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PubMed2005

Origins of extrinsic variability in eukaryotic gene expression.

Variable gene expression within a clonal population of cells has been implicated in a number of important processes including mutation and evolution, determination of cell fates and the development of genetic disease. Recent studies have demonstrated that a significant component of expression variability arises from extrinsic factors thought to influence multiple genes simultaneously, yet the biological origins of this extrinsic variability have received little attention. Here we combine computational modelling with fluorescence data generated from multiple promoter-gene inserts in Saccharomyces cerevisiae to identify two major sources of extrinsic variability. One unavoidable source arising from the coupling of gene expression with population dynamics leads to a ubiquitous lower limit for expression variability. A second source, which is modelled as originating from a common upstream transcription factor, exemplifies how regulatory networks can convert noise in upstream regulator expression into extrinsic noise at the output of a target gene. Our results highlight the importance of the interplay of gene regulatory networks with population heterogeneity for understanding the origins of cellular diversity.

Eukaryotic Cells↗
PubMed2000

A pot-pourri of plasmid paradoxes: effects of a second copy.

Bacterial plasmids are exemplary subjects for study, being conveniently isolated, dissected, reassembled, and introduced into various hosts. Their versatility and power make them eminently worthy of our attention. In what follows I consider some consequences of simply doubling the dosage of particular plasmid genes or of forming a plasmid dimer. These consequences can be perverse, paradoxical, or informative. They bear on questions of cell viability, copy number limitation, clonal homogeneity, check-point control, and the recovery of mutants. They have relevance to biotechnology, evolution and medicine. In reviewing these effects, my motivation is largely to share my enthusiasm for certain kinds of biological narratives, the nature of which is best left for the reader to discern.

Bacteria↗
PubMed2003

Immunobiology of chronic lymphocytic leukemia.

B-cell chronic lymphocytic leukemia increasingly is being recognized as a useful model disease with which to study more general processes involved in the evolution of neoplastic disease. The accessibility of the tumor cells and the capacity to confirm their clonal relatedness allow for evaluation of the processes associated with neoplastic transformation and/or disease progression. Recent studies have provided fascinating insight into the potential pathogenesis and pathophysiology of this disease. In addition, features of leukemia cells have been identified that can distinguish subsets of patients that have different tendencies for disease progression. Gene expression studies have identified a relatively small number of genes that are differentially expressed between these subsets, allowing for focused attention on proteins that might contribute to the noted differences in clinical behavior. Finally, recognition that chronic lymphocytic leukemia cells depend upon specific microenvironmental growth and survival factors identifies novel targets for disease intervention. This article focuses on the reports of the past year that have contributed to these areas of active research on chronic lymphocytic leukemia, the most common adult leukemia in Western societies.

Gene Expression Regulation, Neoplastic↗
PubMed2025

Long-read sequencing of single cell-derived melanoma subclones reveals divergent and parallel genomic and epigenomic evolutionary trajectories.

Tumor evolution is driven by various mutational processes, ranging from single-nucleotide variants (SNVs) to large structural variants (SVs) to dynamic shifts in DNA methylation. Current short-read sequencing methods struggle to accurately capture the full spectrum of these genomic and epigenomic alterations due to inherent technical limitations. To overcome that, here we introduce an approach for long-read sequencing of single-cell derived subclones, and use it to profile 23 subclones of a mouse melanoma cell line, characterized with distinct growth phenotypes and treatment responses. We develop a computational framework for harmonization and joint analysis of different variant types in the evolutionary context. Uniquely, our framework enables detection of recurrent amplifications of putative driver genes, generated by independent SVs across different lineages, suggesting parallel evolution. In addition, our approach revealed gradual and lineage-specific methylation changes associated with aggressive clonal phenotypes. We also show our set of phylogeny-constrained variant calls along with openly released sequencing data can be a valuable resource for the development of new computational methods.

Journal Article↗
PubMed1999

Intraspecific diversity of the 23S rRNA gene and the spacer region downstream in Escherichia coli.

The molecular microevolution of the 23S rRNA gene (rrl) plus the spacer downstream has been studied by sequencing of different operons from some representative strains of the Escherichia coli ECOR collection. The rrl gene was fully sequenced in six strains showing a total of 67 polymorphic sites, a level of variation per nucleotide similar to that found for the 16S rRNA gene (rrs) in a previous study. The size of the gene was highly conserved (2902 to 2905 nucleotides). Most polymorphic sites were clustered in five secondary-structure helices. Those regions in a large number of operons were sequenced, and several variations were found. Sequences of the same helix from two different strains were often widely divergent, and no intermediate forms existed. Intercistronic variability was detected, although it seemed to be lower than for the rrs gene. The presence of two characteristic sequences was determined by PCR analysis throughout all of the strains of the ECOR collection, and some correlations with the multilocus enzyme electrophoresis clusters were detected. The mode of variation of the rrl gene seems to be quite similar to that of the rrs gene. Homogenization of the gene families and transfer of sequences from different clonal lines could explain this pattern of variation detected; perhaps these factors are more relevant to evolution than single mutation. The spacer region between the 23S and 5S rRNA genes exhibited a highly polymorphic region, particularly at the 3' end.

Bacterial Typing Techniques↗
PubMed1993

Dilute passage promotes expression of genetic and phenotypic variants of human immunodeficiency virus type 1 in cell culture.

We have studied the extent of genetic and phenotypic diversification of human immunodeficiency virus type 1 (HIV-1) upon 15 serial passages of clonal viral populations in MT-4 cell cultures. Several genetic and phenotypic modifications previously noted during evolution of HIV-1 in infected humans were also observed upon passages of the virus in cell culture. Notably, the transition from non-syncytium-inducing to syncytium-inducing phenotype (previously observed during disease progression) and fixation of amino acid substitutions at the main antigenic loop V3 of gp120 were observed in the course of replication of the virus in MT-4 cell cultures in the absence of immune selection. Interestingly, most genetic and phenotypic alterations occurred upon passage of the virus at a low multiplicity of infection (0.001 infectious particles per cell) rather than at a higher multiplicity of infection (0.1 infectious particles per cell). The degree of genetic diversification attained by HIV-1, estimated by the RNase A mismatch cleavage method and by nucleotide sequencing, is of about 0.03% of genomic sites mutated after 15 serial passages. This value is not significantly different from previous estimates for foot-and-mouth disease virus when subjected to a similar process and analysis. We conclude that several genetic and phenotypic modifications of HIV-1 previously observed in vivo occur also in the constant environment provided by a cell culture system. Dilute passage promotes in a highly significant way the expression of deviant HIV-1 genomes.

Acquired Immunodeficiency Syndrome↗
PubMed1990

Organization of the bacterial chromosome.

Recent progress in studies on the bacterial chromosome is summarized. Although the greatest amount of information comes from studies on Escherichia coli, reports on studies of many other bacteria are also included. A compilation of the sizes of chromosomal DNAs as determined by pulsed-field electrophoresis is given, as well as a discussion of factors that affect gene dosage, including redundancy of chromosomes on the one hand and inactivation of chromosomes on the other hand. The distinction between a large plasmid and a second chromosome is discussed. Recent information on repeated sequences and chromosomal rearrangements is presented. The growing understanding of limitations on the rearrangements that can be tolerated by bacteria and those that cannot is summarized, and the sensitive region flanking the terminator loci is described. Sources and types of genetic variation in bacteria are listed, from simple single nucleotide mutations to intragenic and intergenic recombinations. A model depicting the dynamics of the evolution and genetic activity of the bacterial chromosome is described which entails acquisition by recombination of clonal segments within the chromosome. The model is consistent with the existence of only a few genetic types of E. coli worldwide. Finally, there is a summary of recent reports on lateral genetic exchange across great taxonomic distances, yet another source of genetic variation and innovation.

Bacteria↗
PubMed1987

Granulomatous slack skin: clonal rearrangement of the T-cell receptor beta gene is evidence for the lymphoproliferative nature of a cutaneous elastolytic disorder.

Granulomatous slack skin (GSS) is characterized by the slow evolution of bulky, erythematous skin folds that have a granulomatous histology, and show destruction of dermal elastic tissue. Several cases have been putatively associated with Hodgkin's disease, and histologic similarities to mycosis fungoides have also been noted. We examined tissue from 3 cases of GSS to determine whether the condition was inflammatory or lymphoproliferative in nature. We found an abnormal, monomorphous T-helper cell immunophenotype, and in all 3 cases, clonal rearrangement of the T-cell receptor beta gene. We conclude that GSS is an indolent cutaneous T-cell lymphoma associated with granulomatous inflammation that mediates elastolysis, producing a distinctive clinical appearance.

Female↗
PubMed2000

Correlation between male and female reproduction in the subdioecious herb Astilbe biternata (Saxifragaceae).

Genotypic trade-offs between male and female reproduction are commonly assumed in theoretical studies of the evolution of gender specialization. Although these trade-offs are supported by higher seed production of females than hermaphrodites in natural populations of gynodioecious species, comparisons between male and female reproductive allocation among hermaphrodite individuals under controlled conditions are rare. We assessed phenotypic and genotypic correlations between stamen and fruit production in fruiting males of the near-dioecious herb Astilbe biternata. In the field, we found a significant negative phenotypic correlation between stamen production and fruit production within individuals that produced both stamens and fruit as well as higher fruit set in females than fruiting males. The negative correlation between fruit and stamen production that was observed in the field was also apparent across clonally propagated genotypes. These results suggest that negative genetic correlations between male and female reproduction may limit the independent evolution of fruit and stamen production in A. biternata.

Journal Article↗
PubMed2001

A novel approach to detecting and measuring recombination: new insights into evolution in viruses, bacteria, and mitochondria.

An accurate estimate of the extent of recombination is important whenever phylogenetic methods are applied to potentially recombining nucleotide sequences. Here, data sets from viruses, bacteria, and mitochondria were examined for deviations from clonality using a new approach for detecting and measuring recombination. The apparent rate heterogeneity (ARH) among sites in a sequence alignment can be inflated as an artifact of recombination. However, the composition of polymorphic sites will differ in a data set with recombination-generated ARH versus a clonal data set that exhibits the equivalent degree of rate heterogeneity. This is because recombinant data sets, encompassing regions of conflicting phylogenetic history, tend to yield "starlike" trees that are superficially similar to those inferred from clonal data sets with weak phylogenetic signal throughout. Specifically, a recombinant data set will be unexpectedly rich in conflicting phylogenetic information compared with clonally generated data sets supporting the same tree shape. Its value of q-defined as the proportion of two-state parsimony-informative sites to all polymorphic sites-will be greater than that expected for nonrecombinant data. The method proposed here, the informative-sites test, compares the value of q against a null distribution of values found using Monte Carlo-simulated data evolved under the null hypothesis of clonality. A significant excess of q indicates that the assumption of clonality is not valid and hence that the ARH in the data is at least partly an artifact of recombination. Investigations of the procedure using simulated sequences indicated that it can successfully detect and measure recombination and that it is unlikely to produce "false positives." Simulations also showed that for recombinant data, naïve use of maximum-likelihood models incorporating rate heterogeneity can lead to overestimation of the time to the most recent common ancestor. Application of the test to real data revealed for the first time that populations of viruses, like those of bacteria, can be brought close to complete linkage equilibrium by pervasive recombination. On the other hand, the test did not reject the hypothesis of clonality when applied to a data set from the coding region of human mitochondrial DNA, despite its high level of ARH and homoplasy.

Bacteria↗
PubMed2003

How clonal is Staphylococcus aureus?

Staphylococcus aureus is an important human pathogen and represents a growing public health burden owing to the emergence and spread of antibiotic-resistant clones, particularly within the hospital environment. Despite this, basic questions about the evolution and population biology of the species, particularly with regard to the extent and impact of homologous recombination, remain unanswered. We address these issues through an analysis of sequence data obtained from the characterization by multilocus sequence typing (MLST) of 334 isolates of S. aureus, recovered from a well-defined population, over a limited time span. We find no significant differences in the distribution of multilocus genotypes between strains isolated from carriers and those from patients with invasive disease; there is, therefore, no evidence from MLST data, which index variation within the stable "core" genome, for the existence of hypervirulent clones of this pathogen. Examination of the sequence changes at MLST loci during clonal diversification shows that point mutations give rise to new alleles at least 15-fold more frequently than does recombination. This contrasts with the naturally transformable species Neisseria meningitidis and Streptococcus pneumoniae, in which alleles change between 5- and 10-fold more frequently by recombination than by mutation. However, phylogenetic analysis suggests that homologous recombination does contribute toward the evolution of this species over the long term. Finally, we note a striking excess of nonsynonymous substitutions in comparisons between isolates belonging to the same clonal complex compared to isolates belonging to different clonal complexes, suggesting that the removal of deleterious mutations by purifying selection may be relatively slow.

Alleles↗
PubMed1992

Clonal expansion in follicular lymphoma occurs subsequent to antigenic selection.

The genesis of human follicular lymphoma (FL) is a multistep process. The initial event is thought to be the chromosomal translocation t(14;18)(q32;q21) juxtaposing the bcl-2 proto-oncogene with the immunoglobulin (Ig) H chain locus joining segment (JH) as an error of D-J or V-D joining in the pre-B cell. However, FL is recognized clinically as a tumor of surface Ig (sIg)-positive B cells with morphologic and phenotypic similarities to the centrocyte of the secondary immune response. Thus, additional steps must be involved in the clonal expansion of the FL tumor cell beyond the activation of bcl-2 as a consequence of the t(14;18) translocation. Like the normal centrocyte, somatic mutations accumulate in the variable (V) genes of FL tumor B cells. To determine if clonal expansion of FL occurs before or after the development of the malignant follicle, we sought to examine the evolution of the FL V gene from its unmutated germline (GL) counterpart. To obtain the GL gene we first cloned the productively rearranged V gene of patient MT FL and obtained the clone rMTF. A hybridization probe derived from the 2.1-kb region upstream of the V gene in clone rMTF identified a single band in Southern blot hybridization of GL DNA. This probe was used to screen a size-selected library, and candidate GL V genes were isolated. Two identical clones, MTGL1 and 2, proved to have upstream regions (USRs) that were colinear with the USR of the rMTF. Thus, the MTGL clones represent the unmutated GL V genes, which were productively rearranged in the MT FL. Comparison of the GL V gene sequence to a consensus of MT FL V gene sequences revealed 42 mutations, demonstrating that malignant clonal expansion occurred subsequent to the activation of somatic mutation, presumably in the malignant follicle. Furthermore, the individual FL V gene sequences segregated into two distinct patterns of mutation. The major population represented 71% of the clones, and the minor population 29%. To investigate possible mechanisms for the parallel selection of distinct tumor cell populations, we analyzed the pattern of silent and replacement mutations within the V gene sequences. We found that in the framework regions (FRs) of both populations there were significantly fewer replacement changes than expected, suggesting that negative selective pressure was maintaining the structural integrity of the sIg. In contrast, the complementarity determining regions (CDRs), which make up the antigen binding domain of Ig, had an excess of replacement changes, suggesting positive selection for altered ligand binding.

Base Sequence↗
PubMed2005

Multilocus sequence analysis and comparative evolution of virulence-associated genes and housekeeping genes of Clostridium difficile.

A multilocus sequence analysis of ten virulence-associated genes was performed to study the genetic relationships between 29 Clostridium difficile isolates of various origins, hosts and clinical presentations, and selected from the main lineages previously defined by multilocus sequence typing (MLST) of housekeeping genes. Colonization-factor-encoding genes (cwp66, cwp84, fbp68, fliC, fliD, groEL and slpA), toxin A and B genes (tcdA and tcdB), and the toxin A and B positive regulator gene (tcdD) were investigated. Binary toxin genes (cdtA and cdtB) were also detected, and internal fragments were sequenced for positive isolates. Virulence-associated genes exhibited a moderate polymorphism, comparable to the polymorphism of housekeeping genes, whereas cwp66 and slpA genes appeared highly polymorphic. Isolates recovered from human pseudomembranous colitis cases did not define a specific lineage. The presence of binary toxin genes, detected in five of the 29 isolates (17 %), was also not linked to clinical presentation. Conversely, toxigenic A-B+ isolates defined a very homogeneous lineage, which is distantly related to other isolates. By clustering analysis, animal isolates were intermixed with human isolates. Multilocus sequence analysis of virulence-associated genes is consistent with a clonal population structure for C. difficile and with the lack of host specificity. The data suggest a co-evolution of several of the virulence-associated genes studied (including toxins A and B and the binary toxin genes) with housekeeping genes, reflecting the genetic background of C. difficile, whereas flagellin, cwp66 and slpA genes may undergo recombination events and/or environmental selective pressure.

Alleles↗
PubMed2004

Evolution of erythromycin-resistant Streptococcus pneumoniae from Asian countries that contains erm(B) and mef(A) genes.

To investigate the genetic characteristics of erythromycin-resistant Streptococcus pneumoniae in Asian countries, 110 pneumococcal isolates were analyzed by multilocus sequence typing (MLST). MLST analysis showed that 2 clonal complexes--CC236 (Taiwan19F-14 clone) and CC81 (Spain23F-1 clone)--are the major lineages of erythromycin-resistant S. pneumoniae in the Asian region. Pneumococcal isolates containing both the erm(B) and the mef(A) genes are thought to have originated from the Taiwan19F-14 clone containing the mef(A) gene, after introduction of the erm(B) gene. Further evolution of this variant clone has generated resistant strains with different sequence types. Dissemination of these variant clones of the Taiwan19F-14 could be the main reason for the high frequency of pneumococcal isolates containing both erm(B) and mef(A) in some Asian countries. Data suggest that the high prevalence of erythromycin-resistant S. pneumoniae in the Asian region is partly due to the clonal spread of a few multidrug-resistant clones.

Asia↗
PubMed2002

Fitness evolution and the rise of mutator alleles in experimental Escherichia coli populations.

We studied the evolution of high mutation rates and the evolution of fitness in three experimental populations of Escherichia coli adapting to a glucose-limited environment. We identified the mutations responsible for the high mutation rates and show that their rate of substitution in all three populations was too rapid to be accounted for simply by genetic drift. In two of the populations, large gains in fitness relative to the ancestor occurred as the mutator alleles rose to fixation, strongly supporting the conclusion that mutator alleles fixed by hitchhiking with beneficial mutations at other loci. In one population, no significant gain in fitness relative to the ancestor occurred in the population as a whole while the mutator allele rose to fixation, but a substantial and significant gain in fitness occurred in the mutator subpopulation as the mutator neared fixation. The spread of the mutator allele from rarity to fixation took >1000 generations in each population. We show that simultaneous adaptive gains in both the mutator and wild-type subpopulations (clonal interference) retarded the mutator fixation in at least one of the populations. We found little evidence that the evolution of high mutation rates accelerated adaptation in these populations.

Adenosine Triphosphatases↗
PubMed2006

Cancer progression by non-clonal chromosome aberrations.

The establishment of the correct conceptual framework is vital to any scientific discipline including cancer research. Influenced by hematologic cancer studies, the current cancer concept focuses on the stepwise patterns of progression as defined by specific recurrent genetic aberrations. This concept has faced a tough challenge as the majority of cancer cases follow non-linear patterns and display stochastic progression. In light of the recent discovery that genomic instability is directly linked to stochastic non-clonal chromosome aberrations (NCCAs), and that cancer progression can be characterized as a dynamic relationship between NCCAs and recurrent clonal chromosome aberrations (CCAs), we propose that the dynamics of NCCAs is a key element for karyotypic evolution in solid tumors. To support this viewpoint, we briefly discuss various basic elements responsible for cancer initiation and progression within an evolutionary context. We argue that even though stochastic changes can be detected at various levels of genetic organization, such as at the gene level and epigenetic level, it is primarily detected at the chromosomal or genome level. Thus, NCCA-mediated genomic variation plays a dominant role in cancer progression. To further illustrate the involvement of NCCA/CCA cycles in the pattern of cancer evolution, four cancer evolutionary models have been proposed based on the comparative analysis of karyotype patterns of various types of cancer.

Animals↗
PubMed2005

Spindle cells and their role in Kaposi's sarcoma.

Spindle cells represent the main cell type of the advanced final nodular stage of Kaposi's sarcoma lesions. Despite some clinical and epidemiological differences, the four Kaposi's sarcoma forms (classic, endemic, post-transplant and epidemic) display very similar histopathological features, with the proliferation of spindle cells (considered as the Kaposi's sarcoma tumor cells) associated with inflammation and neo-angiogenesis. Electron-microscopy and immuno-histochemistry studies have led to the consensus that the spindle cells originated from the endothelial lineage. However, only recently, studies that used specific lymphatic immunological markers (such as podoplanin) and molecular features (gene expression microarrays) strongly linked Kaposi's sarcoma spindle cells to the endothelium lymphatic cell lineage. Both hybridization and immuno-histochemistry techniques have demonstrated that human herpesvirus 8 also known as Kaposi's sarcoma associated herpesvirus was present in spindle cells at all stages of the disease (patch, plaque, nodule). Interestingly, while the human herpesvirus 8 latent genes are expressed in nearly all tumor spindle cells, only a small fraction of them expresses markers of viral lytic replication. Recent findings showing that nodular Kaposi's sarcoma lesions display all patterns of human herpesvirus 8 clonality support the model according to which this tumor begins as a polyclonal disease with a subsequent evolution to a mono/oligoclonal process involving infected spindle cells. Spindle cells appear to be the central masterpiece in KS tumorigenesis, however the exact respective role of each human herpesvirus 8 gene, in the initiation and the disease progression is still under investigation and the question of whether or not this tumor is a reactive process or a true malignant proliferation of spindle cells remains yet unclear.

Cell Lineage↗
PubMed1998

Telomere shortening in uterine leiomyomas.

OBJECTIVE: To gain a better understanding of proliferation control mechanisms in a common benign tumor, we investigated the mean telomere length and the clonality of uterine leiomyomas. STUDY DESIGN: Deoxyribonucleic acid from uterine leiomyomas and from the adjacent normal myometrium of 51 patients (total number of uterine leiomyomas 107; 28 patients with single leiomyoma, 23 patients with multiple leiomyomas ranging from 2 to 8 myoma nodules per case) was hybridized to a telomeric oligonucleotide probe by Southern blot and chemiluminescent detection. The mean telomere length was evaluated by densitometry. Clonality was assessed with use of the phosphoglycerokinase gene polymorphism. RESULTS: The mean telomere length was significantly shorter in uterine leiomyomas (median 7950 bp, interquartile range 7261 to 8372 bp) than in normal myometrium (median 9688 bp, interquartile range 8528 to 10535 bp) (P < .001). There was no correlation between tumor size and telomere attrition. Multiple uterine leiomyomas were found to have an independent clonal origin. CONCLUSIONS: Telomere attrition in uterine leiomyomas reflects enhanced proliferation activity in the course of tumor evolution. The basic telomere lengths differ in the myocytes from which the uterine leiomyomas originate, probably explaining the lack of correlation between telomere attrition and tumor size.

Adult↗