Transcript Identifying differences between humans and non

October 2, 2002
Daryl Thomas
Molecular Evolution of FOXP2
Human Language Abilities Highlighted
by Comparative Genomics
CMPE 280B
Bioinformatics Seminar
October 2, 2002
Daryl 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):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
October 2, 2002
Daryl 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, 2002
Daryl Thomas
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
October 2, 2002
Daryl Thomas
FOXP2
• Highly similar to conserved forkhead family
• R553H mutation in KE gives phenotype
• Translocation also gives phenotype
October 2, 2002
Daryl Thomas
Gene Regulatory Proteins
• Binds upstream regulatory sequence
• Regulates transcription of nearby genes
• Affected by phosphorylation, localization, ...
October 2, 2002
Daryl Thomas
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
October 2, 2002
Daryl 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, 2002
Daryl Thomas
Evolutionary Modeling
• Human-specific
changes
• Coincident with
emergence of
anatomically modern
humans (~200,000
years ago)
October 2, 2002
Silent and replacement nucleotide
substitutions mapped on a phylogeny of
primates. Bars represent nucleotide changes.
Grey bars indicate amino-acid changes.
Daryl 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.
October 2, 2002
Daryl Thomas