Adaptive Evolution of Microcephaly Genes

Abstract

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.