October 2, 2002Daryl Thomas

October 2, 2002Daryl Thomas Molecular Evolution of FOXP2 Human Language Abilities Highlighted by Comparative Genomics CMPE 280B Bioinformatics Seminar

October 2, 2002Daryl Thomas Main References Molecular evolution of FOXP2, a gene involved in speech and language Wolfgang Enard, Molly Przeworski, Simon E. Fisher, Cecila S. L. Lai, Victor Wiebe, Takashi Kitano, Anthony P. Monaco, Svante Pääbo. Nature 22; 418(6900): August 2002 advance online publication (doi: /nature01025) A forkhead-domain gene is mutated in severe speech and language disorder Lai CS, Fisher SE, Hurst JA, Vargha-Khadem F, Monaco AP. Nature 413(6855): October 2001

October 2, 2002Daryl Thomas Biological Relevance If we are so similar to Non-Human Primates (NHPs), what makes us different? Are there many mutations, of just a few important ones? Today’s example: a gene with two amino acid differences between humans and 4 NHPs that arose when humans became anatomically distinct. Human specific trait: complex spoken language as basis of development of human culture.

October 2, 2002Daryl Thomas History of 7q31 Autism primarily associated with 7q : Lai et al., identify mutations in human FOXP2 that associate with speech/grammar problems KE Family 1990 Autosomal Dominant

October 2, 2002Daryl Thomas FOXP2 Highly similar to conserved forkhead family R553H mutation in KE gives phenotype Translocation also gives phenotype

October 2, 2002Daryl Thomas Gene Regulatory Proteins Binds upstream regulatory sequence Regulates transcription of nearby genes Affected by phosphorylation, localization,...

October 2, 2002Daryl Thomas Comparative Genomics No AA polys in 226 human chromosomes All humans have 2 AA differences from NHPs, mouse One mutation introduces PO 4 site (N325S) for regulation

October 2, 2002Daryl Thomas Strong Positive Selection Newbury et al., (2002): five-fold increase in recombination rate in this region Nearest gene 286 Kb away FOXP2 may be target of positive selection

October 2, 2002Daryl Thomas Evolutionary Modeling Human-specific changes Coincident with emergence of anatomically modern humans (~200,000 years ago) Silent and replacement nucleotide substitutions mapped on a phylogeny of primates. Bars represent nucleotide changes. Grey bars indicate amino-acid changes.

October 2, 2002Daryl Thomas Speculation Known: FOXP2 disruption in humans gives rise to multiple difficulties with expressive and receptive aspects of language and grammar Selection and sequencing of fine orofacial movements is typical of humans but not of NHPs. Speculation: Human-specific aspect of FOXP2 (amino acid changes) affects our ability to control orofacial movements and develop spoken language. Time of FOXP2 variant fixation may coincide with the start of human language evolution. Consistent with models of recent human population expansion. Concomitant with or subsequent to emergence of anatomically modern humans. Compatible with model in which the expansion of modern humans was driven by the appearance of a more proficient spoken language.