Adaptive Evolution of Microcephaly Genes


The human brain is dramatically enlarged compared to our closest relatives. Brain expansion is closely linked to the evolution of complex behaviour and cognition in hominins. Identifying the genetic basis of brain expansion provides one route to understanding what is, and what is not, unique about our species. As part of this approach, researchers have turned to neurodevelopmental disorders for candidate mechanisms. Microcephaly, a disorder characterised by a major and specific underdevelopment of brain size, is a well‐studied example. Genes associated with microcephaly evolved adaptively across both primates and nonprimate mammals, and selection on at least two genes, ASPM and CDK5RAP2, is associated with variation in brain size in anthropoid primates, and potentially other mammalian clades. While these results support predictions of a model of brain expansion that focuses on cell fate switches during neurogenesis, the causative mechanisms linking selection on microcephaly genes to the evolution brain size remain unclear.

Key Concepts

  • Microcephaly (MCPH) is a developmental disorder that results in a severely reduced brain size, defined clinically as a head circumference more than 3 standard deviations below the age/sex mean.
  • MCPH genes are thought to regulate brain growth by affecting key cell fate decisions during neurogenesis.
  • Multiple MCPH genes show signatures of positive selection across primates and across nonprimate mammals.
  • In anthropoid primates (monkeys and apes), the rate of evolution of two MCPH genes, ASPM and CDK5RAP2, are associated with variation in brain size.
  • Phylogenetic associations are strongest with absolute neonatal brain size, consistent with an evolutionary model where these loci are involved in extending neural proliferation during gestation.
  • Functional test of this evolutionary role remain challenging but several techniques are being developed, including transgenic mice and cerebral organoids.

Keywords: ASPM; brain evolution; brain size; molecular evolution; neurogenesis; primates

Figure 1. A simplified model of cortical neurogenesis: changes in the timing of the cell fate switch between symmetric divisions (SD) of neural progenitors and asymmetric divisions (AsD) of intermediate progenitors lead to major changes in neuron number, cortical surface area and brain size (a). In patients with MPCH, a premature switch leads to a depletion of neural progenitors and reduced brain size (b). The evolutionary role of MCPH is hypothesised to be to bring about more stable changes in this fate‐switch, most commonly delaying it which would lead to increases in neuron number, cortical surface area and brain size (c).
Figure 2. A summary of phenotypic associations between brain size and the rate of evolution of ASPM and CDK5RAP2 in primates (Montgomery et al., ; Montgomery and Mundy, ). In anthropoids, where brain mass expanded, both genes show a significant, positive association with brain mass. However, for ASPM, callitrichids are outliers (single data point in both top graphs indicates Callithrix jacchus). Within callitrichids, where brain size was reduced, ASPM shows a significant, negative association with brain mass. Again, there is an outlier, this time the pygmy marmoset (Callithrix pygmaea), which has a unique life history and more extreme form of dwarfism (Montgomery et al., ; Montgomery and Mundy, ). There is no significant association between CDK5RAP2 and brain size in callitrichids.


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Further Reading

Enard W (2014) Comparative genomics of brain size evolution. Frontiers in Human Neuroscience 8: 345.

Heide M, Huttner WB and Mora‐Bermúdez F (2018) Brain organoids as models to study human neocortex development and evolution. Current Opinion in Cell Biology 55: 8–16.

Montgomery SH, Mundy NI and Barton RA (2016) Brain evolution and development: adaptation, allometry and constraint. Proceedings of the Royal Society B: Biological Sciences 283: 20160433.

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Montgomery, Stephen H(May 2019) Adaptive Evolution of Microcephaly Genes. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0028393]