Comparative genomics of the Mill family: a rapidly evolving MHC class I gene family

Mill (MHC class I-like located near the leukocyte receptor complex) is a novel family of class I genes identified in mice that is most closely related to the human MICA/B family. In the present study, we isolated Mill cDNA from rats and carried out a comparative genomic analysis. Rats have two Mill genes orthologous to mouse Mill1 and Mill2 near the leukocyte receptor complex, with expression patterns similar to those of their mouse counterparts. Interspecies sequence comparison indicates that Mill is one of the most rapidly evolving class I gene families and that non-synonymous substitutions occur more frequently than synonymous substitutions in its alpha 1 domain, implicating the involvement of Mill in immune defenses. Interestingly, the alpha 2 domain of rat Mill2 contains a premature stop codon in many inbred strains, indicating that Mill2 is not essential for survival. A computer search of the database identified a horse Mill-like expressed sequence tag, indicating that Mill emerged before the radiation of mammals. Hence, the failure to find Mill in human indicates strongly that it was lost from the human lineage. Our present work provides convincing evidence that Mill is akin to the MICA/B family, yet constitutes a distinct gene family.