A Human Specific Change in FZD10 Gene involved in Limb Development
Purpose: The Wnt7a pathway is essential for limb outgrowth and proper dorso-ventral patterning. There is evidence that FZD10, a transmembrane receptor positively interacts with Wnt7a to regulate limb development. Our aim was to find genetic differences and evolutionary signatures in these genes that would account for limb differences between primates and humans.
Methods: The coding regions of Wnt7a and FZD10 genes were sequenced in eight different primates by standard methods. All in silico analysis was performed using MEGA3 and DNASP, Predict Protein and the Eukaryotic Linear Motif Source software tools.
Results: The protein coding region of Wnt7a was conserved absolutely in all primates and vertebrates down to Fugu and under purifying selection. However, the FZD10 receptor has a single non-synonymous amino acid change (P577S) was found only in humans in the predicted cytoplasmic tail. In silico analysis of this Proline to Serine mutation in FZD10 indicates that it may prevent binding to proteins with Src homology 3 type I (SH3 1) domains. By contrast, FZD10 in all other mammals were predicted to bind to these modules.
Conclusions: We have found a human specific amino acid change to the likely Wnt7a receptor, FZD10, that is expressed in the dorsal side of the posterior-distal limb in chick. This change is highly significant as it occurs in an otherwise highly conserved area in all primates, including chimpanzees. The amino acid change occurs in the predicted cytoplasmic tail that could bind to protein factors including SH3-1 modules which have diverse roles including signal transduction and membrane trafficking that may alter downstream targets of Wnt7a signalling pathway in the limb. Humans limbs differ anatomically from primates to allow for hand manoeuvrability and bipedalism. These changes occur in dorsal ray structures are under the control of Wnt7a pathway and may be brought about by the interaction of Wnt7a and FZD10 in humans.