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Molecular Evolution of FOXP2

Molecular Evolution of FOXP2. Human Language Abilities Highlighted by Comparative Genomics CMPE 280B Bioinformatics Seminar. Main References. Molecular evolution of FOXP2, a gene involved in speech and language

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Molecular Evolution of FOXP2

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  1. Daryl Thomas

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

  3. 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):869-72 14 August 2002 advance online publication (doi:10.1038/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):519-23 4 October 2001 Daryl Thomas

  4. 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. Daryl Thomas

  5. History of 7q31 • Autism primarily associated with 7q22-32 • 2001: Lai et al., identify mutations in human FOXP2 that associate with speech/grammar problems • KE Family • 1990 • Autosomal • Dominant Daryl Thomas

  6. FOXP2 • Highly similar to conserved forkhead family • R553H mutation in KE gives phenotype • Translocation also gives phenotype Daryl Thomas

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

  8. Comparative Genomics • No AA polys in 226 human chromosomes • All humans have 2 AA differences from NHPs, mouse • One mutation introduces PO4 site (N325S) for regulation Daryl Thomas

  9. 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 Daryl Thomas

  10. 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. Daryl Thomas

  11. 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. Daryl Thomas

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