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Background: Cetacean brain size expansion is an enigmatic event in mammalian evolution, yet its genetic basis remains poorly explored. Here, all exons of the seven primary microcephaly (MCPH) genes that play key roles in size regulation during brain development were investigated in representative cetacean lineages. Results: Sequences of MCPH2-7 genes were intact in cetaceans but frameshift mutations and stop codons was identified in MCPH1. Extensive positive selection was identified in four of six intact MCPH genes: WDR62, CDK5RAP2, CEP152, and ASPM. Specially, positive selection at CDK5RAP2 and ASPM were examined along lineages of odontocetes with increased encephalization quotients (EQ) and mysticetes with reduced EQ but at WDR62 only found along odontocete lineages. Interestingly, a positive association between evolutionary rate (ω) and EQ was identified for CDK5RAP2 and ASPM. Furthermore, we tested the binding affinities between Calmodulin (CaM) and ASPM IQ motif in cetaceans because only CaM combined with IQ, can ASPM perform the function in determining brain size. Preliminary function assay showed binding affinities between CaM and IQ motif of the odontocetes with increased EQ was stronger than for the mysticetes with decreased EQ. In addition, evolution rate of ASPM and CDK5RAP2 were significantly related to mean group size (as one measure of social complexity). Conclusions: Our study investigated the genetic basis of cetacean brain size evolution. Significant positive selection was examined along lineages with both increased and decreased EQ at CDK5RAP2 and ASPM, which is well matched with cetacean complex brain size evolution. Evolutionary rate of CDK5RAP2 and ASPM were significantly related to EQ, suggesting that these two genes may have contributed to EQ expansion in cetaceans. This suggestion was further indicated by our preliminary function test that ASPM might be mainly linked to evolutionary increases in EQ. Most strikingly, our results suggested that cetaceans evolved large brains to manage complex social systems, consisting with the 'social brain hypothesis', as evolutionary rate of ASPM and CDK5RAP2 were significantly related to mean group size. [ABSTRACT FROM AUTHOR]