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  • 401.
    Zajac, Pawel
    KTH, School of Biotechnology (BIO), Gene Technology.
    Parallel target selection by trinucleotide threading2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    DNA is the code for all life. Via intermediary RNA the information encoded by the genome is relayed to proteins executing the various functions in a cell. Together, this repertoire of inherently linked biological macromolecules determines all characteristics and features of a cell. Technological advancements during the last decades have enabled the pursuit of novel types of studies and the investigation of the cell and its constituents at a progressively higher level of detail. This has shed light on numerous cellular processes and on the underpinnings of several diseases. For the majority of studies focusing on nucleic acids, an amplification step has to be implemented before an analysis, scoring or interrogation method translates the amplified material into relevant biological information. This information can, for instance, be the genotype of particular SNPs or STRs, or the abundance level of a set of interesting transcripts. As such, amplification plays a significant role in nucleic acid assays. Over the years, a number of techniques – most notably PCR – has been devised to meet this amplification need, specifically or randomly multiplying desired regions. However, many of the approaches do not scale up easily rendering comprehensive studies cumbersome, time-consuming and necessitating large quantities of material.Trinucleotide threading (TnT) – forming the red thread throughout this thesis – is a multiplex amplification method, enabling simultaneous targeted amplification of several nucleic acid regions in a specific manner. TnT begins with a controlled linear DNA thread formation, each type of thread corresponding to a segment of interest, by a gap-fill reaction using a restricted trinucleotide set. The whole collection of created threads is subsequently subjected to an exponential PCR amplification employing a single primer pair. The generated material can thereafter be analyzed with a multitude of readout and detection platforms depending on the issue or characteristic under consideration.TnT offers a high level of specificity by harnessing the inherent specificities of a polymerase and a ligase acting on a nucleotide set encompassing three out of the four nucleotide types. Accordingly, several erroneous events have to occur in order to produce artifacts. This necessitates override of a number of control points.The studies constituting this thesis demonstrate integration of the TnT amplification strategy in assays for analysis of various aspects of DNA and RNA. TnT was adapted for expression profiling of intermediately-sized gene sets using both conventional DNA microarrays and massively parallel second generation 454 sequencing for readout. TnT, in conjunction with 454 sequencing, was also employed for allelotyping, defined as determination of allele frequencies in a cohort. In this study, 147 SNPs were simultaneously assayed in a pool comprising genomic DNA of 462 individuals. Finally, TnT was recruited for parallel amplification of STR loci with detection relying on capillary gel electrophoresis. In all investigations, the material generated with TnT was of sufficient quality and quantity to produce reliable and accurate biological information.Taken together, TnT represents a viable multiplex amplification technique permitting parallel amplification of genomic segments, for instance harboring polymorphisms, or of expressed genes. In addition to these, this versatile amplification module can be implemented in assays targeting a range of other features of genomes and transcriptomes.

  • 402. Zajac, Pawel
    et al.
    Ahmadian, Afshin
    KTH, School of Biotechnology (BIO), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Targeted transcript profiling by sequencing2012In: Scientific Reports, ISSN 2045-2322, Vol. 2, p. 821-Article in journal (Refereed)
    Abstract [en]

    In this work we present a targeted gene expression strategy employing trinucleotide threading (TnT) amplification and massive parallel sequencing. We have previously shown that TnT combined with array readout accurately monitors expression levels. However, with this detection strategy spurious products go undetected. Accordingly, we adapted the TnT protocol to massive parallel sequencing to acquire an unbiased view of the entire TnT-generated product population. In this manner we investigated the identity of undesired products, their extent at different oligonucleotide: RNA ratios and their effect on the expression levels. We demonstrate that TnT gene expression profiling with massive sequencing readout renders reliable expression data from as low as 3.5 ng of total RNA. Moreover, using 350 ng of total RNA results in only 0.7% to 1.1% undesired products. When lowering the amount of input material, the undesired product fraction increases but this does not influence the expression profiles.

  • 403.
    Zajac, Pawel
    et al.
    KTH, School of Biotechnology (BIO), Gene Technology.
    Lundeberg, Joakim
    KTH, School of Biotechnology (BIO), Gene Technology.
    Ahmadian, Afshin
    KTH, School of Biotechnology (BIO), Gene Technology.
    Targeted transcript profiling by sequencingManuscript (preprint) (Other academic)
    Abstract [en]

    In recent years, second generation sequencers have been employed to study various facets of the transcriptome in a comprehensive manner. However, intermediary gene sets featuring differentially expressed genes can reduce the dimensionality of experiments while providing researchers with the most significant data. Trinucleotide threading (TnT) is a multiplex amplification method previously implemented in an assay for expression profiling of moderate gene sets. Here, two additional detection systems were evaluated with a focus on lowering the input material requirements. 32 genes were simultaneously assayed with detection either by direct hybridization of TnT products or by sequencing these using the massively parallel 454 sequencer. Both approaches produced reliable transcript abundance data starting from total RNA from about 200 cells. The direct hybridization readout is beneficial for smaller-scale studies, while more ambitious efforts employing numerous individuals are, together with a sample barcoding and pooling scheme, well suited for the second generation sequencing approach. Moreover, with protocol optimizations the starting material requirements for the sequencing strategy may be further reduced. Accordingly, this study presents a targeted RNA-Seq method.

  • 404.
    Zajac, Pawel
    et al.
    KTH, School of Biotechnology (BIO), Gene Technology.
    Pettersson, Erik
    KTH, School of Biotechnology (BIO), Gene Technology.
    Gry, Marcus
    KTH, School of Biotechnology (BIO), Gene Technology.
    Lundeberg, Joakim
    KTH, School of Biotechnology (BIO), Gene Technology.
    Ahmadian, Afshin
    KTH, School of Biotechnology (BIO), Gene Technology.
    Expression profiling of signature gene sets with trinucleotide threading2008In: Genomics, ISSN 0888-7543, E-ISSN 1089-8646, Vol. 9, no 2, p. 209-217Article in journal (Refereed)
    Abstract [en]

    In recent years, studies have shown that expression profiling of carefully chosen intermediary gene sets, comprising approximately 10 to 100 genes, can convey the most relevant information compared to much more complex whole-genome studies. In this paper, we present a novel method suitable for expression profiling of moderate gene sets in a large number of samples. The assay implements the parallel amplification features of the trinucleotide threading technique (TnT), which encompasses linear transcript-based DNA thread formation in conjunction with exponential multiplexed thread amplification. The amplifications bestow the method with high sensitivity. The TnT procedure together with thread detection, relying on thread-specific primer extension followed by hybridization to universal tag arrays, allows for three distinction levels, thus offering high specificity. Additionally, the assay is easily automated and flexible. A gene set, comprising 18 protein epitope signature tags from the Swedish Human Protein Atlas program, was analyzed with the TnT-based approach and the data were compared with those generated by both real-time PCR and genome-wide cDNA arrays, with the highest correlation observed between TnT and real-time PCR. Taken together, expression profiling with trinucleotide threading represents a reliable approach for studies of intermediary gene sets.

  • 405.
    Zajac, Pawel
    et al.
    KTH, School of Biotechnology (BIO), Gene Technology.
    Öberg, Christine
    KTH, School of Biotechnology (BIO), Gene Technology.
    Ahmadian, Afshin
    KTH, School of Biotechnology (BIO), Gene Technology.
    Analysis of Short Tandem Repeats by Parallel DNA Threading2009In: PLoS ONE, ISSN 1932-6203, Vol. 4, no 11, p. e7823-Article in journal (Refereed)
    Abstract [en]

    The majority of studies employing short tandem repeats (STRs) require investigation of several of these genetic markers. As such, we demonstrate the feasibility of the trinucleotide threading (TnT) approach for scalable analysis of STRs. The TnT method represents a parallel amplification alternative that addresses the obstacles associated with multiplex PCR. In this study, analysis of the STR fragments was performed with capillary gel electrophoresis; however, it should be possible to combine our approach with the massive 454 sequencing platform to considerably increase the number of targeted STRs.

  • 406. Zangenah, S.
    et al.
    Andersson, Anders F.
    KTH, School of Biotechnology (BIO), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Ozenci, V.
    Bergman, P.
    Genomic analysis reveals the presence of a class D beta-lactamase with broad substrate specificity in animal bite associated Capnocytophaga species2017In: European Journal of Clinical Microbiology and Infectious Diseases, ISSN 0934-9723, E-ISSN 1435-4373, Vol. 36, no 4, p. 657-662Article in journal (Refereed)
    Abstract [en]

    Capnocytophga canimorsus and Capnocytophga cynodegmi can be transmitted from cats and dogs to humans, and can cause a wide range of infections including wound infections, sepsis, or endocarditis. We and others recently discovered two new Capnocytophaga species, C. canis and C. stomatis, mainly associated with wound infections. The first-line treatment of animal bite related infections is penicillin, and in case of allergy, doxycycline and trimethoprim/sulfamethoxazole. However, there is a lack of antibiotic susceptibility patterns for animal bite associated Capnocytophaga species. Thus, we i >> inverted question markset out to study the antibiotic profiles against animal bite associated Capnocytophaga species isolated from wound and blood cultures after cat and dog bites and coupled the findings to whole genome sequencing data. A total of 24 strains were included in the study. Phenotypic analysis of antibiotic resistance was performed with E-tests. The web-based tool 'Resfinder' was used to identify resistance genes in the whole genome dataset. Two strains of C. cynodegmi and two strains of the recently discovered C. stomatis were resistant to penicillin (MIC 24 mgi >> inverted question mark/L) and cephalosporins (MIC 24 mg/i >> inverted question markL), and three out of these strains also exhibited resistance to imipenem (MIC = 32 mg/i >> inverted question markL). Genomic analysis revealed that these strains carried a class D beta-lactamase gene, which has not previously been found in Capnocytophaga spp. A class D beta lactamase with broad substrate specificity was found in animal bite associated Capnocytophaga species, which could have important implications when treating wound infections after cat and dog bites. It also suggests that pet animal bacteria can harbour resistance genes with relevance for human infections.

  • 407. Zangenah, Salah
    et al.
    Abbasi, Nasir
    Univ Miguel Hernandez,Spain.
    Andersson, Anders F.
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Biotechnology (BIO), Gene Technology.
    Bergman, Peter
    Whole genome sequencing identifies a novel species of the genus Capnocytophaga isolated from dog and cat bite wounds in humans2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 22919Article in journal (Refereed)
    Abstract [en]

    C. canimorsus and C. cynodegmi are dog and cat commensals which can be transmitted to humans via bites or scratches and can cause sepsis, meningitis, endocarditis, and eye- or wound infections. Recently an additional Capnocytophaga species was identified as part of the oral flora of healthy dogs and was given the name "C. canis". We previously identified a Capnocytophaga isolate that could not be typed with available diagnostic tests including MALDI-TOF, 16S rRNA sequencing or species-specific PCR. This strain and 21 other Capnocytophaga spp isolated in Sweden from clinical blood- or wound-cultures were subjected to whole genome sequencing using the Illumina platform. Phylogenetic analysis revealed that the previously non-typable isolate belongs to the putative new species "C. canis". Since this strain was isolated from a wound it also shows that members of "C. canis" have the potential to be pathogenic. In addition, our phylogenetic analysis uncovered an additional species of Capnocytophaga, which can be transmitted from dogs and cats to humans, suggesting a speciation within the Capnocytophaga family that has not been observed before. We propose the name of "C. stomatis" for this putative novel species.

  • 408.
    Zhang, Ai-bing
    et al.
    KTH, School of Biotechnology (BIO), Gene Technology.
    Savolainen, Peter
    KTH, School of Biotechnology (BIO), Gene Technology.
    BPSI2.0: a C/C++ interface program for species identification via DNA barcoding with a BP-neural network by calling the Matlab engine2009Article in journal (Refereed)
    Abstract [en]

    BP-Species Identification (BPSI2.0) is a computer program that performs species identification by training a Back-Propagation Neural Network. A short DNA barcoding segment is used as input for training a three-layer BP network. The trained network can assign an unknown query sequence to a known species in the user's database, and provide the corresponding subvector value of the output vector as a relative probability value.

  • 409.
    Zhang, Ai-bing
    et al.
    KTH, School of Biotechnology (BIO), Gene Technology.
    Sikes, D. S.
    Muster, C.
    Li, S. Q.
    Inferring species membership using DNA sequences with back-propagation neural networks2008In: Systematic Biology, ISSN 1063-5157, E-ISSN 1076-836X, Vol. 57, no 2, p. 202-215Article in journal (Refereed)
    Abstract [en]

    DNA barcoding as a method for species identification is rapidly increasing in popularity. However, there are still relatively few rigorous methodological tests of DNA barcoding. Current distance-based methods are frequently criticized for treating the nearest neighbor as the closest relative via a raw similarity score, lacking an objective set of criteria to delineate taxa, or for being incongruent with classical character-based taxonomy. Here, we propose an artificial intelligence-based approachinferring species membership via DNA barcoding with back-propagation neural networks (named BP-based species identification)as a new advance to the spectrum of available methods. We demonstrate the value of this approach with simulated data sets representing different levels of sequence variation under coalescent simulations with various evolutionary models, as well as with two empirical data sets of COI sequences from East Asian ground beetles (Carabidae) and Costa Rican skipper butterflies. With a 630-to 690-bp fragment of the COI gene, we identified 97.50% of 80 unknown sequences of ground beetles, 95.63%, 96.10%, and 100% of 275, 205, and 9 unknown sequences of the neotropical skipper butterfly to their correct species, respectively. Our simulation studies indicate that the success rates of species identification depend on the divergence of sequences, the length of sequences, and the number of reference sequences. Particularly in cases involving incomplete lineage sorting, this new BP-based method appears to be superior to commonly used methods for DNA-based species identification.

  • 410. Zhang, Bo
    et al.
    Käll, Lukas
    KTH, School of Biotechnology (BIO), Gene Technology.
    Zubarev, Roman A.
    DeMix-Q: Quantification-Centered Data Processing Workflow2016In: Molecular & cellular proteomics (online), ISSN 1535-9476, E-ISSN 1535-9484, Vol. 15, no 4, p. 1467-1478Article in journal (Refereed)
    Abstract [en]

    For historical reasons, most proteomics workflows focus on MS/MS identification but consider quantification as the end point of a comparative study. The stochastic data-dependent MS/MS acquisition (DDA) gives low reproducibility of peptide identifications from one run to another, which inevitably results in problems with missing values when quantifying the same peptide across a series of label-free experiments. However, the signal from the molecular ion is almost always present among the MS1 spectra. Contrary to what is frequently claimed, missing values do not have to be an intrinsic problem of DDA approaches that perform quantification at the MS1 level. The challenge is to perform sound peptide identity propagation across multiple high-resolution LC-MS/MS experiments, from runs with MS/MS-based identifications to runs where such information is absent. Here, we present a new analytical workflow DeMix-Q (https://github.com/userbz/DeMix-Q), which performs such propagation that recovers missing values reliably by using a novel scoring scheme for quality control. Compared with traditional workflows for DDA as well as previous DIA studies, DeMix-Q achieves deeper proteome coverage, fewer missing values, and lower quantification variance on a benchmark dataset. This quantification-centered workflow also enables flexible and robust proteome characterization based on covariation of peptide abundances.

  • 411. Zhang, Bo
    et al.
    Pirmoradian, Mohammad
    Zubarev, Roman
    Käll, Lukas
    KTH, School of Biotechnology (BIO), Gene Technology. KTH, Centres, SeRC - Swedish e-Science Research Centre. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Covariation of Peptide Abundances Accurately Reflects Protein Concentration Differences2017In: Molecular & Cellular Proteomics, ISSN 1535-9476, E-ISSN 1535-9484, Vol. 16, no 5, p. 936-948Article in journal (Refereed)
    Abstract [en]

    Most implementations of mass spectrometry-based proteomics involve enzymatic digestion of proteins, expanding the analysis to multiple proteolytic peptides for each protein. Currently, there is no consensus of how to summarize peptides' abundances to protein concentrations, and such efforts are complicated by the fact that error control normally is applied to the identification process, and do not directly control errors linking peptide abundance measures to protein concentration. Peptides resulting from suboptimal digestion or being partially modified are not representative of the protein concentration. Without a mechanism to remove such unrepresentative peptides, their abundance adversely impacts the estimation of their protein's concentration. Here, we present a relative quantification approach, Diffacto, that applies factor analysis to extract the covariation of peptides' abundances. The method enables a weighted geometrical average summarization and automatic elimination of incoherent peptides. We demonstrate, based on a set of controlled label-free experiments using standard mixtures of proteins, that the covariation structure extracted by the factor analysis accurately reflects protein concentrations. In the 1% peptide-spectrum match-level FDR data set, as many as 11% of the peptides have abundance differences incoherent with the other peptides attributed to the same protein. If not controlled, such contradicting peptide abundance have a severe impact on protein quantifications. When adding the quantities of each protein's three most abundant peptides, we note as many as 14% of the proteins being estimated as having a negative correlation with their actual concentration differences between samples. Diffacto reduced the amount of such obviously incorrectly quantified proteins to 1.6%. Furthermore, by analyzing clinical data sets from two breast cancer studies, our method revealed the persistent proteomic signatures linked to three subtypes of breast cancer. We conclude that Diffacto can facilitate the interpretation and enhance the utility of most types of proteomics data.

  • 412.
    Zhang, Miao
    et al.
    KTH, School of Information and Communication Technology (ICT), Materials- and Nano Physics, Material Physics, MF.
    Schmidt, Torsten
    KTH, School of Information and Communication Technology (ICT), Materials- and Nano Physics, Material Physics, MF.
    Jemt, Anders
    KTH, School of Biotechnology (BIO), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Sahlén, Pelin
    KTH, School of Biotechnology (BIO), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Sychugov, Ilya
    KTH, School of Information and Communication Technology (ICT), Materials- and Nano Physics, Material Physics, MF.
    Lundeberg, Joakim
    KTH, School of Biotechnology (BIO), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Linnros, Jan
    KTH, School of Information and Communication Technology (ICT), Materials- and Nano Physics, Material Physics, MF.
    Nanopore arrays in a silicon membrane for parallel single-molecule detection: DNA translocation2015In: Nanotechnology, ISSN 0957-4484, E-ISSN 1361-6528, Vol. 26, no 31, article id 314002Article in journal (Refereed)
    Abstract [en]

    Optical nanopore sensing offers great potential in single-molecule detection, genotyping, or DNA sequencing for high-throughput applications. However, one of the bottle-necks for fluorophore-based biomolecule sensing is the lack of an optically optimized membrane with a large array of nanopores, which has large pore-to-pore distance, small variation in pore size and low background photoluminescence (PL). Here, we demonstrate parallel detection of single-fluorophore-labeled DNA strands (450 bps) translocating through an array of silicon nanopores that fulfills the above-mentioned requirements for optical sensing. The nanopore array was fabricated using electron beam lithography and anisotropic etching followed by electrochemical etching resulting in pore diameters down to similar to 7 nm. The DNA translocation measurements were performed in a conventional wide-field microscope tailored for effective background PL control. The individual nanopore diameter was found to have a substantial effect on the translocation velocity, where smaller openings slow the translocation enough for the event to be clearly detectable in the fluorescence. Our results demonstrate that a uniform silicon nanopore array combined with wide-field optical detection is a promising alternative with which to realize massively-parallel single-molecule detection.

  • 413. Zheng, Zongli
    et al.
    Andersson, Anders F.
    KTH, School of Biotechnology (BIO), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Ye, Weimin
    Nyrén, Olof
    Normark, Staffan
    Engstrand, Lars
    A Method for Metagenomics of Helicobacter pylori from Archived Formalin-Fixed Gastric Biopsies Permitting Longitudinal Studies of Carcinogenic Risk2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 10, p. e26442-Article in journal (Refereed)
    Abstract [en]

    The human microbiota has come into focus in the search for component causes of chronic diseases, such as gastrointestinal cancers. Presumably long induction periods and altered local environments after disease onset call for the development of methods for characterization of microorganisms colonizing the host decades before disease onset. Sequencing of microbial genomes in old formalin-fixed and paraffin-embedded (FFPE) gastrointestinal biopsies provides a means for such studies but is still challenging. Here we report a method based on laser capture micro-dissection and modified Roche 454 high-throughput pyrosequencing to obtain metagenomic profiles of Helicobacter pylori. We applied this method to two 15 year old FFPE biopsies from two patients. Frozen homogenized biopsies from the same gastroscopy sessions were also available for comparison after re-culture of H. pylori. For both patients, H. pylori DNA dissected from FFPE sections had similar to 96.4% identity with culture DNA from the same patients, while only similar to 92.5% identity with GenBank reference genomes, and with culture DNA from the other patient. About 82% and 60% of the predicted genes in the two genomes were captured by at least a single sequencing read. Along with sequences displaying high similarity to known H. pylori genes, novel and highly variant H. pylori sequences were identified in the FFPE sections by our physical enrichment approach, which would likely not have been detected by a sequence capture approach. The study demonstrates the feasibility of longitudinal metagenomic studies of H. pylori using decade-preserved FFPE biopsies.

  • 414. Zhou, Yongjin J.
    et al.
    Buijs, Nicolaas A.
    Zhu, Zhiwei
    Qin, Jiufu
    Siewers, Verena
    Nielsen, Jens
    KTH, School of Biotechnology (BIO), Gene Technology.
    Production of fatty acid-derived oleochemicals and biofuels by synthetic yeast cell factories2016In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 7, article id 11709Article in journal (Refereed)
    Abstract [en]

    Sustainable production of oleochemicals requires establishment of cell factory platform strains. The yeast Saccharomyces cerevisiae is an attractive cell factory as new strains can be rapidly implemented into existing infrastructures such as bioethanol production plants. Here we show high-level production of free fatty acids (FFAs) in a yeast cell factory, and the production of alkanes and fatty alcohols from its descendants. The engineered strain produces up to 10.4 gl(-1) of FFAs, which is the highest reported titre to date. Furthermore, through screening of specific pathway enzymes, endogenous alcohol dehydrogenases and aldehyde reductases, we reconstruct efficient pathways for conversion of fatty acids to alkanes (0.8 mgl(-1)) and fatty alcohols (1.5 gl(-1)), to our knowledge the highest titres reported in S. cerevisiae. This should facilitate the construction of yeast cell factories for production of fatty acids derived products and even aldehyde-derived chemicals of high value.

  • 415. Zhow, Yongjin J.
    et al.
    Buijs, Nicolaas A.
    Zhu, Zhiwei
    Gomez, Diego Orol
    Boonsombuti, Akarin
    Siewers, Verena
    Nielsen, Jens
    KTH, School of Biotechnology (BIO), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab. Chalmers University of Technology, Sweden; Technical University of Denmark, Denmark.
    Harnessing Yeast Peroxisomes for Biosynthesis of Fatty-Acid-Derived Biofuels and Chemicals with Relieved Side-Pathway Competition2016In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 138, no 47, p. 15368-15377Article in journal (Refereed)
    Abstract [en]

    Establishing efficient synthetic pathways for microbial production of biochemicals is often hampered by competing pathways and/or insufficient precursor supply. Compartmentalization in cellular organelles can isolate synthetic pathways from competing pathways, and provide a compact and suitable environment for biosynthesis. Peroxisomes are cellular organelles where fatty acids are degraded, a process that is inhibited under typical fermentation conditions making them an interesting workhouse for production of fatty-acid-derived molecules. Here, we show that targeting synthetic pathways to peroxisomes can increase the production of fatty-acid-derived fatty alcohols, alkanes and olefins up to 700%. In addition, we demonstrate that biosynthesis of these chemicals in the peroxisomes results in significantly decreased accumulation of byproducts formed by competing enzymes. We further demonstrate that production can be enhanced up to 3-fold by increasing the peroxisome population. The strategies described here could be used for production of other chemicals, especially acyl-CoA-derived molecules.

  • 416. Zhu, Chaoyong
    et al.
    Odeberg, Jacob
    KTH, School of Biotechnology (BIO), Gene Technology.
    Hamsten, Anders
    Eriksson, Per
    Allele-specific MMP-3 transcription under in vivo conditions2006In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 348, no 3, p. 1150-1156Article in journal (Refereed)
    Abstract [en]

    A common matrix metalloproteinases-3 (MMP-3) -1612 5A/6A promoter polymorphism is associated with risk for cardiovascular disease, rheumatoid arthritis, and other diseases. Here we used the haplotype chromatin immunoprecipitation method to study allele-specific MMP-3 expression under in vivo conditions in heterozygous THP-1 cells. Pyrosequencing was used to analyse the ratio of 5A-allele to 6A-allele after chromatin immunoprecipitation using an antibody against phosphorylated active RNA polymerase II. There was no allele-specific difference in transcriptional activity during basal conditions, i.e., in unstimulated monocytic THP-1 cells. However, after stimulation of MMP-3 expression by monocyte differentiation or incubation with IL-1 beta, the haplotype containing the 5A-allete was associated with higher transcriptional activity compared with the 6A-containing haplotype. Electromobility shift assay demonstrated increased binding of nuclear proteins to the 5A-allele after monocyte differentiation. In conclusion, the common MMP-3 5A/6A promoter polymorphism appears to be functional only during specific environmental conditions involving inflammation.

  • 417. Zhu, X.
    et al.
    Shen, Y.
    Chen, X.
    Hu, Yue O. O.
    KTH, School of Biotechnology (BIO), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Xiang, H.
    Tao, J.
    Ling, Y.
    Biodegradation mechanism of microcystin-LR by a novel isolate of Rhizobium sp. TH and the evolutionary origin of the mlrA gene2016In: International Biodeterioration & Biodegradation, ISSN 0964-8305, E-ISSN 1879-0208, Vol. 115, p. 17-25Article in journal (Refereed)
    Abstract [en]

    The frequent presence of microcystin (MC) in eutrophic water bodies worldwide poses a serious threat to ecosystems. Biodegradation has been extensively investigated as a main pathway for MC attenuation, and an mlr-dependent mechanism of MC degradation have been elucidated in detail. However, the evolutionary origin and the distribution of mlr genes in MC-degrading bacteria is poorly understood. In this study, a novel Rhizobium sp. TH, which is the first α-proteobacterial MC-degrading bacterium other than Sphingomonadales, was isolated. Strain TH degraded MC via the mlr-dependent mechanism with a first-order rate constant of 0.18–0.29 h−1 under near-natural conditions. The partial length mlr gene cluster was sequenced, and the function of its key gene, mlrA, was verified by heterologous expression in Escherichia coli. Phylogenetic analyses show that the mlrA gene initially arose in α-proteobacteria by vertical evolution, and the two strains from β- and γ-proteobacteria acquired it by horizontal gene transfer. Therefore, the mlrA gene mainly exists in α-proteobacteria but is seldom present in other bacteria. A pair of primers matching well with mlrA sequences reported so far were designed and could be used to determine the MC-degrading mechanism for novel isolates or to screen for MC-degrading ability among environmental samples.

  • 418. Zhu, Y.
    et al.
    Engström, P. G.
    Tellgren-Roth, C.
    Baudo, C. D.
    Kennell, J. C.
    Sun, S.
    Billmyre, R. B.
    Schröder, M. S.
    Andersson, A.
    Holm, T.
    Sigurgeirsson, Benjamin
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Wu, G.
    Sankaranarayanan, S. R.
    Siddharthan, R.
    Sanyal, K.
    Lundeberg, Joakim
    KTH, School of Biotechnology (BIO), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Nystedt, B.
    Boekhout, T.
    Dawson, T.L., Jr.
    Heitman, J.
    Scheynius, A.
    Lehtiö, J.
    Proteogenomics produces comprehensive and highly accurate protein-coding gene annotation in a complete genome assembly of Malassezia sympodialis2017In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 45, no 5, p. 2629-2643Article in journal (Refereed)
    Abstract [en]

    Complete and accurate genome assembly and annotation is a crucial foundation for comparative and functional genomics. Despite this, few complete eukaryotic genomes are available, and genome annotation remains a major challenge. Here, we present a complete genome assembly of the skin commensal yeast Malassezia sympodialis and demonstrate how proteogenomics can substantially improve gene annotation. Through long-read DNA sequencing, we obtained a gap-free genome assembly for M. sympodialis (ATCC 42132), comprising eight nuclear and one mitochondrial chromosome. We also sequenced and assembled four M. sympodialis clinical isolates, and showed their value for understanding Malassezia reproduction by confirming four alternative allele combinations at the two mating-type loci. Importantly, we demonstrated how proteomics data could be readily integrated with transcriptomics data in standard annotation tools. This increased the number of annotated protein-coding genes by 14% (from 3612 to 4113), compared to using transcriptomics evidence alone. Manual curation further increased the number of protein-coding genes by 9% (to 4493). All of these genes have RNA-seq evidence and 87% were confirmed by proteomics. The M. sympodialis genome assembly and annotation presented here is at a quality yet achieved only for a few eukaryotic organisms, and constitutes an important reference for future host-microbe interaction studies.

  • 419. Zouganelis, George D.
    et al.
    Ogden, Rob
    Nahar, Niru
    Runfola, Valeria
    Bonab, Maziar
    Ardalan, Arman
    KTH, School of Biotechnology (BIO), Gene Technology.
    Radford, David
    Barnett, Ross
    Larson, Greger
    Hildred, Alex
    Jones, Mark
    Scarlett, Garry
    An old dog and new tricks: Genetic analysis of a Tudor dog recovered from the Mary Rose wreck2014In: Forensic Science International, ISSN 0379-0738, E-ISSN 1872-6283, Vol. 245, p. 51-57Article in journal (Refereed)
    Abstract [en]

    The Tudor warship the Mary Rose sank in the Solent waters between Portsmouth and the Isle of Wight on the 19th of July 1545, whilst engaging a French invasion fleet. The ship was rediscovered in 1971 and between 1979 and 1982 the entire contents of the ship were excavated resulting in the recovery of over 25,000 objects, including the skeleton of a small to medium sized dog referred to as the Mary Rose Dog (MRD). Here we report the extraction and analysis of both mitochondrial and genomic DNA from a tooth of this animal. Our results show that the MRD was a young male of a terrier type most closely related to modern Jack Russell Terriers with a light to dark brown coat colour. Interestingly, given the antiquity of the sample, the dog was heterozygotic for the SLC2A9 gene variant that leads to hyperuricosuria when found in modern homozygotic animals. These findings help shed light on a notable historical artefact from an important period in the development of modern dog breeds.

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