Genesis of ancestral haplotypes: RNA modifications and reverse transcription–mediated polymorphisms

Understanding the genesis of the block haplotype structure of the genome is a major challenge. With the completion of the sequencing of the Human Genome and the initiation of the HapMap project the concept that the chromosomes of the mammalian genome are a mosaic, or patchwork, of conserved extended block haplotype sequences is now accepted by the mainstream genomics research community. Ancestral Haplotypes (AHs) can be viewed as a recombined string of smaller Polymorphic Frozen Blocks (PFBs). How have such variant extended DNA sequence tracts emerged in evolution? Here the relevant literature on the problem is reviewed from various fields of molecular and cell biology particularly molecular immunology and comparative and functional genomics. Based on our synthesis we then advance a testable molecular and cellular model. A critical part of the analysis concerns the origin of the strand biased mutation signatures in the transcribed regions of the human and higher primate genome, A-to-G versus T-to-C (ratio ~1.5 fold) and C-to-T versus G-to-A (≥1.5 fold). A comparison and evaluation of the current state of the fields of immunoglobulin Somatic Hypermutation (SHM) and Transcription-Coupled DNA Repair focused on how mutations in newly synthesized RNA might be copied back to DNA thus accounting for some of the genome-wide strand biases (e.g., the A-to-G vs T-to-C component of the strand biased spectrum). We hypothesize that the genesis of PFBs and extended AHs occurs during mutagenic episodes in evolution (e.g., retroviral infections) and that many of the critical DNA sequence diversifying events occur first at the RNA level, e.g., recombination between RNA strings resulting in tandem and dispersed RNA duplications (retroduplications), RNA mutations via adenosine-to-inosine pre-mRNA editing events as well as error prone RNA synthesis. These are then copied back into DNA by a cellular reverse transcription process (also likely to be error-prone) that we have called "reverse transcription-mediated long DNA conversion." Finally we suggest that all these activities and others can be envisaged as being brought physically under the umbrella of special sites in the nucleus involved in transcription known as "transcription factories."

Results of geophysical monitoring over a "leaking" natural analogue site in Italy

CO2 storage in the subsurface is becoming more and more attractive as a means to reduce CO2 emissions to the atmosphere and hence minimize human-induced global warming. The ability to monitor and verify these CO2 storage reservoirs is a key element for further implementation of other storage sites. Since the current sites fortunately do not appear to "leak" CO2, it is difficult to test the most suitable monitoring techniques for their ability to detect CO2 migration pathways. In this study different monitoring methods have been evaluated at a site in the Latera caldera (central Italy) where natural, thermo-metamorphically produced CO2 finds its way to the surface. The aim of the study is to identify which monitoring methods can detect the migrating CO2 and to gain understanding of the preferential migration pathways of the CO2. Different geophysical monitoring techniques have been deployed at a small, 200×500 m study area located in the centre of the caldera: 2D reflection seismics (testing different sources), 2D refraction seismics, multi-channel analysis of surface wave (MASW), ground penetrating radar (GPR), micro-gravity, magnetometer, self-potential (SP), 2D and 3D geo-electrical measurements and electro-magnetic (EM31 and EM34) measurements. Furthermore CO2 flux measurements were performed in a dense grid over the study area, and a limited number of soil gas samples collected along two profiles, to "ground-truth" the geophysical results. In general a good correlation has been observed between the different methods and the presence of CO2. Geophysical responses, especially those of the reflection seismic and magnetometer data, change markedly from one side of the proposed main fault to the other, probably linked to a sharp geological boundary. The observed fractures on the seismic data seem to correspond with the preferred migration pathways of the CO2. The GPR and resistivity measurements detect strong variations in conductivity induced by the presence of the CO2 up to about 2 and 20 m depth, respectively, as supported by the soil gas and flux measurements. © 2009 Elsevier Ltd. All rights reserved

Genomic evolution and polymorphism: Segmental duplications and haplotypes at 108 regions on 21 chromosomes

We describe here extensive, previously unknown, genomic polymorphism in 120 regions, covering 19 autosomes and both sex chromosomes. Each contains duplication within multigene clusters. Of these, 108 are extremely polymorphic with multiple haplotypes.We used the genomic matching technique (GMT), previously used to characterise the major histocompatibility complex (MHC) and regulators of complement activation (RCA).This genome-wide extension of this technique enables the examination of many underlying cis, trans and epistatic interactions responsible for phenotypic differences especially in relation to individuality, evolution and disease susceptibility.The extent of the diversity could not have been predicted and suggests a new model of primate evolution based on conservation of polymorphism rather than de novo mutation

Clinically significant chronic liver disease in people with type 2 diabetes: the Edinburgh Type 2 Diabetes Study

Background: Type 2 diabetes is an independent risk factor for chronic liver disease, however disease burden estimates and knowledge of prognostic indicators are lacking in community populations. Aims: To describe the prevalence and incidence of clinically significant chronic liver disease amongst community-based older people with Type 2 diabetes and to determine risk factors which might assist in discriminating patients with unknown prevalent or incident disease. Design: Prospective cohort study. Methods: Nine hundred and thirty-nine participants in the Edinburgh Type 2 Diabetes Study underwent investigation including liver ultrasound and non-invasive measures of non-alcoholic steatohepatitis (NASH), hepatic fibrosis and systemic inflammation. Over 6-years, cases of cirrhosis and hepatocellular carcinoma were collated from multiple sources. Results: Eight patients had known prevalent disease with 13 further unknown cases identified (prevalence 2.2%) and 15 incident cases (IR 2.9/1000 person-years). Higher levels of systemic inflammation, NASH and hepatic fibrosis markers were associated with both unknown prevalent and incident clinically significant chronic liver disease (all P < 0.001). Conclusions: Our study investigations increased the known prevalence of clinically significant chronic liver disease by over 150%, confirming the suspicion of a large burden of undiagnosed disease. The disease incidence rate was lower than anticipated but still much higher than the general population rate. The ability to identify patients both with and at risk of developing clinically significant chronic liver disease allows for early intervention and clinical monitoring strategies. Ongoing work, with longer follow-up, including analysis of rates of liver function decline, will be used to define optimal risk prediction tools

Charmless Bs→PP,PV,VVB_s\to PP, PV, VV Decays Based on the six-quark Effective Hamiltonian with Strong Phase Effects II

We provide a systematic study of charmless $B_s \to PP, PV, VV$ decays ($P$ and $V$ denote pseudoscalar and vector mesons, respectively) based on an approximate six-quark operator effective Hamiltonian from QCD. The calculation of the relevant hard-scattering kernels is carried out, the resulting transition form factors are consistent with the results of QCD sum rule calculations. By taking into account important classes of power corrections involving "chirally-enhanced" terms and the vertex corrections as well as weak annihilation contributions with non-trivial strong phase, we present predictions for the branching ratios and CP asymmetries of $B_s$ decays into PP, PV and VV final states, and also for the corresponding polarization observables in VV final states. It is found that the weak annihilation contributions with non-trivial strong phase have remarkable effects on the observables in the color-suppressed and penguin-dominated decay modes. In addition, we discuss the SU(3) flavor symmetry and show that the symmetry relations are generally respected

Functional diversity of chemokines and chemokine receptors in response to viral infection of the central nervous system.

Encounters with neurotropic viruses result in varied outcomes ranging from encephalitis, paralytic poliomyelitis or other serious consequences to relatively benign infection. One of the principal factors that control the outcome of infection is the localized tissue response and subsequent immune response directed against the invading toxic agent. It is the role of the immune system to contain and control the spread of virus infection in the central nervous system (CNS), and paradoxically, this response may also be pathologic. Chemokines are potent proinflammatory molecules whose expression within virally infected tissues is often associated with protection and/or pathology which correlates with migration and accumulation of immune cells. Indeed, studies with a neurotropic murine coronavirus, mouse hepatitis virus (MHV), have provided important insight into the functional roles of chemokines and chemokine receptors in participating in various aspects of host defense as well as disease development within the CNS. This chapter will highlight recent discoveries that have provided insight into the diverse biologic roles of chemokines and their receptors in coordinating immune responses following viral infection of the CNS

Committed Global Warming Risks Triggering Multiple Climate Tipping Points

Many scenarios for limiting global warming to 1.5°C assume planetary-scale carbon dioxide removal sufficient to exceed anthropogenic emissions, resulting in radiative forcing falling and temperatures stabilizing. However, such removal technology may prove unfeasible for technical, environmental, political, or economic reasons, resulting in continuing greenhouse gas emissions from hard-to-mitigate sectors. This may lead to constant concentration scenarios, where net anthropogenic emissions remain non-zero but small, and are roughly balanced by natural carbon sinks. Such a situation would keep atmospheric radiative forcing roughly constant. Fixed radiative forcing creates an equilibrium “committed” warming, captured in the concept of “equilibrium climate sensitivity.” This scenario is rarely analyzed as a potential extension to transient climate scenarios. Here, we aim to understand the planetary response to such fixed concentration commitments, with an emphasis on assessing the resulting likelihood of exceeding temperature thresholds that trigger climate tipping points. We explore transients followed by respective equilibrium committed warming initiated under low to high emission scenarios. We find that the likelihood of crossing the 1.5°C threshold and the 2.0°C threshold is 83% and 55%, respectively, if today's radiative forcing is maintained until achieving equilibrium global warming. Under the scenario that best matches current national commitments (RCP4.5), we estimate that in the transient stage, two tipping points will be crossed. If radiative forcing is then held fixed after the year 2100, a further six tipping point thresholds are crossed. Achieving a trajectory similar to RCP2.6 requires reaching net-zero emissions rapidly, which would greatly reduce the likelihood of tipping events

Sortase-Modified Cholera Toxoids Show Specific Golgi Localization

Cholera toxoid is an established tool for use in cellular tracing in neuroscience and cell biology. We use a sortase labeling approach to generate site-specific N-terminally modified variants of both the A2-B5 heterohexamer and B5 pentamer forms of the toxoid. Both forms of the toxoid are endocytosed by GM1-positive mammalian cells, and while the heterohexameric toxoid was principally localized in the ER, the B5 pentamer showed an unexpectedly specific localization in the medial/trans-Golgi. This study suggests a future role for specifically labeled cholera toxoids in live-cell imaging beyond their current applications in neuronal tracing and labeling of lipid rafts in fixed cells

An organelle-specific protein landscape identifies novel diseases and molecular mechanisms

Contains fulltext : 158967.pdf (publisher's version ) (Open Access)Cellular organelles provide opportunities to relate biological mechanisms to disease. Here we use affinity proteomics, genetics and cell biology to interrogate cilia: poorly understood organelles, where defects cause genetic diseases. Two hundred and seventeen tagged human ciliary proteins create a final landscape of 1,319 proteins, 4,905 interactions and 52 complexes. Reverse tagging, repetition of purifications and statistical analyses, produce a high-resolution network that reveals organelle-specific interactions and complexes not apparent in larger studies, and links vesicle transport, the cytoskeleton, signalling and ubiquitination to ciliary signalling and proteostasis. We observe sub-complexes in exocyst and intraflagellar transport complexes, which we validate biochemically, and by probing structurally predicted, disruptive, genetic variants from ciliary disease patients. The landscape suggests other genetic diseases could be ciliary including 3M syndrome. We show that 3M genes are involved in ciliogenesis, and that patient fibroblasts lack cilia. Overall, this organelle-specific targeting strategy shows considerable promise for Systems Medicine