The discovery and evolutionary analysis of divergent homologs involved in cattle immune and reproductive biology.

摘要

A comparative genomics approach for mining databases of expressed sequence tags (ESTs) was used to identify the MHC class I-like gene family A1 (MHCLA1) and MHCLA2 genes which represent distant homologs of the human and mouse NK cell stimulatory ligand genes, ULBP, RAFT, H60 and Raet-1, on the basis of comparative mapping data. Similar to the human and mouse homologs, cattle MHCLA1 is constitutively expressed and does not encode an 0 domain. Southern blotting using MHCLA1 to probe DNA from 14 species representing 5 mammalian orders suggests that the MHCLA genes evolved rapidly by duplication and divergence in the Artiodactyla. Studies in humans demonstrated that the ULBPs interact with the NK cell NKG2D stimulatory receptor and that this interaction is blocked by the human cytomegalovirus UL16 protein. These data suggest the hypothesis that duplication and divergence of the cattle MHCLA genes was driven by selection exerted by viral pathogens.; To conform with the human nomenclature, the cattle MHCLA genes were renamed ULBPs. Genomic sequencing identified 30 cattle ULBP loci existing in two gene clusters that evolved by extensive segmental duplication. Nine loci were designated genes and predicted to encode cell-surface glycoproteins. Substitution analysis identified 11 outwardly directed residues under positive Darwinian selection. These positively selected residues show little overlap with those proposed to interact with NKG2D. This suggests that the extracellular domains of the cattle ULBPs are under adaptive diversifying selection to avoid interaction with a bovine herpesvirus UL 16 molecule while selectively preserving the NKG2D binding site.; Ten divergent homologs were identified using a subtractive bioinformatic analysis of 12,614 cattle placenta ESTs followed by comparative, evolutionary and gene expression studies. Eight have not been identified previously. These were named: CSSMST1, CIST1, HAVCRNDP, PRP8, PRP9, PRP11, SECTM1A and SECTM1B. Nucleotide substitution analysis provided evidence for positive selection in members of the PRP gene family, SECTM1A and SECTM1B. Gene expression profiles, motif predictions, and annotations of homologous sequences indicate immunological and reproductive functions of the divergent homologs. The genes identified in this experiment are thus of evolutionary and physiological importance and may have a role in placental adaptations.