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  • 1
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    Adaptor protein-2 sigma subunit mutations causing familial hypocalciuric hypercalcaemia type 3 (FHH3) demonstrate genotype-phenotype correlations, codon bias and dominant-negative effects (2015)
    Oxford University Press
    Details
    Publication Date: 2015-08-27
    Description: The adaptor protein-2 sigma subunit (AP22) is pivotal for clathrin-mediated endocytosis of plasma membrane constituents such as the calcium-sensing receptor (CaSR). Mutations of the AP22 Arg15 residue result in familial hypocalciuric hypercalcaemia type 3 (FHH3), a disorder of extracellular calcium (Ca 2+ o ) homeostasis. To elucidate the role of AP22 in Ca 2+ o regulation, we investigated 65 FHH probands, without other FHH-associated mutations, for AP22 mutations, characterized their functional consequences and investigated the genetic mechanisms leading to FHH3. AP22 mutations were identified in 17 probands, comprising 5 Arg15Cys, 4 Arg15His and 8 Arg15Leu mutations. A genotype–phenotype correlation was observed with the Arg15Leu mutation leading to marked hypercalcaemia. FHH3 probands harboured additional phenotypes such as cognitive dysfunction. All three FHH3-causing AP22 mutations impaired CaSR signal transduction in a dominant-negative manner. Mutational bias was observed at the AP22 Arg15 residue as other predicted missense substitutions (Arg15Gly, Arg15Pro and Arg15Ser), which also caused CaSR loss-of-function, were not detected in FHH probands, and these mutations were found to reduce the numbers of CaSR-expressing cells. FHH3 probands had significantly greater serum calcium (sCa) and magnesium (sMg) concentrations with reduced urinary calcium to creatinine clearance ratios (CCCR) in comparison with FHH1 probands with CaSR mutations, and a calculated index of sCa x sMg/100 x CCCR, which was ≥ 5.0, had a diagnostic sensitivity and specificity of 83 and 86%, respectively, for FHH3. Thus, our studies demonstrate AP22 mutations to result in a more severe FHH phenotype with genotype–phenotype correlations, and a dominant-negative mechanism of action with mutational bias at the Arg15 residue.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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  • 2
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    ASSIGN: context-specific genomic profiling of multiple heterogeneous biological pathways (2015)
    Oxford University Press
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    Publication Date: 2015-05-27
    Description: Motivation: Although gene-expression signature-based biomarkers are often developed for clinical diagnosis, many promising signatures fail to replicate during validation. One major challenge is that biological samples used to generate and validate the signature are often from heterogeneous biological contexts—controlled or in vitro samples may be used to generate the signature, but patient samples may be used for validation. In addition, systematic technical biases from multiple genome-profiling platforms often mask true biological variation. Addressing such challenges will enable us to better elucidate disease mechanisms and provide improved guidance for personalized therapeutics. Results: Here, we present a pathway profiling toolkit, Adaptive Signature Selection and InteGratioN (ASSIGN), which enables robust and context-specific pathway analyses by efficiently capturing pathway activity in heterogeneous sets of samples and across profiling technologies. The ASSIGN framework is based on a flexible Bayesian factor analysis approach that allows for simultaneous profiling of multiple correlated pathways and for the adaptation of pathway signatures into specific disease. We demonstrate the robustness and versatility of ASSIGN in estimating pathway activity in simulated data, cell lines perturbed pathways and in primary tissues samples including The Cancer Genome Atlas breast carcinoma samples and liver samples exposed to genotoxic carcinogens. Availability and implementation: Software for our approach is available for download at: http://www.bioconductor.org/packages/release/bioc/html/ASSIGN.html and https://github.com/wevanjohnson/ASSIGN . Contact : andreab@genetics.utah.edu or wej@bu.edu Supplementary information: Supplementary data are available at Bioinformatics online.
    Print ISSN: 1367-4803
    Electronic ISSN: 1460-2059
    Topics: Biology , Computer Science , Medicine
    Published by Oxford University Press
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  • 3
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    The Rickettsia type IV secretion system: unrealized complexity mired by gene family expansion (2016)
    Oxford University Press
    Details
    Publication Date: 2016-07-13
    Description: Many prokaryotes utilize type IV secretion systems (T4SSs) to translocate substrates (e.g. nucleoprotein, DNA, protein) across the cell envelope, and/or to elaborate surface structures (i.e. pili or adhesins). Among eight distinct T4SS classes, P-T4SSs are typified by the Agrobacterium tumefaciens vir T4SS, which is comprised of 12 scaffold components (VirB1–VirB11, VirD4). While most P-T4SSs include all 12 Vir proteins, some differ from the vir archetype by either containing additional scaffold components not analogous to Vir proteins or lacking one or more of the Vir proteins. In a special case, the Rickettsiales vir homolog ( rvh ) P-T4SS comprises unprecedented gene family expansion. rvh contains three families of gene duplications ( rvhB9 , rvhB8 , rvhB4 ): RvhB9,8,4-I are conserved relative to equivalents in other P-T4SSs, while RvhB9,8,4-II have evolved atypical features that deviate substantially from other homologs. Furthermore, rvh contains five VirB6-like genes ( rvhB6a – e ), which are tandemly arrayed and contain large N- and C-terminal extensions. Our work herein focuses on the complexity underpinned by rvh gene family expansion. Furthermore, we describe an RvhB10 insertion, which occurs in a region that forms the T4SS pore. The significance of these curious properties to rvh structure and function is evaluated, shedding light on a highly complex T4SS.
    Print ISSN: 0928-8244
    Topics: Biology , Medicine
    Published by Oxford University Press
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  • 4
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    Clustering-based redshift estimation: comparison to spectroscopic redshifts (2015)
    Oxford University Press
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    Publication Date: 2015-01-25
    Description: We investigate the potential and accuracy of clustering-based redshift estimation using the method proposed by Ménard et al. This technique enables the inference of redshift distributions from measurements of the spatial clustering of arbitrary sources, using a set of reference objects for which redshifts are known. We apply it to a sample of spectroscopic galaxies from the Sloan Digital Sky Survey (SDSS) and show that, after carefully controlling the sampling efficiency over the sky, we can estimate redshift distributions with high accuracy. Probing the full colour space of the SDSS galaxies, we show that we can recover the corresponding mean redshifts with an accuracy ranging from z  = 0.001 to 0.01. We indicate that this mapping can be used to infer the redshift probability distribution of a single galaxy. We show how the lack of information on the galaxy bias limits the accuracy of the inference and show comparisons between clustering redshifts and photometric redshifts for this data set. This analysis demonstrates, using real data, that clustering-based redshift inference provides a powerful data-driven technique to explore the redshift distribution of arbitrary data sets, without any prior knowledge of the spectral energy distribution of the sources.
    Print ISSN: 0035-8711
    Electronic ISSN: 1365-2966
    Topics: Physics
    Published by Oxford University Press
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  • 5
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    Exploring the 2MASS extended and point source catalogues with clustering redshifts (2016)
    Oxford University Press
    Details
    Publication Date: 2016-02-28
    Description: The Two-Micron All-Sky Survey (2MASS) has mapped out the low-redshift Universe down to K S  ~ 14 mag. As its near-infrared photometry primarily probes the featureless Rayleigh–Jeans tail of galaxy spectral energy distributions, colour-based redshift estimation is rather uninformative. Until now, redshift estimates for this data set have relied on optical follow-up suffering from selection biases. Here, we use the newly developed technique of clustering-based redshift estimation to infer the redshift distribution of the 2MASS sources regardless of their optical properties. We characterize redshift distributions of objects from the Extended Source Catalogue as a function of near-infrared colours and brightness and report some observed trends. We also apply the clustering redshift technique to dropout populations, sources with non-detections in one or more near-infrared bands, and present their redshift distributions. Combining all extended sources, we confirm with clustering redshifts that the distribution of this sample extends up to z  ~ 0.35. We perform a similar analysis with the Point Source Catalogue and show that it can be separated into stellar and extragalactic contributions with galaxies reaching z  ~ 0.7. We estimate that the Point Source Catalogue contains 1.6 million extragalactic objects: as many as in the Extended Source Catalogue but probing a cosmic volume 10 times larger.
    Print ISSN: 0035-8711
    Electronic ISSN: 1365-2966
    Topics: Physics
    Published by Oxford University Press
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  • 6
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    Alternative preprocessing of RNA-Sequencing data in The Cancer Genome Atlas leads to improved analysis results (2015)
    Oxford University Press
    Details
    Publication Date: 2015-11-05
    Description: Motivation: The Cancer Genome Atlas (TCGA) RNA-Sequencing data are used widely for research. TCGA provides ‘Level 3’ data, which have been processed using a pipeline specific to that resource. However, we have found using experimentally derived data that this pipeline produces gene-expression values that vary considerably across biological replicates. In addition, some RNA-Sequencing analysis tools require integer-based read counts, which are not provided with the Level 3 data. As an alternative, we have reprocessed the data for 9264 tumor and 741 normal samples across 24 cancer types using the Rsubread package. We have also collated corresponding clinical data for these samples. We provide these data as a community resource. Results: We compared TCGA samples processed using either pipeline and found that the Rsubread pipeline produced fewer zero-expression genes and more consistent expression levels across replicate samples than the TCGA pipeline. Additionally, we used a genomic-signature approach to estimate HER2 (ERBB2) activation status for 662 breast-tumor samples and found that the Rsubread data resulted in stronger predictions of HER2 pathway activity. Finally, we used data from both pipelines to classify 575 lung cancer samples based on histological type. This analysis identified various non-coding RNA that may influence lung-cancer histology. Availability and implementation: The RNA-Sequencing and clinical data can be downloaded from Gene Expression Omnibus (accession number GSE62944). Scripts and code that were used to process and analyze the data are available from https://github.com/srp33/TCGA_RNASeq_Clinical . Contact: stephen_piccolo@byu.edu or andreab@genetics.utah.edu Supplementary information: Supplementary material is available at Bioinformatics online.
    Print ISSN: 1367-4803
    Electronic ISSN: 1460-2059
    Topics: Biology , Computer Science , Medicine
    Published by Oxford University Press
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  • 7
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    Exploring the SDSS photometric galaxies with clustering redshifts (2016)
    Oxford University Press
    Details
    Publication Date: 2016-05-22
    Description: We apply clustering-based redshift inference to all extended sources from the Sloan Digital Sky Survey photometric catalogue, down to magnitude r  = 22. We map the relationships between colours and redshift, without assumption of the sources’ spectral energy distributions (SEDs). We identify and locate star-forming quiescent galaxies, and active galactic nuclei, as well as colour changes due to spectral features, such as the 4000 Å break, redshifting through specific filters. Our mapping is globally in good agreement with colour–redshift tracks computed with SED templates, but reveals informative differences, such as the need for a lower fraction of M-type stars in certain templates. We compare our clustering-redshift estimates to photometric redshifts and find these two independent estimators to be in good agreement at each limiting magnitude considered. Finally, we present the global clustering-redshift distribution of all Sloan extended sources, showing objects up to z  ~ 0.8. While the overall shape agrees with that inferred from photometric redshifts, the clustering-redshift technique results in a smoother distribution, with no indication of structure in redshift space suggested by the photometric-redshift estimates (likely artefacts imprinted by their spectroscopic training set). We also infer a higher fraction of high-redshift objects. The mapping between the four observed colours and redshift can be used to estimate the redshift probability distribution function of individual galaxies. This work is an initial step towards producing a general mapping between redshift and all available observables in the photometric space, including brightness, size, concentration, and ellipticity.
    Print ISSN: 0035-8711
    Electronic ISSN: 1365-2966
    Topics: Physics
    Published by Oxford University Press
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  • 8
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    Comparative Genome Analysis of the Daptomycin-Resistant Streptococcus anginosus Strain J4206 Associated with Breakthrough Bacteremia (2017)
    Oxford University Press
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    Publication Date: 2017-01-01
    Description: Streptococcus anginosus is a member of the normal oral flora that can become a pathogen causing pyogenic infections in humans. The genome of daptomycin-resistant strain J4206, originally isolated from a patient suffering from breakthrough bacteremia and septic shock at the University of Texas Health Science Center at San Antonio, was determined. The circular genome is 2,001,352 bp long with a GC content of 38.62% and contains multiple mobile genetic elements, including the phage-like chromosomal island SanCI that mediates a mutator phenotype, transposons, and integrative conjugative elements. Daptomycin resistance involves multiple alterations in the cell membrane and cell wall, and unique features were identified in J4206 that may contribute to resistance. A cluster of capsular polysaccharide (CPS) genes for choline metabolism and transport are present that may help neutralize cell surface charges, destabilizing daptomycin binding. Further, unique J4206 genes encoding sortases and LPXTG-target proteins that are involved in cell wall modification were present. The J4206 genome is phylogenetically closely related to the recently reported vancomycin-resistant SA1 strain; however, these genomes differ with SNPs in cardiolipin synthetase, histidine kinase yycG , teichoic acid modification genes, and other genes involved in cell surface modification. Transmission electron microscopy showed that the cell walls of both strains J4206 and SA1 were significantly thicker and more electron dense than daptomycin- and vancomycin-sensitive strain J4211. This comparative genomic study has identified unique genes as well as allelic variants in the J4206 genome that are involved in cell surface modification and thus might contribute to the acquisition of daptomycin resistance.
    Electronic ISSN: 1759-6653
    Topics: Biology
    Published by Oxford University Press
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  • 9
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    Smarcal1 promotes double-strand-break repair by nonhomologous end-joining (2015)
    Oxford University Press
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    Publication Date: 2015-07-25
    Description: Smarcal1 is a SWI/SNF-family protein with an ATPase domain involved in DNA-annealing activities and a binding site for the RPA single-strand-DNA-binding protein. Although the role played by Smarcal1 in the maintenance of replication forks has been established, it remains unknown whether Smarcal1 contributes to genomic DNA maintenance outside of the S phase. We disrupted the SMARCAL1 gene in both the chicken DT40 and the human TK6 B cell lines. The resulting SMARCAL1 –/– clones exhibited sensitivity to chemotherapeutic topoisomerase 2 inhibitors, just as nonhomologous end-joining (NHEJ) null-deficient cells do. SMARCAL1 –/– cells also exhibited an increase in radiosensitivity in the G 1 phase. Moreover, the loss of Smarcal1 in NHEJ null-deficient cells does not further increase their radiosensitivity. These results demonstrate that Smarcal1 is required for efficient NHEJ-mediated DSB repair. Both inactivation of the ATPase domain and deletion of the RPA-binding site cause the same phenotype as does null-mutation of Smarcal1, suggesting that Smarcal1 enhances NHEJ, presumably by interacting with RPA at unwound single-strand sequences and then facilitating annealing at DSB ends. SMARCAL1 –/– cells showed a poor accumulation of Ku70/DNA-PKcs and XRCC4 at DNA-damage sites. We propose that Smarcal1 maintains the duplex status of DSBs to ensure proper recruitment of NHEJ factors to DSB sites.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 10
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    Opposing effects of substrate quality and site factors on forest floor turnover rates: an example from the tropics (2015)
    Oxford University Press
    In: Forestry
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    Publication Date: 2015-03-06
    Description: In boreal-to-cool temperate regions, there is a consistent relationship between litter quality, litter decay rates in litterbags and forest floor turnover rates across different tree functional types such as conifers and deciduous trees. This is partly due to the synergistic relationship between substrate quality and site conditions (understorey temperatures) in controlling forest floor dynamics. That is, species with higher light penetration have higher understorey temperature and litter of higher quality compared with species with lower light penetration. The findings of our study in Sarawak were partly consistent with this trend, with substrate quality, microbial respiration and mass loss rates of the litter in litterbags being higher for pioneer species from a young secondary forest (YSF) than for climax species from a primary forest (PF). However, the microbial respiration in the forest floor and its turnover rate were lower in the YSF with lower forest floor water content than those in the PF. This discrepancy was explained by the opposing relationship between substrate quality and site conditions (forest floor moisture). That is, in the YSF, the favourable effects of substrate quality on decomposition were overridden by the unfavourable effects of forest floor moisture and the reverse was the case in the PF. It was concluded that the relationship between substrate quality and site factors (synergistic vs. opposing) in controlling decomposition is macroclimate dependent and that the power of substrate quality for predicting forest floor dynamics is lower in the tropics than that in boreal-to-cool temperate regions.
    Print ISSN: 0015-752X
    Electronic ISSN: 1464-3626
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition
    Published by Oxford University Press
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