title: Accelerated evolution of the ASPM gene controlling brain size begins prior to human brain expansion.
abstract: Primary microcephaly (MCPH) is a neurodevelopmental disorder characterized by global reduction in cerebral cortical volume. The microcephalic brain has a volume comparable to that of early hominids, raising the possibility that some MCPH genes may have been evolutionary targets in the expansion of the cerebral cortex in mammals and especially primates. Mutations in ASPM, which encodes the human homologue of a fly protein essential for spindle function, are the most common known cause of MCPH. Here we have isolated large genomic clones containing the complete ASPM gene, including promoter regions and introns, from chimpanzee, gorilla, orangutan, and rhesus macaque by transformation-associated recombination cloning in yeast. We have sequenced these clones and show that whereas much of the sequence of ASPM is substantially conserved among primates, specific segments are subject to high Ka/Ks ratios (nonsynonymous/synonymous DNA changes) consistent with strong positive selection for evolutionary change. The ASPM gene sequence shows accelerated evolution in the African hominoid clade, and this precedes hominid brain expansion by several million years. Gorilla and human lineages show particularly accelerated evolution in the IQ domain of ASPM. Moreover, ASPM regions under positive selection in primates are also the most highly diverged regions between primates and nonprimate mammals. We report the first direct application of TAR cloning technology to the study of human evolution. Our data suggest that evolutionary selection of specific segments of the ASPM sequence strongly relates to differences in cerebral cortical size.
authors.affiliation: Laboratory of Biosystems and Cancer, National Cancer Institute, Bethesda, Maryland, USA.
authors.forename: Natalay
authors.initials: N
authors.lastname: Kouprina
authors.forename: Adam
authors.initials: A
authors.lastname: Pavlicek
authors.forename: Ganeshwaran H
authors.initials: GH
authors.lastname: Mochida
authors.forename: Gregory
authors.initials: G
authors.lastname: Solomon
authors.forename: William
authors.initials: W
authors.lastname: Gersch
authors.forename: Young-Ho
authors.initials: YH
authors.lastname: Yoon
authors.forename: Randall
authors.initials: R
authors.lastname: Collura
authors.forename: Maryellen
authors.initials: M
authors.lastname: Ruvolo
authors.forename: J Carl
authors.initials: JC
authors.lastname: Barrett
authors.forename: C Geoffrey
authors.initials: CG
authors.lastname: Woods
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Walsh
authors.forename: Jerzy
authors.initials: J
authors.lastname: Jurka
authors.forename: Vladimir
authors.initials: V
authors.lastname: Larionov
mesh_terms: D000818:Animals; D005075:Biological Evolution; D019556:COS Cells; D002522:Chlorocebus aethiops; D003001:Cloning, Molecular; D017124:Conserved Sequence; D017931:DNA Primers / Q000737:chemistry; D019143:Evolution, Molecular; D005091:Exons; D017353:Gene Deletion; D006071:Gorilla gorilla; D006801:Humans; D007438:Introns; D008253:Macaca mulatta; D051379:Mice; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000502:physiology*; D002679:Pan troglodytes; D010802:Phylogeny; D011110:Polymorphism, Genetic; D011148:Pongo pygmaeus; D011401:Promoter Regions, Genetic; D017434:Protein Structure, Tertiary; D011995:Recombination, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA
chemical_list: C467202:ASPM protein, human; D017931:DNA Primers; D009419:Nerve Tissue Proteins