Origin and evolution of the TKDP gene family.

The placenta is arguably the most diverse mammalian organ, and several gene families expressed in trophoblast tissue are evolving unusually rapidly. The trophoblast Kunitz domain protein (TKDP) gene family arose relatively recently within the Artiodactyla order in the lineage leading to modern day ruminants. Each contains a classical Kunitz-type serine peptidase inhibitory domain at the carboxyl-terminus and one or more unique N-domains preceded by the signal peptide/propeptide (SP/PP) region. We isolated, mapped and fully sequenced the ovine (ov) TKDP-1 gene. Making use of available cDNA sequences to other TKDP family members and recent information from the bovine genome sequence, we have been able to make inferences about the origin and evolution of the entire gene family. The crucial event that created the initial TKDP gene was when a short exon was inserted into the intron that separated the sequences encoding the SP/PP and Kunitz domains of an ancestral Kunitz gene. This short exon was flanked by endogenous retroviral repetitive elements that likely promoted subsequent duplication events to provide a tripartite N-domain containing three repeats. This three-exon structure further duplicated once in its entirety to provide the progenitor of the present day ovTKDP-1 gene, which has two N-domains, and most probably twice to provide the progenitor of the bovine TKDP-1 gene, which has three N-domains. The TKDPs provide an example of a gene family that is evolving rapidly by whole gene duplication, intragenic duplication events, and selection for amino acid (aa) change.