Abstract
BackgroundBrain-expressed proteins that have undergone functional change during human evolution may contribute to human cognitive capacities, and may also leave us vulnerable to specifically human diseases, such as schizophrenia, autism or Alzheimer’s disease. In order to search systematically for those proteins that have changed the most during human evolution and that might contribute to brain function and pathology, all proteins with orthologs in chimpanzee, orangutan and rhesus macaque and annotated as being expressed on the surface of cells in the human central nervous system were ordered by the number of human-specific amino acid differences that are fixed in modern populations.ResultsPCDHB11, a beta-protocadherin homologous to murine cell adhesion proteins, stood out with 12 substitutions and maintained its lead after normalizing for protein size and applying weights for amino acid exchange probabilities. Human PCDHB11 was found to cause homophilic cell adhesion, but at lower levels than shown for other clustered protocadherins. Homophilic adhesion caused by a PCDHB11 with reversion of human-specific changes was as low as for modern human PCDHB11; while neither human nor reverted PCDHB11 adhered to controls, they did adhere to each other. A loss of function in PCDHB11 is unlikely because intra-human variability did not increase relative to the other human beta-protocadherins.ConclusionsThe brain-expressed protein with the highest number of human-specific substitutions is PCDHB11. In spite of its fast evolution and low intra-human variability, cell-based tests on the only proposed function for PCDHB11 did not indicate a functional change.
Highlights
Brain-expressed proteins that have undergone functional change during human evolution may contribute to human cognitive capacities, and may leave us vulnerable to human diseases, such as schizophrenia, autism or Alzheimer’s disease
The most useful comparison is with living primates, on whose cognitive phenotype we do have information [22, 23]: a DNA variant might contribute to human cognitive capabilities if it is present in all cognitively normal modern humans, but not in the aligned de Freitas et al BMC Evolutionary Biology (2016) 16:75 genomes of other primates
Selection of candidate protein A comparison of the protein-coding regions of the reference chimpanzee, orangutan and rhesus macaque genomes to 100 haploid human genomes, sampled from diverse human populations, has been published before [34] and resulted in a list of amino acid positions where all modern human genomes agree with each other and are different from the non-human primates
Summary
Brain-expressed proteins that have undergone functional change during human evolution may contribute to human cognitive capacities, and may leave us vulnerable to human diseases, such as schizophrenia, autism or Alzheimer’s disease. In order to search systematically for those proteins that have changed the most during human evolution and that might contribute to brain function and pathology, all proteins with orthologs in chimpanzee, orangutan and rhesus macaque and annotated as being expressed on the surface of cells in the human central nervous system were ordered by the number of human-specific amino acid differences that are fixed in modern populations. Other human-specific differences have been discovered in proteins expressed in the brain, but have not yet been linked to a behavioral phenotype [5,6,7,8]. The analysis of primate genomes has yielded lists of such variants [24,25,26,27]; the statistical tests for positive selection are necessarily of low statistical power and selectivity, and the necessary biochemical analysis of such candidate genes has rarely been reported [28]
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