ProtocadherinX and ProtocadherinY as candidate genes for cerebral asymmetry and language: Positive selective pressures in Hominid Evolution.

TJ Crow and NA Williams
<tim.crow@psychiatry.oxford.ac.uk>
SANE POWIC, Warneford Hospital, Oxford OX3 7JX.
     
The Out of Africa hypothesis implies that a discontinuity in hominid evolution occurred between 150 and 100,000 years ago and that this was associated with the innovation of symbolic representation. The implication is that the transition was mediated by a genetic change, and that this genetic change accounts for the capacity for language uniformly present in modern human populations.

What was the nature of this change and with what brain structural and functional rearrangements was it associated? Broca first suggested that directional asymmetry is the characteristic that defines the human brain and the correlate of language. The possibility of locating a gene was opened up by i) observations on deviations in cerebral asymmetry and the development of language associated with aneuploidies (anomalies of number) of the X and Y chromosomes, and ii) the discovery that specific changes in the structure of these chromosomes have occurred in the course of hominid evolution.

Through a translocation approximately 3 million years ago (followed by an undated paracentric inversion) the brain-expressed genes ProtocadherinY and X (that code for cell surface adhesion molecules) are present on the human Y and X chromosomes respectively whereas there is a single gene (ProtocadherinX) on the X in other primates. Sequence comparisons with the chimpanzee, bonobo, gorilla, and orangutan reveal negative (stabilising) selection on ProtocadherinX genes during great ape evolution but evidence of positive selection (selection for change) in hominids on the ProtocadherinX ectodomain and ProtocadherinY cytoplasmic domain. 

We interpret these changes as consistent with the original translocation being the event that defined the Australopithecus-hominid boundary. We suppose that the presence of the gene on the Y was selected by advantages to males, probably through mate selection by females. Subsequently there were phases of selection on the Y and X sequence that we envisage are related to intermediate hominid species (Homo ergaster, erectus, heidelbergensis) and to the increases in encephalization quotient that occurred at one or more of the transitions between species. These changes all preceded the advent of modern human populations to which we speculate the paracentric inversion on the Y was critical.

There have been 21 significant (amino-acid altering) changes in the sequence of ProtocadherinX and ProtocadherinY (compared to two in FOXP2) in the course of hominid evolution. This pair of genes is the only gene sequence so far to be shown to be subject to positive selection selective to the hominid relative to the great ape lineage.
We argue that these chromosomal changes and the selective pressures on this pair of genes are relevant to the evolution of the sexual dimorphism of cerebral asymmetry, Broca’s putative correlate of language

Williams NA, Crow TJ.  Domain-specific positive selection on the gametologues ProtocaherinY and ProtocadherinX in the course of hominid evolution. (submitted).