IDH1(R132H) mutation increases murine haematopoietic progenitors and alters epigenetics

Mutations in the IDH1 and IDH2 genes encoding isocitrate dehydrogenases are frequently found in human glioblastomas and cytogenetically normal acute myeloid leukaemias (AML). These alterations are gain-of-function mutations in that they drive the synthesis of the ‘oncometabolite’ R-2-hydroxyglutarate (2HG). It remains unclear how IDH1 and IDH2 mutations modify myeloid cell development and promote leukaemogenesis. Here we report the characterization of conditional knock-in (KI) mice in which the most common IDH1 mutation, IDH1(R132H), is inserted into the endogenous murine Idh1 locus and is expressed in all haematopoietic cells (Vav-KI mice) or specifically in cells of the myeloid lineage (LysM-KI mice). These mutants show increased numbers of early haematopoietic progenitors and develop splenomegaly and anaemia with extramedullary haematopoiesis, suggesting a dysfunctional bone marrow niche. Furthermore, LysM-KI cells have hypermethylated histones and changes to DNA methylation similar to those observed in human IDH1- or IDH2-mutant AML. To our knowledge, our study is the first to describe the generation and characterization of conditional IDH1(R132H)-KI mice, and also the first report to demonstrate the induction of a leukaemic DNA methylation signature in a mouse model. Our report thus sheds light on the mechanistic links between IDH1 mutation and human AML.     

Massive gene decay in the leprosy bacillus

Leprosy, a chronic human neurological disease, results from infection with the obligate intracellular pathogen Mycobacterium leprae, a close relative of the tubercle bacillus. Mycobacterium leprae has the longest doubling time of all known bacteria and has thwarted every effort at culture in the laboratory. Comparing the 3.27-megabase (Mb) genome sequence of an armadillo-derived Indian isolate of the leprosy bacillus with that of Mycobacterium tuberculosis (4.41 Mb) provides clear explanations for these properties and reveals an extreme case of reductive evolution. Less than half of the genome contains functional genes but pseudogenes, with intact counterparts in M. tuberculosis, abound. Genome downsizing and the current mosaic arrangement appear to have resulted from extensive recombination events between dispersed repetitive sequences. Gene deletion and decay have eliminated many important metabolic activities including siderophore production, part of the oxidative and most of the microaerophilic and anaerobic respiratory chains, and numerous catabolic systems and their regulatory circuits.     

A superfamily of variant genes encoded in the subtelomeric region of Plasmodium vivax

The malarial parasite Plasmodium vivax causes disease in humans, including chronic infections and recurrent relapses, but the course of infection is rarely fatal, unlike that caused by Plasmodium falciparum. To investigate differences in pathogenicity between P. vivax and P. falciparum, we have compared the subtelomeric domains in the DNA of these parasites. In P. falciparum, subtelomeric domains are conserved and contain ordered arrays of members of multigene families, such as var, rif and stevor, encoding virulence determinants of cytoadhesion and antigenic variation. Here we identify, through the analysis of a continuous 155,711-base-pair sequence of a P. vivax chromosome end, a multigene family called vir, which is specific to P. vivax. The vir genes are present at about 600-1,000 copies per haploid genome and encode proteins that are immunovariant in natural infections, indicating that they may have a functional role in establishing chronic infection through antigenic variation.     

Intensified deep Pacific inflow and ventilation in Pleistocene glacial times

The production of cold, deep waters in the Southern Ocean is an important factor in the Earth's heat budget. The supply of deep water to the Pacific Ocean is presently dominated by a single source, the deep western boundary current east of New Zealand. Here we use sediment records deposited under the influence of this deep western boundary current to reconstruct deep-water properties and speed changes during the Pleistocene epoch. In physical and isotope proxies we find evidence for intensified deep Pacific Ocean inflow and ventilation during the glacial periods of the past 1.2 million years. The changes in throughflow may be directly related to an increased production of Antarctic Bottom Water during glacial times. Possible causes for such an increased bottom-water production include increasing wind strengths in the Southern Ocean or an increase in annual sea-ice formation, leaving dense water after brine rejection and thereby enhancing deep convection. We infer also that the global thermohaline circulation was perturbed significantly during the mid-Pleistocene climate transition between 0.86 and 0.45 million years ago.     

Radio source counts from the Ohio survey

The Ohio survey shows a decrease in the number of faint sources relative to the number which would be expected for a uniform, Euclidean universe. This confirms the results of the Cambridge 5C2 survey at 408 MHz, but the decrease is sharper for the Ohio counts at 1415 MHz.     

Microbialite resurgence after the Late Ordovician extinction

Microbialites, including biogenic stromatolites, thrombolites and dendrolites, were formed by various microbial mats that trapped and bound sediments or formed the locus of mineral precipitation. Microbialites were common and diverse during the Proterozoic, but declined in abundance and morphological diversity when multicellular life diversified during the Cambrian Radiation. A second decline occurred during the Ordovician Radiation of marine animals, and from then until the present microbialites have been confined largely to high-stress environments where multicellular organisms are rare. The microbialite declines in the Phanerozoic are attributed to disruption of the mats by animals. A resurgence of stromatolite abundance and size during reduced animal diversity after the Permian extinction has been documented anecdotally. Here we show, with statistical support, that a microbialite resurgence also occurred after the Late Ordovician extinction event in western North America. The resurgences were associated with loss of mat-inhibiting animals, providing insights into shallow-water community structures after extinction events.