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

Abstract

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 § 1 domain, implicating the involvement of Mill in immune defenses. Interestingly, the § 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.

MHC Class I-Like MILL Molecules Are β2-Microglobulin-Associated, GPI-Anchored Glycoproteins That Do Not Require TAP for Cell Surface Expression

“…Our previous work has revealed several unique features of this class I family (19,20). First, not all mammalian species have the MILL family; although mice and rats have this family, it is absent in humans.…”

“…Fifth, RT-PCR analysis indicated that the members of the MILL family are poorly transcribed in most adult tissues, suggesting a role other than conventional Ag presentation. Sixth, sequence comparison of rat and mouse MILL molecules revealed that Mill is one of the most rapidly evolving class I gene families, and that, in both Mill1 and Mill2, non-synonymous substitutions occur more frequently than synonymous substitutions in the ␣1 domain whereas the opposite is the case in the ␣2 and ␣3 domains, suggesting that the ␣1 domain may be under positive selection (20). Taking all of these points into consideration, we suggested that MILL may perform specialized immune functions required only in certain species or some redundant functions, part of which are executed by other molecules (20).…”

“…We initially assumed that MILL1 and MILL2 were transmembrane proteins (19,20). However, different prediction algorithms yielded inconsistent results concerning the presence or absence of transmembrane regions.…”

“…Recently, we identified a new family of class Ib genes designated Mill (MHC class I-like located near the leukocyte receptor complex) in mice (19) and rats (20). The two members of the Mill family, Mill1 and Mill2, are located close to the leukocyte receptor complex, thus outside the MHC.…”

Chicken CD1 genes are located in the MHC: CD1 and endothelial protein C receptor genes constitute a distinct subfamily of class-I-like genes that predates the emergence of mammals

“…Although the majority of nonclassical class I genes located in the MHC show reasonably high sequence similarity to classical class I genes with the exception of MICA/B (Bahram et al 1994) and HFE (the gene for hemochromatosis) (Feder et al 1996), most of those encoded outside the MHC are quite divergent from classical class I genes . Among such divergent class-I-like genes are CD1 , AZGP1 (the gene for zinc-α2-glycoprotein) (Araki et al 1988), FCGRT (the gene for the heavy chain of the neonatal IgG Fc receptor) (Simister and Mostov 1989), PROCR (the gene for the endothelial protein C receptor) (Fukudome and Esmon 1994), MR1 (Hashimoto et al 1995), RAET/ULBP (the genes for retinoic acid early transcripts 1) (Zou et al 1996), and Mill (MHC class-I-like genes located near the leukocyte receptor complex) (Kasahara et al 2002;Watanabe et al 2004). Accumulated evidence indicates that class-I-like genes have diverse functions ranging from specialized antigen presentation (Bahram 2000;Treiner et al 2003;Vincent et al 2003) to the transport of IgG (Simister and Rees 1985) and lipid mobilization and catabolism (Todorov et al 1998).…”