Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia

Chromosomal aberrations are a hallmark of acute lymphoblastic leukaemia (ALL) but alone fail to induce leukaemia. To identify cooperating oncogenic lesions, we performed a genome-wide analysis of leukaemic cells from 242 paediatric ALL patients using high-resolution, single-nucleotide polymorphism arrays and genomic DNA sequencing. Our analyses revealed deletion, amplification, point mutation and structural rearrangement in genes encoding principal regulators of B lymphocyte development and differentiation in 40% of B-progenitor ALL cases. The PAX5 gene was the most frequent target of somatic mutation, being altered in 31.7% of cases. The identified PAX5 mutations resulted in reduced levels of PAX5 protein or the generation of hypomorphic alleles. Deletions were also detected in TCF3 (also known as E2A), EBF1, LEF1, IKZF1 (IKAROS) and IKZF3 (AIOLOS). These findings suggest that direct disruption of pathways controlling B-cell development and differentiation contributes to B-progenitor ALL pathogenesis. Moreover, these data demonstrate the power of high-resolution, genome-wide approaches to identify new molecular lesions in cancer.     

Non-volcanic tremor and low-frequency earthquake swarms

Non-volcanic tremor is a weak, extended duration seismic signal observed episodically on some major faults, often in conjunction with slow slip events. Such tremor may hold the key to understanding fundamental processes at the deep roots of faults, and could signal times of accelerated slip and hence increased seismic hazard. The mechanism underlying the generation of tremor and its relationship to aseismic slip are, however, as yet unresolved. Here we demonstrate that tremor beneath Shikoku, Japan, can be explained as a swarm of small, low-frequency earthquakes, each of which occurs as shear faulting on the subduction-zone plate interface. This suggests that tremor and slow slip are different manifestations of a single process.     

Gating pore current in an inherited ion channelopathy

Ion channelopathies are inherited diseases in which alterations in control of ion conductance through the central pore of ion channels impair cell function, leading to periodic paralysis, cardiac arrhythmia, renal failure, epilepsy, migraine and ataxia. Here we show that, in contrast with this well-established paradigm, three mutations in gating-charge-carrying arginine residues in an S4 segment that cause hypokalaemic periodic paralysis induce a hyperpolarization-activated cationic leak through the voltage sensor of the skeletal muscle Na(V)1.4 channel. This 'gating pore current' is active at the resting membrane potential and closed by depolarizations that activate the voltage sensor. It has similar permeability to Na+, K+ and Cs+, but the organic monovalent cations tetraethylammonium and N-methyl-D-glucamine are much less permeant. The inorganic divalent cations Ba2+, Ca2+ and Zn2+ are not detectably permeant and block the gating pore at millimolar concentrations. Our results reveal gating pore current in naturally occurring disease mutations of an ion channel and show a clear correlation between mutations that cause gating pore current and hypokalaemic periodic paralysis. This gain-of-function gating pore current would contribute in an important way to the dominantly inherited membrane depolarization, action potential failure, flaccid paralysis and cytopathology that are characteristic of hypokalaemic periodic paralysis. A survey of other ion channelopathies reveals numerous examples of mutations that would be expected to cause gating pore current, raising the possibility of a broader impact of gating pore current in ion channelopathies.     

Functional diversification of closely related ARF-GEFs in protein secretion and recycling

Guanine-nucleotide exchange factors on ADP-ribosylation factor GTPases (ARF-GEFs) regulate vesicle formation in time and space by activating ARF substrates on distinct donor membranes. Mammalian GBF1 (ref. 2) and yeast Gea1/2 (ref. 3) ARF-GEFs act at Golgi membranes, regulating COPI-coated vesicle formation. In contrast, their Arabidopsis thaliana homologue GNOM (GN) is required for endosomal recycling, playing an important part in development. This difference indicates an evolutionary divergence of trafficking pathways between animals and plants, and raised the question of how endoplasmic reticulum-Golgi transport is regulated in plants. Here we demonstrate that the closest homologue of GNOM in Arabidopsis, GNOM-LIKE1 (GNL1; NM_123312; At5g39500), performs this ancestral function. GNL1 localizes to and acts primarily at Golgi stacks, regulating COPI-coated vesicle formation. Surprisingly, GNOM can functionally substitute for GNL1, but not vice versa. Our results suggest that large ARF-GEFs of the GBF1 class perform a conserved role in endoplasmic reticulum-Golgi trafficking and secretion, which is done by GNL1 and GNOM in Arabidopsis, whereas GNOM has evolved to perform an additional plant-specific function of recycling from endosomes to the plasma membrane. Duplication and diversification of ARF-GEFs in plants contrasts with the evolution of entirely new classes of ARF-GEFs for endosomal trafficking in animals, which illustrates the independent evolution of complex endosomal pathways in the two kingdoms.     

Tibetan plateau aridification linked to global cooling at the Eocene-Oligocene transition

Continental aridification and the intensification of the monsoons in Asia are generally attributed to uplift of the Tibetan plateau and to the land-sea redistributions associated with the continental collision of India and Asia, whereas some studies suggest that past changes in Asian environments are mainly governed by global climate. The most dramatic climate event since the onset of the collision of India and Asia is the Eocene-Oligocene transition, an abrupt cooling step associated with the onset of glaciation in Antarctica 34 million years ago. However, the influence of this global event on Asian environments is poorly understood. Here we use magnetostratigraphy and cyclostratigraphy to show that aridification, which is indicated by the disappearance of playa lake deposits in the northeastern Tibetan plateau, occurred precisely at the time of the Eocene-Oligocene transition. Our findings suggest that this global transition is linked to significant aridification and cooling in continental Asia recorded by palaeontological and palaeoenvironmental changes, and thus support the idea that global cooling is associated with the Eocene-Oligocene transition. We show that, with sufficient age control on the sedimentary records, global climate can be distinguished from tectonism and recognized as a major contributor to continental Asian environments.