Jan Klein

Nomenclature for the major histocompatibility complexes of different species: a proposal.

The major histocompatibility complex (MHC) has been given different names in different species (Klein 1986). It is designatedH-2 in the mouse, HLA in humans, B in the domestic fowl, RT1 in the rat, and Smh in the mole rat. In most other species that have been studied, the MHC is referred to by the LA symbol (for lymphocyte or leukocyte antigen), prefixed by an abbreviation of the species’ common name. Thus, it is called ChLa in the chimpanzee, GoLA in the gorilla, RhLA in the rhesus macaque, RLA in the rabbit, BoLA in the domestic cattle, SLA in the pig, and so on. This practice has two problems associated with it. First, MHC products are expressed on many other tissues in addition to lymphocyte or leukocyte (and lymphocytes express many other antigens in addition to those controlled by the MHC) and their antigenicity is secondary to their biological function. Second, the use of common names to identify a species is a potential source of confusion. Common names are notoriously vague and imprecise. The designation “lemur”, for example, can refer to any of the genera Lemur, Hapalemur, Varecia, Lepilemur; Avahi, Propithecus, and Indri, of which only the first four belong to the family Lemuridae; the last three are members of the family Indriidae. A “bushbaby” can be a Galago, Otolemur, or Euoticus. A “mouse” could be a Notomys, ylcomys, Uranomys, Pogomys, Chiruromys, Chiropodomys, Neohydromys, and so on. Obviously, common names not only fail to identify the species appropriately, they often do not even identify the genes or the family. If the trend in choosing common names for MHC symbols were to continue, chaos would soon ensue because we can expect MHCs in many different species to be identified in the future.

Molecular evolution of the major histocompatibility complex

Organization and evolution of the MHC chromosomal region: An overview.- Reconstruction of phylogenetic trees and evolution of major histocompatibility complex genes.- Trans-species polymorphism of HLA molecules, founder principle, and human evolution.- Calibrating evolutionary rates at major histocompatibility complex loci.- Concerted mutagenesis: Its potential impact on interpretation of evolutionary relationships.- Two models of evolution of the class I MHC.- Evolution of MHC domains: Strategy for isolation of MHC genes from primitive animals.- Generation of allelic polymorphism at the DRB1 locus of primates by exchange of polymorphic domains: A plausible hypothesis?.- A phylogenetic investigation of MHC class II DRB genes reveals convergent evolution in the antigen binding site.- Diversification of class II A? within the genus Mus.- Molecular and genetic mechanisms involved in the generation of Mhc diversity.- Evidence for multiple mutational mechanisms which generate polymorphism at H-2K.- Contributions of interlocus exchange to the structural diversity of the H-2K, D, and L alleles.- Evolution of Great Ape MHC class I genes.- Evolution of New World primate MHC class I genes.- Polymorphisms of the major histocompatibility complex in Old and New World primates.- Mhc class I genes of New World monkeys and their relationship to human genes.- Selective inactivation of the primate Mhc-DQA2 locus.- Is DQB2 functional among nonhuman primates?.- Alu repeats and evolution of the HLA-DQA1 locus.- The Alu repeats of the primate DRB genes.- Interpreting MHC disequilibrium.- Frozen haplotypes in Mhc evolution.- The age and evolution of the DRB pseudogenes.- Organization and evolution of the HLA-DRB genes.- The MHC of Peromyscus Leucopus (Mhc-Pele) illustrates large- and small-scale expansion in the phylogeny of MHC loci.- Sequence and evolution of bovine MHC class I genes.- Evolution of MHC molecules in nonmammalian vertebrates.- The polymorphic B-G antigens of the chicken MHC - Do the structure and tissue distribution suggest a function?.- Evolution of primate C4 and CYP21 genes.- Mapping of a hot spot in the major recombination area of the mouse H-2 complex.- Conservation versus polymorphism of the MHC in relation to transplantation, immune responses, and autoimmune disease.- HLA associations with malaria in Africa: Some implications for MHC evolution.- The evolution of MHC-based mating preferences in Mus.- Possible MHC associated heterozygous advantage in wild mouse populations.- Antigen presentation by neoclassical MHC class I gene products in murine rodents.- Mls antigens (superantigens), class II MHC, and Tcr repertoire: Co-adaptive evolution.- Diversity and evolution at the Eb recombinational hotspot in the mouse.- Molecular dissection of the Eb recombinational hotspot in the mouse.- Molecular cloning of nurse shark cDNAs with high sequence similarity to nucleoside diphosphate kinase genes.- Author Index.

Shared class II MHC polymorphisms between humans and chimpanzees

To gain an insight into the evolution of the major histocompatibility complex alleles, three DRB and one DRA genes were isolated from chimpanzee cDNA libraries. The nucleotide sequences of the chimpanzee DRB (ChLA-DRB) genes were then compared with those of the available HLA-DRB alleles by constructing unrooted phylogenetic trees. All three ChLA-DRB genes were found to be more closely related to certain HLA-DRB alleles than unrelated HLA-DRB alleles are to each other. Since available evidence does not support the convergent evolution of MHC alleles, this result is consistent with the idea that closely related ChLA-DRB and HLA-DRB alleles are derived from common ancestral alleles, the existence of which predates the divergence of human and chimpanzee lineages. The predicted amino acid sequences of mature ChLA-DRA and HLA-DRA molecules differ by only one amino acid.

Cloning and characterization of class I Mhc genes of the zebrafish, Brachydanio rerio.

The zebrafish (Brachydanio rerio) offers many advantages for immunological and immunogenetic research and has the potential for becoming one of the most important nonmammalian vertebrate research models. With this in mind, we initiated a systematic study of the zebrafish major histocompatibility complex (Mhc) genes. In this report, we describe the cloning and characteristics of the zebrafish class I A genes coding for the α chains of the αβ heterodimer and thus complete the identification of all four classes and subclasses of the Mhc in this species. We describe the full class I α cDNA sequence as well as the exon-intron organization of the class I A genes, including intron sequences. We identify three families of class I A genes which we designate Bree-UAA,-UBA, and -UCA. The three families originated about the time of the divergence of cyprinid and salmonid fishes. All three families are members of an ancient lineage that diverged from another, older lineage also represented in cyprinid fishes before the radiation of teleost orders. The fish class I A genes therefore evolve differently from mammalian class I A genes, in which the establishment of lineages and families mostly postdates the divergence of orders.

Primate ABO glycosyltransferases: Evidence for trans-species evolution

The human ABO blood group system is controlled by alleles at a single locus on chromosome 9. The alleles encode glycosyltransferases, which add different sugar residues to the terminal part of the oligosaccharide core, thus generating the A or B antigens; an allele encoding enzymatically inactive protein is responsible for the blood group O. The A and B antigens are present not only in humans, but also in many other primate species and it has been proposed that the AB polymorphism was established long before these species diverged. Here we provide molecular evidence for the trans-species evolution of the AB polymorphism. Polymerase-chain reaction (PCR) amplification and sequencing has revealed that the critical substitutions differentiating the A and B genes occurred before the divergence of the lineages leading to humans, chimpanzees, gorillas, and orangutans. This polymorphism is therefore at least 13 million years old and is most likely maintained by selection. Comparison of the sequences derived from different species indicates that the difference in enzymatic activities between the A and B transferases is caused by two single nucleotide substitutions responsible for Leu-Met and Gly-Ala replacement at positions 265 and 267 in the polypeptide chains, respectively.

The Major Histocompatibility Complex and the Quest for Origins

Article synthese sur levolution moleculaire des molecules du systeme histocompatibilite majeur. La phylogenese de levolution par lutilisation de la dendrometrie a ete realisee

Class II B Mhc motifs in an evolutionary perspective.

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HOMOLOGY BETWEEN IMMUNE RESPONSES IN VERTEBRATES AND INVERTEBRATES : DOES IT EXIST?

Increasingly larger numbers of immunologists realize that there is more to their discipline than the human body and its animal model, the mouse body, reveal. Many are beginning to appreciate that studying organisms other than humans and mice can not only be rewarding intellectually but may also be relevant to human health. However, as immunologists widen their horizon of interest and include in their experimental menageries creatures as disparate as earthworms, fruit flies, and horseshoe crabs, they often fall into what could best be termed the ’homology trap’. An example will explain. An exchange of tissue patches between genetically dissimilar earthworms of the same species will often have a similar outcome to the exchange of tissue grafts between two mice belonging to different inbred strains [1, 2]. In both instances the grafts at first heal in, only to be destroyed, ‘rejected’, subsequently. Moreover, in both cases the rejection is preceded by an infiltration of the graft by mononuclear cells from the circulating fluid, the haemolymph in earthworms and the blood in the mouse. Also, when a second graft from the same donor is placed on the recipient, it is rejected earlier than the first graft — in the mouse always and in the earthworm sometimes. The striking superficial similarity between the processes taking place in the earthworm and mouse presents a great temptation to consider the two phenomena to be homologous; that is, to have the same evolutionary origin. The temptation is rarely resisted, as is reflected in the frequent use of the term ‘allograft reaction’ for both phenomena, with the implicit or explicit inference that the mechanisms underlying them are similar in principle. Comparative immunology is rife with such inferences of homology between similar phenomena or structures: investigators studying invertebrates speak routinely of ‘second-set reactions’, ‘immunological memory’, ‘antigen presentation’, ‘lymphocytes’, ‘granulocytes’, and ‘interleukins’—all terms borrowed from vertebrate immunology [3]. In all these instances, the basis for the application of these terms to invertebrates is functional similarity with vertebrates, mostly mammals, and particularly humans and mice. Homology is an ill-defined concept [4, 5]. Opinions differ as to what should be considered homologous and the debate, which often has overt or covert philosophical undertones, has not yet yielded any consensus. The one thing all the experts agree on, however, is that implications of homology must not be based on functional similarity. Homology can exist at different levels [6]. Anatomical and morphological comparisons of adult organisms belonging to different species reveal similarities at the level of structure ( 1⁄4 morphological homology ). Comparisons of embryos provide information about similar origin of two structures during development ( 1⁄4 developmental homology ). Correspondence between gene expression patterns brings to light similarity in cascades of transcription factors regulating the formation of similar structures ( 1⁄4 regulatory homology ). Finally, alignments of gene or protein sequences disclose similarities at the DNA or protein level ( 1⁄4 gene homology ). Often a character is homologous at one or more but not all of the levels, giving rise to the question which of the levels is more important in deciding whether a feature is homologous. Functional similarity is excluded from the definition of homology because it so easily and so often arises independently during evolution. A feature shared by two taxa but absent in their common ancestor is analogous but not homologous, and the sets of inferences that can be made from analogous or homologous characters are different. Homologous structures may have different functions and nonhomologous structures often have a similar function. Hence ‘functional homology’ makes the entire concept of homology meaningless [7]. If function cannot be used in defining homology of immune phenomena, which criterion can? Or, somewhat more specifically, how should one go about deciding which immune responses of vertebrates and invertebrates are homologous? Before I attempt to answer these questions, I must introduce two other concepts: the deuterostome–protostome split of the metazoan (animal) phylogenetic tree, and the anticipatory–nonanticipatory schism in the metazoan immune responses.

Analysis of zebrafish Mhc using BAC clones

Abstractu2003Although major histocompatibility complex (Mhc) genes have been identified in a number of species, little is yet known about their organization in species other than human and mouse. The zebrafish, Danio rerio, is a good candidate for full elucidation of the organization of its Mhc. As a step toward achieving this goal, a commercially available zebrafish BAC library was screened with probes specific for previously identified zebrafish class I and class II genes, as well as for genes controlling the proteasome subunits LMP7 and LMP2. Restriction maps of the individual positive clones were prepared and the Mhc (LMP7) genes localized to specific fragments. The total length of genomic DNA fragments with Mhc genes was approximately 1700 kilobases (kb) (200 kb of fragments bearing class I loci and 1500 kb of fragments bearing class II loci). One of the two class I loci (Dare-UCA) is closely associated with the LMP7 locus; the second class I locus (Dare-UAA) is more than 50 kb distant from the UCA locus and has no LMP genes associated with it. None of the class II genes are linked to the class I or the LMP genes. All six of the previously identified class II B genes and one of the three class II A genes were found to be present in the BAC clones; no new Mhc loci could be identified in the library. Each of the six previously identified class II B loci was found to be borne by a separate group of BAC clones. The Dare-DAB and -DAA loci were found on the same clone, approximately 15 kb apart from each other. An expansion of DCB and DDB loci was detected: the zebrafish genome may contain at least five closely related DCB and two closely related DDB loci which are presumably the products of relatively recent tandem duplication. These results are consistent with linkage studies and indicate that in the zebrafish, the class I and class II loci are on different chromosomes, and the class II loci are in three different regions, at least two of which are on different chromosomes.

Composite origin of major histocompatibility complex genes

Major histocompatibility complex (MHC) genes have now been cloned from representatives of all vertebrate classes except Agnatha. The recent accumulation of sequence data has given great insight into the course of evolution of these genes. Although the primary structure of the MHC genes varies greatly from class to class and also within the individual classes, the general features of the tertiary and quaternary structure have been conserved remarkably well during more than 400 million years of evolution. The ancestral MHC genes may have been assembled from at least three structural elements derived from different gene families. Class II MHC genes appear to have been assembled first, and then to have given rise to class I genes.