FOXP2 , verbal dyspraxia, and the evolution of human language
Andrew Tritt
Verbal Dyspraxia
Speech disorder affecting individuals ability to correctly pronounce sounds, syllables, and words
Inconsistent speech
Trouble ordering things (not just speech)
Difficulty learning how to read and spell
Difficulties with other motor tasks
Estimated 5-20% affected
Jewel and Brush
FOXP2 – forkhead box P2
715 AA, 78900.04 Da, located on chromosome 7
Gene Ontology: Biological processes
Caudate nucleus development Putamen development
Molecular function DNA binding Protein homodimerization
Cellular component Nucleus
FOXP2 – forkhead box P2
Member of forkhead box transcription factors Subgroup of helix-turn-helix class Forkhead box (a.k.a. winged-helix)
Mutations in FOXP2 linked to verbal dyspraxia Also thought to play a role in autism
Linked to: Song in song-birds Echolocation in bats Pattern learning in mice
Forkhead box proteins
FOXA1, FOXA2, FOXA3 FOXB1, FOXB2 FOXC1, FOXC2 FOXD1, FOXD2, FOXD3, FOXD4, FOXD5,
FOXD6
FOXE1, FOXE2, FOXE3 FOXF1, FOXF2 FOXG1 FOXH1 FOXI1, FOXI2 FOXJ1, FOXJ2, FOXJ3 FOXK1, FOXK2 FOXL1, FOXL2 FOXM1 FOXN1, FOXN2, FOXN3, FOXN4 FOXO1, FOXO2, FOXO3, FOXO4 FOXP1, FOXP2, FOXP3, FOXP4 FOXQ1 FOXR1, FOXR2
Image from http://www.neuroscience.ox.ac.uk/directory/simon-fisher
Protein structure
Leucine-zipper domain Required for dimerization
Forkhead box domain Required for DNA recognition Mutations here linked to disease
Similar in other organisms Polyglutamine tract
Image from SMART
Protein Structure
Protein highly conserved given phylogenetic distance
Mouse
Human
Zebra finch
Images from SMART
Why FOXP2?
KE family 30 members
across three generations
Roughly half of the family members have impairment
Correlation between FOXP2 and impairment
Genetic origins of language
Image from http://www.well.ox.ac.uk/~simon/SPCH1/index.shtml
Root of Human Language
Two mutations since divergence of chimp and humans
Fixation estimated to be within last 200,000 years
Show signs of natural selection
Some targets show signs of natural selectionImage from
http://www.imagingnotes.com/go/article_free.php?mp_id=1&Udo
Phylogeny
Wooly horseshoe bat and zebra finch ???
Done using parsimony
Use ML!
Image created using PAUP*
Future Directions
Make this harder to read!
Identify other TFs that FOXP2 interacts with
TAP-tag Look into these
proteins further NFATc2 – Down’s
Syndrome
Future Directions
Look into target genes of FOXP2 Determine function of targets Tests for selection
Study other organisms with conspicuous traits Mouse - pattern-learning and vocalization Zebra finch – singing ChIP-chip
Questions
???
References
1. Enard W, Przeworski M, Fisher SE, Lai CSL, Kitano WV, et al. (2002) Molecular evolution of FOXP2, a gene involved in speech and language. Nature 418:869–87.
2. SMART (2009) http://smart.embl-heidelberg.de/ 3. Spiteri E, Konopka G, Coppola G, Bornar J, Oldham M, Ou J, Vernes S,
Fisher SE, Ren B, Geschwind DH (2007) Identification of transcription targets of FOXP2, a gene linked to speech and language in developing human brain. Cell 81:114-1157
4. Swofford, D.L. 2002. PAUP*. Phylogenetic Analysis Using Parsimony (*and Other Methods). Version 4. Sinauer Associates, Sunderland, Massachusetts.
5. Vargha-Khadem F, Gadian DG, Copp A, Mishkin M (2005) FOXP2 and the neuroanatomy of speech and language. Nat Rev Neurosci 6:131–138.