Molecular evolution of microcephalin, a gene determining human brain size

Microcephalin gene is one of the major players in regulating human brain development. It was reported that truncated mutations in this gene can cause primary microcephaly in humans with a brain size comparable with that of early hominids. We studied the molecular evolution of microcephalin by sequencing the coding region of microcephalin gene in humans and 12 representative non-human primate species covering great apes, lesser apes, Old World monkeys and New World monkeys. Our results showed that microcephalin is highly polymorphic in human populations. We observed 22 substitutions in the coding region of microcephalin gene in human populations, with 15 of them causing amino acid changes. The neutrality tests and phylogenetic analysis indicated that the rich sequence variations of microcephalin in humans are likely caused by the combination of recent population expansion and Darwinian positive selection. The synonymous/non-synonymous analyses in primates revealed positive selection on microcephalin during the origin of the last common ancestor of humans and great apes, which coincides with the drastic brain enlargement from lesser apes to great apes. The codon-based neutrality test also indicated the signal of positive selection on five individual amino acid sites of microcephalin, which may contribute to brain enlargement during primate evolution and human origin.