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.</p