Positive Selection in ASPM Is Correlated with Cerebral Cortex Evolution across Primates but Not with Whole-Brain Size

Molecular Biology and Evolution, Nov 2008

The rapid increase of brain size is a key event in human evolution. Abnormal spindle-like microcephaly associated (ASPM) is discussed as a major candidate gene for explaining the exceptionally large brain in humans but ASPM’s role remains controversial. Here we use codon-specific models and a comparative approach to test this candidate gene that was initially identified in Homo–chimp comparisons. We demonstrate that accelerated evolution of ASPM (ω = 4.7) at 16 amino acid sites occurred in 9 primate lineages with major changes in relative cerebral cortex size. However, ASPM’s evolution is not correlated with major changes in relative whole-brain or cerebellum sizes. Our results suggest that a single candidate gene such as ASPM can influence a specific component of the brain across large clades through changes in a few amino acid sites. We furthermore illustrate the power of using continuous phenotypic variability across primates to rigorously test candidate genes that have been implicated in the evolution of key human traits.

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Positive Selection in ASPM Is Correlated with Cerebral Cortex Evolution across Primates but Not with Whole-Brain Size

Advance Access publication August Positive Selection in ASPM Is Correlated with Cerebral Cortex Evolution across Primates but Not with Whole-Brain Size Farhan Ali 0 0 Department of Psychology, National University of Singapore, Singapore; and Department of Biological Sciences and University Scholars Programme, National University of Singapore , Singapore The rapid increase of brain size is a key event in human evolution. Abnormal spindle-like microcephaly associated (ASPM) is discussed as a major candidate gene for explaining the exceptionally large brain in humans but ASPM's role remains controversial. Here we use codon-specific models and a comparative approach to test this candidate gene that was initially identified in Homo-chimp comparisons. We demonstrate that accelerated evolution of ASPM (x 5 4.7) at 16 amino acid sites occurred in 9 primate lineages with major changes in relative cerebral cortex size. However, ASPM's evolution is not correlated with major changes in relative whole-brain or cerebellum sizes. Our results suggest that a single candidate gene such as ASPM can influence a specific component of the brain across large clades through changes in a few amino acid sites. We furthermore illustrate the power of using continuous phenotypic variability across primates to rigorously test candidate genes that have been implicated in the evolution of key human traits. - Mutations in abnormal spindle-like microcephaly associated (ASPM) are responsible for a severely reduced brain size with no other significant abnormality (primary microcephaly) in a clinical sample of humans (Bond et al. 2002) . Comparative study of sequence evolution limited mostly to humans and other apes revealed that this gene has an accelerated rate of evolution in the Homo lineage (Zhang 2003; Evans et al. 2004) , with ASPM possibly affecting brain size through controlling the spindle assembly during neural cell division (Fish et al. 2006). However, ASPM’s role as a candidate gene for brain size has recently been challenged based on gene expression studies (Kouprina et al. 2005) , strong homology to genes not associated with the brain (Ponting 2006) , and a lack of correlation between ASPM haplotypes and normal human brain size variability (Rushton et al. 2006; Woods et al. 2006; DobsonStone et al. 2007 ; Thimpson et al. 2007). One avenue for addressing such controversies surrounding candidate genes is through employing the comparative method (Goodman et al. 2005) by testing whether sequence evolution of candidate genes is correlated with quantitative phenotypic changes across a large clade. Such tests can now rely on recently developed techniques in evolutionary genetics that allow for detecting positive selection in specific codons as opposed to whole genes (Yang and Nielsen 2002; Zhang et al. 2005) . Here we use these approaches to test whether changes in brain size found across primates are correlated with molecular evolution of ASPM. We sequenced the two large exons of ASPM (exons 3 and 18; 70% of the transcribed ASPM protein) for 23 primate species to complement existing ASPM data for 11 species from GenBank (supplementary table S1, Supplementary Material online). We chose these exons because they contain most of the mutations that cause human primary microcephaly (Bond et al. 2002) , have elevated rates of gene average x in humans (Zhang 2003; Evans et al. where we excluded each of the remaining 8 foreground branches. All 2Dl remained significant, indicating that no single branch was driving the results (supplementary table S2, Supplementary Material online). Second, we randomly selected 9 branches among the background branches in figure 1 (Model B). The model did not explain the data significantly better than the null model of no positive selection (Ps . 0.05). Third, we tested for the specificity of the evolutionary correlate of ASPM by correlating the gene’s evolution with relative whole-brain size as well as the size of the cerebellum, a major subcortical brain component not known to have ASPM expression. We again examined a model of positive selection in ASPM whereby foreground branches had major changes in either of these structures (1 or more SDs). These models did not explain the data significantly better than the null model (all Ps . 0.05; table 1); that is, positive selection in ASPM is only significantly correlated with cerebral cortex size but not with relative whole-brain or cerebellum sizes. Our result provides strong evidence that the singlegene ASPM is associated with major changes in relative cerebral cortex size across primates. It thus questions the validity of recent reviews that implicated ASPM in the brain size expansion of humans only (Ponting and Jackson 2005; Woods et al. 2005) . Particularly, striking is the result that only major changes of cerebral cortex size and not major changes in whole-brain or cerebellum size are associated with positive selection in ASPM. This is (...truncated)


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Farhan Ali, Rudolf Meier. Positive Selection in ASPM Is Correlated with Cerebral Cortex Evolution across Primates but Not with Whole-Brain Size, Molecular Biology and Evolution, 2008, pp. 2247-2250, 25/11, DOI: 10.1093/molbev/msn184