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.     

Expert judgments of political riskiness

Professional analysts' judgments of the political riskiness of 49 focal countries for the period 1983-1985 were studied. Data were collected on nine predictor variables; each was significantly correlated at the 0.01 level with ratings of political riskiness. The highest correlation was with infant mortality and life expectancy; either accounted for roughly 50% of the variance in ratings. Different variables were better predictors of political risk within different geographic regions. A factor analysis suggested the presence of three underlying factors. The predictor variable with the highest loading was chosen to represent each of the three factors. These were: exchange rate differential; estimated inflation rate; and infant mortality rate. Approximately 75% of the variance in ratings could be accounted for on the basis of a linear combination of the three predictor variables. These three variables were capable of good prediction even for various subsets of countries based on geographic region or other criteria. Using all nine variables as predictors resulted in only marginal improvement. A cluster analysis revealed little difference among clusters of judges. Ratings by undergraduate students closely paralled those of professional analysts. As in previous studies of expert predictions and forecasts, claims of expertise in political risk analysis were better supported by command of factual knowledge than by differentially superior predictive ability.     

Network modeling links breast cancer susceptibility and centrosome dysfunction

Many cancer-associated genes remain to be identified to clarify the underlying molecular mechanisms of cancer susceptibility and progression. Better understanding is also required of how mutations in cancer genes affect their products in the context of complex cellular networks. Here we have used a network modeling strategy to identify genes potentially associated with higher risk of breast cancer. Starting with four known genes encoding tumor suppressors of breast cancer, we combined gene expression profiling with functional genomic and proteomic (or 'omic') data from various species to generate a network containing 118 genes linked by 866 potential functional associations. This network shows higher connectivity than expected by chance, suggesting that its components function in biologically related pathways. One of the components of the network is HMMR, encoding a centrosome subunit, for which we demonstrate previously unknown functional associations with the breast cancer-associated gene BRCA1. Two case-control studies of incident breast cancer indicate that the HMMR locus is associated with higher risk of breast cancer in humans. Our network modeling strategy should be useful for the discovery of additional cancer-associated genes.     

In search of the tumour-suppressor functions of BRCA1 and BRCA2

Hereditary breast and ovarian cancer syndromes can be caused by loss-of-function germline mutations in one of two tumour-suppressor genes, BRCA1 and BRCA2 (ref. 1). Each gene product interacts with recombination/DNA repair proteins in pathways that participate in preserving intact chromosome structure. However, it is unclear to what extent such functions specifically suppress breast and ovarian cancer. Here we analyse what is known of BRCA gene function and highlight some unanswered questions in the field.     

Biogeographic significance of low-elevation records for Neotoma cinerea from the northern Bonneville Basin, Utah

The existence of low-elevation populations of Neotoma cinera in the northern Bonneville Basin shows either that these mammals can survive thousands of years in xeric habitats or that they can move across xeric lowlands far more readily than has been appreciated, or both. Current models of Great Basin small mammal biogeography are far too static to encompass properly the interaction of the wide range of geographical and biological variability that has produced the modern distribution of those mammals that have, for several decades, been treated as ""montane"" within the Great Basin.     

Long-term fire history in Great Basin sagebrush reconstructed from macroscopic charcoal in spring sediments, Newark Valley, Nevada

We use macroscopic charcoal analysis to reconstruct fire history in sagebrush ( Artemisia tridentata var. wyomingensis and A. tridentata var. tridentate ), in Newark Valley, Nevada. We analyzed charcoal at continuous 1-cm intervals (～7-127 years), and pollen at 2- to 10-cm intervals (～70-263 years) in a core spanning the last 5500 cal yr BP (calendar years before present). A charcoal peak in the historic period was associated with a >1400-ha fire dated to 1986 that burned in the watershed. We reconstructed the prehistoric fire history by inferring fires from similar charcoal peaks that were significantly greater than the background charcoal accumulation. Our results suggest the fire regime is climate and fuel driven. During periods of wetter climate, sagebrush increased and fires were more abundant, and during extended dry periods when sagebrush decreased, fires were less frequent. Our method does not allow calculation of a fire-return interval; however, our results support models that estimate a mean fire-return interval of up to a century in Artemisia tridentata var. wyomingensis . The charcoal record indicates that fires have increased within the historic period. This contrasts with pinyon/juniper studies that indicate an expansion of woodland associated with fewer fires in the historic period. We suggest that in the central Great Basin, a regime of frequent fires in sagebrush that limits woodland expansion is true for the sagebrush-woodland ecotone, but in sagebrush-dominated valleys with lower fuel loads, fires have always been less frequent. Protecting sagebrush-dominated valleys from frequent fire would appear to be consistent with the prehistoric fire regime.     

A function for cyclin D1 in DNA repair uncovered by protein interactome analyses in human cancers

Cyclin D1 is a component of the core cell cycle machinery. Abnormally high levels of cyclin D1 are detected in many human cancer types. To elucidate the molecular functions of cyclin D1 in human cancers, we performed a proteomic screen for cyclin D1 protein partners in several types of human tumours. Analyses of cyclin D1 interactors revealed a network of DNA repair proteins, including RAD51, a recombinase that drives the homologous recombination process. We found that cyclin D1 directly binds RAD51, and that cyclin D1-RAD51 interaction is induced by radiation. Like RAD51, cyclin D1 is recruited to DNA damage sites in a BRCA2-dependent fashion. Reduction of cyclin D1 levels in human cancer cells impaired recruitment of RAD51 to damaged DNA, impeded the homologous recombination-mediated DNA repair, and increased sensitivity of cells to radiation in vitro and in vivo. This effect was seen in cancer cells lacking the retinoblastoma protein, which do not require D-cyclins for proliferation. These findings reveal an unexpected function of a core cell cycle protein in DNA repair and suggest that targeting cyclin D1 may be beneficial also in retinoblastoma-negative cancers which are currently thought to be unaffected by cyclin D1 inhibition.     

Fanconi anemia is associated with a defect in the BRCA2 partner PALB2

The Fanconi anemia and BRCA networks are considered interconnected, as BRCA2 gene defects have been discovered in individuals with Fanconi anemia subtype D1. Here we show that a defect in the BRCA2-interacting protein PALB2 is associated with Fanconi anemia in an individual with a new subtype. PALB2-deficient cells showed hypersensitivity to cross-linking agents and lacked chromatin-bound BRCA2; these defects were corrected upon ectopic expression of PALB2 or by spontaneous reversion.     

Chernobyl radionuclides in a Black Sea sediment trap

The Chernobyl nuclear power station accident released large quantities of vaporized radionuclides, and, to a lesser extent, mechanically released small (less than 1-10 micron) aerosol particles. The total release of radioactivity is estimated to be out of the order of 1-2 x 10(18) Bq (3-5 x 10(7) Ci) not allowing for releases of the xenon and krypton gases. The 137Cs releases of 3.8 x 10(16) Bq from Chernobyl can be compared to 1.3 x 10(18) Bq 137Cs released due to atmospheric nuclear weapons testing. Chernobyl-derived radionuclides can be used as transient tracers to study physical and biogeochemical processes. Initial measurements of fallout Chernobyl radionuclides from a time-series sediment trap at 1,071 m during June-September 1986 in the southern Black Sea are presented. The specific activities of 137Cs, 144Ce and 106Ru in the trap samples (0.5-2, 4-12 and 6-13 Bq g-1) are independent of the particle flux while their relative activities reflect their rates of scavenging in the order Ce greater than Ru greater than Cs.     

Mutations in the gene encoding the 3'-5' DNA exonuclease TREX1 cause Aicardi-Goutières syndrome at the AGS1 locus

Aicardi-Goutières syndrome (AGS) presents as a severe neurological brain disease and is a genetic mimic of the sequelae of transplacentally acquired viral infection. Evidence exists for a perturbation of innate immunity as a primary pathogenic event in the disease phenotype. Here, we show that TREX1, encoding the major mammalian 3' --> 5' DNA exonuclease, is the AGS1 gene, and AGS-causing mutations result in abrogation of TREX1 enzyme activity. Similar loss of function in the Trex1(-/-) mouse leads to an inflammatory phenotype. Our findings suggest an unanticipated role for TREX1 in processing or clearing anomalous DNA structures, failure of which results in the triggering of an abnormal innate immune response.