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.