Diversity and evolution of the immunoglobulin gene superfamily

Citation

Hunkapiller, Tim (1993) Diversity and evolution of the immunoglobulin gene superfamily. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/mcbv-n026. https://resolver.caltech.edu/CaltechTHESIS:12182012-093217041

Abstract

The Immunoglobulin Gene Superfamily is characterized by a common protein homology unit that is present in arguably the largest and most diverse set of genes and gene families of any protein motif. This distribution indicates that the homology unit is a remarkably versatile functional unit. Its central role in defining the complex phenotypes of the immune and nervous systems, likewise, is testament to the ability of the motif to support an amazing and unique degree of diversification. Understanding more about the function, structure and evolution of the Immunoglobulin Gene Superfamily can provide insights into both the general issues of complex system evolution as well as the specific nature of the various systems the superfamily plays a central role in. This thesis is a collection of work aimed at a more thorough understanding of these elements. Particularly, these works summarize much of our current understanding of the members of the Immunoglobulin Gene Superfamily along with speculations on their evolutionary history as well as both the evolutionary and somatic mechanisms responsible for their diversity. This work includes initial descriptions of several features relevant to somatic diversification of rearranging immune receptors, including: l) the role of joining imprecision in the generation of junctional diversity in immunoglobulin kappa chain; 2) the initial description of the T-cell beta chain J/C locus; 3) the translation of T-cell beta chain D gene segments in all three reading frames; 4) the occurrence of a cryptic rearrangement signal in most rearranging V families; 5) the first description of the mechanisms of class switching between heavy chain mu and delta genes; 6) the limited diversity of germline T-cell beta chains; 7) the shared complementary determining region structure of T-cell beta chains and immunoglobulin heavy chains. Also, from these efforts, new members of the superfamily have been identified including MHC class I molecules, L3T4 and Myelin Associated Glycoprotein. Various observations concerning the evolutionary relationships of these molecules and motifs have been made. Particularly, a variation on the basic homology unit motif has been proposed that probably more nearly represents the primordial sequence and function.

As a result of these discoveries, a new, comprehensive picture of the immunoglobulin superfamily is emerging that has implications for interpreting current functional relationships in the context of the evolutionary history of the members. Particularly, it is suggested from this work that the ability of the homology unit to accommodate diversity has made possible the evolution of the superfamily. Given the tremendous diversity within the superfamily, it might be assumed that selective pressures favoring diversity have driven its evolution. However, much of the analysis within this collection suggests that, on the contrary, diversity is an inherent feature of the conserved protein and gene structure of the homology unit and that it was the a priori diversity itself that drove and shaped the evolution of the complex systems that employ the homology unit today. This basic diversity is the consequence of three characteristics of the homology unit. First, the tertiary structure of the protein motif is such that homology units tend to interact preferentially to form homo- or heterodimers, forming the basis of many of the receptors and the receptor/ligand interactions common within the superfamily. These combinatorial associations increase both the somatic and evolutionary potential for diversification. This can lead to the rather sudden appearance of new functional associations between existing members of the superfamily preadapted for otherwise unrelated functions. Second, except for a minimal number of amino acid residues involved in critical intra- and interchain interactions, the primary structure of these units can vary dramatically and still provide for essentially the same tertiary structure. This has been borne out by various crystallographic studies. The variability is particularly true of the loop structures normally identified with antigen specificity, but seen in other extended families as well. Reduced constraints on structural sequences inherently promote the establishment of variation within populations. Third, with very few exceptions the genes of the superfamily, the homology units are not only encoded by discrete exons, but these exons have a shared 1/2 splicing rule. That is, each is begun with the second 2 bases of a codon and ended with the first base. This allows the in-frame splicing of any number of tandem homology units, while maintaining functional protein domains. This rule generally applies to the non-homology unit exons of member genes as well. This allows, through relatively simple genetic events, the development of new contexts for homology unit expression, both by simple expansion and contraction of homology unit number and exon shuffling. This is probably at work, as well, in the frequent occurrence and utilization of alternative transcripts seen throughout the superfamily. Many of the recognized occurrences of alternative splicing, such as that between membrane-bound and secreted forms, indicate that this gene structure provides for a further level of functional diversity and the expansion of the virtual genetic information.

Beyond the explicit discussion of the superfamily members, this work also speaks to various issues of evolution in general. In particular, the history of the superfamily suggests the importance of canalization and non-gradual episodes of evolutionary change. It can contribute, as well, to the discussion of adaptive versus neutral change.

Thesis Files