The Immunoglobulin Gene Superfamily is characterized by a common proteinhomology unit that is present in arguably the largest and most diverse set of genes andgene families of any protein motif. This distribution indicates that the homology unit isa remarkably versatile functional unit. Its central role in defining the complexphenotypes of the immune and nervous systems, likewise, is testament to the ability ofthe motif to support an amazing and unique degree of diversification. Understandingmore about the function, structure and evolution of the Immunoglobulin GeneSuperfamily can provide insights into both the general issues of complex systemevolution as well as the specific nature of the various systems the superfamily plays acentral role in. This thesis is a collection of work aimed at a more thoroughunderstanding of these elements. Particularly, these works summarize much of ourcurrent understanding of the members of the Immunoglobulin Gene Superfamily alongwith speculations on their evolutionary history as well as both the evolutionary andsomatic mechanisms responsible for their diversity. This work includes initialdescriptions of several features relevant to somatic diversification of rearrangingimmune receptors, including: l) the role of joining imprecision in the generation ofjunctional diversity in immunoglobulin kappa chain; 2) the initial description of the T-cellbeta chain J/C locus; 3) the translation of T-cell beta chain D gene segments in allthree reading frames; 4) the occurrence of a cryptic rearrangement signal in mostrearranging V families; 5) the first description of the mechanisms of class switchingbetween heavy chain mu and delta genes; 6) the limited diversity of germline T-cellbeta chains; 7) the shared complementary determining region structure of T-cell betachains and immunoglobulin heavy chains. Also, from these efforts, new members ofthe superfamily have been identified including MHC class I molecules, L3T4 andMyelin Associated Glycoprotein. Various observations concerning the evolutionaryrelationships of these molecules and motifs have been made. Particularly, a variationon the basic homology unit motif has been proposed that probably more nearlyrepresents the primordial sequence and function.
As a result of these discoveries, a new, comprehensive picture of theimmunoglobulin superfamily is emerging that has implications for interpreting currentfunctional 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 toaccommodate diversity has made possible the evolution of the superfamily. Given thetremendous diversity within the superfamily, it might be assumed that selectivepressures favoring diversity have driven its evolution. However, much of the analysiswithin this collection suggests that, on the contrary, diversity is an inherent feature ofthe conserved protein and gene structure of the homology unit and that it was the apriori diversity itself that drove and shaped the evolution of the complex systems thatemploy the homology unit today. This basic diversity is the consequence of threecharacteristics of the homology unit. First, the tertiary structure of the protein motif issuch 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 commonwithin the superfamily. These combinatorial associations increase both the somatic andevolutionary potential for diversification. This can lead to the rather suddenappearance of new functional associations between existing members of the superfamilypreadapted for otherwise unrelated functions. Second, except for a minimal number ofamino acid residues involved in critical intra- and interchain interactions, the primarystructure of these units can vary dramatically and still provide for essentially the sametertiary structure. This has been borne out by various crystallographic studies. Thevariability is particularly true of the loop structures normally identified with antigenspecificity, but seen in other extended families as well. Reduced constraints onstructural sequences inherently promote the establishment of variation withinpopulations. Third, with very few exceptions the genes of the superfamily, thehomology units are not only encoded by discrete exons, but these exons have a shared1/2 splicing rule. That is, each is begun with the second 2 bases of a codon and endedwith the first base. This allows the in-frame splicing of any number of tandemhomology units, while maintaining functional protein domains. This rule generallyapplies to the non-homology unit exons of member genes as well. This allows, throughrelatively simple genetic events, the development of new contexts for homology unitexpression, both by simple expansion and contraction of homology unit number andexon shuffling. This is probably at work, as well, in the frequent occurrence andutilization of alternative transcripts seen throughout the superfamily. Many of therecognized occurrences of alternative splicing, such as that between membrane-boundand secreted forms, indicate that this gene structure provides for a further level offunctional diversity and the expansion of the virtual genetic information.
Beyond the explicit discussion of the superfamily members, this work alsospeaks to various issues of evolution in general. In particular, the history of thesuperfamily suggests the importance of canalization and non-gradual episodes ofevolutionary change. It can contribute, as well, to the discussion of adaptive versusneutral change.
