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Open Access Research article

Functional divergence of the brain-size regulating gene MCPH1 during primate evolution and the origin of humans

Lei Shi1, Ming Li12, Qiang Lin12, Xuebin Qi1 and Bing Su1*

Author Affiliations

1 State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, 32 East Jiao-Chang Road, Kunming, Yunnan 650223, PR China

2 University of the Chinese Academy of Sciences, No.19A Yuquan Road, Shijingshan District, Beijing, 100049, China

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BMC Biology 2013, 11:62  doi:10.1186/1741-7007-11-62

Published: 22 May 2013



One of the key genes that regulate human brain size, MCPH1 has evolved under strong Darwinian positive selection during the evolution of primates. During this evolution, the divergence of MCPH1 protein sequences among primates may have caused functional changes that contribute to brain enlargement.


To test this hypothesis, we used co-immunoprecipitation and reporter gene assays to examine the activating and repressing effects of MCPH1 on a set of its down-stream genes and then compared the functional outcomes of a series of mutant MCPH1 proteins that carry mutations at the human- and great-ape-specific sites. The results demonstrate that the regulatory effects of human MCPH1 and rhesus macaque MCPH1 are different in three of eight down-stream genes tested (p73, cyclinE1 and p14ARF), suggesting a functional divergence of MCPH1 between human and non-human primates. Further analyses of the mutant MCPH1 proteins indicated that most of the human-specific mutations could change the regulatory effects on the down-stream genes. A similar result was also observed for one of the four great-ape-specific mutations.


Collectively, we propose that during primate evolution in general and human evolution in particular, the divergence of MCPH1 protein sequences under Darwinian positive selection led to functional modifications, providing a possible molecular mechanism of how MCPH1 contributed to brain enlargement during primate evolution and human origin.

MCPH1; E2F1; Brain size; Primates; Evolution; Functional divergence