The origins and evolution of higher cognitive functions, including complex forms of learning, attention and executive functions, are unknown. A potential mechanism driving the evolution of vertebrate cognition early in the vertebrate lineage (550 million years ago) was genome duplication and subsequent diversification of postsynaptic genes. Here we report, to our knowledge, the first genetic analysis of a vertebrate gene family in cognitive functions measured using computerized touchscreens. Comparison of mice carrying mutations in each of the four Dlg paralogs showed that simple associative learning required Dlg4, whereas Dlg2 and Dlg3 diversified to have opposing functions in complex cognitive processes. Exploiting the translational utility of touchscreens in humans and mice, testing Dlg2 mutations in both species showed that Dlg2's role in complex learning, cognitive flexibility and attention has been highly conserved over 100 million years. Dlg-family mutations underlie psychiatric disorders, suggesting that genome evolution expanded the complexity of vertebrate cognition at the cost of susceptibility to mental illness.
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We thank K. Elsegood and D. Fricker for mouse husbandry and genotyping, T.W. Robbins for advice on CANTAB, J. Barnett for assistance with CANTAB control data and T.W. Robbins and T.J. O'Dell for comments on the manuscript. Figure illustration contribution by D.J. Maizels. J.N., N.H.K., L.N.L. and S.G.N.G. was supported by The Wellcome Trust, Genes to Cognition Program, The Medical Research Council (MRC) and European Union programs (Project GENCODYS no. 241995, Project EUROSPIN no. 242498 and Project SYNSYS no. 242167). M.J. was supported by grants from RS Macdonald Charitable Trust and Academy of Medical Sciences/The Wellcome Trust.
T.J.B. and L.M.S. consult for Campden Instruments.
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Nithianantharajah, J., Komiyama, N., McKechanie, A. et al. Synaptic scaffold evolution generated components of vertebrate cognitive complexity. Nat Neurosci 16, 16–24 (2013). https://doi.org/10.1038/nn.3276
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