Patterns of somatic mutation in human cancer genomes

Cancers arise owing to mutations in a subset of genes that confer growth advantage. The availability of the human genome sequence led us to propose that systematic resequencing of cancer genomes for mutations would lead to the discovery of many additional cancer genes. Here we report more than 1,000 somatic mutations found in 274 megabases (Mb) of DNA corresponding to the coding exons of 518 protein kinase genes in 210 diverse human cancers. There was substantial variation in the number and pattern of mutations in individual cancers reflecting different exposures, DNA repair defects and cellular origins. Most somatic mutations are likely to be 'passengers' that do not contribute to oncogenesis. However, there was evidence for 'driver' mutations contributing to the development of the cancers studied in approximately 120 genes. Systematic sequencing of cancer genomes therefore reveals the evolutionary diversity of cancers and implicates a larger repertoire of cancer genes than previously anticipated.     

Relative and seasonal abundance of three bark beetle predators (Coleoptera: Trogositidae, Cleridae) across an elevation gradient in ponderosa pine forests of north central Arizona

We examined abundance and flight periodicity of 3 predators of bark beetles (Coleoptera: Curculionidae, Scolytinae), Temnochila chlorodia (Mannerheim) (Coleoptera: Trogositidae), Enoclerus sphegeus (Fabricius) (Coleoptera: Cleridae), and E. lecontei (Wolcott) (Coleoptera: Cleridae), across an elevational gradient of ponderosa pine ( Pinus ponderosa Lawson) forests in north central Arizona. Predator populations were estimated at 10 sites in each of 3 elevation bands (low: 1600–1736 m; mid: 2058–2230 m; high: 2505–2651 m) for 3 years (2004–2006) using pheromone-baited funnel traps targeting 3 primary bark beetle species. We also investigated how predator abundance and flight seasonality related to those of 5 bark beetle species: Ips pini (Say), I. lecontei Swaine, Dendroctonus frontalis Zimmermann, D. brevicomis LeConte, and D. adjunctus Blandford. Temnochila chlorodia was most abundant in the low- and mid-elevation bands, whereas E. sphegeus was most abundant in the high-elevation band. Enoclerus lecontei showed no consistent elevational trend in abundance. Within each elevation band, changes in annual abundance of pooled predator species tracked shifts in abundance of pooled bark beetle species. In general, predator flight initiation coincided with or closely followed bark beetle flight initiation in the spring, but predator flight terminated before flight activity ended for most bark beetle species in the fall. In addition, the ratio of prey to predators was lowest in the summer and highest in the fall. This suggests that all bark beetle species examined may be provided temporal escape from their predators in the fall. For all 3 predator species, the pheromone-baited trap targeting D. brevicomis was less attractive than the pheromone-baited traps targeting I. pini and I. lecontei.     

The transmembrane protein meckelin (MKS3) is mutated in Meckel-Gruber syndrome and the wpk rat

Meckel-Gruber syndrome is a severe autosomal, recessively inherited disorder characterized by bilateral renal cystic dysplasia, developmental defects of the central nervous system (most commonly occipital encephalocele), hepatic ductal dysplasia and cysts and polydactyly. MKS is genetically heterogeneous, with three loci mapped: MKS1, 17q21-24 (ref. 4); MKS2, 11q13 (ref. 5) and MKS3 (ref. 6). We have refined MKS3 mapping to a 12.67-Mb interval (8q21.13-q22.1) that is syntenic to the Wpk locus in rat, which is a model with polycystic kidney disease, agenesis of the corpus callosum and hydrocephalus. Positional cloning of the Wpk gene suggested a MKS3 candidate gene, TMEM67, for which we identified pathogenic mutations for five MKS3-linked consanguineous families. MKS3 is a previously uncharacterized, evolutionarily conserved gene that is expressed at moderate levels in fetal brain, liver and kidney but has widespread, low levels of expression. It encodes a 995-amino acid seven-transmembrane receptor protein of unknown function that we have called meckelin.     

Assembly and function of the two ABC transporter proteins encoded in the human major histocompatibility complex.

Presentation of cytoplasmic antigens to class I-restricted cytotoxic T cells implied the existence of a specialized peptide transporter. For most class I heavy chains, association with peptides of the appropriate length is required for stable assembly with beta 2-microglobulin. Mutant cells RMA-S and .174/T2 neither assemble stable class I molecules nor present intracellular antigens, and we have suggested that they have lost a function required for the transport of short peptides from the cytosol to the endoplasmic reticulum. The genetic defect in .174 has been localized to a large deletion in the class II region of the major histocompatibility complex, within which two genes (RING4 and RING11) have been identified that code for 'ABC' (ATP-binding cassette) transporters. We report here that the protein products of these two genes assemble to form a complex. Defects in either protein result in the formation of unstable class I molecules and loss of presentation of intracellular antigens. The molecular defect in a new mutant, BM36.1, is shown to be in the ATP-binding domain of the RING11/PSF2 protein. This is in contrast to the mutant .134, which lacks the RING4/PSF1 protein.     

Widespread iron-rich conditions in the mid-Proterozoic ocean

The chemical composition of the ocean changed markedly with the oxidation of the Earth's surface, and this process has profoundly influenced the evolutionary and ecological history of life. The early Earth was characterized by a reducing ocean-atmosphere system, whereas the Phanerozoic eon (less than 542 million years ago) is known for a stable and oxygenated biosphere conducive to the radiation of animals. The redox characteristics of surface environments during Earth's middle age (1.8-1 billion years ago) are less well known, but it is generally assumed that the mid-Proterozoic was home to a globally sulphidic (euxinic) deep ocean. Here we present iron data from a suite of mid-Proterozoic marine mudstones. Contrary to the popular model, our results indicate that ferruginous (anoxic and Fe(2+)-rich) conditions were both spatially and temporally extensive across diverse palaeogeographic settings in the mid-Proterozoic ocean, inviting new models for the temporal distribution of iron formations and the availability of bioessential trace elements during a critical window for eukaryotic evolution.     

Inhibitory effects of LHRH on LH receptors in the rat testis]

A single injection of LHRH to the adult male rat, as of its analog [D-Ala6, des-Gly-NH102] LHRH ethylamide, resulted in a marked decrease in LH receptors in the tests. Plasma testosterone level and the weight of the seminal vesicles and prostate were also decreased after treatment. These data demonstrate that LHRH can decrease the sensitivity of LH receptors and testicular function in the rat.     

The effects of age and nutritional state on m.e.p.p. amplitude

Summary A quantitative restriction of food intake for 7 days reduced the amplitude of spontaneous miniature endplate potentials by about 1/3 in rats aged 30 days but not in rats aged 110 days.I would like to thank Dr D. V. Roberts for encouragement and advice and the Medical Research Council and the Muscular Dystrophy Group of Great Britain for financial support.