Different Evolutionary Histories of the Two Classical Class I Genes BF1 and BF2 Illustrate Drift and Selection within the Stable MHC Haplotypes of Chickens

Abstract

Compared with the MHC of typical mammals, the chicken MHC (BF/BL region) of the B12 haplotype is smaller, simpler, and rearranged, with two classical class I genes of which only one is highly expressed. In this study, we describe the development of long-distance PCR to amplify some or all of each class I gene separately, allowing us to make the following points. First, six other haplotypes have the same genomic organization as B12, with a poorly expressed (minor) BF1 gene between DMB2 and TAP2 and a well-expressed (major) BF2 gene between TAP2 and C4. Second, the expression of the BF1 gene is crippled in three different ways in these haplotypes: enhancer A deletion (B12, B19), enhancer A divergence and transcription start site deletion (B2, B4, B21), and insertion/rearrangement leading to pseudogenes (B14, B15). Third, the three kinds of alterations in the BF1 gene correspond to dendrograms of the BF1 and poorly expressed class II B (BLB1) genes reflecting mostly neutral changes, while the dendrograms of the BF2 and well-expressed class II (BLB2) genes each have completely different topologies reflecting selection. The common pattern for the poorly expressed genes reflects the fact the BF/BL region undergoes little recombination and allows us to propose a pattern of descent for these chicken MHC haplotypes from a common ancestor. Taken together, these data explain how stable MHC haplotypes predominantly express a single class I molecule, which in turn leads to striking associations of the chicken MHC with resistance to infectious pathogens and response to vaccines.

The dominantly expressed class I molecule of the chicken MHC is explained by coevolution with the polymorphic peptide transporter (TAP) genes

“…If a class I molecule does not receive peptides efficiently, it will not have the opportunity to present antigen or be recognized by T cells at a high level. Therefore, there will be little pressure over evolutionary time to maintain expression of such class I molecules, which will then become minor genes or pseudogenes, as is found for the BF1 locus (3,4).…”

“…For the B4 haplotype, there are two classical class I genes, with the BF2 gene encoding the dominantly expressed (or major) class I molecule, but cDNA for the BF1 (or minor) gene barely detectable (3,4). The peptides isolated from class I molecules on erythrocytes have a distinctive motif, mainly octamers with exclusively Asp or Glu found in both positions 2 and 5, and Glu (with small levels of hydrophobic amino acids) found in the final position.…”

“…In the B15 haplotypes we have examined, only the BF2 gene is functional, with the BF1 gene being disrupted (3,4). The peptides isolated from class I molecules on B15 erythrocytes are mainly octamers and nonamers with exclusively Lys and Arg at position 1, exclusively Arg at position 2, and overwhelmingly Tyr (with very low levels of Phe and Trp) in the final position (1, 3).…”

“…Moreover, such coevolution in the primordial MHC may have been responsible for the appearance of the antigen presentation pathways at the birth of the adaptive immune system. avian | evolution | bird C ompared with typical mammals, the chicken MHC has only a single classical class I and class II molecule expressed at high level (1)(2)(3)(4). Moreover, the chicken MHC can determine decisive resistance and susceptibility to several infectious pathogens, as well as response to live and killed commercial vaccines (5)(6)(7).…”

“…Moreover, the chicken MHC can determine decisive resistance and susceptibility to several infectious pathogens, as well as response to live and killed commercial vaccines (5)(6)(7). We developed the hypothesis of a "minimal essential MHC" to provide a molecular explanation for the infectious disease associations of chickens, in comparison with what is known for well characterized mammals (1)(2)(3)(4)(8)(9)(10)(11). In this view, multigene families of well expressed class I and class II molecules, as well as other disease resistance genes of the huge and complex mammalian MHC, confer more or less protection against most pathogens (leading to weak associations with infectious disease).…”