Evidence for the coevolution of axon guidance molecule Netrin and its receptor Frazzled

• Positive selection of Netrin and Fra was identified from same lineages.
• Many sites under positive selection were detected in the interaction domains.
• Positive selection is essential for the coevolution of Netrin and Fra.

Coevolution of a ligand and its receptor is critical for maintaining their function in different species, but how ligand and its receptor coevolve is poorly understood. The axon guidance molecule Netrin and its receptor Frazzled (Fra) are useful to study the mechanisms of ligand–receptor coevolution. Here, we have applied codon substitution models to identify positive selection of the netrin and fra genes. The sites under positive selection in netrin and fra were detected in same lineage, such as nematode, dipteran, hymenopteran, hemichordate, and teleost. Several amino acid residues that are under positive selection were identified in the interaction domains. Here we provide evidence that positive selection is essential for the coevolution of Netrin and Fra during central nervous system evolution.