Molecular evolution of the vertebrate immune system

Adaptive immunity is unique to the vertebrates, and the molecules involved (including immunoglobulins, T cell receptors and the major histocompatibility complex molecules) seem to have diversified very rapidly early in vertebrate history. Reconstruction of gene phylogenies has yielded insights into the evolutionary origin of a number of molecular systems, including the complement system and the major histocompatibility complex (MHC). These analyses have indicated that the C5 component of complement arose by gene duplication prior to the divergence of C3 and C4, which suggests that the alternative complement pathway was the first to evolve. In the case of the MHC, phylogenetic analysis supports the hypothesis that MHC class II molecules evolved before class I molecules. The fact that the MHC-linked proteasome components that specifically produce peptides for presentation by class I MHC appear to have originated before the separation of jawed and jawless vertebrates suggests that the MHC itself may have been present at this time. Immmune system gene families have evolved by gene duplication, interlocus recombination and (in some cases) positive Darwinian selection favoring diversity at the amino acid level.     

Piecing together evolution of the vertebrate endocrine system

One of the great challenges in biology is to understand how particular complex morphological and physiological characters originated in specific evolutionary lineages. In this article, we address the origin of the vertebrate hypothalamic-pituitary-peripheral gland (H-P-PG) endocrine system, a complex network of specialized tissues, ligands and receptors. Analysis of metazoan nucleotide and protein sequences reveals a patchwork pattern of H-P-PG gene conservation between vertebrates and closely related invertebrates (ascidians). This is consistent with a model of how the vertebrate H-P-PG endocrine system could have emerged in relatively few steps by gene family expansion and by regulatory and structural modifications to genes that are present in a chordate ancestor. Some of these changes might have resulted in new connections between metabolic or signaling pathways, such as the bridging of 'synthesis islands' to form an efficient system for steroid hormone synthesis.     

Appearance of Myelin proteins during vertebrate evolution

Myelin, defined as an arrangement of spirally fused unit membranes, is an acquisition of vertebrates and first appeared during evolution in Gnathostomata. In all species studied PNS and CNS myelins contain the myelin-associated glycoprotein (MAG) and the myelin basic protein (MBP). Throughout phylogeny PNS myelin is characterized by the major P₀ glycoprotein which is called IP in fishes. The PNS myelin proteins did not evolve further except for the addition of P₂ protein from reptiles onward. In Elasmobranchii and Chondrostei, PNS and CNS myelin proteins are similar. CNS myelin of actinopterygian fishes possesses a 36,000 Da protein (36K) in addition to P₀-like IP glycoproteins. In tetrapod CNS myelin, P₀ is replaced by the proteolipid protein (PLP) and the Wolfgram protein (WP). Of particular interest in a transitional phylogenetic sense are the lungfish Protopterus, carrying glycosylated PLP (g-PLP) but no P₀, 36K or WP, and the bichir Polypterus, showing simultaneous presence of P₀, 36K and PLP.

These results indicate that myelin proteins could be valuable molecular markers in establishing vertebrate phylogenetic relationships and in reconstructing the fish-tetrapod transition.     

Patterning of retinotectal connections in the vertebrate visual system.

Recent work on the retinotectal projection clearly establishes the roles of neuronal activity and position-based cues in the patterning of nerve connections. In some species, the high degree of spatial order has been shown to emerge from a continued process of terminal growth and refinement. The future challenge is now to determine how multiple cues work together to guide the sculpting of the final pattern.     

Conservation of engrailed-like homeobox sequences during vertebrate evolution

The Drosophila melanogaster developmental gene engrailed (en) is a member of a distinct subfamily of homeobox genes with a wide phylogenetic distribution. Here we report the use of reduced stringency polymerase chain reaction (PCR) to amplify and clone 8 genes related to en from 5 vertebrate species, including representatives of the most ancient vertebrate lineages. Nucleotide and deduced amino acid sequence comparisons between mouse, toad, zebrafish, lamprey and hagfish genes reveal extensive evolutionary conservation, and suggests that 2 en-like genes have been retained in most vertebrate lineages.     

Appearance of new tetraspanin genes during vertebrate evolution

A detailed phylogenetic analysis of tetraspanins from 10 fully sequenced metazoan genomes and several fungal and protist genomes gives insight into their evolutionary origins and organization. Our analysis suggests that the superfamily can be divided into four large families. These four families-the CD family, CD63 family, uroplakin family, and RDS family-are further classified as consisting of several ortholog groups. The clustering of several ortholog groups together, such as the CD9/Tsp2/CD81 cluster, suggests functional relatedness of those ortholog groups. The fact that our studies are based on whole genome analysis enabled us to estimate not only the phylogenetic relationships among the tetraspanins, but also the first appearance in the tree of life of certain tetraspanin ortholog groups. Taken together, our data suggest that the tetraspanins are derived from a single (or a few) ancestral gene(s) through sequence divergence, rather than convergence, and that the majority of tetraspanins found in the human genome are vertebrate (21 instances), tetrapod (4 instances), or mammalian (6 instances) inventions.     

Interacting gene clusters and the evolution of the vertebrate immune system

Unraveling the "code" of genome structure is an important goal of genomics research. Colocalization of genes in eukaryotic genomes may facilitate preservation of favorable allele combinations between epistasic loci or coregulation of functionally related genes. However, the presence of interacting gene clusters in the human genome has remained unclear. We systematically searched the human genome for evidence of closely linked genes whose protein products interact. We find 83 pairs of interacting genes that are located within 1 Mbp in the human genome or 37 if we exclude hub proteins. This number of interacting gene clusters is significantly more than expected by chance and is not the result of tandem duplications. Furthermore, we find that these clusters are significantly more conserved across vertebrate (but not chordate) genomes than other pairs of genes located within 1 Mbp in the human genome. In many cases, the genes are both present but not clustered in older vertebrate lineages. These results suggest gene cluster creation along the human lineage. These clusters are not enriched for housekeeping genes, but we find a significant contribution from genes involved in "response to stimulus." Many of these genes are involved in the immune response, including, but not limited to, known clusters such as the major histocompatibility complex. That these clusters were formed contemporaneously with the origin of adaptive immunity within the vertebrate lineage suggests that novel evolutionary and regulatory constraints were associated with the operation of the immune system.     

Mammary glands and feathers: comparing two skin appendages which help define novel classes during vertebrate evolution

It may appear counter-intuitive to compare feathers and mammary glands. However, through this Evo-Devo analysis, we appreciate how species interact with the environment, requiring different ectodermal organs. Novel ectodermal organs help define evolutionary directions, leading to new organism classes as exemplified by feathers for Aves and mammary glands for Mammals. Here, we review their structure, function, morphogenesis and regenerative cycling. Interestingly, both organs undergo extensive branching for different reasons; feather branching is driven by mechanical advantage while mammary glands nourish young. Besides natural selection, both are regulated by sex hormones and acquired a secondary function for attracting mates, contributing to sexual selection.     

Origin and evolution of the vertebrate vomeronasal system viewed through system-specific genes

Tetrapods have two distinct nasal chemosensory systems, the main olfactory system and the vomeronasal system (VNS). Defined by certain morphological components, the main olfactory system is present in all groups of vertebrates, while the VNS is found only in tetrapods. Previous attempts to identify a VNS precursor in teleost fish were limited by functional and morphological characters that could not clearly distinguish between homologous and analogous systems. In the past decade, several genes that specifically function in the VNS have been discovered. Here we first describe recent evolutionary studies of mammalian VNS-specific genes. We then review evidence showing the presence and tissue-specific expression of the VNS-specific genes in teleosts, as well as co-expression patterns of these genes in specific regions of the teleost olfactory epithelium. We propose that a VNS precursor exists in teleosts and that its evolutionary origin predated the separation between teleosts and tetrapods.     

Indirect genetic effects and the evolution of aggression in a vertebrate system

Aggressive behaviours are necessarily expressed in a social context, such that individuals may be influenced by the phenotypes, and potentially the genotypes, of their social partners. Consequently, it has been hypothesized that indirect genetic effects (IGEs) arising from the social environment will provide a major source of heritable variation on which selection can act. However, there has been little empirical scrutiny of this to date. Here we test this hypothesis in an experimental population of deer mice (Peromyscus maniculatus). Using quantitative genetic models of five aggression traits, we find repeatable and heritable differences in agonistic behaviours of focal individuals when presented with an opponent mouse. For three of the traits, there is also support for the presence of IGEs, and estimated correlations between direct and indirect genetic (rAO,F) effects were high. As a consequence, any selection for aggression in the focal individuals should cause evolution of the social environment as a correlated response. In two traits, strong positive rAO,F will cause the rapid evolution of aggression, while in a third case changes in the phenotypic mean will be constrained by negative covariance between direct and IGEs. Our results illustrate how classical analyses may miss important components of heritable variation, and show that a full understanding of evolutionary dynamics requires explicit consideration of the genetic component of the social environment.     

Promoter shuffling has occurred during the evolution of the vertebrate growth hormone gene

Comparative studies of vertebrate gene promoter regions seldom detect gross rearrangements ('promoter shuffling') since such analyses usually employ relatively similar DNA sequences. Conversely, attempts to compare evolutionarily more divergent promoter sequences have been largely unsuccessful owing to the inability of conventional alignment procedures to deal with gross rearrangements. These limitations have been circumvented in the present study by using the novel technique of complexity analysis to identify modular components ('blocks') in the growth hormone (GH) gene promoter sequences of some 22 vertebrate species, from salmon to human. Significant rearrangement of blocks was found to have occurred, indicating that they have evolved as independent units. Some blocks appear to be ubiquitous, whereas others are restricted to a specific taxon. Considerable variation between orthologous GH gene promoters was apparent in terms of block length, copy number and relative location. It may be inferred that a wide variety of different mutational mechanisms have operated upon the GH gene promoter over evolutionary time. These include gross changes such as deletion, duplication, amplification, elongation, contraction, transposition, inversion and fusion, as well as the slow, steady accumulation of single base-pair substitutions. Thus the patchwork structure of the modular GH promoter region, and those of its paralogous GH2 and prolactin (PRL) counterparts, have continually been shuffled into new combinations through the rearrangement of pre-existing blocks. Although some of these changes may have had no influence on promoter function, others could have served to alter either the level of gene expression or the responsiveness of the promoter to external stimuli.     

Modelling of the vertebrate visual system 3. topological analysis of the cone mosaic

Spatial organization of the cone mosaic of the generalized vertebrate retina consists of rows of red and green cones alternating with rows of blue and blank cones. Cone inputs to retinal elements are defined spatially by red and green unit hexagons. Topological analysis entails determining for each cone in the mosaic the number of each cone type present in the unit hexagon which the activated cone can influence via electrical coupling between cones and/or stray light. Only weighted inputs in one-half of a sextant of the unit hexagon need be designated, since all other weighted inputs can be determined by rules giving systematic transformations of all cone types from one sextant to another: these rules arise from symmetries of the cone mosaic. Four retinal types are possible depending on replacement of blank cones by specific cone types; three cone-dominant retinas, where all blank cones are replaced by a specific cone type, and two forms of a trichromatic retina, where blank cones are replaced by equal numbers of red and green cones. The weighted input is the sum of individual cone type contributions and depends on the number of each cone type in the unit hexagon which can influence the cone in question. Weighted inputs for cone-dominant retinas are readily found by replacing blank cones with the proper cone type, while weighted inputs for trichromatic retinas require use of a specified cone mosaic to determine extra red and green cones. Receptive field size of post-cone elements as well as overlap of the center and surround fields of annular organized receptive fields of retinal elements increased with increasing values for attenuation factors.