Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk

A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10−8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers

Review of seismic probabilistic risk assessment and the use of sensitivity analysis

This paper presents results of sensitivity reviews performed to address a range of questions which arise in the context of seismic probabilistic risk assessment (PRA). These questions are the subject of this paper. A seismic PRA involves evalution of seismic hazard, component fragilities, and system responses. They are combined in an integrated analysis to obtain various risk measures, such as frequency of plant damage states. Calculation of these measures depends on combination of non-linear functions based on a number of parameters and assumptions used in the quantification process. Therefore it is often difficult to examine seismic PRA results and derive useful insights from them if detailed sensitivity studies are absent. This has been exempified in the process of trying to understand the role of low acceleration earthquakes in overall seismic risk. It is useful to understand, within a probabilistic framework, what uncertainties in the physical properties of the plant can be tolerated, if the risk from a safe shutdown earthquake is to be considered negligible. Seismic event trees and fault trees were developed to model the difference system and plant accident sequences. Hazard curves which represent various sites on the east coast were obtained; alternate structure and equipment fragility data were postulated. Various combinations of hazard and fragility data were analyzed. In addition, system modeling was perturbed to examine the impact upon the final results. Orders of magnitude variation were observed in the plant damage state frequency among the different cases. 7 refs

Review of seismic probabilistic risk assessment and the use of sensitivity analysis

This paper presents results of sensitivity reviews performed to address a range of questions which arise in the context of seismic probabilistic risk assessment (PRA). These questions are the subject of this paper. A seismic PRA involves evaluation of seismic hazard, component fragilities, and system responses. They are combined in an integrated analysis to obtain various risk measures, such as frequency of plant damage states. Calculation of these measures depends on combination of non-linear functions based on a number of parameters and assumptions used in the quantification process. Therefore, it is often difficult to examine seismic PRA results and derive useful insights from them if detailed sensitivity studies are absent. In a seismic PRA, sensitivity evaluations can be divided into three areas: hazard, fragility, and system modeling. As a part of the review of a standard boiling water reactor seismic PRA, a reassessment of the plant damage states frequency and a detailed sensitivity analysis were conducted. Seismic event trees and fault trees were developed to model the different system and plant accident sequences. Hazard curves which represent various sites on the east coast were obtained; alternate structure and equipment fragility data were postulated. Various combinations of hazard and fragility data were analyzed. In addition, system modeling was perturbed to examine the impact upon the final results. Orders of magnitude variation were observed in the plant damage state frequency among the different cases. 6 refs., 2 figs., 3 tabs

Testing long-term patterns of basin sedimentation by detrital zircon geochronology, Centralian Superbasin, Australia

The definitive version is available at www.blackwell-synergy.comDetrital zircon geochronology of Neoproterozoic to Devonian sedimentary rocks from the Georgina and Amadeus basins has been used to track changes in provenance that reflect the development and inversion of the former Australian Superbasin. Through much of the Neoproterozoic, sediments appear to have been predominantly derived from local sources in the Arunta and Musgrave inliers. Close similarities between the detrital age signatures of late Neoproterozoic sedimentary rocks in the two basins suggests that they were contiguous at this time. A dominant population of 1.2–1.0 Ga zircon in Early Cambrian sediments of the Amadeus Basin reflects the uplift of the Musgrave Inlier during the Petermann Orogeny between 560 and 520 Ma, which shed a large volume of detritus northwards into the Amadeus Basin. Early Cambrian sedimentary rocks in the Georgina Basin have a much smaller proportion of 1.2–1.0 Ga detritus, possibly due to the formation of sub-basins along the northern margin of the Amadeus Basin which might have acted as a barrier to sediment transfer. An influx of 0.6–0.5 Ga zircon towards the end of the Cambrian coincides with the transgression of the Larapintine Sea across central Australia, possibly as a result of intracratonic rifting. Detrital zircon age spectra of sedimentary rocks deposited within this epicontinental sea are very similar to those of coeval sedimentary rocks from the Pacific Gondwana margin, implying that sediment was transported into central Australia from the eastern continental margin. The remarkably consistent ‘Pacific Gondwana’ signature of Cambro-Ordovician sediments in central and eastern Australia reflects a distal source, possibly from east Antarctica or the East African Orogen. The peak of the marine incursion into central Australia in the early to mid Ordovician coincides with granulite-facies metamorphism at mid-crustal depths between the Amadeus and Georgina basins (the Larapinta Event). The presence of the epicontinental sea, the relative lack of a local basement zircon component in Cambro-Ordovician sedimentary rocks and their maturity suggest that metamorphism was not accompanied by mountain building, consistent with an extensional or transtensional setting for this tectonism. Sediments deposited at 435–405 and 365 Ma during the Alice Springs Orogeny have detrital age signatures similar to those of Cambro-Ordovician sedimentary rocks, reflecting uplift and reworking of the older succession into narrow foreland basins adjacent to the orogen.D. W. Maidment, I. S. Williams, M. Han

Scd5p and Clathrin Function Are Important for Cortical Actin Organization, Endocytosis, and Localization of Sla2p in Yeast

SCD5 was identified as a multicopy suppressor of clathrin HC-deficient yeast. SCD5 is essential, but an scd5-Δ338 mutant, expressing Scd5p with a C-terminal truncation of 338 amino acids, is temperature sensitive for growth. Further studies here demonstrate that scd5-Δ338 affects receptor-mediated and fluid-phase endocytosis and normal actin organization. The scd5-Δ338 mutant contains larger and depolarized cortical actin patches and a prevalence of G-actin bars. scd5-Δ338 also displays synthetic negative genetic interactions with mutations in several other proteins important for cortical actin organization and endocytosis. Moreover, Scd5p colocalizes with cortical actin. Analysis has revealed that clathrin-deficient yeast also have a major defect in cortical actin organization and accumulate G-actin. Overexpression of SCD5 partially suppresses the actin defect of clathrin mutants, whereas combining scd5-Δ338 with a clathrin mutation exacerbates the actin and endocytic phenotypes. Both Scd5p and yeast clathrin physically associate with Sla2p, a homologue of the mammalian huntingtin interacting protein HIP1 and the related HIP1R. Furthermore, Sla2p localization at the cell cortex is dependent on Scd5p and clathrin function. Therefore, Scd5p and clathrin are important for actin organization and endocytosis, and Sla2p may provide a critical link between clathrin and the actin cytoskeleton in yeast, similar to HIP1(R) in animal cells