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Proceedings of the National Academy of Sciences of... 104건

  1. [해외논문]   A mouse model for achondroplasia produced by targeting fibroblast growth factor receptor 3.  

    Wang, Y , Spatz, M K , Kannan, K , Hayk, H , Avivi, A , Gorivodsky, M , Pines, M , Yayon, A , Lonai, P , Givol, D
    Proceedings of the National Academy of Sciences of the United States of America v.96 no.8 ,pp. 4455 - 4460 , 1999 , 0027-8424 ,

    초록

    Achondroplasia, the most common form of dwarfism in man, is a dominant genetic disorder caused by a point mutation (G380R) in the transmembrane region of fibroblast growth factor receptor 3 (FGFR3). We used gene targeting to introduce the human achondroplasia mutation into the murine FGFR3 gene. Heterozygotes for this point mutation that carried the neo cassette were normal whereas neo+ homozygotes had a phenotype similar to FGFR3-deficient mice, exhibiting bone overgrowth. This was because of interference with mRNA processing in the presence of the neo cassette. Removal of the neo selection marker by Cre/loxP recombination yielded a dominant dwarf phenotype. These mice are distinguished by their small size, shortened craniofacial area, hypoplasia of the midface with protruding incisors, distorted brain case with anteriorly shifted foramen magnum, kyphosis, and narrowed and distorted growth plates in the long bones, vertebrae, and ribs. These experiments demonstrate that achondroplasia results from a gain-of-FGFR3-function leading to inhibition of chondrocyte proliferation. These achondroplastic dwarf mice represent a reliable and useful model for developing drugs for potential treatment of the human disease.

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  2. [해외논문]   Bicoid functions without its TATA-binding protein-associated factor interaction domains.  

    Schaeffer, V , Janody, F , Loss, C , Desplan, C , Wimmer, E A
    Proceedings of the National Academy of Sciences of the United States of America v.96 no.8 ,pp. 4461 - 4466 , 1999 , 0027-8424 ,

    초록

    Four maternal systems are known to pattern the early Drosophila embryo. The key component of the anterior system is the homeodomain protein Bicoid (Bcd). Bcd needs the contribution of another anterior morphogen, Hunchback (Hb), to function properly: Bcd and Hb synergize to organize anterior development. A molecular mechanism for this synergy has been proposed to involve specific interactions of Bcd and Hb with TATA-binding protein-associated factors (TAFIIs) that are components of the general transcription machinery. Bcd contains three putative activation domains: a glutamine-rich region, which interacts in vitro with TAFII110; an alanine-rich domain, which targets TAFII60; and a C-terminal acidic region, which has an unknown role. We have generated flies carrying bcd transgenes lacking one or several of these domains to test their function in vivo. Surprisingly, a bcd transgene that lacks all three putative activation domains is able to rescue the bcdE1 null phenotype to viability. Moreover, the development of these embryos is not affected by the presence of dominant negative mutations in TAFII110 or TAFII60. This means that the interactions observed in vitro between Bcd and TAFII60 or TAFII110 aid transcriptional activation but are dispensable for normal development.

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  3. [해외논문]   Environmental variation shapes sexual dimorphism in red deer.  

    Post, E , Langvatn, R , Forchhammer, M C , Stenseth, N C
    Proceedings of the National Academy of Sciences of the United States of America v.96 no.8 ,pp. 4467 - 4471 , 1999 , 0027-8424 ,

    초록

    Sexual dimorphism results from dichotomous selection on male and female strategies of growth in relation to reproduction. In polygynous mammals, these strategies reflect sexual selection on males for access to females and competitive selection on females for access to food. Consequently, in such species, males display rapid early growth to large adult size, whereas females invest in condition and early sexual maturity at the expense of size. Hence, the magnitude of adult size dimorphism should be susceptible to divergence of the sexes in response to environmental factors differentially influencing their growth to reproduction. We show that divergent growth of male and female red deer after 32 years of winter warming and 15 years of contemporaneously earlier plant phenology support this prediction. In response to warmer climate during their early development, males grew more rapidly and increased in size, while female size declined. Conversely, females, but not males, responded to earlier plant phenology with increased investment in condition and earlier reproduction. Accordingly, adult size dimorphism increased in relation to warmer climate, whereas it declined in relation to forage quality. Thus, the evolutionary trajectories of growth related to reproduction in the sexes (i) originate from sexual and competitive selection, (ii) produce sexual size dimorphism, and (iii) are molded by environmental variation.

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  4. [해외논문]   Scaling in animal group-size distributions.  

    Bonabeau, E , Dagorn, L , Fr?on, P
    Proceedings of the National Academy of Sciences of the United States of America v.96 no.8 ,pp. 4472 - 4477 , 1999 , 0027-8424 ,

    초록

    An elementary model of animal aggregation is presented. The group-size distributions resulting from this model are truncated power laws. The predictions of the model are found to be consistent with data that describe the group-size distributions of tuna fish, sardinellas, and African buffaloes.

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  5. [해외논문]   A tradeoff between immunocompetence and sexual ornamentation in domestic fowl.  

    Verhulst, S , Dieleman, S J , Parmentier, H K
    Proceedings of the National Academy of Sciences of the United States of America v.96 no.8 ,pp. 4478 - 4481 , 1999 , 0027-8424 ,

    초록

    Females often select their mates on the basis of the size or intensity of sexual ornaments, and it is thought that such traits are reliable indicators of male quality because the costliness of these traits prevents cheating. The immunocompetence handicap hypothesis is a recently proposed mechanistic explanation of these costs and states that males carry ornaments at the expense of their resistance to disease and parasites. The tradeoff between immunocompetence and sexual ornamentation was hypothesized to arise as a consequence of the dual effect of androgens on ornamentation (+) and immune function (-). To test this hypothesis, we compared comb size between male domestic chickens Gallus domesticus of lines divergently selected for antibody responses to sheep erythrocytes (three lines: selected for low response or high response and a control line). The importance of comb size in inter- and intrasexual selection is well established, and comb size is strongly dependent on testosterone level. Comb size was larger in the males of the low line than in the high line, and comb size of control males was intermediate, indicating a tradeoff between ornamentation and immunocompetence. Testosterone (T) levels varied in a similar fashion (TLow > TControl > THigh), suggesting that this hormone could mediate the tradeoff between ornamentation and immunocompetence. These results support the idea that a tradeoff with immune function may constrain the expression of secondary sexual ornaments.

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  6. [해외논문]   Expression pattern and, surprisingly, gene length shape codon usage in Caenorhabditis, Drosophila, and Arabidopsis.  

    Duret, L , Mouchiroud, D
    Proceedings of the National Academy of Sciences of the United States of America v.96 no.8 ,pp. 4482 - 4487 , 1999 , 0027-8424 ,

    초록

    We measured the expression pattern and analyzed codon usage in 8,133, 1,550, and 2,917 genes, respectively, from Caenorhabditis elegans, Drosophila melanogaster, and Arabidopsis thaliana. In those three species, we observed a clear correlation between codon usage and gene expression levels and showed that this correlation is not due to a mutational bias. This provides direct evidence for selection on silent sites in those three distantly related multicellular eukaryotes. Surprisingly, there is a strong negative correlation between codon usage and protein length. This effect is not due to a smaller size of highly expressed proteins. Thus, for a same-expression pattern, the selective pressure on codon usage appears to be lower in genes encoding long rather than short proteins. This puzzling observation is not predicted by any of the current models of selection on codon usage and thus raises the question of how translation efficiency affects fitness in multicellular organisms.

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  7. [해외논문]   Genetic dissection of protein-protein interactions in multi-tRNA synthetase complex.  

    Rho, S B , Kim, M J , Lee, J S , Seol, W , Motegi, H , Kim, S , Shiba, K
    Proceedings of the National Academy of Sciences of the United States of America v.96 no.8 ,pp. 4488 - 4493 , 1999 , 0027-8424 ,

    초록

    Cytoplasmic aminoacyl-tRNA synthetases of higher eukaryotes acquired extra peptides in the course of their evolution. It has been thought that these appendices are related to the occurrence of the multiprotein complex consisting of at least eight different tRNA synthetase polypeptides. This complex is believed to be a signature feature of metazoans. In this study, we used multiple sequence alignments to infer the locations of the peptide appendices from human cytoplasmic tRNA synthetases found in the multisynthetase complex. The selected peptide appendices ranged from 22 aa of aspartyl-tRNA synthetase to 267 aa of methionyl-tRNA synthetase. We then made genetic constructions to investigate interactions between all 64 combinations of these peptides that were individually fused to nonsynthetase test proteins. The analyses identified 11 (10 heterologous and 1 homologous) interactions. The six peptide-dependent interactions paralleled what had been detected by crosslinking methods applied to the isolated multisynthetase complex. Thus, small peptide appendices seem to link together different synthetases into a complex. In addition, five interacting pairs that had not been detected previously were suggested from the observed peptide-dependent complexes.

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  8. [해외논문]   Comparative genomic hybridization, loss of heterozygosity, and DNA sequence analysis of single cells.  

    Klein, C A , Schmidt-Kittler, O , Schardt, J A , Pantel, K , Speicher, M R , Riethm?ller, G
    Proceedings of the National Academy of Sciences of the United States of America v.96 no.8 ,pp. 4494 - 4499 , 1999 , 0027-8424 ,

    초록

    A PCR strategy is described for global amplification of DNA from a single eukaryotic cell that enables the comprehensive analysis of the whole genome. By comparative genomic hybridization, not only gross DNA copy number variations, such as monosomic X and trisomic 21 in single male cells and cells from Down's syndrome patients, respectively, but multiple deletions and amplifications characteristic for human tumor cells are reliably retrieved. As a model of heterogeneous cell populations exposed to selective pressure, we have studied single micrometastatic cells isolated from bone marrow of cancer patients. The observed congruent pattern of comparative genomic hybridization data, loss of heterozygosity, and mutations as detected by sequencing attests to the technique's fidelity and demonstrates its usefulness for assessing clonal evolution of genetic variants in complex populations.

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  9. [해외논문]   Identification by UV resonance Raman spectroscopy of an imino tautomer of 5-hydroxy-2'-deoxycytidine, a powerful base analog transition mutagen with a much higher unfavored tautomer frequency than that of the natural residue 2'-deoxycytidine.  

    Suen, W , Spiro, T G , Sowers, L C , Fresco, J R
    Proceedings of the National Academy of Sciences of the United States of America v.96 no.8 ,pp. 4500 - 4505 , 1999 , 0027-8424 ,

    초록

    UV resonance Raman spectroscopy was used to detect and estimate the frequency of the unfavored imino tautomer of the transition mutagen 5-hydroxy-2'-deoxycytidine (HO5dCyt) in its anionic form. In DNA, this 2'-deoxycytidine analog arises from the oxidation of 2'-deoxycytidine and induces C --> T transitions with 10(2) greater frequency than such spontaneous transitions. An imino tautomer marker carbonyl band (approximately 1650 cm-1) is enhanced at approximately 65 degrees C against an otherwise stable spectrum of bands associated with the favored amino tautomer. This band is similarly present in the UV resonance Raman spectra of the imino cytidine analogs N3-methylcytidine at high pH and N4-methoxy-2'-deoxycytidine at pH 7 and displays features attributable to the imino form of C residues and their derivatives. The fact that the imino tautomer of HO5dCyt occurs at a frequency consistent with its high mutagenic enhancement lends strong support to the hypothesis that unfavored base tautomers play important roles in the mispair intermediates of replication leading to substitution mutations.

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  10. [해외논문]   High recombination rate in natural populations of Plasmodium falciparum.  

    Conway, D J , Roper, C , Oduola, A M , Arnot, D E , Kremsner, P G , Grobusch, M P , Curtis, C F , Greenwood, B M
    Proceedings of the National Academy of Sciences of the United States of America v.96 no.8 ,pp. 4506 - 4511 , 1999 , 0027-8424 ,

    초록

    Malaria parasites are sexually reproducing protozoa, although the extent of effective meiotic recombination in natural populations has been debated. If meiotic recombination occurs frequently, compared with point mutation and mitotic rearrangement, linkage disequilibrium between polymorphic sites is expected to decline with increasing distance along a chromosome. The rate of this decline should be proportional to the effective meiotic recombination rate in the population. Multiple polymorphic sites covering a 5-kb region of chromosome 9 (the msp1 gene) have been typed in 547 isolates from six populations in Africa to test for such a decline and estimate its rate in populations of Plasmodium falciparum. The magnitude of two-site linkage disequilibrium declines markedly with increasing molecular map distance between the sites, reaching nonsignificant levels within a map range of 0.3-1.0 kb in five of the populations and over a larger map distance in the population with lowest malaria endemicity. The rate of decline in linkage disequilibrium over molecular map distance is at least as rapid as that observed in most chromosomal regions of other sexually reproducing eukaryotes, such as humans and Drosophila. These results are consistent with the effective recombination rate expected in natural populations of P. falciparum, predicted on the basis of the underlying molecular rate of meiotic crossover and the coefficient of inbreeding caused by self-fertilization events. This is conclusive evidence to reject any hypothesis of clonality or low rate of meiotic recombination in P. falciparum populations. Moreover, the data have major implications for the design and interpretation of population genetic studies of selection on P. falciparum genes.

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