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Progressive immunoglobulin gene mutations in chronic lymphocytic leukemia: evidence for antigen-driven intraclonal diversification.

Somatic mutations of immunoglobulin genes characterize mature memory B cells, and intraclonal B-cell diversification is typically associated with expansion of B-cell clones with greater affinity for antigen (antigen drive). Evidence for a role of antigen in progression of intraclonal chronic lymphocytic leukemia (CLL) cell diversification in patients with mutated immunoglobulin genes has not been previously presented. We performed a single-cell analysis of immunoglobulin heavy and light chains in 6 patients with somatically mutated CLL-cell immunoglobulin genes and identified 2 patients with multiple related (oligoclonal) subgroups of CLL cells. We constructed genealogic trees of these oligoclonal CLL-cell subgroups and assessed the effects of immunoglobulin somatic mutations on the ratios of replacement and silent amino acid changes in the framework and antigen-binding regions (CDRs) of the immunoglobulin heavy and light chains from each oligoclonal CLL-cell population. In one subject, the amino acid changes were consistent with an antigen-driven progression of clonally related CLL-cell populations. In the other subject, intraclonal diversification was associated with immunoglobulin amino acid changes that would have likely lessened antigen affinity. Taken together, these studies support the hypothesis that in some CLL cases intraclonal diversification is dependent on antigen interactions with immunoglobulin receptors.

Aged↗

Diversity begets diversity: host expansions and the diversification of plant-feeding insects.

BACKGROUND: Plant-feeding insects make up a large part of earth's total biodiversity. While it has been shown that herbivory has repeatedly led to increased diversification rates in insects, there has been no compelling explanation for how plant-feeding has promoted speciation rates. There is a growing awareness that ecological factors can lead to rapid diversification and, as one of the most prominent features of most insect-plant interactions, specialization onto a diverse resource has often been assumed to be the main process behind this diversification. However, specialization is mainly a pruning process, and is not able to actually generate diversity by itself. Here we investigate the role of host colonizations in generating insect diversity, by testing if insect speciation rate is correlated with resource diversity. RESULTS: By applying a variant of independent contrast analysis, specially tailored for use on questions of species richness (MacroCAIC), we show that species richness is strongly correlated with diversity of host use in the butterfly family Nymphalidae. Furthermore, by comparing the results from reciprocal sister group selection, where sister groups were selected either on the basis of diversity of host use or species richness, we find that it is likely that diversity of host use is driving species richness, rather than vice versa. CONCLUSION: We conclude that resource diversity is correlated with species richness in the Nymphalidae and suggest a scenario based on recurring oscillations between host expansions - the incorporation of new plants into the repertoire - and specialization, as an important driving force behind the diversification of plant-feeding insects.

Animals↗

Functional diversification of MYB23 and GL1 genes in trichome morphogenesis and initiation.

The functional diversification of duplicated genes is one of the driving forces in evolution. To understand the molecular mechanisms of gene diversification, we studied the functional relationship of the two Arabidopsis paralogous MYB-related genes GL1 and MYB23. We show that MYB23 controls trichome branching and trichome initiation at leaf edges. The latter is controlled redundantly together with GL1. We show that the two proteins are functionally equivalent during trichome initiation but not during trichome branching. RT-PCR and reporter construct analysis revealed spatial, temporal and genetic differences in transcriptional regulation of the GL1 and MYB23 genes. Presented data indicate that the diversification of GL1 and MYB23 gene functions occurred at the level of cis-regulatory sequences with respect to trichome initiation, and that, in parallel, the diversification with respect to regulation of trichome branching also involved changes in respective proteins.

Arabidopsis↗

Comparative diversification dynamics among palaeocontinents during the Ordovician Radiation.

The Ordovician Radiation was among the most extensive intervals of diversification in the history of life. However, a delineation of the proximal cause(s) of the Radiation remains elusive. Any such determination should involve an analysis of geographic overprints on diversification: did the Radiation occur randomly around the world or, alternatively, was it focused in particular geographic or depositional regimes? Here, I present a comparative evaluation of Ordovician diversification among several palaeocontinents to determine whether biotas associated with certain palaeocontinents exhibited different diversification patterns than others; in part, this involves a numerical "correction" to raw diversity trajectories. Clear disparities among palaeocontinents are indicated by the data, which appear to reflect differences in the extent of siliciclastic input partly in association with tectonic activity. Further testing will be required to fully substantiate the implication that siliciclastic influx was a predominant factor in the Ordovician Radiation, affecting a variety of higher taxa among all three Phanerozoic evolutionary faunas.

Animals↗

Contingent predictability in evolution: key traits and diversification.

Key innovations have often been invoked to explain the exceptional diversification of particular groups. However, there are few convincing examples of traits that are repeatedly and consistently associated with increased diversification. The paucity of such cases may reflect the contingent nature of the diversifying effect of key traits. These contingencies can be viewed as statistical interactions between the trait and at least three kinds of factors: (1) other taxa, (2) other traits of the group itself, and (3) the physical environment. I describe tentative examples in each of these categories: (1) a dampening of the diversification of clades with image-forming eyes by groups that earlier evolved such eyes, (2) an effect of growth form (woody or herbaceous) on the diversifying effect of biotic seed dispersal in angiosperms, and (3) an effect of atmospheric CO(2) level on the diversifying effect of C(4) photosynthesis in monocots. These examples suggest the need for more complex analyses of the relationship between possible key traits and diversification. They also suggest that radiations may be predictable given certain circumstances, thus supporting a view of evolution as both predictable and contingent. Ironically, a certain degree of predictability may be critical to arguments for evolutionary contingency.

Biological Evolution↗

Origin and rapid diversification of a tropical moss.

Molecular sequences rarely evolve at a constant rate. Yet, even in instances where a clock can be assumed or approximated for a particular set of sequences, fossils or clear patterns of vicariance are rarely available to calibrate the clock. Thus, obtaining absolute timing for diversification of natural lineages can prove difficult. Unfortunately, without absolute time we cannot develop a complete understanding of important evolutionary processes, including adaptive radiations and key innovations. In the present study, the coding sequence of the nuclear gene, glyceraldehyde 3-phosphate dehydrogenase (gpd), extracted from the paleotropical moss, Mitthyridium, was found to exhibit clocklike behavior and used to reconstruct the history of 80 distinct molecular lineages that cover the full geographic range of Mitthyridium. Two separate clades endemic to two geographically distinct oceanic archipelagos were revealed by this phylogenetic analysis. This allowed the use of island age (as derived from potassium-argon dating) as a maximum age of origin of each monophyletic group, providing two independent time anchors for the clock found in gpd, the final piece needed to study absolute time. Based on results from both maximum age calibrations, which separately yielded highly consistent estimates, the ancestor of this moss group arose approximately 8 million years ago, and then diversified at the rapid rate of 0.56 +/- 0.004 new lineages per million years. Such a rate is on par with the highest diversification rates reported in the literature including rapidly radiating insular groups like the Hawaiian silversword alliance, a classic example of an adaptive radiation. Using independent sources of data, it was found that neither the age nor diversification estimates were affected by the use of molecular lineages rather than species as the operational taxonomic units. Identifying the cause for this rapid diversification requires further testing, but it appears to be related to a general shift in reproductive strategy from sexual to asexual, which may be a key innovation for this young group.

Asia, Southeastern↗

Shared and unique features of diversification in Greater Antillean Anolis ecomorphs.

Examples of convergent evolution suggest that natural selection can often produce predictable evolutionary outcomes. However, unique histories among species can lead to divergent evolution regardless of their shared selective pressures-and some contend that such historical contingencies produce the dominant features of evolution. A classic example of convergent evolution is the set of Anolis lizard ecomorphs of the Greater Antilles. On each of four islands, anole species partition the structural habitat into at least four categories, exhibiting similar morphologies within each category. We assessed the relative importance of shared selection due to habitat similarity, unique island histories, and unique effects of similar habitats on different islands in the generation of morphological variation in anole ecomorphs. We found that shared features of diversification across habitats were of greatest importance, but island effects on morphology (reflecting either island effects per se or phylogenetic relationships) and unique aspects of habitat diversification on different islands were also important. There were three distinct cases of island-specific habitat diversification, and only one was confounded by phylogenetic relatedness. The other two unique aspects were not related to shared ancestry but might reflect as-yet-unmeasured environmental differences between islands in habitat characteristics. Quantifying the relative importance of shared and unique responses to similar selective regimes provides a more complete understanding of phenotypic diversification, even in this much-studied system.

Animals↗

Pitfalls and promises of diversification.

Diversification came upon the health-care scene with the promise of an expanded market base and financial solvency for all. Now with several diversification models advanced and successes and failures widely available for examination, what do we know about the potential pitfalls and promises of diversification? This article will present an overview of tried diversification models and analyze opportunities for success and warning signals of financial risk.

Economic Competition↗

Hospital diversification: bibliography on pharmaceutical services.

A pharmacy diversification bibliography is presented. The bibliography includes a selection of references to descriptive reports, research papers, editorials, letters, and commentaries on diversified pharmaceutical services. This bibliography represents important literature from the past 12 years on diversification strategies as well as specific diversified services. For additional information, references have also been included to articles that suggest opportunities for diversification, describe pharmacists' roles in specific services, discuss legal or reimbursement aspects of a service, or could be used to help justify the implementation of a service or "sell' a service to hospital administrators or consumers. The bibliography can be helpful to pharmacy managers and clinicians who are interested in becoming involved in diversification of pharmaceutical services.

Bibliographies as Topic↗

Dependence of antibody somatic diversification on gut-associated lymphoid tissue in rabbits.

By approximately 4 to 8 wk of age, the IgH VDJ genes of essentially all rabbit B lymphocytes have undergone somatic diversification. Some of this diversification occurs in the appendix, which is a gut-associated lymphoid tissue (GALT). To determine whether GALT is essential for somatic diversification, we surgically removed the appendix, sacculus rotundus, and Peyer's patches from neonatal rabbits (designated GALT-less) and examined the extent to which VDJ genes were somatically diversified. We found that the IgM VDJ genes of peripheral B cells from 2- to 5-mo-old GALT-less rabbits had undergone considerably less somatic diversification than those of control rabbits. Further, the percentage of peripheral B cells in the GALT-less rabbits was generally less than that of controls. Our data suggest that, in rabbits, the primary Ab repertoire develops in GALT, and B cell expansion also occurs there. Hence, GALT may function as a mammalian bursal homologue.

Animals↗

Immunoglobulin diversification in bursal duct-ligated chickens.

The role of external antigen contact on immunoglobulin (Ig) diversification occurring in chicken bursal cells was evaluated. The entry of environmental antigens into the lumen of the bursa of Fabricius was prevented by ligating the bursal duct prior to hatching (BDL: bursal duct ligation). We used two-dimensional gel electrophoresis to compare the heterogeneity of Ig molecules from bursa cells of normal and BDL chickens. We have found that Ig diversity obtained from BDL chickens' bursae in two-dimensional gel analysis was similar to that of control birds. Furthermore, by using two monoclonal anti-idiotype antibodies to study intrabursal Ig diversification we have shown that frequencies of the Cld-1 and Cld-2 idiotypes were also unaltered following bursal ligation. We conclude that primary B cell diversification in the bursa is independent of the external antigen flow from the bursal lumen.

Age Factors↗

The ontogeny of diversification at the immunoglobulin heavy chain locus in Xenopus.

Since the larval and adult antibody responses are distinct and restricted in the clawed toad Xenopus, it offers a near ideal model for studying the ontogeny of antibody repertoires and the mechanisms involved. Immunoglobulin heavy chain (IgH) cDNA clones and B cell IgH DNA clones from various larval and adult libraries have been analysed in isogenic Xenopus. Some features are similar in adults and tadpoles, while others differ and explain the particularities observed previously at the protein level. Among the similarities we found are: (i) the mode of rearrangements (there are approximately 50% abortive events in B cells from both stages), (ii) VH family usage (10 of 11 known VH families are expressed proportionally to the number of VH elements per family), and (iii) JH usage (of the eight to nine Xenopus JH elements, two are used in approximately 70% of the VH regions in both stages of development). We found that there is relatively higher membrane exon expression in tadpoles compared with adults; and that most of the differences come from the diversification of CDR3 through DH usage and N diversification. Unlike in mammals, Xenopus DH elements are used with a remarkable flexibility with inversion, fusions and usage in different reading frames, but tadpoles show a strong bias for the usage of only a few DH elements and of a preferred reading frame. There is N diversification, which further increases CDR3 heterogeneity, in adult Xenopus but virtually none in tadpoles. These observations can account for the fact that larval antibody responses are less heterogeneous than those of adults.

Amino Acid Sequence↗

Diversification of brain morphology in antarctic notothenioid fishes: basic descriptions and ecological considerations.

The Notothenioidei, a perciform suborder of 120 species, dominates the ichthyofauna of the Southern Ocean around Antarctica. Unlike most teleost groups, notothenioids have undergone a corresponding ecological and phyletic diversification and therefore provide an excellent opportunity to study the divergence of the nervous system in an unusual environment. Our goal is to evaluate notothenioid brain variation in light of this diversification. To provide a baseline morphology, we examine the gross morphology and histology of the brain of Trematomus bernacchii, a generalized member of the family Nototheniidae. We then examine the variation in brain gross anatomy (32 species) and histology (10 species) of other notothenioids. Our sample represents about 27% of the species in this group and includes species from each of the six families, as well as species representing diverse ecologies. For comparison we reference the well-studied brains of two species of temperate perciformes (Perca flavescens and Lepomis humilis). Our results show that, in general, notothenioid brains are more similar to the brains of temperate perciforms than to the unusual brains of cave-dwelling and deep-sea fishes. Interspecific variation in gross brain morphology is comparable to that in Old World cyprinids and is illustrated for 17 species. Variation is especially noteworthy in the ecologically and geographically diverse family Nototheniidae. Measurements indicate that sensory regions (olfactory bulbs, eminentia granularis, and crista cerebellaris) exhibit the most pronounced variation in relative surface area. Association areas, including the corpus cerebelli and the telencephalon, exhibit moderate variation in size, shape, and lobation patterns. Regulatory areas of the brain, including the saccus vasculosus and the subependyma of the third ventricle, are also variable. These regions are best developed in species living in the subfreezing water close to the continent. In some species the expanded ependymal lining forms ventricular sacs, not previously described in any other vertebrate. Three species, including two nototheniids (Eleginops maclovinus and Pleuragramma antarcticum) and the only artedidraconid in our sample, have distinctive brains. The unique brain morphology of Pleuragramma is probably related to a sensory (lateral line) specialization for feeding. Within the Nototheniidae, a phyletic effect on cerebellar morphology is evident in the Coriiceps group and in the Pleuragramminae. Neither phyletic position nor ecological factors (water temperature, position in the water column, dietary habits) alone fully explain the pattern of notothenioid brain diversification.

Animals↗

Diversification of Cellulose Synthase (CESA) Genes in Mosses Suggests Both Ancient and Recent Gene duplications.

Cellulose is an important polysaccharide that constitutes all plant cell walls, giving them strength and stability. The plant cellulose synthase (CESA) gene family, which encodes the catalytic subunits of cellulose synthesis complexes (CSCs), has diversified independently in several plant lineages, providing an interesting model for understanding selection for gene duplication. Here we quantified the presence of CESA genes across mosses to understand how the process of gene family diversification occurred in this group and how it parallels diversification in other groups. We first examined the CESA gene family in eight species of mosses across seven families for which whole genome assemblies were available. We then identified CESA genes from additional species, for which only short-read sequence data was available, by using BLAST searches and targeted gene assemblies. We validated this approach by comparing the assembled paralogs from the short-read data to the genes identified from whole genome assemblies in the eight reference species. This approach allowed us to identify paralogs directly from short-read data and greatly expand our sample set. Results from the combined empirical data support the hypothesis that CESA genes diversified within the moss lineage at least as early as the mesozoic period, during or possibly even prior to the onset of moss diversification, but also continue to diversify within modern species. In addition, we found evidence for purifying selection as the dominant force shaping these genes and observed that different lineages experienced different levels of evolutionary constraint. Lastly, our approach to assemble paralogs has the potential to allow researchers to improve analyses of gene duplication events.

Physcomitrium patens↗

Somatic diversification of the chicken immunoglobulin light chain gene is limited to the rearranged variable gene segment.

Previous studies have shown that the chicken lambda immunoglobulin light chain gene undergoes a single rearrangement that results in functional VJ joining of the unique variable (V lambda 1) and joining (J lambda) coding regions. The immunologic repertoire of lambda genes is created through extensive sequence diversification within the rearranged locus during B cell development in the bursa of Fabricius. This sequence diversification was detected only at the rearranged V lambda 1 segment and not within the 5' leader sequence, the J lambda segment, or the unrearranged V lambda 1 segment. The selective diversification of the rearranged V lambda 1 segment was associated with unique DNAase I-hypersensitive sites on the rearranged allele. While probes for V lambda 1 sequences detect multiple homologous V lambda segments, probes for both the 5' leader and J lambda segments fail to detect homologous sequences. Taken together, these results suggest that a highly selective process, possibly gene conversion, operates during B cell ontogeny to generate diversity within the lambda gene.

Alleles↗

Staphylococcus aureus strain designation by agr and cap polymorphism typing and delineation of agr diversification by sequence analysis.

The allelic variations of the regulatory operon agr (groups I-IV) and the cap polymorphism (capsular types 5 and 8) were used as a typing scheme for rapid strain designation in Staphylococcus aureus. In combining 10 agr subgroups resolved by restriction fragment length polymorphism (RFLP) analysis with the two cap polymorphisms 12 types could be defined. To assess whether this type designation is informative for the population structure of the species S. aureus, agr and cap types were determined in clonal lineages defined by pulsed-field gel electrophoresis (PFGE) of a collection of 219 isolates. agr groups and cap types were both linked to certain clone complexes. However, little correlation was found between the two polymorphic loci. By PFGE cluster analysis 11 prevalent and 52 sporadic clones were defined. Most of the prevalent clones (9/11) could be discriminated by agr/cap typing. Thus, this technique allows a first subdivision of isolates and an inter-center comparable designation of S. aureus clones preceding a more detailed clonal analysis by PFGE or multi-locus sequence typing (MLST). To get insight into agr diversification, sequence analysis of the variable and conserved part of agr from selected S. aureus clones was performed. Strains of agr-I displayed the highest sequence divergence on the nucleotide and amino acid level, suggesting an early diversification of this group. When analyzing the relationship between the four agr interference groups we could show: (i) one intermediate between agr-I and agr-IV alleles; (ii) agr-IV sequences seem to bridge the agr-I and -III groups and (iii) two cases of horizontal transfer of the variable gene cassette from an agr-I strain to an agr-II strain. Thus, stepwise evolutionary progression and rare events of recombination were evident in the diversification of the agr locus.

Alleles↗

Germline and somatic diversification of immune recognition elements in Metazoa.

The histories of the immune systems of Metazoa during evolution are envisaged like as many adaptations to the continuous diversification of immune receptors and effectors genes under the pressure of changing environments. A basic diversity of potential immune receptor genes existed in primitive Metazoa. Their subsequent recruitment into immunity, their diversification revolving around the conservation of signaling cascades was paralleled by cell specialization and the introduction of regulatory networks. Polymorphism, duplication and somatic mechanisms of diversification affected independently and still affect different gene families in many phyla, creating a greater variety of immune system exhibiting sometimes little homology but much analogy to one another. Diversity and multiplicity of receptors was generated by duplication and creation of multigene families. Independently in several phyla further diversity is created somatically by alternate splicing, somatic mutation, gene conversion and gene rearrangement. In several instances combinatorial usage of polypeptide chains or genes segments increases the repertoire of the recognition structures. Metazoa had to adapt to the conditions generated by this diversity: the control of expression of multiple genes and the risk of autoimmunity.

Adaptation, Physiological↗

Antibody diversification in cartilaginous fishes: Mechanistic insights from the nurse shark and comparative perspectives across jawed vertebrates.

Antibody diversity in vertebrates arises through the coordinated actions of V(D)J recombination and somatic hypermutation (SHM). Cartilaginous fishes occupy a key phylogenetic position as the sister lineage to bony vertebrates and therefore provide important comparative insights into the evolution of adaptive immunity. This review focuses on the nurse shark (Ginglymostoma cirratum) as a representative model for examining antibody-diversification mechanisms in cartilaginous fishes. Shark immunoglobulin genes exhibit a multicluster organization, while immunoglobulin new antigen receptor (IgNAR), a heavy-chain-only isotype, contains a single variable domain with an extended complementarity-determining region 3 (CDR3) that can be stabilized by non-canonical disulfide bonds. These structural features, together with intracluster multi-D V(D)J recombination and distinctive SHM characterized by single and tandem substitutions and insertions/deletions, contribute to antibody diversification in sharks. By comparing cartilaginous fishes, ray-finned fishes, and mammals, this review highlights lineage-specific combinations of immunoglobulin gene organization, recombination, mutational processing, and affinity maturation. Within the heuristic framework proposed here, shark and mammalian systems are described as emphasizing "breadth-first" repertoire generation and "precision-first" affinity optimization, respectively. These terms indicate relative mechanistic emphases rather than mutually exclusive categories or sequential evolutionary stages, while ray-finned fishes exhibit a distinct combination of genomic organization and mutational features. Investigating antibody diversification in cartilaginous fishes not only advances our understanding of vertebrate immune evolution but also provides structural and mechanistic insights that may inform the development of engineered antibodies based on the IgNAR scaffold.

Antibody diversity↗