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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.
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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)