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PubMed2003

Speciation in North American black basses, Micropterus (Actinopterygii: Centrarchidae).

The Pleistocene Epoch has been frequently cited as a period of intense speciation for a significant portion of temperate continental biotas. To critically assess the role of Pleistocene glaciations on the evolution of the freshwater fish clade Micropterus, we use a phylogenetic analysis of complete gene sequences from two mitochondrial genes (cytochrome b and ND2), and a fossil calibration of the molecular clock to estimate ages of speciation events and rates of diversification. The absence of substantial morphological and ecological divergence together with endemism of five of the eight species in North American tributaries of the Gulf of Mexico may be interpreted as the result of a recent Pleistocene origin for these species. Speciation dates in Micropterus range from 1.01 +/- 0.32 to 11.17 +/- 1.02 million years ago. Only one speciation event is dated to the Pleistocene, and rates of diversification are not significantly variable in Micropterus. The premise that the Pleistocene was an exceptional period of speciation in Micropterus is not supported. Instead, a Gulf Coast allopatric speciation model is proposed, and predicts periods of dynamic speciation driven by sea level fluctuations in the Late Miocene and Pliocene. The Pleistocene, however, was a period of significant intraspecific mitochondrial lineage diversification. The application of the Gulf Coast allopatric speciation model to the remaining aquatic fauna of the Gulf of Mexico coast in North America will rely on robust phylogenetic hypotheses and accurate age estimations of speciation events.

Animals↗
PubMed2003

Recent radiation of endemic Caribbean Drosophila of the dunni subgroup inferred from multilocus DNA sequence variation.

Studies of island endemism provide a unique opportunity to elucidate fundamental mechanisms of speciation. Here we examine intra- and interspecific DNA sequence variation at four unlinked genetic loci among populations of the Drosophila dunni subgroup to provide a detailed genealogical portrait of the process of speciation among these island endemic species. Our data indicate two major rounds of diversification that have shaped the D. dunni subgroup. The first occurred 1.6-2.6 million years ago and separated three major lineages, one in Puerto Rico and the Virgin Islands, a second in the northern Lesser Antilles and Barbados, and a third in St. Vincent and Grenada. A second round of diversification occurred in the last 96,000 years in the northern Lesser Antilles and Barbados. The four distinct species that resulted from this recent round of diversification maintain relatively high amounts of genetic variation, similar to that of a closely related mainland species, and share extensive ancestral polymorphism. These data suggest a minimal role for population bottlenecks linked to founder events in the history of the D. dunni subgroup. Further, the recent divergence of these island populations highlights the extremely rapid development of reproductive isolation and distinct patterns of abdominal pigmentation that has occurred in these species.

Animals↗
PubMed2005

Antibody repertoire development in fetal and neonatal piglets. XI. The thymic B-cell repertoire develops independently from that in blood and mesenteric lymph nodes.

The origin and function of thymic B cells is currently unresolved. In the present study we compared V(H) gene repertoire diversification in >3500 cloned VDJs (from 11 animals at three time-points, using three to five animals per time-point) that were expressed with immunoglobulin (Ig)M, IgD, IgG, IgA and IgE in thymus, mesenteric lymph nodes (MLN) and peripheral blood B cells (PBB) of newborn piglets and 5-week-old isolator piglets maintained germfree (GF) or colonized with Escherichia coli. The results showed that the repertoire expressed with IgM, IgD, IgG and IgA in PBB and MLN remained polyclonal, undiversified and unselected in piglets maintained GF for 5 weeks, that age and colonization resulted in significant repertoire diversification of IgG and IgA in the MLN and of IgG in blood, that the thymic B-cell repertoire was polyclonal, unaffected by colonization and showed no clonal selection in any isotype, and that the thymic IgA and IgE repertoires were more diverse at birth than the repertoire of any isotype in MLN or PBB. IgD was seldom recovered from the PBB of newborn piglets or at any time-point in thymus, but was recovered in the MLN of all 11 animals examined. The IgD and IgM repertoires in all tissues remained polyclonal and unselected, although V(H) usage by IgD transcripts did not always parallel that of IgM in the same tissue. Therefore, isotype-switched B cells in the thymic medulla cannot be accounted for by immigration of B cells diversified by colonization of the gut, and thymic B cells undergo switch recombination and repertoire diversification before birth without clonal selection.

Animals↗
PubMed2006

Tempo, mode and phylogenetic associations of relative embryo size evolution in angiosperms.

Relative embryo size (E : S, the ratio of embryo to seed) is a key trait related to germination ecology and seed plant evolution. A small, underdeveloped embryo is a primitive feature of angiosperms, which has led to the hypothesis that an evolutionary trend towards increasing E : S has occurred. Here, I examine first the tempo and mode of E : S evolution in angiosperms; then I test for phylogenetic associations of E : S with traits hypothetically related to anagenetic (germination time) and cladogenetic (number of species per family and differential speciation) change, and finally I test the existence of a directional increasing trend in E : S. The analysis of the evolutionary tempo suggests that E : S changed very fast early in evolutionary time and remained stable later, which is consistent with early radiations and fits well with the history of angiosperms consisting of rapid spread associated with great diversification rates soon after their origin. E : S evolution in angiosperms has not followed a punctuational mode of evolution but a scaled-gradualism evolution in which stasis has occurred in longer branches of the phylogeny. An evolutionary trend towards increasing E : S has not been actively driven by anagenesis nor cladogenesis, although large E : S is associated with high levels of diversification (i.e. number of species per family). This rapid ecological diversification occurring in the early radiation probably produced an increasing phenotypic variance in the E : S. Because the ancestral embryo was so small, an increase in variance might have produced a passive trend towards the only direction allowed for the ancestral embryo to evolve. Thus, a passive diffusion away from a lower bound may explain the average increase in E : S.

Biological Evolution↗
PubMed2003

Molecular mechanism of serial VH gene replacement.

The molecular mechanism of serial VH replacement was analyzed using a human B cell line, EU12, that undergoes continuous spontaneous differentiation from pro-B to pre-B and then to B cell stage. In earlier studies, we found that this cell line undergoes intraclonal V(D)J diversification. Analysis of the IgH gene sequences in EU12 cells predicted the occurrence of serial VH replacement involving the cryptic recombination signal sequences (cRSS) embedded within framework 3 regions and concurrent extension of the CDR3 region. Detection of double-stranded DNA breaks at the cRSS site and different VH replacement excision circles confirm the ongoing nature of this diversification process in the EU12 cells. In vitro binding and cleavage assays using recombinant RAG-1 and RAG-2 proteins further validated the cRSS participation in this RAG-mediated recombination process. Serial VH replacements may represent an additional mechanism for diversification of the primary B cell repertoire.

Immunoglobulin Heavy Chains↗
PubMed2025

Are We Witnessing a Speciation Continuum? Evidence From Current and Past Gene Flow in the Genus Oritrophium s.s. (Asteraceae) From the Tropical High Andes.

Determining species boundaries is key for appropriately assessing biodiversity. However, the continuity of the speciation process makes delimiting species a difficult task, especially for recently diverged taxa. Furthermore, past introgression may leave traces that result in reticulate evolutionary patterns, challenging the estimation of species relationships. The fastest-evolving biodiversity hotspot on Earth is the Páramo. Its flora in the tropical high Andes is known for extraordinarily high species richness and endemism. However, the recent origin, fast diversification and complex taxonomy of many genera challenge species delimitation and phylogenetic reconstruction. In this study, we reconstructed phylogenetic relationships and addressed the role of introgression in the diversification of Oritrophium s.s. (Asteraceae) based on phylogenomic data. We combined genomic, phenotypic and ecological data to test species boundaries and compared trajectories across the speciation continuum within the taxonomically complex 'O. peruvianum group'. We found that historical introgression played an important role in the evolution of Oritrophium s.s., and many of the taxa within the 'O. peruvianum group' are at various stages of speciation. These results highlight the importance of testing for introgression to understand the diversification of recently evolved groups. Likewise, they suggest that heterogeneous speciation trajectories associated with geographic isolation and secondary contact, possibly during the Pleistocene, contributed to plant diversity in the tropical high Andes.

Genetic Speciation↗
PubMed2025

Eco-Evolutionary Genomics Reveal Mountain Range-Specific Adaptation and Intraspecific Variation in Vulnerability to Climate Change of Alpine Endemics.

Alpine plants restricted to rocky habitats exhibit intraspecific diversification due to range fragmentation during Holocene warming, complicating predictions of their climate vulnerability. A lack of understanding of eco-evolutionary mechanisms driving their response to climate change results in ineffective conservation efforts. To uncover the genomic basis of their diversification and explain spatial patterns of their vulnerability, we combine landscape genomics and species distribution modelling. Our model, the Campanula lehmanniana complex, occurs in three distinct central Asian mountain ranges, considered both a biodiversity hotspot and a vascular plant diversity darkspot. Genome-environment association confirmed the adaptive basis of intraspecific diversification, driven by numerous loci of small effect. Genomic and ecological data indicate mountain range-specific climate sensitivity driven by altitude, temperature and precipitation. The cold-dry adapted group from Zeravshan-Hissar Mts will face niche decline but show a higher degree of preadaptation to future climate, while the temperate-humid group from Tian Shan shows an opposite response, with a higher risk of maladaptation despite predicted niche expansion. Maladapted populations at northern margins may require an influx of adaptive variation to cope with predicted changes. However, limited landscape connectivity between island-like habitats, combined with long migration distances required to minimise genotype-environment disruption, highlights the role of human-assisted migration in enabling evolutionary rescue. These results underscore the need to facilitate gene flow from pre- to maladapted populations and the importance of population-specific approaches to inform effective conservation strategies in heterogeneous mountain ecosystems. The results may be relevant to numerous Central Asian mountain species that show similar phylogeographic patterns.

Climate Change↗
PubMed2025

Unraveling evolutionary pathways: allopolyploidization and introgression in polyploid Prunus (Rosaceae).

Allopolyploidization, resulting from hybridization and subsequent whole-genome duplication (WGD), is a fundamental mechanism driving evolutionary diversification across various lineages within the Tree of Life. The polyploid Prunus (Rosaceae), significant for its economic and agricultural value, provides an ideal model for investigating the evolutionary dynamics associated with allopolyploidy. In this study, we utilized deep genome skimming (DGS) data to demonstrate a comprehensive analytical framework for elucidating the underlying allopolyploidy that includes a newly adapted tool (DGS-Tree2GD) tailored explicitly for accurately detecting WGD events. Additionally, we introduced two methods to evaluate the contribution of incomplete lineage sorting (ILS) to lineage diversification. Phylogenomic discordance analyses revealed that allopolyploidization, rather than ILS, played a dominant role in the origin and dynamics of polyploid Prunus. Moreover, we inferred that the uplift of the Himalayas from the Middle to Late Miocene was a key driver in the rapid diversification of the Maddenia clade, an endemic group in East Asia. This geological event facilitated extensive hybridization and allopolyploidization, particularly the introgression between the Himalayas-Hengduan and Central-Eastern China clades. This case study demonstrates the robustness and efficacy of our analytical approach in precisely identifying WGD events and elucidating the evolutionary mechanisms underlying allopolyploidization in polyploid Prunus.

Polyploidy↗
PubMed2003

The effects of Cenozoic global change on squirrel phylogeny.

By modifying habitats and creating bridges and barriers between landmasses, climate change and tectonic events are believed to have important consequences for diversification of terrestrial organisms. Such consequences should be most evident in phylogenetic histories of groups that are ancient, widespread, and diverse. The squirrel family (Sciuridae) is one of very few mammalian families endemic to Eurasia, Africa, and North and South America and is ideal for examining these issues. Through phylogenetic and molecular-clock analyses, we infer that arrival and diversification of squirrels in Africa, on Sunda Shelf islands, across Beringea, and across the Panamanian isthmus coincide in timing and location with multiple well-documented sea-level, tectonic, and paleontological events. These precise correspondences point to an important role for global change in the diversification of a major group of mammals.

Africa↗
PubMed2003

Tempo and mode of evolutionary radiation in iguanian lizards.

Identification of general properties of evolutionary radiations has been hindered by the lack of a general statistical and phylogenetic approach applicable across diverse taxa. We present a comparative analytical framework for examining phylogenetic patterns of diversification and morphological disparity with data from four iguanian-lizard taxa that exhibit substantially different patterns of evolution. Taxa whose diversification occurred disproportionately early in their evolutionary history partition more of their morphological disparity among, rather than within, subclades. This inverse relationship between timing of diversification and morphological disparity within subclades may be a general feature that transcends the historically contingent properties of different evolutionary radiations.

Adaptation, Biological↗
PubMed2000

Dominant role of host selective pressure in driving hepatitis C virus evolution in perinatal infection.

The dynamics of the genetic diversification of hepatitis C virus (HCV) populations was addressed in perinatal infection. Clonal sequences of hypervariable region 1 of the putative E2 envelope protein of HCV were obtained from four HCV-infected newborns (sequential samples spanning a period of 6 to 13 months after birth) and from their mothers (all samples collected at delivery). The data show that the variants detected between birth and the third month of life in samples from the four newborns were present in the HCV populations of their mothers at delivery. In the newborns, a unique viral variant (or a small group of closely related variants) remained stable for weeks despite active viral replication. Diversification of the intrahost HCV population was observed 6 to 13 months after birth and was substantially higher in two of the four subjects, as documented by the intersample genetic distance (GD) (P = 0.007). Importantly, a significant correlation between increasing GD and high values for the intersample K(a)/K(s) ratio (the ratio between anoffymous and synonymous substitutions; an index of the action of selective forces) was observed, as documented by the increase of both parameters over time (P = 0.01). These data argue for a dominant role of positive selection for amino acid changes in driving the pattern of genetic diversification of HCV populations, indicate that the intrahost evolution of HCV populations is compatible with a Darwinian model system, and may have implications in the designing of future antiviral strategies.

Amino Acid Sequence↗
PubMed1988

Expression of v-rel induces mature B-cell lines that reflect the diversity of avian immunoglobulin heavy- and light-chain rearrangements.

The infection of newly hatched chickens with reticuloendotheliosis virus strain T (REV-T) and a nonimmunosuppressive helper virus, chicken syncytial virus, induces rapidly metastatic B-cell lymphomas. In vivo analysis of these tumors with monoclonal antibodies detected the expression of the B-cell surface markers immunoglobulin M (IgM), CIa, Bu2, and CLA-1, but not IgG, Bu1, or a T-cell surface marker, CT-1. Cell lines derived from tumors exhibited the same pattern of staining, suggesting that expression of cell surface markers does not change during in vitro cell line development. All cell lines examined synthesized IgM in varying amounts. Northern (RNA blot) analysis confirmed abundant expression of v-rel mRNA, and Southern analysis revealed rearrangement of both heavy- and light-chain immunoglobulin loci. Analysis of the light-chain locus demonstrated that 20 of 22 lines contained a single rearranged allele. With respect to specific restriction enzyme sites within the V lambda 1 gene, the active allele in any given clone was either diversified or nondiversified. In contrast, examination of the heavy-chain loci within these lines demonstrated that 16 of the 22 had both alleles rearranged. Further diversification of the V lambda 1 locus did not occur after prolonged in vitro passage of the cell lines. We propose that v-rel expression arrests diversification of the light-chain locus in these lymphoid cells, allowing the production of stable, clonal B-cell populations. The development of these and similar cell lines will make it possible to identify specific stages of avian lymphoid ontogeny and to study the mechanism of rearrangement and diversification in the avian B lymphocyte.

Animals↗
PubMed2004

Pigment pattern evolution by differential deployment of neural crest and post-embryonic melanophore lineages in Danio fishes.

Latent precursors or stem cells of neural crest origin are present in a variety of post-embryonic tissues. Although these cells are of biomedical interest for roles in human health and disease, their potential evolutionary significance has been underappreciated. As a first step towards elucidating the contributions of such cells to the evolution of vertebrate form, we investigated the relative roles of neural crest cells and post-embryonic latent precursors during the evolutionary diversification of adult pigment patterns in Danio fishes. These pigment patterns result from the numbers and arrangements of embryonic melanophores that are derived from embryonic neural crest cells, as well as from post-embryonic metamorphic melanophores that are derived from latent precursors of presumptive neural crest origin. In the zebrafish D. rerio, a pattern of melanophore stripes arises during the larval-to-adult transformation by the recruitment of metamorphic melanophores from latent precursors. Using a comparative approach in the context of new phylogenetic data, we show that adult pigment patterns in five additional species also arise from metamorphic melanophores, identifying this as an ancestral mode of adult pigment pattern development. By contrast, superficially similar adult stripes of D. nigrofasciatus (a sister species to D. rerio) arise by the reorganization of melanophores that differentiated at embryonic stages, with a diminished contribution from metamorphic melanophores. Genetic mosaic and molecular marker analyses reveal evolutionary changes that are extrinsic to D. nigrofasciatus melanophore lineages, including a dramatic reduction of metamorphic melanophore precursors. Finally, interspecific complementation tests identify a candidate genetic pathway for contributing to the evolutionary reduction in metamorphic melanophores and the increased contribution of early larval melanophores to D. nigrofasciatus adult pigment pattern development. These results demonstrate an important role for latent precursors in the diversification of pigment patterns across danios. More generally, differences in the deployment of post-embryonic neural crest-derived stem cells or their specified progeny may contribute substantially to the evolutionary diversification of adult form in vertebrates, particularly in species that undergo a metamorphosis.

Animals↗
PubMed2004

Exploring the concept of clonality in bacteria.

Isolates of bacterial species that are indistinguishable in genotype are assigned as a clone, with the implication that they are descended from the same recent ancestor. Clones are difficult to define with precision since bacteria are not truly asexual, and recombinational replacements result in diversification of the ancestral genotype of a clone, to produce a cluster of increasingly diverse genotypes (a clonal complex). The rate at which clonal diversification occurs depends on the extent of recombination, which varies among bacteria, so that some species have rather stable clones (e.g., Salmonella enterica), whereas in other species (e.g., Helicobacter pylori) clones may be so transient that they cannot readily be discerned. Clones and clonal complexes need to be assigned by indexing genetic variation that is selectively neutral, and currently this is best achieved using multilocus sequence typing. Some species of bacterial pathogens are very diverse, whereas others are genetically uniform, and some are, in essence, a single clone of a mother species that has been raised to species status due to the distinctiveness of the disease it causes (e.g., Yersinia pestis, Salmonella typhi, or Burkholderia mallei). The population structures of bacteria depend on the rate of recombination, and comparative measures of the extent of recombination during clonal diversification can be obtained from multilocus sequence typing data, as can measures of the longer-term impact of recombination. These studies show a wide range of recombination rates among bacterial species, and indicate that recombination in many bacteria has been sufficiently extensive that a reliable evolutionary history of the species cannot be inferred.

Bacteria↗
PubMed2026

Evolutionary adaptation of CCD4 enzymes in Buddleja alternifolia for crocetin biosynthesis.

INTRODUCTION: Carotenoid cleavage dioxygenase 4 (CCD4) enzymes play central roles in carotenoid turnover and apocarotenoid biosynthesis in plants. Despite their importance, the evolutionary mechanisms underlying diversification of CCD4 catalytic functions remain poorly understood. This study investigated the CCD gene family in Buddleja alternifolia, with particular emphasis on the expansion and functional evolution of the CCD4 subfamily. METHODS: A genome-wide identification and comparative analysis of CCD genes were performed in B. alternifolia. Genomic organization, phylogenetic relationships, and syntenic patterns were analyzed to investigate gene family expansion. Functional characterization of 11 BaCCD4 paralogs was conducted through biochemical assays, while structural analyses were used to identify sequence features associated with differences in substrate cleavage specificity. Gene expression profiling was performed to assess patterns of tissue-specific regulation. RESULTS: Twenty-three CCD genes were identified, including 12 CCD4 paralogs, representing one of the largest CCD4 expansions reported within Lamiales. Syntenic and genomic analyses revealed that recent tandem duplication events, particularly within a CCD4-rich region on chromosome 10, were the primary drivers of this expansion. The presence of pseudogenes in the same region supported an ongoing birth-and-death evolutionary process. Functional analyses demonstrated extensive biochemical diversification among BaCCD4 enzymes despite their high sequence similarity. Several paralogs catalyzed asymmetric carotenoid cleavage leading to citraurin production, whereas two paralogs, KAG8367281 and KAG8375220, exhibited symmetric zeaxanthin cleavage activity, producing crocetin dialdehyde, the direct precursor of crocins. Notably, these crocetin-producing enzymes belonged to closely related paralogous pairs whose counterparts displayed distinct cleavage specificities, indicating rapid neofunctionalization after duplication. Structural analyses suggested that subtle sequence variations, including indels affecting loop regions adjacent to the substrate access channel, may underlie changes in regioselectivity. Expression profiling further revealed tissue-specific expression patterns consistent with functional divergence among paralogs. DISCUSSION: These findings indicate that crocetin-forming activity in B. alternifolia likely evolved through progressive modifications of ancestral CCD4 functions rather than through a single evolutionary event. The remarkable expansion and diversification of the CCD4 subfamily provide evidence for the role of gene duplication and neofunctionalization in shaping carotenoid cleavage specificity. Collectively, this work establishes B. alternifolia as a valuable model for investigating the molecular evolution of CCD4 enzymes and the emergence of specialized apocarotenoid metabolism in plants.

CCD4 evolution↗
PubMed2000

Accumulation of clonally related B lymphocytes in the cerebrospinal fluid of multiple sclerosis patients.

The accumulation of B lymphocyte clones in the cerebrospinal fluid (CSF) of patients with multiple sclerosis (MS) and patients with other neurological disorders was investigated using PCR technologies. Oligoclonal B cell accumulations were detected in 10 of 10 MS patients, but only in 3 of 10 of the patients with other neurological disorders. Analyses of the Ig V(D)J sequences on the CSF from MS patients disclosed that VH3 and VH4 genes were extensively mutated compared with germline sequences. Moreover, a substantial proportion of the molecular clones analyzed shared the same third CDR of the H chain variable region gene (HCDR3) and the same VH genes, albeit with different numbers and locations of point mutations, thus indicating an ongoing process of intraclonal diversification. A larger number of clonally related VH sequences could be obtained by using a VH3 gene-specific PCR so that genealogical trees depicting the process of diversification could be drawn. Analyses of the Ig V(D)J from the CSF of a patient with viral meningitis and oligoclonal B cell accumulations revealed that VH3 genes were extensively mutated. However, no intraclonal diversification could be observed even using VH3 gene-specific PCR methodologies. Clone-specific PCR and sequencing was used to detect the V(D)J found in the CSF of one MS patient in the PBL of the same patient. Only 1/3 of the V(D)J sequences investigated could be demonstrated in the PBL, indicating that the V(D)J genes utilized by B cells in the CSF are much less represented in the PBL. Collectively, the data suggest that in MS there is a compartmentalized clonal expansion.

Adolescent↗
PubMed2004

Genetic dissection of lupus pathogenesis: Sle3/5 impacts IgH CDR3 sequences, somatic mutations, and receptor editing.

Sle3/5 is a lupus susceptibility locus identified on mouse chromosome 7 of the New Zealand Black/New Zealand White (NZB/NZW)-derived NZM2410 strain. Based on previous observations, this locus appears to contribute to lupus pathogenesis through its impact on diversification of immune responses. To understand how Sle3/5 affects somatic diversification of humoral responses, we analyzed IgH rearrangements preferentially encoding hapten-reactive IgG1 repertoires after immunization and assessed peripheral IgH VDJ recombination activities in C57BL/6 (B6) mice congenic for Sle3/5 (B6.Sle3/5). In addition to altered somatic V(H) mutation profiles, sequences from B6.Sle3/5 mice exhibited atypical IgH CDR3 structures characteristic of autoreactive B cells and consistent with peripheral B cells bearing putatively edited receptors. Significant expression of Rag genes and circular V(H)D gene excision products were detected in splenic mature B cells of B6.Sle3/5 but not B6 mice, showing that peripheral IgH rearrangements occurred beyond allelic exclusion. Taken together, on the nonautoimmune background, Sle3/5 affected V(H)DJ(H) junctional diversity and V(H) mutational diversity and led to recombinational activation of allelically excluded IgH genes in the periphery. Such impact on somatic IgH diversification may contribute to the development of autoreactive B cell repertoires. This is the first report to present evidence for significant association of a lupus susceptibility locus, which has been mapped to a chromosomal region in which no Ig genes have been identified, with somatic IgH sequence diversity and peripheral H chain receptor editing or revision without relying upon Ig transgene strategies.

Animals↗
PubMed2026

Distributed Clonal Deletion Prevents Autoimmune Disease Progression.

Self-reactive B cells are generated during normal development and can acquire increased pathogenicity through activation-induced cytidine deaminase (AID)-mediated diversification following activation. Clonal deletion is thought to eliminate these cells, yet how deletion is distributed across developmental and activation stages to prevent autoimmune disease remains unclear. Here, we show that clonal deletion is enforced through temporally distinct mitochondrial apoptosis (MOMP) checkpoints that differentially regulate autoreactive B cell fate and disease progression. Using conditional Bcl-2 expression to inhibit MOMP either before or after B cell activation, we find that early inhibition permits the survival and maturation of autoreactive B cells after peripheral egress, expanding the pool of cells available for activation. These cells subsequently undergo AID-dependent diversification, producing class-switched IgG autoantibodies with expanded antigen breadth that target a wider range of self-antigens and drive lethal, female-biased autoimmune disease characterized by complement activation and kidney pathology. In contrast, inhibition of MOMP only after activation allows the accumulation of germinal center, switched memory, and plasma cells and promotes autoantibody production, but results in more restricted IgG autoreactivity, limited complement activation and limited tissue damage, and normal survival. Notably, early MOMP inhibition does not expand immature bone marrow B cells, indicating that a major clonal deletion checkpoint operates in the periphery rather than during initial B cell generation. Together, these findings support a Distributed Clonal Deletion Model in which early checkpoints restrict the entry of autoreactive B cells into diversification pathways, while later checkpoints limit the persistence of diversified autoreactive clones, thereby constraining autoimmune disease progression.

Journal Article↗