Comparative Genomics of NGF, NTRK1, and NGFR Across Chordates: Joint Gene Recovery and Region-Specific Constraint

Nerve growth factor (NGF) is a neurotrophin central to sensory neuron biology and pain signaling. NGF and NTRK1 are gnathostome paralogs within the older neurotrophin and Trk families, respectively, whereas NGFR encodes p75NTR, a member of the tumor necrosis factor receptor superfamily. Orthology assessment of NGF, NTRK1, and NGFR across vertebrates is challenging because mature neurotrophins are short, cysteine-rich ligands, NTRK1 has closely related paralogs, and NGFR lies outside the Trk receptor family. We assessed species-level joint genomic recovery of the three genes and compared evolutionary constraint among predefined ligand and receptor regions. The analysis covered 94 chordates and combined graded recovery evidence with family phylogenies, locus and domain evidence, codon models, amino acid conservation, and structural mapping. Sixteen non-gnathostome species were included to provide evolutionary context and were not used to calculate recovery rates for the three focal genes. Among 78 sampled gnathostomes, 52 had high-confidence joint recovery, eight had supported provisional joint recovery, four had component-level evidence consistent with possible co-recovery, and 14 remained incomplete. Mature NGF had a numerically lower estimate of the ratio of nonsynonymous to synonymous substitution rates (dN/dS, ω) than the pro-domain (0.067 versus 0.352). All six scaffold cysteines were invariant; in the residue-class comparison, the cysteine scaffold was the only structural class that differed from the coordinate-resolved background after correction. The dimer-interface, TrkA-contact, and p75NTR-contact classes did not differ significantly from that background after correction. Receptor analyses yielded low ω estimates in Trk kinase domains and p75NTR intracellular regions. Together, these results provide a confidence-graded map of focal-gene recovery and regional purifying constraint while placing non-gnathostome homologs within the older neurotrophin system.