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PubMed2005

MRE11/RAD50 cleaves DNA in the AID/UNG-dependent pathway of immunoglobulin gene diversification.

MRE11/RAD50/NBS1 (MRN) is a ubiquitous complex that participates in the response to DNA damage and in immunoglobulin (Ig) gene diversification. Ig gene diversification is initiated by deamination of cytosine to uracil, followed by removal of uracil to create an abasic (AP) site. We find that MRE11 associates specifically with rearranged Ig genes in hypermutating B cells, whereas APE1, the major AP-endonuclease in faithful base excision repair, does not. We show that purified, recombinant MRE11/RAD50 can cleave DNA at AP sites and that this AP-lyase activity is conserved from humans to Archaea. MRE11/RAD50 cleaves at AP sites within single-stranded regions of DNA, suggesting that at transcribed Ig genes, cleavage may be coordinated with deamination by AID and deglycosylation by UNG2 to produce single-strand breaks (SSBs) that undergo subsequent mutagenic repair and recombination. These results identify MRN with DNA cleavage in the AID-initiated pathway of Ig gene diversification.

Acid Anhydride Hydrolases↗
PubMed2004

Prevention and control of reciprocal T-B cell diversification: implications for lupus-like autoimmunity.

Autoimmunity is fundamentally a continuously evolving process. The autoimmune responses shift, drift and diversify with time not only to other epitopes in the original antigen but also to other related and sometimes to unrelated antigens. We have described a form of immune diversification--reciprocal T-B epitope spreading--where the activation of first T cells by epitopes from an autoantibody molecule could lead to help provided to a variety of B cells displaying a cross-reactive version of the original epitope. The response spreads in this way until large cohorts of T and B cells have expanded in lupus-prone mice. Such reciprocal T-B cell response can also be induced in normal animals, its extent is limited by the emergence of inhibitory T cells. The induction of such inhibitory T cells is generally impaired in lupus mice. The delivery of T cell epitopes via plasmid DNA vectors, however, can overcome this impairment in lupus mice. The inhibitory T cells thus induced can suppress autoantibody production and lupus disease by ablating or inhibiting autoreactive B cells. Thus, T-B diversification that develops spontaneously in lupus mice could be curtailed in normal animals by inhibitory T cells that emerge whenever there is an impending 'danger' of pathologic autoimmunity. We have successfully exploited this regulatory potential of the normal immune response to inhibit clinical autoimmunity. Understanding the mechanisms of autoimmune diversification in lupus mice and of its down-regulation in normal animals may pave the way for developing novel treatments for autoantibody-mediated diseases such as lupus.

Animals↗
PubMed2005

MDM2 can interact with the C-terminus of AID but it is inessential for antibody diversification in DT40 B cells.

Activation-induced deaminase (AID) is essential for immunoglobulin gene diversification by the distinct processes of class switch recombination, somatic hypermutation and gene conversion. Most evidence indicates that AID triggers these reactions through the direct deamination of cytosine residues in the DNA. However, AID is predominantly cytoplasmic and the mechanism that directs it to the immunoglobulin loci remains elusive. Like its homolog APOBEC1, which requires at least one additional factor to efficiently edit APOB RNA, other proteins are likely to be required for the proper targeting of AID to the immunoglobulin loci. Here, we show that AID can interact with MDM2, an oncoprotein that shuttles between the nucleus and the cytoplasm and targets p53 for nuclear export and degradation. This interaction mapped to the carboxy-terminal region of AID that harbors a nuclear export sequence, suggesting that MDM2 may be involved in the nucleo-cytoplasmic trafficking of AID. We therefore assessed the role of MDM2 in immunoglobulin gene diversification by disrupting MDM2 in DT40, an avian B cell line that constitutively undergoes AID-dependent immunoglobulin gene diversification. The subcellular localization of AID was unaffected in MDM2-deficient DT40 cells. However, slight hyper-and hypo-conversion phenotypes were caused by MDM2-abrogation and overexpression, respectively. These observations suggested that MDM2 has the capacity to negatively regulate AID. Intriguingly, the same carboxy-terminal residues of AID were recently shown to be inessential for somatic hypermutation and immunoglobulin gene conversion but they were strictly required for class switch recombination.

Animals↗
PubMed2006

A role for Runx transcription factor signaling in dorsal root ganglion sensory neuron diversification.

Subpopulations of sensory neurons in the dorsal root ganglion (DRG) can be characterized on the basis of sensory modalities that convey distinct peripheral stimuli, but the molecular mechanisms that underlie sensory neuronal diversification remain unclear. Here, we have used genetic manipulations in the mouse embryo to examine how Runx transcription factor signaling controls the acquisition of distinct DRG neuronal subtype identities. Runx3 acts to diversify an Ngn1-independent neuronal cohort by promoting the differentiation of proprioceptive sensory neurons through erosion of TrkB expression in prospective TrkC+ sensory neurons. In contrast, Runx1 controls neuronal diversification within Ngn1-dependent TrkA+ neurons by repression of neuropeptide CGRP expression and controlling the fine pattern of laminar termination in the dorsal spinal cord. Together, our findings suggest that Runx transcription factor signaling plays a key role in sensory neuron diversification.

Animals↗
PubMed2026

Beyond species trees: pervasive gene flow limits phylogenomic resolution in the diversification of Juniperus from the Qinghai-Tibet Plateau.

Understanding how lineages diversify despite persistent ancestral polymorphism and recurrent gene flow remains a central challenge in evolutionary biology. Juniperus distributed across the Qinghai-Tibet Plateau provide an ideal system for addressing this question because repeated geological uplift and climatic oscillations have likely promoted cycles of lineage divergence, range shifts, and secondary contact. Here, we combined approximately 1.08 million genome-wide SNPs from 164 individuals representing thirteen Juniperus lineages with phylogenomic datasets comprising 3,381 nuclear single-copy genes and nearly complete plastomes. We detected extensive phylogenomic discordance and cytonuclear incongruence across genomic datasets. Topology weighting, coalescent simulations, quartet-based tests, and analyses of gene flow and reticulation collectively support the interpretation that these patterns were shaped by the combined effects of prolonged incomplete lineage sorting and gene flow during lineage diversification. Ecological niche analyses further provide a spatial and climatic context in which environmentally similar lineages may have had greater opportunities for secondary contact during historical range shifts. Collectively, our results reveal that the evolutionary history of Qinghai-Tibet Plateau Juniperus is characterized by reticulate diversification rather than strictly bifurcating evolution, and demonstrate how genome-wide discordance can provide biological insights into the evolutionary processes underlying lineage diversification.

Gene Flow↗
PubMed2000

Technical efficiency and economies of diversification in health care.

In national health services, where there is a tendency towards a lack of resources and a continuous increase in demand, it is necessary to implement decisions that promote efficiency. In this paper we focus on potential diversification economies as a strategy to increase efficiency levels. We evaluate the change in efficiency in Catalan hospitals between 1987 and 1992, and analyse the presence of possible diversification economies in each hospital. We use Data Envelopment Analysis, which does not need information on either input or output prices. The results are that the majority of hospitals could increase their efficiency and reduce their costs by diversification to the output-mix offered. Potential productivity gains are between 29% and 46%.

Benchmarking↗
PubMed2004

Ecological constraints on diversification in a model adaptive radiation.

Taxonomic diversification commonly occurs through adaptive radiation, the rapid evolution of a single lineage into a range of genotypes or species each adapted to a different ecological niche. Radiation size (measured as the number of new types) varies widely between phylogenetically distinct taxa and between replicate radiations within a single taxon where the ecological opportunities available seem to be identical. Here we show how variation in energy input (productivity) and environmental disturbance combine to determine the extent of diversification in a single radiating lineage of Pseudomonas fluorescens adapting to laboratory conditions. Diversity peaked at intermediate rates of both productivity and disturbance and declined towards the extremes in a manner reminiscent of well-known ecological patterns. The mechanism responsible for the decrease in diversity arises from pleiotropic fitness costs associated with niche specialization, the effects of which are modulated by gradients of productivity and disturbance. Our results indicate that ecological gradients may constrain the size of adaptive radiations, even in the presence of the strong diversifying selection associated with ecological opportunity, by decoupling evolutionary diversification from ecological coexistence.

Animals↗
PubMed2004

Giant tortoises are not so slow: rapid diversification and biogeographic consensus in the Galápagos.

Isolated oceanic archipelagos have played a major role in the development of evolutionary theory by offering a unique setting for studying spatial and temporal patterns of biological diversification. However, the evolutionary events that cause associations between genetic variation and geography in archipelago radiations are largely unknown. This finding is especially true in the Galápagos Islands, where molecular studies have revealed conflicting biogeographic patterns. Here, we elucidate the history of diversification of giant Galápagos tortoises by using mtDNA sequences from 802 individuals representing all known extant populations. We test biogeographic predictions based on geological history and assess the roles of volcano emergence and island formation in driving evolutionary diversification. Patterns of colonization and lineage sorting appear highly consistent with the chronological formation of the archipelago. Populations from older islands are composed exclusively of endemic haplotypes that define divergent monophyletic clades. Younger populations, although currently differentiated, exhibit patterns of colonization, demographic variation and genetic interchange shaped by recent volcanism. Colonization probably occurs shortly after a volcano emerges through range expansion from older volcanoes. Volcanism can also create temporal shifts from historical to recurrent events, such as promoting gene flow by creating land bridges between isolated volcanoes. The association of spatial and temporal patterns of genetic variation with geophysical aspects of the environment can best be attributed to the limited dispersal and migration of tortoises following an oceanographic current. The endangered giant Galápagos tortoises represent a rapid allopatric radiation and further exemplify evolutionary processes in one of the world's greatest natural laboratories of evolution.

Animals↗
PubMed2004

Molecular evidence links cryptic diversification in polar planktonic protists to Quaternary climate dynamics.

It is unknown how pelagic marine protists undergo diversification and speciation. Superficially, the open ocean appears homogeneous, with few clear barriers to gene flow, allowing extensive, even global, dispersal. Yet, despite the apparent lack of opportunity for genetic isolation, diversity is prevalent within marine taxa. A lack of candidate isolating mechanisms would seem to favor sympatric over allopatric speciation models to explain the diversity and biogeographic patterns observed in the oceans today. However, the ocean is a dynamic system, and both current and past circulation patterns must be considered in concert to gain a true perspective of gene flow through time. We have derived a comprehensive picture of the mechanisms potentially at play in the high latitudes by combining molecular, biogeographic, fossil, and paleoceanographic data to reconstruct the evolutionary history of the polar planktonic foraminifer Neogloboquadrina pachyderma sinistral. We have discovered extensive genetic diversity within this morphospecies and that its current "extreme" polar affinity did not appear until late in its evolutionary history. The molecular data demonstrate a stepwise progression of diversification starting with the allopatric isolation of Atlantic Arctic and Antarctic populations after the onset of the Northern Hemisphere glaciation. Further diversification occurred only in the Southern Hemisphere and seems to have been linked to glacial-interglacial climate dynamics. Our findings demonstrate the role of Quaternary climate instability in shaping the modern high-latitude plankton. The divergent evolutionary history of N. pachyderma sinistral genotypes implies that paleoceanographic proxies based on this taxon should be calibrated independently.

Animals↗
PubMed1992

Diversification of the Wnt gene family on the ancestral lineage of vertebrates.

Diversification of the Wnt genes, a family of powerful developmental regulator molecules, is inferred by molecular evolutionary analyses. Fifty-five recently determined partial sequences from a variety of vertebrates and invertebrates, together with 17 published sequences, mostly from the mouse and Drosophila melanogaster, are analyzed. Wnt-1 through -7 originated before the last common ancestor of arthropods and deuterostomes lived. Another round of gene duplication, involving Wnt-3, -5, -7, and -10, occurred after the echinoderm lineage arose, on the ancestral lineage of jawed vertebrates. Increased constraints were imposed on the Wnt genes when jawed vertebrates originated, as indicated by an overall 4-fold lower rate of amino acid replacements in jawed vertebrates compared with invertebrates and jawless vertebrates. The Wnt genes are thus inferred to have undergone a disproportionately high amount of structural and functional evolution in the relatively short time (approximately 100 million years) between the origin of the echinoderm lineage and the first diversification of jawed vertebrates. A model is presented for the relationship of functional diversification of developmental regulators and their rates of amino acid replacement.

Amino Acid Sequence↗
PubMed2000

Adaptive diversification within a large family of recently duplicated, placentally expressed genes.

The pregnancy-associated glycoproteins (PAG) are putative peptide-binding proteins and products of a large family of genes whose expression is localized to the placental surface epithelium of artiodactyl species. We have tested the hypothesis that natural selection has favored diversification of these genes by examining patterns of nucleotide substitution in a sample of 28 closely related bovine, caprine, and ovine family members that are expressed only in trophoblast binucleate cells. Three observations were made. First, in codons encoding highly variable domains of the proteins, there was a greater accumulation of both synonymous and nonsynonymous mutations than in the more conserved regions of the genes. Second, in the variable regions, the mean number of nonsynonymous nucleotide substitutions per site was significantly greater than the mean number of synonymous substitutions per site. Third, nonsynonymous changes affecting amino acid charge occurred more frequently than expected under random substitution. This unusual pattern of nucleotide substitution implies that natural selection has acted to diversify these PAG molecules at the amino acid level, which in turn suggests that these molecules have undergone functional diversification. We estimate that the binucleate cell-expressed PAG originated 52 +/- 6 million years ago, soon after the divergence of the ruminant lineage. Thus, rapid functional diversification of PAG expressed in trophoblast binucleate cells seems to have been associated with the origin of this unique placental adaptation.

Amino Acid Sequence↗
PubMed2004

Shared and unique features of evolutionary diversification.

A fundamental question in evolutionary biology asks whether organisms experiencing similar selective pressures will evolve similar solutions or whether historical contingencies dominate the evolutionary process and yield disparate evolutionary outcomes. It is perhaps most likely that both shared selective forces as well as unique histories play key roles in the course of evolution. Consequently, when multiple species face a common environmental gradient, their patterns of divergence might exhibit both shared and unique elements. Here we describe a general framework for investigating and evaluating the relative importance of these contrasting features of diversification. We examined morphological diversification in three species of livebearing fishes across a predation gradient. All species (Gambusia affinis from the United States of America, Brachyrhaphis rhabdophora from Costa Rica, and Poecilia reticulata from Trinidad) exhibited more elongate bodies, a larger caudal peduncle, and a relatively lower position of the eye in predator populations. This shared response suggests that common selective pressures generated parallel outcomes within three different species. However, each species also exhibited unique features of divergence, which might reflect phylogenetic tendencies, chance events, or localized environmental differences. In this system, we found that shared aspects of divergence were of larger magnitude than unique elements, suggesting common natural selective forces have played a greater role than unique histories in producing the observed patterns of morphological diversification. Assessing the nature and relative importance of shared and unique responses should aid in elucidating the relative generality or peculiarity in evolutionary divergence.

Animals↗
PubMed2004

SYMMETREE: whole-tree analysis of differential diversification rates.

UNLABELLED: SymmeTREE implements several tests of differential diversification rates that exploit information on the topological distribution of species diversity throughout entire trees to address two general questions: (1) Has a given tree experienced significant variation in diversification rates among its branches? and (2) If so, along which branches have significant shifts in diversification rate occurred? These explicitly model-based methods are robust to uncertainty in estimates of branch length/duration and can accommodate incompletely resolved trees and other forms of phylogenetic uncertainty. AVAILABILITY: http://www.phylodiversity.net/bmoore/software.html CONTACT: brian.moore@yale.edu.

Algorithms↗
PubMed2026

Evolutionary diversification of invertase paralogs couples carbon metabolism and sexual reproduction in fission yeasts.

Dynamic patterns of gene gain and loss play a major role in the diversification of eukaryotes, reflecting adaptation to a broad range of ecological contexts. Reconstructing the evolutionary history of genes provides a powerful framework for understanding how functional innovation shapes life-history traits. Here we report a comprehensive analysis of gene gain and loss across the fission yeast clade, whose evolutionary trajectory remains elusive. Reductive evolution of metabolic genes is a major contributor to species diversification, as observed in other fungal taxa. Notably, we uncovered an evolutionary scenario in which an ancestral gene duplication was followed by lineage-specific loss of one or the other paralog, except in S. pombe, which retained both. We demonstrate that these paralogs encode catalytically-active invertases, named Inv1 and Inv2, with distinct enzymatic properties, localization, regulation, and physiological roles. Inv1 is a secreted enzyme subject to glucose catabolite repression and is the sole invertase required for sucrose assimilation, resembling canonical yeast invertases. In contrast, Inv2 is intracellular, constitutively expressed, and required for inducing sexual differentiation in response to nutrient availability. Overall, these findings reveal an unexpected role for carbon metabolism in modulating the haploid-diploid cycle of fission yeasts, suggesting that diversification of core metabolic functions may contribute to adaptation to environments with distinct sugar compositions.

Evolution↗
PubMed2006

Functional diversification of B MADS-box homeotic regulators of flower development: Adaptive evolution in protein-protein interaction domains after major gene duplication events.

B-class MADS-box genes have been shown to be the key regulators of petal and stamen specification in several eudicot model species such as Arabidopsis thaliana, Antirrhinum majus, and Petunia hybrida. Orthologs of these genes have been found across angiosperms and gymnosperms, and it is thought that the basic regulatory function of B proteins is conserved in seed plant lineages. The evolution of B genes is characterized by numerous duplications that might represent key elements fostering the functional diversification of duplicates with a deep impact on their role in the evolution of the floral developmental program. To evaluate this, we performed a rigorous statistical analysis with B gene sequences. Using maximum likelihood and Bayesian methods, we estimated molecular substitution rates and determined the selective regimes operating at each residue of B proteins. We implemented tests that rely on phylogenetic hypotheses and codon substitution models to detect significant differences in substitution rates (DSRs) and sites under positive adaptive selection (PS) in specific lineages before and after duplication events. With these methods, we identified several protein residues fixed by PS shortly after the origin of PISTILLATA-like and APETALA3-like lineages in angiosperms and shortly after the origin of the euAP3-like lineage in core eudicots, the 2 main B gene duplications. The residues inferred to have been fixed by positive selection lie mostly within the K domain of the protein, which is key to promote heterodimerization. Additionally, we used a likelihood method that accommodates DSRs among lineages to estimate duplication dates for AP3-PI and euAP3-TM6, calibrating with data from the fossil record. The dates obtained are consistent with angiosperm origins and diversification of core eudicots. Our results strongly suggest that novel multimer formation with other MADS proteins could have been crucial for the functional divergence of B MADS-box genes. We thus propose a mechanism of functional diversification and persistence of gene duplicates by the appearance of novel multimerization capabilities after duplications. Multimer formation in different combinations of regulatory proteins can be a mechanistic basis for the origin of novel regulatory functions and a gene regulatory mechanism for the appearance of morphological innovations.

Amino Acid Sequence↗
PubMed2000

The alpha-mannosidases: phylogeny and adaptive diversification.

alpha-Mannosidase enzymes comprise a class of gylcoside hydrolases involved in the maturation and degradaton of glycoprotein-linked oligosaccharides. Various alpha-mannosidase enzymatic activities are encoded by an ancient and ubiquitous gene superfamily. A comparative sequence analysis was employed here to characterize the evolutionary relationships and dynamics of the alpha-mannosidase superfamily. A series of lineage-specific BLAST searches recovered the first ever recognized archaean and eubacterial alpha-mannosidase sequences, in addition to numerous eukaryotic sequences. Motif-based alignment and subsequent phylogenetic analysis of the entire superfamily revealed the presence of three well-supported monophyletic clades that represent discrete alpha-mannosidase families. The comparative method was used to evaluate the phylogenetic distribution of alpha-mannosidase functional variants within families. Results of this analysis demonstrate a pattern of functional diversification of alpha-mannosidase paralogs followed by conservation of function among orthologs. Nucleotide polymorphism among the most closely related pair of duplicated genes was analyzed to evaluate the role of natural selection in the functional diversification of alpha-mannosidase paralogs. Ratios of nonsynonymous and synonymous variation show an increase in the rate of nonsynonymous change after duplication and a relative excess of fixed nonsynonymous changes between the two groups of paralogs. These data point to a possible role for positive Darwinian selection in the evolution of alpha-mannosidase functional diversification following gene duplication.

Amino Acid Sequence↗
PubMed2006

Rapid lineage accumulation in a non-adaptive radiation: phylogenetic analysis of diversification rates in eastern North American woodland salamanders (Plethodontidae: Plethodon).

Adaptive radiations have served as model systems for quantifying the build-up of species richness. Few studies have quantified the tempo of diversification in species-rich clades that contain negligible adaptive disparity, making the macroevolutionary consequences of different modes of evolutionary radiation difficult to assess. We use mitochondrial-DNA sequence data and recently developed phylogenetic methodologies to explore the tempo of diversification of eastern North American Plethodon, a species-rich clade of woodland salamanders exhibiting only limited phenotypic disparity. Lineage-through-time analysis reveals a high rate of lineage accumulation, 0.8 species per million years, occurring 11-8 million years ago in the P. glutinosus species group, followed by decreasing rates. This high rate of lineage accumulation is exceptional, comparable to the most rapid of adaptive radiations. In contrast to classic models of adaptive radiation where ecological niche divergence is linked to the origin of species, we propose that phylogenetic niche conservatism contributes to the rapid accumulation of P. glutinosus-group lineages by promoting vicariant isolation and multiplication of species across a spatially and temporally fluctuating environment. These closely related and ecologically similar lineages persist through long-periods of evolutionary time and form strong barriers to the geographic spread of their neighbours, producing a subsequent decline in lineage accumulation. Rapid diversification among lineages exhibiting long-term maintenance of their bioclimatic niche requirements is an under-appreciated phenomenon driving the build-up of species richness.

Animals↗
PubMed2004

The tempo of avian diversification during the Quaternary.

It is generally assumed that the Quaternary was a period of heightened diversification in temperate vertebrate organisms. Previous molecular systematics studies have challenged this assertion. We re-examined this issue in north temperate birds using log-lineage plots and distributions of sister-taxon distances. Log-lineage plots support earlier conclusions that avian diversification slowed during the Quaternary. To test plots of empirical sister-taxon distances we simulated three sets of phylogenies: constant speciation and extinction, a pulse of recent speciation, and a pulse of recent extinction. Previous opinions favour the model of recent speciation although our empirical dataset on 74 avian comparisons failed to reject a distribution derived from the constant and extinction models. Hence, it does not appear that the Quaternary was a period of exceptional rates of diversification, relative to the background rate.

Animals↗