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.
Highlights
The human brain, the cerebral cortex, has undergone a dramatic increase in its volume during the course of primate evolution, but the underlying molecular mechanisms that caused this expansion are not known
The yield of ASPM-positive clones from chimpanzee, gorilla, orangutan, and rhesus macaque was the same as that from the human DNA, suggesting that most homologous regions from nonhuman primates can be efficiently cloned by in vivo recombination in yeast using targeting hooks developed from human sequences
ASPM sequences share a high degree of conservation (Figure 2H), and pairwise DNA identity ranges from 94.5% for macaque and gorilla to 99.3% for the human– chimpanzee comparison (Table 1)
Summary
The human brain, the cerebral cortex, has undergone a dramatic increase in its volume during the course of primate evolution, but the underlying molecular mechanisms that caused this expansion are not known. One approach shedding light on the molecular mechanisms of brain evolution is the analysis of the gene mutations that lead to defects in brain development. Among the best examples of such defects is the human primary microcephaly syndrome. Primary microcephaly (MCPH) is an autosomal recessive neurodevelopmental disorder in which the brain fails to achieve normal growth. The affected individuals have severe reduction in brain size; the gyral pattern is relatively well preserved, with no major abnormality in cortical architecture (McCreary et al 1996; Mochida and Walsh 2001). The most common cause of MCPH appears to be mutations in the ASPM gene (Roberts et al 2002)
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