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  • Articles  (515)
  • Oxford University Press  (515)
  • American Institute of Physics (AIP)
  • Biology  (500)
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  • Articles  (515)
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  • 1
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    Molecular Evolution of the Neural Crest Regulatory Network in Ray-Finned Fish (2015)
    Oxford University Press
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    Publication Date: 2015-11-22
    Description: Gene regulatory networks (GRN) are central to developmental processes. They are composed of transcription factors and signaling molecules orchestrating gene expression modules that tightly regulate the development of organisms. The neural crest (NC) is a multipotent cell population that is considered a key innovation of vertebrates. Its derivatives contribute to shaping the astounding morphological diversity of jaws, teeth, head skeleton, or pigmentation. Here, we study the molecular evolution of the NC GRN by analyzing patterns of molecular divergence for a total of 36 genes in 16 species of bony fishes. Analyses of nonsynonymous to synonymous substitution rate ratios (d N /d S ) support patterns of variable selective pressures among genes deployed at different stages of NC development, consistent with the developmental hourglass model. Model-based clustering techniques of sequence features support the notion of extreme conservation of NC-genes across the entire network. Our data show that most genes are under strong purifying selection that is maintained throughout ray-finned fish evolution. Late NC development genes reveal a pattern of increased constraints in more recent lineages. Additionally, seven of the NC-genes showed signs of relaxation of purifying selection in the famously species-rich lineage of cichlid fishes. This suggests that NC genes might have played a role in the adaptive radiation of cichlids by granting flexibility in the development of NC-derived traits—suggesting an important role for NC network architecture during the diversification in vertebrates.
    Electronic ISSN: 1759-6653
    Topics: Biology
    Published by Oxford University Press
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  • 2
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    Transcription yield of fully 2'-modified RNA can be increased by the addition of thermostabilizing mutations to T7 RNA polymerase mutants (2015)
    Oxford University Press
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    Publication Date: 2015-08-29
    Description: On average, mutations are deleterious to proteins. Mutations conferring new function to a protein often come at the expense of protein folding or stability, reducing overall activity. Over the years, a panel of T7 RNA polymerases have been designed or evolved to accept nucleotides with modified ribose moieties. These modified RNAs have proven useful, especially in vivo , but the transcriptional yields tend to be quite low. Here we show that mutations previously shown to increase the thermal tolerance of T7 RNA polymerase can increase the activity of mutants with expanded substrate range. The resulting polymerase mutants can be used to generate 2' -O- methyl modified RNA with yields much higher than enzymes currently employed.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 3
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    Draft Genome of the Scarab Beetle Oryctes borbonicus on La Reunion Island (2016)
    Oxford University Press
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    Publication Date: 2016-07-14
    Description: Beetles represent the largest insect order and they display extreme morphological, ecological and behavioral diversity, which makes them ideal models for evolutionary studies. Here, we present the draft genome of the scarab beetle Oryctes borbonicus , which has a more basal phylogenetic position than the two previously sequenced pest species Tribolium castaneum and Dendroctonus ponderosae providing the potential for sequence polarization. Oryctes borbonicus is endemic to La Réunion, an island located in the Indian Ocean, and is the host of the nematode Pristionchus pacificus , a well-established model organism for integrative evolutionary biology. At 518 Mb, the O. borbonicus genome is substantially larger and encodes more genes than T. castaneum and D. ponderosae . We found that only 25% of the predicted genes of O. borbonicus are conserved as single copy genes across the nine investigated insect genomes, suggesting substantial gene turnover within insects. Even within beetles, up to 21% of genes are restricted to only one species, whereas most other genes have undergone lineage-specific duplications and losses. We illustrate lineage-specific duplications using detailed phylogenetic analysis of two gene families. This study serves as a reference point for insect/coleopteran genomics, although its original motivation was to find evidence for potential horizontal gene transfer (HGT) between O. borbonicus and P. pacificus . The latter was previously shown to be the recipient of multiple horizontally transferred genes including some genes from insect donors. However, our study failed to provide any clear evidence for additional HGTs between the two species.
    Electronic ISSN: 1759-6653
    Topics: Biology
    Published by Oxford University Press
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  • 4
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    INstruct: a database of high-quality 3D structurally resolved protein interactome networks (2013)
    Oxford University Press
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    Publication Date: 2013-06-06
    Description: : INstruct is a database of high-quality, 3D, structurally resolved protein interactome networks in human and six model organisms. INstruct combines the scale of available high-quality binary protein interaction data with the specificity of atomic-resolution structural information derived from co-crystal evidence using a tested interaction interface inference method. Its web interface is designed to allow for flexible search based on standard and organism-specific protein and gene-naming conventions, visualization of protein architecture highlighting interaction interfaces and viewing and downloading custom 3D structurally resolved interactome datasets. Availability: INstruct is freely available on the web at http://instruct.yulab.org with all major browsers supported. Contact: haiyuan.yu@cornell.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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  • 5
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    Most RNAs regulating ribosomal protein biosynthesis in Escherichia coli are narrowly distributed to Gammaproteobacteria (2013)
    Oxford University Press
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    Publication Date: 2013-04-02
    Description: In Escherichia coli , 12 distinct RNA structures within the transcripts encoding ribosomal proteins interact with specific ribosomal proteins to allow autogenous regulation of expression from large multi-gene operons, thus coordinating ribosomal protein biosynthesis across multiple operons. However, these RNA structures are typically not represented in the RNA Families Database or annotated in genomic sequences databases, and their phylogenetic distribution is largely unknown. To investigate the extent to which these RNA structures are conserved across eubacterial phyla, we created multiple sequence alignments representing 10 of these messenger RNA (mRNA) structures in E. coli . We find that while three RNA structures are widely distributed across many phyla of bacteria, seven of the RNAs are narrowly distributed to a few orders of Gammaproteobacteria. To experimentally validate our computational predictions, we biochemically confirmed dual L1-binding sites identified in many Firmicute species. This work reveals that RNA-based regulation of ribosomal protein biosynthesis is used in nearly all eubacterial phyla, but the specific RNA structures that regulate ribosomal protein biosynthesis in E. coli are narrowly distributed. These results highlight the limits of our knowledge regarding ribosomal protein biosynthesis regulation outside of E. coli, and the potential for alternative RNA structures responsible for regulating ribosomal proteins in other eubacteria.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 6
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    Molecular mechanism of CHRDL1-mediated X-linked megalocornea in humans and in Xenopus model (2015)
    Oxford University Press
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    Publication Date: 2015-05-09
    Description: Chordin-Like 1 ( CHRDL1 ) mutations cause non-syndromic X-linked megalocornea (XMC) characterized by enlarged anterior eye segments. Mosaic corneal degeneration, presenile cataract and secondary glaucoma are associated with XMC. Beside that CHRDL1 encodes Ventroptin, a secreted bone morphogenetic protein (BMP) antagonist, the molecular mechanism of XMC is not well understood yet. In a family with broad phenotypic variability of XMC, we identified the novel CHRDL1 frameshift mutation c.807_808delTC [p.H270Wfs*22] presumably causing CHRDL1 loss of function. Using Xenopus laevis as model organism, we demonstrate that chrdl1 is specifically expressed in the ocular tissue at late developmental stages. The chrdl1 knockdown directly resembles the human XMC phenotype and confirms CHRDL1 deficiency to cause XMC. Interestingly, secondary to this bmp4 is down-regulated in the Xenopus eyes. Moreover, phospho-SMAD1/5 is altered and BMP receptor 1A is reduced in a XMC patient. Together, we classify these observations as negative-feedback regulation due to the deficient BMP antagonism in XMC. As CHRDL1 is preferentially expressed in the limbal stem cell niche of adult human cornea, we assume that CHRDL1 plays a key role in cornea homeostasis. In conclusion, we provide novel insights into the molecular mechanism of XMC as well as into the specific role of CHRDL1 during cornea organogenesis, among others by the establishment of the first XMC in vivo model. We show that unravelling monogenic cornea disorders like XMC—with presumably disturbed cornea growth and differentiation—contribute to the identification of potential limbal stem cell niche factors that are promising targets for regenerative therapies of corneal injuries.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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  • 7
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    Loss of MITF expression during human embryonic stem cell differentiation disrupts retinal pigment epithelium development and optic vesicle cell proliferation (2014)
    Oxford University Press
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    Publication Date: 2014-11-07
    Description: Microphthalmia-associated transcription factor ( MITF ) is a master regulator of pigmented cell survival and differentiation with direct transcriptional links to cell cycle, apoptosis and pigmentation. In mouse, Mitf is expressed early and uniformly in optic vesicle (OV) cells as they evaginate from the developing neural tube, and null Mitf mutations result in microphthalmia and pigmentation defects. However, homozygous mutations in MITF have not been identified in humans; therefore, little is known about its role in human retinogenesis. We used a human embryonic stem cell (hESC) model that recapitulates numerous aspects of retinal development, including OV specification and formation of retinal pigment epithelium (RPE) and neural retina progenitor cells (NRPCs), to investigate the earliest roles of MITF. During hESC differentiation toward a retinal lineage, a subset of MITF isoforms was expressed in a sequence and tissue distribution similar to that observed in mice. In addition, we found that promoters for the MITF-A , -D and -H isoforms were directly targeted by Visual Systems Homeobox 2 (VSX2), a transcription factor involved in patterning the OV toward a NRPC fate. We then manipulated MITF RNA and protein levels at early developmental stages and observed decreased expression of eye field transcription factors, reduced early OV cell proliferation and disrupted RPE maturation. This work provides a foundation for investigating MITF and other highly complex, multi-purposed transcription factors in a dynamic human developmental model system.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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  • 8
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    Long-Term Balancing Selection in LAD1 Maintains a Missense Trans-Species Polymorphism in Humans, Chimpanzees, and Bonobos (2015)
    Oxford University Press
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    Publication Date: 2015-04-25
    Description: Balancing selection maintains advantageous genetic and phenotypic diversity in populations. When selection acts for long evolutionary periods selected polymorphisms may survive species splits and segregate in present-day populations of different species. Here, we investigate the role of long-term balancing selection in the evolution of protein-coding sequences in the Homo–Pan clade. We sequenced the exome of 20 humans, 20 chimpanzees, and 20 bonobos and detected eight coding trans-species polymorphisms (trSNPs) that are shared among the three species and have segregated for approximately 14 My of independent evolution. Although the majority of these trSNPs were found in three genes of the major histocompatibility locus cluster, we also uncovered one coding trSNP (rs12088790) in the gene LAD1 . All these trSNPs show clustering of sequences by allele rather than by species and also exhibit other signatures of long-term balancing selection, such as segregating at intermediate frequency and lying in a locus with high genetic diversity. Here, we focus on the trSNP in LAD1 , a gene that encodes for Ladinin-1, a collagenous anchoring filament protein of basement membrane that is responsible for maintaining cohesion at the dermal-epidermal junction; the gene is also an autoantigen responsible for linear IgA disease. This trSNP results in a missense change (Leucine257Proline) and, besides altering the protein sequence, is associated with changes in gene expression of LAD1 .
    Print ISSN: 0737-4038
    Electronic ISSN: 1537-1719
    Topics: Biology
    Published by Oxford University Press
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  • 9
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    The MG-RAST metagenomics database and portal in 2015 (2016)
    Oxford University Press
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    Publication Date: 2016-01-07
    Description: MG-RAST ( http://metagenomics.anl.gov ) is an open-submission data portal for processing, analyzing, sharing and disseminating metagenomic datasets. The system currently hosts over 200 000 datasets and is continuously updated. The volume of submissions has increased 4-fold over the past 24 months, now averaging 4 terabasepairs per month. In addition to several new features, we report changes to the analysis workflow and the technologies used to scale the pipeline up to the required throughput levels. To show possible uses for the data from MG-RAST, we present several examples integrating data and analyses from MG-RAST into popular third-party analysis tools or sequence alignment tools.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 10
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    Diabetogenic milieus induce specific changes in mitochondrial transcriptome and differentiation of human pancreatic islets (2015)
    Oxford University Press
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    Publication Date: 2015-08-27
    Description: In pancreatic β-cells, mitochondria play a central role in coupling glucose metabolism to insulin secretion. Chronic exposure of β-cells to metabolic stresses impairs their function and potentially induces apoptosis. Little is known on mitochondrial adaptation to metabolic stresses, i.e. high glucose, fatty acids or oxidative stress; being all highlighted in the pathogenesis of type 2 diabetes. Here, human islets were exposed for 3 days to 25 m m glucose, 0.4 m m palmitate, 0.4 m m oleate and transiently to H 2 O 2 . Culture at physiological 5.6 m m glucose served as no-stress control. Expression of mitochondrion-associated genes was quantified, including the transcriptome of mitochondrial inner membrane carriers. Targets of interest were further evaluated at the protein level. Three days after acute oxidative stress, no significant alteration in β-cell function or apoptosis was detected in human islets. Palmitate specifically increased expression of the pyruvate carriers MPC1 and MPC2, whereas the glutamate carrier GC1 and the aspartate/glutamate carrier AGC1 were down-regulated by palmitate and oleate, respectively. High glucose decreased mRNA levels of key transcription factors (HNF4A, IPF1, PPARA and TFAM) and energy-sensor SIRT1. High glucose also reduced expression of 11 mtDNA-encoded respiratory chain subunits. Interestingly, transcript levels of the carriers for aspartate/glutamate AGC2, malate DIC and malate/oxaloacetate/aspartate UCP2 were increased by high glucose, a profile suggesting important mitochondrial anaplerotic/cataplerotic activities and NADPH-generating shuttles. Chronic exposure to high glucose impaired glucose-stimulated insulin secretion, decreased insulin content, promoted caspase-3 cleavage and cell death, revealing glucotoxicity. Overall, expression profile of mitochondrion-associated genes was selectively modified by glucose, delineating a glucotoxic-specific signature.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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