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91.
Fang G Haznadar M Wang W Yu H Steinbach M Church TR Oetting WS Van Ness B Kumar V 《PloS one》2012,7(4):e33531
There has been increased interest in discovering combinations of single-nucleotide polymorphisms (SNPs) that are strongly associated with a phenotype even if each SNP has little individual effect. Efficient approaches have been proposed for searching two-locus combinations from genome-wide datasets. However, for high-order combinations, existing methods either adopt a brute-force search which only handles a small number of SNPs (up to few hundreds), or use heuristic search that may miss informative combinations. In addition, existing approaches lack statistical power because of the use of statistics with high degrees-of-freedom and the huge number of hypotheses tested during combinatorial search. Due to these challenges, functional interactions in high-order combinations have not been systematically explored. We leverage discriminative-pattern-mining algorithms from the data-mining community to search for high-order combinations in case-control datasets. The substantially improved efficiency and scalability demonstrated on synthetic and real datasets with several thousands of SNPs allows the study of several important mathematical and statistical properties of SNP combinations with order as high as eleven. We further explore functional interactions in high-order combinations and reveal a general connection between the increase in discriminative power of a combination over its subsets and the functional coherence among the genes comprising the combination, supported by multiple datasets. Finally, we study several significant high-order combinations discovered from a lung-cancer dataset and a kidney-transplant-rejection dataset in detail to provide novel insights on the complex diseases. Interestingly, many of these associations involve combinations of common variations that occur in small fractions of population. Thus, our approach is an alternative methodology for exploring the genetics of rare diseases for which the current focus is on individually rare variations. 相似文献
92.
BM Zamft AH Marblestone K Kording D Schmidt D Martin-Alarcon K Tyo ES Boyden G Church 《PloS one》2012,7(8):e43876
High-throughput recording of signals embedded within inaccessible micro-environments is a technological challenge. The ideal recording device would be a nanoscale machine capable of quantitatively transducing a wide range of variables into a molecular recording medium suitable for long-term storage and facile readout in the form of digital data. We have recently proposed such a device, in which cation concentrations modulate the misincorporation rate of a DNA polymerase (DNAP) on a known template, allowing DNA sequences to encode information about the local cation concentration. In this work we quantify the cation sensitivity of DNAP misincorporation rates, making possible the indirect readout of cation concentration by DNA sequencing. Using multiplexed deep sequencing, we quantify the misincorporation properties of two DNA polymerases - Dpo4 and Klenow exo(-) - obtaining the probability and base selectivity of misincorporation at all positions within the template. We find that Dpo4 acts as a DNA recording device for Mn(2+) with a misincorporation rate gain of ~2%/mM. This modulation of misincorporation rate is selective to the template base: the probability of misincorporation on template T by Dpo4 increases >50-fold over the range tested, while the other template bases are affected less strongly. Furthermore, cation concentrations act as scaling factors for misincorporation: on a given template base, Mn(2+) and Mg(2+) change the overall misincorporation rate but do not alter the relative frequencies of incoming misincorporated nucleotides. Characterization of the ion dependence of DNAP misincorporation serves as the first step towards repurposing it as a molecular recording device. 相似文献
93.
Multiplex automated genome engineering (MAGE) uses short oligonucleotides to scarlessly modify genomes; however, insertions >10 bases are still inefficient but can be improved substantially by selection of highly modified chromosomes. Here we describe 'coselection' MAGE (CoS-MAGE) to optimize biosynthesis of aromatic amino acid derivatives by combinatorially inserting multiple T7 promoters simultaneously into 12 genomic operons. Promoter libraries can be quickly generated to study gain-of-function epistatic interactions in gene networks. 相似文献
94.
95.
Boyle PM Burrill DR Inniss MC Agapakis CM Deardon A Dewerd JG Gedeon MA Quinn JY Paull ML Raman AM Theilmann MR Wang L Winn JC Medvedik O Schellenberg K Haynes KA Viel A Brenner TJ Church GM Shah JV Silver PA 《Journal of biological engineering》2012,6(1):8
ABSTRACT: BACKGROUND: Plant biotechnology can be leveraged to produce food, fuel, medicine, and materials. Standardized methods advocated by the synthetic biology community can accelerate the plant design cycle, ultimately making plant engineering more widely accessible to bioengineers who can contribute diverse creative input to the design process. RESULTS: This paper presents work done largely by undergraduate students participating in the 2010 International Genetically Engineered Machines (iGEM) competition. Described here is a framework for engineering the model plant Arabidopsis thaliana with standardized, BioBrick compatible vectors and parts available through the Registry of Standard Biological Parts (www.partsregistry.org). This system was used to engineer a proof-of-concept plant that exogenously expresses the taste-inverting protein miraculin. CONCLUSIONS: Our work is intended to encourage future iGEM teams and other synthetic biologists to use plants as a genetic chassis. Our workflow simplifies the use of standardized parts in plant systems, allowing the construction and expression of heterologous genes in plants within the timeframe allotted for typical iGEM projects. 相似文献
96.
Gonadectomy not only affects hormonal homeostasis but also alters the turnover of different components of the extracellular matrix in urogenital tissues. Collagen is an important component of the bladder and urethral walls and thus crucial for the mechanical properties of normal lower urinary tract (LUT) functions. This study aimed at investigating the possibility of differences in the proportion of collagen and muscle tissues in the LUT of intact and gonadectomised male and female dogs. Twenty clinically healthy dogs were used including 10 sexually intact dogs (5 males, 5 anoestrus females) and 10 gonadectomised dogs (4 males and 6 females). Four regions of the LUT, i.e. body and neck of the bladder as well as proximal and distal urethra were collected. The tissue sections were stained with Masson's Trichrome. Quantitative evaluation of the blue-stained area for collagen and red-counterstained area for muscle was performed using colour image analysis. The relative proportion of collagen and muscle significantly differed with the gonadal status, the gender and the region. Overall, gonadectomised dogs had a higher (P < 0.001) proportion of collagen and consequently a lower (P < 0.001) proportion of muscle than intact dogs. Regardless of gonadal statuses, females had a higher (P < 0.05) proportion of collagen and a lower (P < 0.05) proportion of muscle tissues than males. Gender differences were found in all four regions of the LUT in intact dogs but only in proximal urethra in gonadectomised dogs where spayed females had a higher (P < 0.05) proportion of collagen and less muscle (P < 0.05). Regional differences were observed in females; a higher proportion of collagen and therefore less muscle were found in the urethra compared with the bladder. Proportional differences in collagen and muscle between intact and gonadectomised animals suggest a relation of different hormonal statuses to structural changes in the canine LUT. Excessive collagen deposits and less muscular volume may impair structural and functional integrity of the LUT which may associate with the development of post-neutering urinary incontinence in the dog. 相似文献
97.
Ian T. Lawson Kevin J. Edwards Mike J. Church Anthony J. Newton Gordon T. Cook Freddy J. Gathorne-Hardy Andrew J. Dugmore 《Journal of Biogeography》2008,35(6):1130-1152
Aim To investigate the form and dynamics of ecosystems on an isolated island in the North Atlantic before human settlement in the first millennium ad , and the effects of human activities thereafter. Location The island of Sandoy, Faroes (61°50′ N, 6°45′ W). Methods Two sequences of lake sediments and one of peat were studied using pollen analysis and sedimentological techniques. Age models were constructed on the basis of radiocarbon dating and, in one case, tephrochronology. The data were analysed statistically and compared with existing data from the region. Results The pollen data indicate that early Holocene vegetation consisted of fell‐field communities probably growing on raw, skeletal soils. These communities gave way to grass‐ and sedge‐dominated communities, which in turn were largely replaced by dwarf shrub‐dominated blanket mire communities well before the first arrival of humans. There is evidence for episodic soil erosion, particularly in the uplands. Changes in the records attributable to human impact are minor in comparison with many other situations in the North Atlantic margins, and with certain published sequences from elsewhere in the Faroes. They include: (1) the appearance of cereal pollen and charcoal, (2) an expansion of ruderal taxa, (3) a decline in certain taxa, notably Juniperus communis and Filipendula ulmaria, and (4) a renewed increase in rates of upland soil erosion. The reliability of palaeoecological inferences drawn from these sites, and more generally from sites in similar unforested situations, is discussed. Main conclusions The subdued amplitude of palynological and sedimentological responses to settlement at these sites can be explained partly in terms of their location and partly in terms of the sensitivity of different parts of the ecosystem to human activities. This study is important in establishing that the imposition of people on the pristine environment of Sandoy, while far from negligible, especially in the immediate vicinity of early farms and at high altitudes, had relatively little ecological impact in many parts of the landscape. 相似文献
98.
99.