Abstract
BackgroundGenes associated with the neurodevelopmental disorder microcephaly display a strong signature of adaptive evolution in primates. Comparative data suggest a link between selection on some of these loci and the evolution of primate brain size. Whether or not either positive selection or this phenotypic association are unique to primates is unclear, but recent studies in cetaceans suggest at least two microcephaly genes evolved adaptively in other large brained mammalian clades.ResultsHere we analyse the evolution of seven microcephaly loci, including three recently identified loci, across 33 eutherian mammals. We find extensive evidence for positive selection having acted on the majority of these loci not just in primates but also across non-primate mammals. Furthermore, the patterns of selection in major mammalian clades are not significantly different. Using phylogenetically corrected comparative analyses, we find that the evolution of two microcephaly loci, ASPM and CDK5RAP2, are correlated with neonatal brain size in Glires and Euungulata, the two most densely sampled non-primate clades.ConclusionsTogether with previous results, this suggests that ASPM and CDK5RAP2 may have had a consistent role in the evolution of brain size in mammals. Nevertheless, several limitations of currently available data and gene-phenotype tests are discussed, including sparse sampling across large evolutionary distances, averaging gene-wide rates of evolution, potential phenotypic variation and evolutionary reversals. We discuss the implications of our results for studies of the genetic basis of brain evolution, and explicit tests of gene-phenotype hypotheses.
Highlights
Genes associated with the neurodevelopmental disorder microcephaly display a strong signature of adaptive evolution in primates
Across primates Across the 12 primate species for which full coding sequences are available for all 7 loci, four loci - ASPM, CDK5RAP2, CENPJ and CEP152 - show a consistent signature of positive selection (Table 1a)
Our results indicate that the majority of loci linked to microcephaly, a severe neurodevelopmental disorder, have been targeted by positive selection throughout the evolution of eutherian mammals, in both primates and non-primates
Summary
Genes associated with the neurodevelopmental disorder microcephaly display a strong signature of adaptive evolution in primates. Whether or not either positive selection or this phenotypic association are unique to primates is unclear, but recent studies in cetaceans suggest at least two microcephaly genes evolved adaptively in other large brained mammalian clades. Mendelian inheritance of microcephaly has been linked to deleterious mutations at seven unlinked loci [8,9,10,11,12,13,14,15] These loci encode proteins with central roles in neurogenesis, largely in the formation and function of the centrioles, which in turn control the way in which neural progenitor cells divide [16,17,18]. Tentative evidence has been found linking the evolution of MCPH1 to sexual dimorphism in brain mass in primates [22], a surprising finding supported, in part, by human population studies of sex-specific associations between SNPs in microcephaly genes and brain size [23,24] and functional analyses of base pair substitutions that may interact with sexspecific developmental pathways [25]
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