All organisms need defense systems to ward off infection. These defenses typically mobilize in response to antigens, bits of protein fragments derived from a pathogen. Vertebrates have a superbly efficient system of adaptive immunity that uses proteins to recognize and bind billions of different antigens via a process known as antigen presentation. Ultimately, this process leads to removal of the antigen. Antigen binding proteins are encoded within one large genomic region known as the major histocompatibility complex (MHC). The high level of polymorphism, or variation, in this genomic region allows the adaptive immune system to keep pace with an ever-changing array of antigens.
Genes in the MHC region are subdivided into Class I, Class II, and Class III based on their structure and function. The organization of MHC genes in present-day species can provide insight into how immunity has evolved. To date, maps of the MHC are available from eutherian (placental) mammals and nonmammalian species, including birds, bony fish, and cartilaginous fish such as sharks. But MHC organization and complexity differ substantially between mammals and nonmammals, making it difficult to infer the region's evolutionary history, or phylogeny.
Using available marsupial opossum
In eutherian mammals, the MHC is large and dense, with 264 genes and pseudogenes (remnants of once functional genes) scattered over 3.6 Mb and ordered as Class I–III–II in adjacent gene blocks in humans. In nonmammals, the MHC has fewer genes (the chicken has only 19 genes over 92 kb) ordered as Class III–I–II. The authors found that the MHC in the opossum is flanked at either end by the same marker genes that border the human MHC. This noneutherian mammalian MHC spans 3.95 Mb and encodes 114 genes (identified via sequence similarity to genes from other species), sharing 87 with the human MHC. The authors have provided a Web-based genome browser (
Belov et al. found that while the size and complexity of the opossum MHC is closer to eutherian mammals, its organization is closer to fish and birds: in the opossum, Class I genes are interspersed with the Class II genes—this has not been seen in any other animals. This similar grouping of Class I and II genes implies that they may have been arranged this way in the mammalian ancestor (supported also by the presence of the Class I pseudogenes in the human Class II region).
Humans and mice have a conserved framework region, consisting of a set of genes that are interspersed among the Class I loci. The opossum also contains these genes next to the Class III region. The authors deduced that this framework region assembled in the ancestral mammalian MHC before Class I genes moved to this location in eutherians.
Only one of the opossum MHC genes,
The authors identified three marsupial-specific classical Class II gene families (
Significantly, the authors also found data supporting the idea that there was an ancient relationship between the MHC and another critical component of the immune system, the natural killer complex (NKC), which contains natural killer (NK) cell receptor loci. Two NKC genes,
The authors conclude that vertebrates once possessed an “immune supercomplex” that performed the MHC functions. While this complex no longer exists in modern genomes, scientists can probe its remnant traces for clues to its history. Gaining a better understanding of how our mammalian immunity evolved will lead to a much broader appreciation of how organisms' internal defense systems work across a wide range of species.
Genome sequence data from the opossum fills a gap in our understanding of the evolution of the mammalian immune system.