Inherited variants of MYH associated with somatic G:C-->T:A mutations in colorectal tumors

Inherited defects of base excision repair have not been associated with any human genetic disorder, although mutations of the genes mutM and mutY, which function in Escherichia coli base excision repair, lead to increased transversions of G:C to T:A. We have studied family N, which is affected with multiple colorectal adenomas and carcinoma but lacks an inherited mutation of the adenomatous polyposis coli gene (APC) that is associated with familial adenomatous polyposis. Here we show that 11 tumors from 3 affected siblings contain 18 somatic inactivating mutations of APC and that 15 of these mutations are G:C-->A transversions--a significantly greater proportion than is found in sporadic tumors or in tumors associated with familial adenomatous polyposis. Analysis of the human homolog of mutY, MYH, showed that the siblings were compound heterozygotes for the nonconservative missense variants Tyr165Cys and Gly382Asp. These mutations affect residues that are conserved in mutY of E. coli (Tyr82 and Gly253). Tyrosine 82 is located in the pseudo-helix-hairpin-helix (HhH) motif and is predicted to function in mismatch specificity. Assays of adenine glycosylase activity of the Tyr82Cys and Gly253Asp mutant proteins with 8-oxoG:A and G:A substrates show that their activity is reduced significantly. Our findings link the inherited variants in MYH to the pattern of somatic APC mutation in family N and implicate defective base excision repair in predisposition to tumors in humans.     

A bizarre predatory dinosaur from the Late Cretaceous of Madagascar

Here we report the discovery of a small-bodied (approximately 1.8 m) predatory dinosaur from the Late Cretaceous (Maastrichtian) of Madagascar. Masiakasaurus knopfleri, gen. et sp. nov., represented by several skull elements and much of the postcranial skeleton, is unique in being the only known theropod with a highly procumbent and distinctly heterodont lower dentition. Such a derived dental morphology is otherwise unknown among dinosaurs. Numerous skeletal characteristics indicate that Masiakasaurus is a member of Abelisauroidea, an enigmatic clade of Gondwanan theropods. Previously, small-bodied abelisauroids were known only from Argentina. The occurrence of Masiakasaurus on Madagascar suggests that small-bodied abelisauroids, like their larger-bodied counterparts, were more cosmopolitan, radiating throughout much of Gondwana and paralleling the diversification of small coelurosaur theropods in Laurasia.     

Synergistic response to oncogenic mutations defines gene class critical to cancer phenotype

Understanding the molecular underpinnings of cancer is of critical importance to the development of targeted intervention strategies. Identification of such targets, however, is notoriously difficult and unpredictable. Malignant cell transformation requires the cooperation of a few oncogenic mutations that cause substantial reorganization of many cell features and induce complex changes in gene expression patterns. Genes critical to this multifaceted cellular phenotype have therefore only been identified after signalling pathway analysis or on an ad hoc basis. Our observations that cell transformation by cooperating oncogenic lesions depends on synergistic modulation of downstream signalling circuitry suggest that malignant transformation is a highly cooperative process, involving synergy at multiple levels of regulation, including gene expression. Here we show that a large proportion of genes controlled synergistically by loss-of-function p53 and Ras activation are critical to the malignant state of murine and human colon cells. Notably, 14 out of 24 'cooperation response genes' were found to contribute to tumour formation in gene perturbation experiments. In contrast, only 1 in 14 perturbations of the genes responding in a non-synergistic manner had a similar effect. Synergistic control of gene expression by oncogenic mutations thus emerges as an underlying key to malignancy, and provides an attractive rationale for identifying intervention targets in gene networks downstream of oncogenic gain- and loss-of-function mutations.     

A primitive therizinosauroid dinosaur from the Early Cretaceous of Utah

Therizinosauroids are an enigmatic group of dinosaurs known mostly from the Cretaceous period of Asia, whose derived members are characterized by elongate necks, laterally expanded pelves, small, leaf-shaped teeth, edentulous rostra and mandibular symphyses that probably bore keratinized beaks. Although more than a dozen therizinosauroid taxa are known, their relationships within Dinosauria have remained controversial because of fragmentary remains and an unusual suite of characters. The recently discovered 'feathered' therizinosauroid Beipiaosaurus from the Early Cretaceous of China helped to clarify the theropod affinities of the group. However, Beipiaosaurus is also poorly represented. Here we describe a new, primitive therizinosauroid from an extensive paucispecific bonebed at the base of the Cedar Mountain Formation (Early Cretaceous) of east-central Utah. This new taxon represents the most complete and most basal therizinosauroid yet discovered. Phylogenetic analysis of coelurosaurian theropods incorporating this taxon places it at the base of the clade Therizinosauroiden, indicating that this species documents the earliest known stage in the poorly understood transition from carnivory to herbivory within Therizinosauroidea. The taxon provides the first documentation, to our knowledge, of therizinosauroids in North America during the Early Cretaceous.     

Near-surface wetland sediments as a source of arsenic release to ground water in Asia

Tens of millions of people in south and southeast Asia routinely consume ground water that has unsafe arsenic levels. Arsenic is naturally derived from eroded Himalayan sediments, and is believed to enter solution following reductive release from solid phases under anaerobic conditions. However, the processes governing aqueous concentrations and locations of arsenic release to pore water remain unresolved, limiting our ability to predict arsenic concentrations spatially (between wells) and temporally (future concentrations) and to assess the impact of human activities on the arsenic problem. This uncertainty is partly attributed to a poor understanding of groundwater flow paths altered by extensive irrigation pumping in the Ganges-Brahmaputra delta, where most research has focused. Here, using hydrologic and (bio)geochemical measurements, we show that on the minimally disturbed Mekong delta of Cambodia, arsenic is released from near-surface, river-derived sediments and transported, on a centennial timescale, through the underlying aquifer back to the river. Owing to similarities in geologic deposition, aquifer source rock and regional hydrologic gradients, our results represent a model for understanding pre-disturbance conditions for other major deltas in Asia. Furthermore, the observation of strong hydrologic influence on arsenic behaviour indicates that release and transport of arsenic are sensitive to continuing and impending anthropogenic disturbances. In particular, groundwater pumping for irrigation, changes in agricultural practices, sediment excavation, levee construction and upstream dam installations will alter the hydraulic regime and/or arsenic source material and, by extension, influence groundwater arsenic concentrations and the future of this health problem.     

Detectable clonal mosaicism and its relationship to aging and cancer

In an analysis of 31,717 cancer cases and 26,136 cancer-free controls from 13 genome-wide association studies, we observed large chromosomal abnormalities in a subset of clones in DNA obtained from blood or buccal samples. We observed mosaic abnormalities, either aneuploidy or copy-neutral loss of heterozygosity, of >2 Mb in size in autosomes of 517 individuals (0.89%), with abnormal cell proportions of between 7% and 95%. In cancer-free individuals, frequency increased with age, from 0.23% under 50 years to 1.91% between 75 and 79 years (P = 4.8 × 10(-8)). Mosaic abnormalities were more frequent in individuals with solid tumors (0.97% versus 0.74% in cancer-free individuals; odds ratio (OR) = 1.25; P = 0.016), with stronger association with cases who had DNA collected before diagnosis or treatment (OR = 1.45; P = 0.0005). Detectable mosaicism was also more common in individuals for whom DNA was collected at least 1 year before diagnosis with leukemia compared to cancer-free individuals (OR = 35.4; P = 3.8 × 10(-11)). These findings underscore the time-dependent nature of somatic events in the etiology of cancer and potentially other late-onset diseases.