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PubMedDate not supplied

Somatic mutations at microsatellite loci in western Redcedar (Thuja plicata: Cupressaceae).

A per-generation somatic mutation rate for microsatellites was estimated in western redcedar (Thuja plicata, Donn ex D. Don.: Cupressaceae). A total of 80 trees representative of the average size and age of reproductive trees were sampled in four natural populations in southwestern British Columbia. Samples of bulked haploid megagametophytes were collected from two or three positions on each tree, assuming that the collections were far enough apart that the same mutant sector was not sampled twice. All samples were genotyped at eight microsatellite loci. A single mutation corresponding to a stepwise increase in one dinucleotide repeat was detected. The estimated mutation rate for microsatellites was 6.3 x 10(-4) mutations per locus per generation (or 3.1 x 10(-4) per allele per generation), with a 95% confidence interval of 3.0 x 10(-5) to 4.0 x 10(-3) mutations per locus. Somatic mutations can contribute to a greater mutational load in trees, as compared to shorter lived plants, and genotypic mosaics within an individual have important implications for plant defense strategies and plant evolution.

Alleles↗
PubMed2000

Acquired loss of p53 induces blastic transformation in p210(bcr/abl)-expressing hematopoietic cells: a transgenic study for blast crisis of human CML.

Chronic myelogenous leukemia (CML) begins with an indolent chronic phase but inevitably progresses to a fatal blast crisis. Although the Philadelphia chromosome, which generates p210(bcr/abl), is a unique chromosomal abnormality in the chronic phase, additional chromosomal abnormalities are frequently detected in the blast crisis, suggesting that superimposed genetic events are responsible for disease progression. To investigate whether loss of p53 plays a role in the evolution of CML, we crossmated p210(bcr/abl)-transgenic (BCR/ABL(tg/-)) mice with p53-heterozygous (p53(+/-)) mice and generated p210(bcr/abl)-transgenic, p53-heterozygous (BCR/ABL(tg/-)p53(+/-)) mice, in which a somatic alteration in the residual normal p53 allele directly abrogates p53 function. The BCR/ABL(tg/-)p53(+/-) mice died in a short period compared with their wild-type (BCR/ABL(-/-)p53(+/+)), p53 heterozygous (BCR/ABL(-/-)p53(+/-)), and p210(bcr/abl) transgenic (BCR/ABL(tg/-)p53(+/+)) litter mates. They had rapid proliferation of blast cells, which was preceded by subclinical or clinical signs of a myeloproliferative disorder resembling human CML. The blast cells were clonal in origin and expressed p210(bcr/abl) with an increased kinase activity. Interestingly, the residual normal p53 allele was frequently and preferentially lost in the tumor tissues, implying that a certain mechanism facilitating the loss of p53 allele exists in p210(bcr/abl)-expressing hematopoietic cells. Our study presents in vivo evidence that acquired loss of p53 contributes to the blastic transformation of p210(bcr/abl)-expressing hematopoietic cells and provides insights into the molecular mechanism for blast crisis of human CML. (Blood. 2000;95:1144-1150)

Animals↗
PubMed2005

[The role of the primary care physician in the care of the psychotic patient].

The primary care physician (PCP) plays an important role in the outpatient care of psychotic patients, particularly in the early detection of these disorders. Through the PCP's status as a trusted individual who knows the patient and his/her family, his/her opinion and attitude influence treatment acceptance and, consequently, the prognosis. By ensuring the continuity of care, in collaboration with a psychiatrist, the PCP helps prevent relapse and the evolution towards chronicity and long-term handicaps. A high incidence of cardiopulmonary disease and concomitant substance abuse in the population of chronic psychotic patients, as well as the monitoring of potential somatic side effects of psychotropic medication, require regular somatic follow-up by the PCP.

Continuity of Patient Care↗
PubMedDate not supplied

In search of a stem cell hierarchy in the human breast and its relevance to breast cancer evolution.

By deliberate analogy with the well-established concept of hematopoiesis, the term "mammopoiesis" is occasionally used to describe the development of the different cellular lineages and functional units in the mammary gland. The use of this term signifies a strong bias towards the idea that tissue homeostasis during mammary development, pregnancy, lactation and involution is brought about by the action of somatic stem cells characterized by longevity and multipotency. The progenies hereof eventually differentiate into structurally and functionally well-defined ductal-lobular units. During the past two decades evidence of such a notion in the mouse has developed from being largely circumstantial based on non-clonal in vivo experiments to a quite elaborate characterization of individual candidate stem cells by a number of different properties. Within tumor biology this has led to a renaissance of the concept of tumors as caricatures of tissue renewal. Thus, recent molecular classification of breast cancer based on genome wide expression analysis operates with different subtypes with specific reference to the normal luminal epithelial and myoepithelial/basal lineages in the breast. Apparently some tumors are lineage restricted and others differentiate more broadly as if they have preserved some stem-like properties. This holds promise for the existence of a stem cell hierarchy, the understanding of which may prove to be instrumental in further dissecting the histogenesis of breast cancer evolution. Most attention has been devoted to the question of different cellular origins of cancer subtypes and different susceptibilities of possible stem cells to gain or loss of oncogenes and tumor suppressor genes, respectively. Invaluable progress has been made over the past two decades in culture technology not only in terms of population doubling and clonal growth, but also the availability of lineage specific markers, cell sorting, and three-dimensional functional assays for tissue specific morphogenesis. Transcriptional profiling of stem cell zones has unraveled a hitherto unknown preservation of signaling pathways for maintenance of stem cell properties across tissue boundaries and species. Somatic stem cells have therefore been narrowed down to specific anatomic locations not only in rapidly renewing tissues such as skin and skin derivatives, but also in tissues with slower turnover times, such as lung, kidney and prostate. It is therefore now possible to integrate this information in a search for similar cells within the breast. Even if cell turnover after birth is provided exclusively by dividing lineage-restricted cells, more information about the robustness of breast differentiation programs during tumor progression is still very much required. Complete knowledge of the primary cell of origin of breast cancer and the mechanisms that influence differentiation programs during tumor initiation, promotion and progression may be crucial for the development of novel non-toxic therapies that influence tumor cell behaviour. The scope of this review is to discuss reports that have begun to elucidate the topographic location, key cellular type and lineage fidelity in culture and xenograft models of candidate human breast stem cells and their differentiated progenies with particular emphasis on comparison with the differentiation programs of tumor subtypes.

Animals↗
PubMed1994

A potential role for antigen selection in the clonal evolution of Burkitt's lymphoma.

Burkitt's lymphoma (BL) is a monoclonal lymphoproliferative disorder characterized by the presence of specific chromosomal translocations that involve the c-myc proto-oncogene. Two subtypes of BL exist (endemic and sporadic) that differ in the prevalence of EBV genome expression. Although EBV infection may promote cellular proliferation in endemic BL, little is known about the forces that drive clonal expansion and evolution in the majority of EBV-negative sporadic BL. This study on an EBV-negative sporadic BL cell line derived from an AIDS patient provides evidence that antigenic stimulation may play a role in the development and/or expansion of such tumors. This cell line (BRG-P) contained a series of cellular clones that elaborated both IgM and IgA. Southern blot analyses of the line and its sublines indicated that both the IgM+ and IgA+ cells had identical c-myc and Ig JH gene rearrangements, indicating that they were derived from a common precursor, some of which eventually underwent an isotype switch. Ig VH gene sequence analyses of 21 molecular clones derived from the parental BRG BL line and two of its sublines demonstrated that all the clones used the same VH3 gene. Five unique intraclonal variants were identified at four distinct nucleotide positions (125, 161, 355, 375), which undoubtedly represented somatic mutations. Four of these five mutations occurred within complementary determining regions; all resulted in amino acid replacements. Moreover, an identical G to A nucleotide substitution that resulted in an identical amino acid change occurred at two distinct points in clonal evolution that were separated by the isotype class switch. Thus, the locations and types of the VH gene mutations, together with the occurrence of an isotype switch, are highly suggestive of an ongoing role for Ag stimulation and selection in the evolution of the malignant clone.

Adult↗
PubMed1991

Structural and functional conservation of synaptotagmin (p65) in Drosophila and humans.

Synaptotagmin (p65) is an abundant synaptic vesicle protein that contains two copies of a sequence that is homologous to the regulatory region of protein kinase C. Full length cDNAs encoding human and Drosophila synaptotagmins were characterized to study its structural and functional conservation in evolution. The deduced amino acid sequences for human and rat synaptotagmins show 97% identity, whereas Drosophila and rat synaptotagmins are only 57% identical but exhibit a selective conservation of the two internal repeats that are homologous to the regulatory region of protein kinase C (78% invariant residues in all three species). The two internal repeats of synaptotagmin are only slightly more homologous to each other than to protein kinase C, and the differences between the repeats are conserved in evolution, suggesting that they might not be functionally equivalent. The cytoplasmic domains of human and Drosophila synaptotagmins produced as recombinant proteins in Escherichia coli specifically bound phosphatidylserine similar to rat synaptotagmin. They also hemagglutinated trypsinized erythrocytes at nanomolar concentrations. Hemagglutination was inhibited both by negatively charged phospholipids and by a recombinant fragment from rat synaptotagmin that contained only a single copy of the two internal repeats. Together these results demonstrate that synaptotagmin is highly conserved in evolution compatible with a function in the trafficking of synaptic vesicles at the active zone. The similarity of the phospholipid binding properties of the cytoplasmic domains of rat, human, and Drosophila synaptotagmins and the selective conservation of the sequences that are homologous to protein kinase C suggest that these are instrumental in phospholipid binding. The human gene for synaptotagmin was mapped by Southern blot analysis of DNA from somatic cell hybrids to chromosome 12 region cen-q21, and the Drosophila gene by in situ hybridization to 23B.

Amino Acid Sequence↗
PubMed2004

Rapid evolution through gene duplication and subfunctionalization of the testes-specific alpha4 proteasome subunits in Drosophila.

Gene duplication is an important mechanism for acquiring new genes and creating genetic novelty in organisms. Evidence suggests that duplicated genes are retained at a much higher rate than originally thought and that functional divergence of gene copies is a major factor promoting their retention in the genome. We find that two Drosophila testes-specific alpha4 proteasome subunit genes (alpha4-t1 and alpha4-t2) have a higher polymorphism within species and are significantly more diverged between species than the somatic alpha4 gene. Our data suggest that following gene duplication, the alpha4-t1 gene experienced relaxed selective constraints, whereas the alpha4-t2 gene experienced positive selection acting on several codons. We report significant heterogeneity in evolutionary rates among all three paralogs at homologous codons, indicating that functional divergence has coincided with genic divergence. Reproductive subfunctionalization may allow for a more rapid evolution of reproductive traits and a greater specialization of testes function. Our data add to the increasing evidence that duplicated genes experience lower selective constraints and in some cases positive selection following duplication. Newly duplicated genes that are freer from selective constraints may provide a mechanism for developing new interactions and a pathway for the evolution of new genes.

Animals↗
PubMed2005

[Chromosomal behaviors in plant wide hybridizations and their genetic and evolutionary implications].

The wide hybridization and polyploidization play a significant role in the evolution of higher plants. On the contrary, the artificially synthesized allopolyploids are genetically unstable and fail to be used as crops. One reason for this situation may be that the allopolyploids in nature are the products of natural selection and evolution and it is difficult for human to repeat and perform the process in short periods. Another reason is that we know little about the interaction mechanisms between the genomes of different origins. So the genetics and epigenetics after allopolyploidizations are now studied by multidisciplinary approaches. The spatial separation of parental genomes in hybrid cells have been observed in some sexual and somatic hybrids, but the biological meanings remain to clarify. The abnormal chromosome behaviors in plant wide crosses, such as pseudogamy, semigamy, chromosome elimination and the mitotic and meiotic separation of parental genomes, may indicate the incompatibility of two parental species at gametic and chromosomal levels. The systematic studies at different levels on chromosomal behavior and genetics in plant hybridizations are needed to undermine the mechanisms responsible for the formation and evolution of new species.

Chromosome Mapping↗
PubMedDate not supplied

Grandmothers and the evolution of human longevity.

Great apes, our closest living relatives, live longer and mature later than most other mammals and modern humans are even later-maturing and potentially longer-lived. Evolutionary life-history theory seeks to explain cross-species differences in these variables and the covariation between them. That provides the foundation for a hypothesis that a novel role for grandmothers underlies the shift from an ape-like ancestral pattern to one more like our own in the first widely successful members of genus Homo. This hypothesis links four distinctive features of human life histories: 1). our potential longevity, 2). our late maturity, 3). our midlife menopause, and 4). our early weaning with next offspring produced before the previous infant can feed itself. I discuss the problem, then, using modern humans and chimpanzees to represent, respectively, genus Homo and australopithecines, I focus on two corollaries of this grandmother hypothesis: 1). that ancestral age-specific fertility declines persisted in our genus, while 2). senescence in other aspects of physiological performance slowed down. The data are scanty but they illustrate similarities in age-specific fertility decline and differences in somatic durability that are consistent with the hypothesis that increased longevity in our genus is a legacy of the "reproductive" role of ancestral grandmothers.

Aging↗
PubMed1993

Differential time course and spatial expression of Fos, Jun, and Krox-24 proteins in spinal cord of rats undergoing subacute or chronic somatic inflammation.

We have used the evoked expression of both immediate early gene (IEG)-encoded proteins (Krox-24, c-Fos, Fos B, Jun D, Jun B, c-Jun), and dynorphin to monitor sensory processing in the spinal cords of rats undergoing subacute or chronic somatic inflammation (i.e., subcutaneous inflammation of the plantar foot and monoarthritis, respectively). Behavioral and immunocytochemical approaches were conducted in parallel up to 15 weeks postinjection in order to detect possible relationships between clinical evolution and spatiotemporal pattern of IEG-encoded protein expression. Each disease had specific characteristics both in terms of their clinical evolution and pattern of evoked protein expression. All IEG proteins were expressed in both cases. Most of the staining was observed in both the superficial layers of the dorsal horn and deep dorsal horn (laminae V-VII and X). Monoarthritis was distinguished by a high level of total protein expression. Staining was especially dense in the deep dorsal horn. More labelled cells were observed at 1-2 days and at 2 weeks postinjection, corresponding to the initiation and progressive phases of the disease, respectively. Subcutaneous inflammation was characterized by a moderate level of total IEG expression. More labelled cells were observed in the first day following injection. It is the relative degree of expression of each IEG-encoded protein with regard to the others that characterized the progression of the diseases. Early stages of the diseases coincided with the expression of all Fos and Jun proteins, while late stages showed an increase in Jun D and Fos B involvement; Krox-24 was induced mostly during the early phases and/or periods of paroxysm of the diseases. Persistent stimulation was characterized by a predominant expression in deep versus superficial layers of the dorsal horn. Evoked expression of c-Jun in motoneurons was only observed in monoarthritis. The peak of dynorphin expression was late in regard to both the induction of inflammation and period of maximal IEG-encoded protein expression. The present work indicates that the neural processing that takes place during progression of these diseases can be monitored well at the spinal cord level by using the expression of an array of IEG-encoded proteins. Study of long term evolutive diseases and especially those that evolve into chronicity can largely benefit from such an approach.

Acute Disease↗
PubMed1990

Detection of somatic mutations in tumours of diverse types by DNA fingerprinting with M13 phage DNA.

Hybridization of M13 phage DNA to Southern blots of human DNA produces an individual-specific DNA fingerprint. In this study, tumour and lymphocyte DNA from a series of patients with melanoma, Merkel-cell carcinoma, Burkitt's lymphoma and Wilms' tumour was probed with M13 DNA to detect somatic mutations in the DNA of the tumours. Somatic changes were observed in tumour DNA of 16 out of the 28 cases examined. This frequency compared favourably with the frequency with which tumour-specific changes have been found when using the Jeffreys DNA fingerprinting probe 33.15, and demonstrates that M13 DNA provides a useful additional probe for the study of somatic changes in tumours. The finding that multiple DNA fragments were lost or gained in DNA fingerprints from individual tumours indicates a marked degree of complexity in the genetic changes involved in the evolution of certain human cancers.

Bacteriophages↗
PubMed1989

The human alpha-amylase multigene family consists of haplotypes with variable numbers of genes.

Polymorphic amylase protein patterns have suggested the presence in the human genome of various haplotypes encoding these allozymes. To investigate the genomic organization of the human alpha-amylase genes, we isolated the pertinent genes from a cosmid library constructed of DNA from an individual expressing three different salivary amylase allozymes. From the restriction maps of the overlapping cosmids and a comparison of these maps with the restriction enzyme patterns of DNA from the donor and family members, we were able to identify two haplotypes consisting of very different numbers of salivary amylase genes. The short haplotype contains two pancreatic genes (AMY2A and AMY2B) and one salivary amylase gene (AMY1C), arranged in the order 2B-2A-1C, encompassing a total length of approximately 100 kb. The long haplotype spans about 300 kb and contains six additional genes arranged in two repeats, each one consisting of two salivary amylase genes (AMY1A and AMY1B) and a pseudogene lacking the first three exons (AMYP1). The order of the amylase genes within the repeat is 1A-1B-P1. All genes are in a head-to-tail orientation except AMY1B, which has the reverse orientation with respect to the other genes. Analysis of somatic cell hybrids confirmed the presence of these short and long haplotypes. Furthermore, we present evidence for the existence of additional haplotypes in the human population and propose a general model for the evolution of the human alpha-amylase multigene family. A general designation 2B-2A-(1A-1B-P)n-1C can describe these haplotypes, n being 0 and 2 for the short and the long haplotypes presented in this paper, respectively.

Biological Evolution↗
PubMed2006

A set of duplicons on human chromosome 9 is involved in the origin of a supernumerary marker chromosome.

Human chromosome 9 is involved in a number of recurrent structural rearrangements; moreover, its pericentromeric region exhibits a remarkable evolutionary plasticity. In this study we present the molecular characterization of a constitutional rearrangement, involving the 9p21.1q13 region, which led to the formation of a supernumerary marker chromosome (SMC). We defined the sequence of the breakpoints and identified a new set of duplicons on human chromosome 9, named LCR9s (chromosome 9 low-copy repeats). Two of these duplicons were shown to be involved in a somatic exchange leading to the formation of the SMC. High-resolution FISH coupled to database search demonstrated that a total number of 35 LCR9 paralogs are present in the human genome. These newly described chromosome 9 duplicons have features that may be crucial in driving structural chromosome rearrangements in germinal and somatic cells.

Base Sequence↗
PubMed2000

Jumping translocations of 11q in acute myeloid leukemia and 1q in follicular lymphoma.

Jumping translocation is a rare cytogenetic aberration in leukemia and lymphoma, and its etiologic mechanisms are not clearly known. We report two cases with jumping translocations. One had follicular lymphoma and jumping translocations of 1q onto the telomeric regions of 5p, 9p, and 15q in three cell lines, co-existing with the specific translocation t(14;18)(q32;q21). The second case had acute myeloid leukemia (AML) and jumping translocations of 11q as the sole aberration, onto multiple derivative chromosomes in each of the abnormal cells. A total of 17 telomeric regions were seen as the recipients of 11q in this case, and 9q was always involved as one of the recipients in all abnormal cells. Fluorescence in situ hybridization (FISH) confirmed the identification of 11q material in the derivative chromosomes. While 1q has been the most common donor of acquired jumping translocations, this is the first report on jumping translocations of 11q. Different from all previously reported jumping translocations which involve only one recipient in each cell line and lead to a mosaic trisomy, multiple recipients in most of the abnormal cells in this case had led to a tetrasomy, or a pentasomy of 11q. The pattern of chromosome involvement as the recipients of 11q appears to show a continuing evolutionary process of jumping, stabilization, and spreading of the donor material into other chromosomes. Somatic recombinations between the interstitial telomeric or subtelomeric sequences of a derivative chromosome and the telomeric sequences of normal chromosomes are believed to be the underlying mechanism of jumping translocations and their clonal evolution.

Acute Disease↗
PubMed1997

H3.3A variant histone mRNA containing an alpha-globin insertion: modulated expression during mouse gametogenesis correlates with meiotic onset.

Replacement-variant H3.3 histones have been isolated and sequenced in different eukaryotes, but no functional H3.3A gene has been characterized in the mouse so far. We have cloned an H3.3A cDNA from a mouse fetal ovary library, differentially screened with testis versus somatic cDNA probes. We showed this gene contains a region homologous to the reverse and complementary alpha-globin gene. We believe such a structure could have been generated by retroposition during the evolution of both globin and histone gene families. The sequence coding for H3.3A is 76.6% homologous to the mouse H3.3B gene at the nucleotide level and differs in only one amino acid at the protein level. The high degree of homology between these genes and the H3.3 variant histones from other eukaryotes reveals the conservation of these replication-independent class of histones throughout evolution. Analysis of gene expression reveals a developmental regulation concurrent with meiotic progression, with the highest level of transcript detection coincident with meiotic onset during both oogenesis and spermatogenesis.

Amino Acid Sequence↗
PubMed2025

SISTEM: simulation of tumor evolution, metastasis, and DNA-seq data under genotype-driven selection.

SUMMARY: SISTEM is a software package and mathematical framework for simulating tumor evolution and cell migrations at single-cell resolution. Unlike existing frameworks which simulate cancer cell populations under the neutral coalescent or using simple birth-death models, SISTEM simulates tumor populations under somatic clonal selection using an agent-based framework. SISTEM can generate mutation profiles, read counts, and DNA sequencing reads along with ground truth cell lineages and migration graphs under a number of easily customizable mutation and selection models. For improved realism, SISTEM allows for cell fitness to be driven by genomic events of various scales including single nucleotide variants, segmental gains and losses, whole-chromosomal and chromosome-arm aberrations, and whole-genome duplications. SISTEM also includes numerous migration models to simulate metastatic cancers, facilitating the exploration and evaluation of diverse migration patterns. AVAILABILITY AND IMPLEMENTATION: SISTEM is written in Python and is freely available open-source under GNU GPLv3 from: https://github.com/samsonweiner/sistem.

Software↗
PubMedDate not supplied

A psychodynamic view of psychosomatic medicine.

OBJECTIVE: The objective of this article is to assess the relevance of psychodynamic observations and theory for psychosomatic medicine. METHODS: The evolution of the psychodynamic formulation of psychosomatic symptom formation is described in a brief historical review. RESULTS: There are two distinctly different pathways along which stress-induced psychological arousal is transformed into somatic symptoms. CONCLUSIONS: Psychodynamic observations and theory have important implications for psychosomatic research and treatment.

Affective Symptoms↗
PubMed1978

Antibody diversity.

Three important aspects of immunoglobulin gene organization and structure have emerged from studies of cloned immunoglobulin kappa chain genes. (i) Multiple variable genes are encoded separately in the genome of both immunoglobulin-producing and uncommitted (embryonic) cells, thereby establishing the evolutionary base for generating immunoglobulin diversity. (ii) These genes exist as many small, closely related families (subgroups) that share close sequence homology largely within their own subgroup. (iii) Comparison of two cloned variable gene segments derived from a single subgroup reveals a feature of their structure that distinguishes them from fixed genes (that is, globin genes) and provides, through extensive surrounding sequence homology, a large target for intergenic recombination. This last observation suggests that a simple recombination mechanism may account for their genetic instability in both germ line and somatic cells.

Animals↗