The myogenesis program drives clonal selection and drug resistance in rhabdomyosarcoma

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Mathematical model of clonal selection and antibody production. II

Several modifications are proposed to a recent mathematical model (Bell, 1970) of the clonal selection and antibody production which take place when an adult animal is injected with an antigen. In the original model, antigen molecules were assumed univalent, i.e. to have only one combining site per molecule, and the first modification is an allowance for multivalent antigens by permitting an antigen molecule to interact with only one cell at a time. It is found that, for antigens with few (? 10) sites per molecule this modification is not important while for many sites per molecule, the modification will reduce the response as compared to that from the same number of independent antigenic sites. In section 3, it is seen that by restricting the number of cells which can arise in an immune response, much more realistic responses to high antigen doses are obtained. Moreover, the response is made more predictable by assuming that both target and proliferating cells are stimulated by antigen when a fraction of their receptors, between f_min and f_max, is bound to antigen. The parameter f_min is shown to determine the extent to which a molecule which can be recognized by antibodies will also serve as an immunogen giving rise to cellular proliferation and antibody production. In section 4, it is found that if more plasma cells than memory cells result from antigen stimulation, then weak stimulation will lead to a depletion of target plus memory cells and to at least partial immunological paralysis. Optimum antigen doses and times for the induction of such paralysis are examined. In section 5, precipitation of antigen-antibody mixtures is considered and it is shown that the number of doubly bound antibody molecules per antigen site determines whether precipitation will occur. This number is easily computed for heterogeneous bivalent antibodies.     

Variability of the 3'APOB minisatellite locus in Eastern Slavonic populations

OBJECTIVE: To describe and compare the 3' apolipoprotein (Apo) B minisatellite allele frequency distributions of Eastern Slavonic populations and their Uralic, Altaic, and Caucasian speaking neighbors. METHODS: Healthy individuals of 10 populations among Russians, Byelorussians, Komis and Bashkirs were studied for variable number tandem repeats (VNTRs) in the 3'ApoB minisatellite region. Data were analyzed with other results reported for this polymorphism in eastern Europeans and Siberians. RESULTS: Allele frequency spectra in Eastern Slavonic, Northern Caucasian and Finno-Ugric speaking populations are bimodal with the main peak in alleles 34-36 and a secondary mode around allele 48, whereas Altaic speaking populations have a unimodal allele frequency distribution with a peak of around 34-36 VNTRs. Population relationships were revealed using both multidimensional scaling analysis (based on Nei's genetic distance estimate) and testing for genetic heterogeneity. Eastern Slavonic populations (Russians, Ukrainians, Byelorussians) were most closely related to each other and formed a separate tight clusterwhen plotted. Testing for genetic heterogeneity among the Eastern Slavonic ethnic groups revealed maximum diversity among Byelorussians, followed by Russians, then Ukrainians.The 3'ApoB minisatellite variability reveals little heterogeneityamong the Eastern Slavonic ethnic groups, whereas there wassignificant heterogeneity for Northern Caucasian and Altaic speakers. CONCLUSION: For this 3'ApoB polymorphism the Eastern Slavonic populations, despite their wide geographical distribution, appear to be much more homogenous than other ethnic groups of the region. Multidimensional scaling analysis of these data allowed for differentiation between individual populations from an ethnic group even if there is little heterogeneity.     

Reconstruction of pedigrees in clonal plant populations

We present a Bayesian method for the reconstruction of pedigrees in clonal populations using co-dominant genomic markers such as microsatellites and single nucleotide polymorphisms (SNPs). The accuracy of the algorithm is demonstrated for simulated data. We show that the joint estimation of parameters of interest such as the rate of self-fertilization is possible with high accuracy even with marker panels of moderate power. Classical methods can only assign a very limited number of statistically significant parentages in this case and would therefore fail. Statistical confidence is estimated by Markov Chain Monte Carlo (MCMC) sampling. The method is implemented in a fast and easy to use open source software that scales to large datasets with many thousand individuals.     

Evolutionary vestigialization of sex in a clonal plant: selection versus neutral mutation in geographically peripheral populations

The loss of traits that no longer contribute to fitness is widespread; however, the causative evolutionary mechanisms are poorly understood. Vestigialization could proceed through the fixation of selectively neutral degenerative mutations via genetic drift. Alternatively, selection may facilitate vestigialization if trait loss results in enhanced fitness. We tested these hypotheses using Decodon verticillatus, a clonal plant in which sexual sterility has arisen repeatedly in populations across the northern geographical range limit. We compared growth and survival of replicated genotypes from 7 sexually fertile and 18 sterile populations, over 3 years in a common environment. Survival of sterile genotypes was 53% greater than for fertile genotypes, but there was no difference in biomass accumulation. Almost all mortality, and hence increased performance of sterile genotypes, occurred during simulated overwinter dormancy. These observations suggest that selection has facilitated the vestigialization of sex, and thus do not support the neutral mutation hypothesis. The selective mechanism probably involves the relaxation of a genetic trade-off between sexual reproduction and survival: alleles that increase vegetative performance at the expense of sexual fertility are selected in geographically peripheral populations where sexual reproduction is suppressed by adverse environmental conditions.     

Cellular basis of B cell clonal populations in old mice.

Previous studies from this laboratory have shown that >85% of old mice have stable B cell clonal populations detectable by Ig heavy chain complementary-determining region 3 mRNA size analysis and confirmed by sequence analysis. B cells from the same clone are frequently detected in several lymphoid compartments of the same mouse. We now report the phenotype of all ten stable B cell clonal populations detected in five 20-month-old C57BL/6 mice. These clonal B cells appear to develop in the periphery and nine of the ten B cell clonal populations expressed the CD5 cell surface marker. Stable B cell expansions may be dominated by cells at two stages of differentiation. Some B cell populations were detected with DNA as well as RNA and represent large clonal populations of B cells, detectable in several lymphoid compartments. These populations are found predominantly in B cell populations expressing CD45R/B220 and the mRNA coding for the membrane-bound form of the mu Ig heavy chain, which suggests a predominance of B lymphocytes in these populations. In other cases, smaller clonal populations were detected only in splenic RNA samples. These clonal populations were found predominantly among CD45R/B220- B cells and did not express the membrane-bound form of the micro Ig heavy chain. We offer the hypothesis that the B cell clonal populations present in old mice may be precursors of the two types of B cell neoplasms which are dominated by CD5+ B cells (B cell chronic lymphocytic leukemia) or plasma cells (multiple myeloma).     

Variability of chromosome 1 with HSR insertions in natural and synanthropous populations of house mouse Mus musculus L. 1758

House mice carrying aberrant chromosome 1 with an insertion of homogeneously stained regions (HSR) have been studied. The mice were collected in the North Caucasus, Chita and Amur oblasts, Spitzbergen and Kunashir Islands, Altai krai, Khabarovsk krai, Primorye, Sakhalin, Kamchatka, Turkmenistan, and Kazakhstan. In these mice, the aberrant chromosomes were assigned to the "Asian" type, i.e. they carried two HSR insertions. The aberrant chromosome 1 in house mice from different geographic regions was shown to differ in size of HSR, staining intensity, and some other features of Q-H, C, and G-banding, which suggests independent origin of this aberration in house mouse populations from different taxa and regions. A novel variant of chromosome 1 in mice of the subspecies M. m. wagneri was found.     

Kin selection in density regulated populations.

The process of kin selection has both intra- and inter-group components (Hamilton, 1975, in: Biosocial Anthropology Wade, 1980). Group advantageous characteristics can evolve when inter-group differences in fertility are sufficiently great to overcome any within-group disadvantage of the trait. The potential magnitude of inter-group differences in fertility is determined largely by the way a population is regulated. Inter-group differences decrease as the spatial scale over which a population is regulated becomes increasingly localized. The present paper extends previous work by Boyd (1982, Anim. Behav. 30, 972-982) on the quantitative relation between kin selection and density regulation. A simple genetic model is employed to examine the conditions under which the interaction of local density regulation and kin selection can maintain a stable polymorphism. The ecological factors determining the spatial and temporal scale of density regulation are discussed. Finally, the results are applied to two biological cases in which local density regulation may be influencing the direction of phenotypic plasticity in group advantageous characters.     

Negative clonal selection in tumor evolution

Development of cancer requires the acquisition of multiple oncogenic mutations and selection of the malignant clone. Cancer evolves within a finite host lifetime and mechanisms of carcinogenesis that accelerate this process may be more likely to contribute to the development of clinical cancers. Mutator mutations are mutations that affect genome stability and accelerate the acquisition of oncogenic mutations. However, mutator mutations will also accelerate the accumulation of mutations that decrease cell proliferation, increase apoptosis, or affect other key fitness parameters. These "reduced-fitness" mutations may mediate "negative clonal selection," i.e., selective elimination of premalignant mutator clones. Target reduced-fitness loci may be "recessive" (both copies must be mutated to reduce fitness) or "dominant" (single-copy mutation reduces fitness). A direct mathematical analysis is applied to negative clonal selection, leading to the conclusion that negative clonal selection against mutator clones is unlikely to be a significant effect under realistic conditions. In addition, the relative importance of dominant and recessive reduced-fitness mutations is quantitatively defined. The relative predominance of mutator mutations in clinical cancers will depend on several variables, including the tolerance of the genome for reduced-fitness mutations, particularly the number and potency of dominant reduced-fitness loci.     

IgG anti-DNA autoantibodies within an individual autoimmune mouse are the products of clonal selection

Although mice from almost all inbred strains produce IgM anti-DNA antibody in response to B cell mitogens, only (NZB x NZW)F1 mice and mice from other strains that are genetically predisposed to autoimmunity spontaneously produce anti-DNA antibody of the IgG isotype. Because (NZB x NZW)F1 mice display marked B cell hyperactivity, anti-DNA antibody production in these mice has been thought to result from spontaneous, polyclonal B cell activation. Although this may be true for IgM anti-DNA antibodies, our results demonstrate that IgG anti-DNA antibodies are not polyclonal. Rather, IgG anti-DNA autoantibodies within an individual autoimmune mouse are oligoclonal and somatically mutated. These results demonstrate that IgG anti-DNA autoantibodies are the products of clonally selective B cell stimulation and exhibit the same characteristics as secondary immune antibodies to conventional immunogens: they are IgG, they are clonally restricted, and they are somatically mutated.