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Human Molecular Genetics Advance Access published online on January 13, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddh055
© 2004 by Oxford University Press
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©2004 Oxford University Press

Article

Adaptive evolution of ASPM, a major determinant of cerebral cortical size in humans

Patrick D. Evans 1, Jeffrey R. Anderson 2, Eric J. Vallender 1, Sandra L. Gilbert 2, Christine M. Malcom 2, Steve Dorus 1, and Bruce T. Lahn 2*

1 Howard Hughes Medical Institute, Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA; Committee on Genetics, University of Chicago, Chicago, IL 60637, USA
2 Howard Hughes Medical Institute, Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA

* To whom correspondence should be addressed. E-mail: blahn{at}genetics.uchicago.edu.


  Abstract

A prominent trend in the evolution of humans is the progressive enlargement of the cerebral cortex. The ASPM (Abnormal spindle-like microcephaly associated) gene has the potential to play a role in this evolutionary process, because mutations in this gene cause severe reductions in the cerebral cortical size of affected humans. Here, we show that the evolution of ASPM is significantly accelerated in great apes, especially along the ape lineages leading to humans. Additionally, the lineage from the last human/chimpanzee ancestor to humans shows an excess of nonsynonymous over synonymous substitutions, which is a signature of positive Darwinian selection. A comparison of polymorphism and divergence using the McDonald-Kreitman test confirms that ASPM has indeed experienced intense positive selection during recent human evolution. This test also reveals that, on average, ASPM fixed one advantageous amino acid change in every 300,000-400,000 years since the human lineage diverged from chimpanzees. We therefore conclude that ASPM underwent strong adaptive evolution in the descent of Homo sapiens, which is consistent with its putative role in the evolutionary enlargement of the human brain.


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