six million years since the divergence of man and chimpanzee lineages two changes have occurred in the human lineage.This speaks volume about the strong positive selection on FOXP2 gene during evolution.
Humanized Foxp2 in Mice : Latest article in cell journal
As mentinoed in the introduction mutations in Foxp2 gene leads to developmental defects especially affecting speech and language in humans. However to proving their involvement in human specific phenotype is difficult task as genetic manipulations is out of question in humans and rather impossible in chimpanzees also. Analysis of Foxp2 genes has shown two amino acids changes between chimps and humans and only one conservative amino acid change between Mice and Chimps , which provides an opportunity to be used as model for ancestral human Foxp2 gene. These two amino acids changes between humans and chimps always could be involved in our speech and language skills, but till no one were able to decipher their role. However with Foxp2 of Mice being almost similar to that of chimps (with only one conservative mutation ), Wolfgang Enard and co authors modified the mice Foxp2 by introducing two human specific amino acids and used this humanized version of Foxp2 in Mice for their experiments. This provided scientists with an opportunity to study how human Foxp2 gene functions in vivo. This study indicates that mice can not only be used to study diseases, but also can be used for studying our own history.
The results show that the human form of the FOXP2 gene increases synaptic plasticity and dendrite connectivity in the basal ganglia.These experiments for the first time show that the human-specific amino-acid changes do indeed have functional effects, and that they are particularly relevant to the brain.Although FoxP2 is active in many other tissues of the body, the altered version did not appear to have other effects on the mice, which appeared to be generally healthy.
Ed Yong has few remarkable articles on his blog “Not Exactly Rocket Science” related to language gene Foxp2 .
References :
1) Lai et al, ‘A forkhead-domain gene is mutated in a severe speech and language disorder’, Nature 413, 519 – 523 (2001)
2) Enard et al. A Humanized Version of Foxp2 Affects Cortico-Basal Ganglia Circuits in Mice. Cell, 2009; DOI: 10.1016/j.cell.2009.03.041
Image Credit : Wikimedia commons
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