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PubMed1999

Evolutionary process and the ecology of human immune function.

Evolutionary principles inform central design features of human immune defenses and provide key insights into this complicated host defense system. This article explores the selection pressures and adaptive responses that have elaborated the immune system over the course of evolution and discusses their implications for understanding contemporary immune development and function. Special attention is given to the challenges posed by diverse, rapidly evolving pathogens and the mammalian response to these challenges. The process of lymphocyte diversity generation and subsequent clonal selection is quintessentially Darwinian: pathogens provide selection pressure that drives differential replication of host immune cell lines, resulting in changes in genetic frequencies within an individual's population of lymphocytes. The immune system also incorporates nongenetic transgenerational processes in the transfer of antibodies from mother to offspring through the placenta and breast milk. The consequences of these observations for human development, health, and the ecology of immune function are considered throughout the life cycle. Specifically, evolutionary processes provide insight into autoimmunity, thymic function, lymphocyte development, infectious disease risk, and lactation. While much work in evolutionary medicine focuses on the discordance between evolved biology and rapidly changing cultural environments, with respect to the immune system, evolutionary processes may be most revealing when applied within individuals. Am. J. Hum. Biol. 11:705-717, 1999. Copyright 1999 Wiley-Liss, Inc.

Journal Article↗

PubMed2001

Optochin resistance in Streptococcus pneumoniae: mechanism, significance, and clinical implications.

Traditionally, Streptococcus pneumoniae is identified in the laboratory by demonstrating susceptibility to optochin. Between 1992 and 1998, 4 pneumococcal isolates exhibiting optochin resistance were recovered from patients at Children's National Medical Center. Three of the 4 isolates consisted of mixed populations of optochin-resistant and -susceptible organisms. Both subpopulations had identical antibiograms, serotypes, and restriction fragment profiles. The other isolate was uniformly resistant to optochin. Resistant strains had MICs of optochin 4-30-fold higher than susceptible strains, belonged to different serotypes, and had dissimilar restriction fragment profiles, indicating clonal unrelatedness. Resistance arose from single point mutations in either the a-subunit (W206S) or the c-subunit (G20S, M23I, and A49T) of H(+)-ATPase. There is speculation of a possible association between exposure to antimalarial drugs and evolution of optochin resistance. alpha-Hemolytic streptococci resistant to optochin, particularly invasive isolates, should be tested for bile solubility or with an S. pneumoniae DNA probe before identification as viridans streptococci.

Amino Acid Sequence↗

PubMed1998

Alterations in DNA methylation: a fundamental aspect of neoplasia.

Neoplastic cells simultaneously harbor widespread genomic hypomethylation, more regional areas of hypermethylation, and increased DNA-methyltransferase (DNA-MTase) activity. Each component of this "methylation imbalance" may fundamentally contribute to tumor progression. The precise role of the hypomethylation is unclear, but this change may well be involved in the widespread chromosomal alterations in tumor cells. A main target of the regional hypermethylation are normally unmethylated CpG islands located in gene promoter regions. This hypermethylation correlates with transcriptional repression that can serve as an alternative to coding region mutations for inactivation of tumor suppressor genes, including p16, p15, VHL, and E-cad. Each gene can be partially reactivated by demethylation, and the selective advantage for loss of gene function is identical to that seen for loss by classic mutations. How abnormal methylation, in general, and hypermethylation, in particular, evolve during tumorigenesis are just beginning to be defined. Normally, unmethylated CpG islands appear protected from dense methylation affecting immediate flanking regions. In neoplastic cells, this protection is lost, possibly by chronic exposure to increased DNA-MTase activity and/or disruption of local protective mechanisms. Hypermethylation of some genes appears to occur only after onset of neoplastic evolution, whereas others, including the estrogen receptor, become hypermethylated in normal cells during aging. This latter change may predispose to neoplasia because tumors frequently are hypermethylated for these same genes. A model is proposed wherein tumor progression results from episodic clonal expansion of heterogeneous cell populations driven by continuous interaction between these methylation abnormalities and classic genetic changes.

Aging↗

PubMed1986

Mitochondrial DNA and the evolutionary genetics of higher animals.

Mitochondrial DNA (mtDNA) in higher animals is rapidly becoming a well characterized genetic system at the molecular level. In this paper, I shift the focus to consider questions in organismal evolution that can be addressed by mtDNA assay. For the first time, it is possible to estimate empirically matriarchal phylogeny; to determine directionality in crosses producing hybrids; and to study the population genetic consequences of varying female demographies and life histories. The data obtainable from mtDNA may be especially well suited for studies of population genetic structure, dispersal, and historical zoogeography. The female-mediated, clonal transmission of mtDNA is also stimulating new ways of thinking about times to common ancestry of asexual lineages within otherwise sexually reproducing populations; about the possible relevance of mtDNA-nuclear DNA interactions to reproductive isolation; and about the very meaning of the phylogenetic status of related species with respect to particular kinds of genetic characters. These and other topics are reviewed.

Animals↗

PubMed2005

Effect of alternating passage on adaptation of sindbis virus to vertebrate and invertebrate cells.

Mosquito-borne alphaviruses, which replicate alternately and obligately in mosquitoes and vertebrates, appear to experience lower rates of evolution than do many RNA viruses that replicate solely in vertebrates. This genetic stability is hypothesized to result from the alternating host cycle, which constrains evolution by imposing compromise fitness solutions in each host. To test this hypothesis, Sindbis virus was passaged serially, either in one cell type to eliminate host alteration or alternately between vertebrate (BHK) and mosquito (C6/36) cells. Following 20 to 50 serial passages, mutations were identified and changes in fitness were assessed using competition assays against genetically marked, surrogate parent viruses. Specialized viruses passaged in a single cell exhibited more mutations and amino acid changes per passage than those passaged alternately. Single host-adapted viruses exhibited fitness gains in the cells in which they specialized but fitness losses in the bypassed cell type. Most but not all viruses passaged alternately experienced lesser fitness gains than specialized viruses, with fewer mutations per passage. Clonal populations derived from alternately passaged viruses also exhibited adaptation to both cell lines, indicating that polymorphic populations are not required for simultaneous fitness gains in vertebrate and mosquito cells. Nearly all passaged viruses acquired Arg or Lys substitutions in the E2 envelope glycoprotein, but enhanced binding was only detected for BHK cells. These results support the hypothesis that arbovirus evolution may be constrained by alternating host transmission cycles, but they indicate a surprising ability for simultaneous adaptation to highly divergent cell types by combinations of mutations in single genomes.

Adaptation, Physiological↗

PubMed2004

Morphological and molecular variation of Morus laevigata in India.

Morus spp., commonly known as mulberry, is significantly associated with human civilization and spread of silk-culture from Asia to Europe, Africa and Latin America. One of its species, Morus laevigata, traditionally well known for its timber value, forage use and silkworm's feed, is widely distributed in India extending from Himalayan foothill to Andaman islands. The variability occurring for 12 morpho-biochemical parameters and RAPD profiles, generated with 13 selected RAPD primers, for M. laevigata accessions from six different zones were investigated. Analyses revealed high degree of genotypic similarity of collection from Himalayan foothill (West Bengal) with those from Andaman Islands. Specific accessions from central India and south India also revealed genotypic similarities with specific accessions from north-east India. These observations are discussed in the context of clonal propagation of mulberry and evolutionary perspective of dispersal of this species, through human activities

Biological Evolution↗

PubMed1994

Clonal divergence in Escherichia coli as a result of recombination, not mutation.

Nucleotide sequence analysis was performed on 12 natural isolates of Escherichia coli in four loci located in close proximity on the chromosome. A comparison of gene genealogies indicated that three recombination events have occurred in a subset of the strains (ECOR group A) in the time since their divergence from a common ancestor, while during the same time, no mutational divergence has occurred. The common ancestor of this subset existed no more than 2400 years ago, and recombination was shown to occur at a rate of 5.0 x 10(-9) changes per nucleotide per generation--50-fold higher than the mutation rate. Thus, recombination has been the dominant force driving the clonal divergence of the ECOR group A strains and must be considered a significant factor in structuring E. coli populations.

Biological Evolution↗

PubMed1991

The unusual sexual preferences of a chlamydomonas mutant may provide insight into mating-type evolution.

Chlamydomonas monoica undergoes intraclonal mating-type differentiation (homothallism). Although the species differs in this regard from the more commonly studied heterothallic C. reinhardtii, cell-cell interactions and progression of the sexual cycle are similar for many homothallic and heterothallic species of the genus. Regulation of chloroplast gene transmission by the nuclear mating-type alleles (mt+ and mt-) is another common denominator for Chlamydomonas species studied thus far. We have previously reported the use of chloroplast inheritance patterns to identify mutants of C. monoica that have lost the potential to function as the mt+ mating-type. A similar screening procedure led to the isolation of an unusual mutant, mtl-3 whose phenotype is less readily explained. Chloroplast gene transmission patterns in crosses involving mtl-3 suggest that the mtl-3 strain mates preferentially as mt+. However, normal mating efficiencies and high zygospore viability are observed in clonal culture, indicating the unbiased production of functional opposite mating-types. By construction of appropriately marked strains we have been able to show that mtl-3 mt- gametes prefer the mt+ gametes of their own strain. A model is presented which invokes unequal crossing over between highly homologous flagellar agglutinin genes to account for the unusual properties of the mtl-3 strain and for the evolution of mating barriers within the genus.

Alleles↗

PubMed1979

The evolution of an immune system.

A model for the molecular evolution of an imune system is presented. It suggests how a system of cell surface-fixed antigen receptors, called FR, to be thought of as "primitive" but still functional antibodies, could evolve into the "modern" labile T cell and antibody system, the receptors for which may be called CER (clonal expansion receptors). Perhaps the most significant insight to be gained from the theory concerns the conclusion that the immune system of an embryo may be primed by the interaction between two types of cells with complementary surface specificities. In the first type of cell the interacting molecule is an FR molecule coded by a gene of the Major Histocompatibility Complex (MHC) which has undergone a somatic mutation; in the second type it is a CER molecule also coded by a gene which has undergone a recent somatic mutation. It is believed that this insight eliminates some of the problems experienced in understanding generation of diversity, and renders unnecessary some of the more complex hypotheses about immune networks. The mechanism of action of immune response genes is easily explained by the theory.

Adaptation, Physiological↗

PubMed2004

Silent nucleotide polymorphisms and a phylogeny for Mycobacterium tuberculosis.

Much remains unknown of the phylogeny and evolution of Mycobacterium tuberculosis, an organism that kills 2 million people annually. Using a population-based approach that analyzes multiple loci around the chromosome, we demonstrate that neutral genetic variation in genes associated with antimicrobial drug resistance has sufficient variation to construct a robust phylogenetic tree for M. tuberculosis. The data describe a clonal population with a minimum of four distinct M. tuberculosis lineages, closely related to M. bovis. The lineages are strongly geographically associated. Nucleotide substitutions proven to cause drug resistance are distributed throughout the tree, whereas nonsynonymous base substitutions unrelated to drug resistance have a restricted distribution. The phylogenetic structure is concordant with all the previously described genotypic and phenotypic groupings of M. tuberculosis strains and provides a unifying framework for both epidemiologic and evolutionary analysis of M. tuberculosis populations.

Amidohydrolases↗

PubMed1992

The evolution of insertion sequences within enteric bacteria.

To identify mechanisms that influence the evolution of bacterial transposons, DNA sequence variation was evaluated among homologs of insertion sequences IS1, IS3 and IS30 from natural strains of Escherichia coli and related enteric bacteria. The nucleotide sequences within each class of IS were highly conserved among E. coli strains, over 99.7% similar to a consensus sequence. When compared to the range of nucleotide divergence among chromosomal genes, these data indicate high turnover and rapid movement of the transposons among clonal lineages of E. coli. In addition, length polymorphism among IS appears to be far less frequent than in eukaryotic transposons, indicating that nonfunctional elements comprise a smaller fraction of bacterial transposon populations than found in eukaryotes. IS present in other species of enteric bacteria are substantially divergent from E. coli elements, indicating that IS are mobilized among bacterial species at a reduced rate. However, homologs of IS1 and IS3 from diverse species provide evidence that recombination events and horizontal transfer of IS among species have both played major roles in the evolution of these elements. IS3 elements from E. coli and Shigella show multiple, nested, intragenic recombinations with a distantly related transposon, and IS1 homologs from diverse taxa reveal a mosaic structure indicative of multiple recombination and horizontal transfer events.

Base Sequence↗

PubMed2004

Evolution of responding CD4+ and CD8+ T-cell repertoires during the development of graft-versus-host disease directed to minor histocompatibility antigens.

Graft-versus-host disease (GVHD) can be induced in lethally irradiated mice after allogeneic bone marrow transplantation between major histocompatibility complex-matched strains expressing multiple minor histocompatibility antigen differences. In the B6 --> BALB.B irradiation model, both CD4(+) and CD8(+) donor T cells have the capacity to mediate lethal GVHD. Previously, CDR3-size spectratyping was used to analyze these T-cell responses at a single early time point (day 5) after transplantation and revealed clonal or oligoclonal expansions of the V beta 2, 4, and 6 to 14 families for the CD4(+) response and of the V beta 4, 6, 8 to 11, and 14 families for the B6 CD8(+) response. Appropriate positive selection of these T-cell receptor V beta-skewed CD4(+) and CD8(+) T-cell subsets and their subsequent transfer into lethally irradiated BALB.B recipients resulted in fatal GVHD induction. In contrast, BALB.B mice transplanted with nonskewed V beta CD4(+) T cells survived, with minimal symptoms of GVHD. This study was undertaken to investigate the evolution of the donor/antihost minor histocompatibility antigen T-cell repertoire responses throughout the course of GVHD development. The results indicated that a number of V beta families were consistently involved throughout the course of GVHD, whereas some V beta families exhibited skewed expansions only in either the early or late stages of disease. In addition, sequence analysis of relevant representative skewed CDR3 bands from the CD4(+) V beta 11(+) and the CD8(+) V beta 14(+) families, both of which exhibited strong consistent responses, demonstrated increased use of the J beta 2.5 and J beta 2.4 segments, respectively, thus identifying the T-cell receptor specificities involved.

Animals↗

PubMed2001

The evolution of pandemic clones of methicillin-resistant Staphylococcus aureus: identification of two ancestral genetic backgrounds and the associated mec elements.

Previous surveillance studies carried out by our laboratories, primarily in Southern and Eastern Europe, Latin America, and the United States, have characterized 3,067 methicillin-resistant Staphylococcus aureus (MRSA) hospital isolates by a combination of molecular typing methods. Nearly 70% of these isolates could be classified into five clonal types showing extensive geographic spread. Representative isolates of these clonal types were now reexamined for their genetic relatedness by multilocus sequence typing (MLST) and by sequencing the polymorphic region of protein A (spaA typing), and also for the type of the Staphylococcal Chromosomal Cassette (SCCmec) resident in the bacteria. Three of the previously classified clonal types (Iberian, Brazilian, and Hungarian clones) shared a common or closely related genetic background A, which was the same as the background of the earliest European isolates of MRSA from England and Denmark. The Pediatric and New York/Japan clones belonged to a completely different genetic background B. The three recently described SCCmec types were specifically associated with different pandemic clones: types I and III with isolates of genetic background A and type II with isolates of genetic background B. A novel SCCmec related to type I, called SCCmec type IV, was identified in some MRSA strains belonging to genetic background A as well as B. Structural variations in SCCmec types I and III were also observed. The data allow tentative identification of an evolutionary pathway for the emergence of pandemic MRSA clones and also provide evidence for the multiple, yet restricted, numbers of acquisition of the mec element by S. aureus.

Bacterial Proteins↗

PubMed2026

Reframing early gastric carcinogenesis through lineage, niche, and evolution.

Early gastric cancer is still commonly conceptualized as the endpoint of a linear sequence from chronic gastritis to intestinal metaplasia, dysplasia, and invasion. Yet recent single-cell, spatial, genomic, and functional studies indicate that this model incompletely captures the biology of early gastric carcinogenesis. Malignant potential is established progressively within a precancerous gastric field already shaped by somatic evolution, chronic inflammatory injury, and epithelial lineage distortion. Within this field, progression is concentrated in a restricted set of precursor states, particularly incomplete, hybrid, and stem-like metaplastic populations that display plasticity, persistence, and increasing compatibility with a supportive microenvironment. Fibroblast niche remodeling, immune protection loss, endothelial rewiring, genomic instability, epigenetic drift, and selective retention of advantageous molecular alterations further promote malignant commitment. In parallel, diffuse gastric cancer appears to follow a distinct route that may arise independently of conventional intestinal metaplasia through E-cadherin-deficient epithelial transformation and downstream chromatin reprogramming. Here, we synthesize recent evidence to propose an updated framework for early gastric carcinogenesis based on field evolution, lineage instability, ecosystem support, and pathway divergence. Rather than replacing the classical Correa cascade, this framework seeks to refine it by shifting the unit of risk assessment from histologic stage alone to biologically defined precursor states shaped by lineage instability, clonal persistence, niche permissiveness, and pathway-specific molecular constraints. This perspective shifts the emphasis of prevention from detecting smaller cancers to identifying and intercepting biologically committed precursor states before invasion occurs.

Humans↗

PubMed2004

A graph model for the evolution of specificity in humoral immunity.

The immune system protects the body against health-threatening entities, known as antigens, through very complex interactions involving the antigens and the system's own entities. One remarkable feature resulting from such interactions is the immune system's ability to improve its capability to fight antigens commonly found in the individual's environment. This adaptation process is called the evolution of specificity. In this paper, we introduce a new mathematical model for the evolution of specificity in humoral immunity, based on Jerne's functional, or idiotypic, network. The evolution of specificity is modeled as the dynamic updating of connection weights in a dynamic graph whose nodes are related to the network's idiotypes. At the core of this weight-updating mechanism are the increase in specificity caused by clonal selection and the decrease in specificity due to the insertion of uncorrelated idiotypes by the bone marrow. As we demonstrate through numerous computer experiments, for appropriate choices of parameters the new model correctly reproduces, in qualitative terms, several immune functions.

Antibody Formation↗

PubMed1999

Genetic and fitness changes accompanying adaptation of an arbovirus to vertebrate and invertebrate cells.

The alternating host cycle and persistent vector infection may constrain the evolution of arboviruses. To test this hypothesis, eastern equine encephalitis virus was passaged in BHK or mosquito cells, as well as in alternating (both) host cell passages. High and low multiplicities were used to examine the effect of defective interfering particles. Clonal BHK and persistent mosquito cell infections were also evaluated. Fitness was measured with one-step growth curves and competition assays, and mutations were evaluated by nucleotide sequencing and RNA fingerprinting. All passages and assays were done at 32 degrees C to eliminate temperature as a selection factor. Viruses passaged in either cell type alone exhibited fitness declines in the bypassed cells, while high-multiplicity and clonal passages caused fitness declines in both types of cells. Bypassed cell fitness losses were mosquito and vertebrate specific and were not restricted to individual cell lines. Fitness increases occurred in the cell line used for single-host-adaptation passages and in both cells for alternately passaged viruses. Surprisingly, single-host-cell passage increased fitness in that cell type no more than alternating passages. However, single-host-cell adaptation resulted in more mutations than alternating cell passages. Mosquito cell adaptation invariably resulted in replacement of the stop codon in nsP3 with arginine or cysteine. In one case, BHK cell adaptation resulted in a 238-nucleotide deletion in the 3' untranslated region. Many nonsynonymous substitutions were shared among more than one BHK or mosquito cell passage series, suggesting positive Darwinian selection. Our results suggest that alternating host transmission cycles constrain the evolutionary rates of arboviruses but not their fitness for either host alone.

Adaptation, Biological↗

PubMed2003

First demonstration of a lack of viral sequence evolution in a nonprogressor, defining replication-incompetent HIV-1 infection.

It is universally acknowledged that genetic diversity is a hallmark of HIV-1 infection, and it is one of the traits that has considerably hampered the development of an effective vaccine. In a study of full-length HIV-1 genomic sequences (>9 kb), we show unique evidence for complete absence of viral evolution in an individual with truly nonprogressive infection. Gross gene defects were not detected, but the state of replication incompetence was attributed to the presence of stop codons in the structural genes gag p17 and p24 and in pol RT, which emerged as a consequence of G-A hypermutation. These inactivating mutations may have occurred early, soon after infection, during the clonal stage of primary viral replication, since these are the sole archival strains present today. This genetic homogeneity, with <1% variation between strains over an 8-year period, suggests that only limited proviral integration events occurred in this patient. Further study on the antigenic properties of this strain may assist in the development of HIV vaccines and therapeutics.

Amino Acid Sequence↗

PubMed1995

Genotypic and immunohistological demonstration of the progression of an unusual reactive-like B-cell lymphoproliferative disorder to a high grade diffuse lymphoma.

In the present study the clinical and pathological evolution of a reactive-like B-cell lymphoproliferative disorder with an unusually high content of T cells is described. Immunogenotypic analysis showed that the same phenotypically atypical B-cell clone, characterized by the unusual presence of an immunoglobulin (Ig)K gene rearrangement, with the heavy chain (IgH) gene in germline configuration, was invariantly present in all phases of the disease. The disorder showed an indolent course for a long period of time during which the clonal B-cell population coexisted with an abundant, reactive T-cell component in different locations of the disease. These findings, together with the observation of spontaneous progression and regression phases of the disorder and its responsiveness to corticosteroids, suggest that functional interactions between the B-cell clone and the polyclonal infiltrating T cells probably were involved in the pathogenesis of the disease. After the administration of the antiblastic treatment, a progressive reduction of the reactive T-cell component was observed with the concomitant evolution to a diffuse large cell (immunoblastic) B-cell lymphoma and the appearance of an IgH gene rearrangement. The biological characteristics and the clinical evolution of the case described here are similar to those reported for the so-called "T-cell-rich B-cell lymphomas" (TCRBCLs). These findings suggest that the T-cell-rich pattern may identify a group of B-cell lymphoproliferations with common pathogenetic mechanisms and clinical behavior.

Adult↗