Mhc Evolution Of

Jan Klein, Department of Immunogenetics, Max-Planck-lnstitute for Biology, Tübingen, Germany

The presence of major histocompatibility complex (MHC) class I and class II genes has been demonstrated in all classes of jawed vertebrates (gnathostomes); no trace of these genes has thus far been found in jawless vertebrates (agnathans, represented by hagfish and lamprey) or in nonver-tebrate chordates (cephalochordates, urochordates). Whether agnathans truly lack MHC genes or possess genes that are very different from those of the gnathostomes remains an unanswered question. From the rate of nonsynonymous substitutions it can be calculated that the class I and class II genes diverged more than 500 million years ago and hence before vertebrate radiation, but this estimate has a large range of error.

In all jawed vertebrates that have been studied, the organization of the MHC genes (and, by implication, of the MHC molecules) is the same: 1) the genes fall into two classes (I and II); 2) in each class there are multiple gene families; 3) in each family there are two types of genes, A and B, encoding the a and /3 polypeptide chains of the MHC heterodimers, respectively; 4) the exon-intron organization is largely conserved in the various genes of the same class; 5) the polymorphism, when present, is concentrated in the same exons (in class I genes in exons 2 and 3, in class II genes in exon 2); and 6) within the variable exons, the polymorphism is concentrated into 3-4 short segments. These observations, particularly the last two, imply that the function of the MHC molecules has been conserved for at least 400 million years, since the emergence of the jawed vertebrates. The focusing of the polymorphism onto the putative peptide-binding regions (PBRs) in all gna-thostome classes suggests that the MHC function has been, from the beginning, to bind peptides, presumably for presentation to T cell receptors (TCRs), and thus to initiate the anticipatory (adaptive) immune response. It can therefore be expected that MHC and TCR (and by extension also immunoglobulins, Ig) emerged simultaneously, and that their emergence marked the appearance of the anticipatory response. By this reasoning, the anticipatory immune system is an innovation restricted to vertebrates or perhaps to chor-dates, as experimental observations indeed indicate.

The primordial MHC gene seems to have been assembled from two or three other genes, each of which originally had a different function. One of the contributing genes came from the immunoglobulin superfamily, another from a family of genes encoding structures with an a helix rising from a ^-stranded platform (= MHC fold), and the third from a gene encoding membrane-anchoring and possibly signal-transmission structures. The identity of the gene family that donated the peptide-binding domains characterized by the MHC fold is not known. The HSP70 family has been proposed as a possible candidate, but newer data on the tertiary structure of HSP70 proteins do not support this suggestion. Another possible candidate is the proteasomal gene family, but here, too, no significant structural similarity to the peptide-binding domains of the MHC molecules has been found. In the tertiary structure, the MHC peptide-binding domains superficially resemble proteins of the interleukin 8 (IL-8) family, and in the primary structure there is a weak sequence similarity between MHC proteins and the endothelial cell protein receptor (EPCR). The significance of these similarities is obscure.

It is generally assumed that the primordial class I and class II genes arose from a common ancestor by gene duplication. Whether this ancestor had the structure of a class I or class II gene is controversial. The most parsimonious hypothesis seems to be that the ancestor resembled a class II gene and that the first MHC molecules were homodimers in which each protein chain contributed one half of the peptide-binding module. A duplication of this gene and subsequent divergence of the two copies produced the primordial class II A and B genes encoding, respectively, the a and 0 chains of the class II hetero-dimers. A second round of duplication followed by a deletion-fusion process then created a primordial class I gene with two exons specifying the two halves of the peptide-binding module. The product of this gene came to associate noncovalently with a single domain encoded in another member of the immunoglobulin superfamily, the ^-microglobulin gene.

The process of duplication (expansion) and deletion (contraction) of the class 1 and class II genes has continued throughout subsequent MHC evolution and has lead to the emergence of new MHC gene families and the demise of old ones. In bony-fish, for instance, every major order possesses different MHC class I and class II gene families, each derived from a separate ancestor. The families persist for a variable length of time. In eutherian mammals, for example, the class II DR, DQ, DP, DN/DO, and DM families are shared by the different orders, whereas the primate class I A, B, C family is restricted to this order and possibly only to one suborder. Within each MHC class I or class II family, different genes are functional for a variable length of time. Thus, for example, while orthologous DQB and DPB genes have apparently remained functional for the entire period of primate evolution, functional DRB genes have been replaced at least three times by their paralogs: in prosimians, New World monkeys, and Old World monkeys (together with apes). The nonfunctional copies, can, however, persist as pseudo-genes for a long time. The primate DRB6 gene, for example, may have been nonfunctional for more than 30 million years.

The average substitution rates at the synonymous and nonsynonymous PBR sites of the MHC genes are 1.2 X 10~9 and 5.9 X 10~9 per site per year, respectively. The synonymous rate is lower and the nonsynonymous rate higher than that of most non-MHC genes. The MHC genes therefore contain a region (PBR) that evolves faster than most other genes, while the rest of the MHC gene evolves at a comparable or a lower rate. In contrast to other genes, however, the MHC genes do not contain regions highly conserved over long evolutionary periods. Although some amino acid residues at certain positions are invariant or nearly so in the encoded proteins, they are scattered, and sharing of long stretches between distantly related molecules is rare. Cloning of MHC genes from unrelated taxa is therefore always a challenge not obviated by the steady accumulation of sequences from a variety of vertebrates.

MHC genes are subjected to both positive (balancing) and negative (purifying) selection. The positive selection is restricted to the nonsynonymous PBR sites, whereas the negative selection affects various nonsynonymous sites scattered over the rest of the coding sequence. The intensity of the positive selection has been estimated to be less than 0.02. (For comparison, the selection intensity exerted by the causative agent of malaria on the hemoglobin S allele is 0.3.) A selection coefficient this low will therefore be difficult to measure experimentally in any but the most prolific vertebrate species. The selection is presumably effected by parasites or would-be parasites via the interaction of parasite-derived peptides with the PBR of functional MHC molecules. The mechanism of selection is believed to be heterozygous advantage (an MHC heterozygote being protected from more parasites than an MHC homozygote), although a case for frequency-dependent selection (protection effected for as long as an allele is rare) has also been made. The intensity of the negative selection can be expressed in terms of a functional constraint on the non-PBR site. On a scale on which 0 indicates a complete conservation (no amino acid replacements are allowed) and 1 a complete absence of conservation (any substitution is allowed as in a nonfunctional gene), the MHC genes score a functional constraint value of 0.33, the average for non-MHC genes being 0.189. Hence, functional MHC genes are less constrained in terms of purifying selection than most non-MHC genes.

Balancing selection is responsible for the maintenance of MHC alleles in the population, without fixation (attainment of frequency of 100%), for periods in excess of those expected for neutral alleles. This long allele persistence time has two major consequences. First, during their tenure in the population the polymorphic alleles are in a position to diversify by additional mutations. A polymorphic allele incorporates an additional nonsynonymous mutation at a PBR site, or a synonymous mutation on average every 1-4 and 3-5 million years, respectively. Alleles differing in up to 10% of their coding sequence are a common appearance at functional MHC loci. Second, the allelic lineage persistence time can be longer than the lifespan of a species and the MHC polymorphism is therefore transmitted from ancestral to descendant species in a trans-specific manner. Some MHC allelic lineages have been shown to be more than 30 million years old; these must have 'survived' several rounds of speciation.

Old allelic lineages are often characterized by the presence of diagnostic motifs - short, largely invariant stretches of sequences idiomatic to a particular group of alleles. Sequence motifs, which are usually part of the PBR, are normally indicative of shared ancestry, particularly if a given group of alleles has more than one motif in common. Evidence is accumulating, however, that identical or very similar motifs can also arise independently in different genes, presumably by selection. Some motifs, particularly those shared by the MHC genes of very distant taxa, therefore represent instances of convergent evolution, possibly driven by the need to respond to similar parasite-derived peptides.

Although the class I and class II loci occur in clus ters, they are, in all vertebrates thus far studied, intermingled with other loci. The latter are often referred to as class III loci although they are occupied by a heterogeneous group of mostly unrelated genes. In bony fish (represented by the zebrafish), on the other hand, the class II loci are dispersed to two different chromosomes, the class I loci are on yet another chromosome, and each of the clusters is associated with class III loci different from those in mammals. The LMP2 and LMP7 loci, which in mammals are part of the class II cluster, are in the zebrafish in the class I cluster. Since the l.MP loci are functionally tied to the class I loci, the zebrafish arrangement might be ancestral to that found in mammals. The zebrafish MHC organization rules out the suggestion that class I and class II must be linked to coordinate their expression. Which of the two types of MHC organizations (the human or the zebrafish type) is more ancient remains an unresolved question.

See also: Antigen presentation via MHC class I molecules; Antigen presentation via MHC class II molecules; MHC peptide-binding specificity; p2-microglobulin; H2 class I; H2 class II; H2 class III; HLA class I; HLA class II; HLA class III region; Immunoglobulin gene superfamily; MHC disease associations; MHC, functions of; MHC restriction; Mixed lymphocyte reaction (MLR); Phytogeny of the immune response; T cell receptor, evolution of.

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