CRISPR screens identify gene targets at breast cancer risk loci

Background: Genome-wide association studies (GWAS) have identified > 200 loci associated with breast cancer risk. The majority of candidate causal variants are in noncoding regions and likely modulate cancer risk by regulating gene expression. However, pinpointing the exact target of the association, and identifying the phenotype it mediates, is a major challenge in the interpretation and translation of GWAS. Results: Here, we show that pooled CRISPR screens are highly effective at identifying GWAS target genes and defining the cancer phenotypes they mediate. Following CRISPR mediated gene activation or suppression, we measure proliferation in 2D, 3D, and in immune-deficient mice, as well as the effect on DNA repair. We perform 60 CRISPR screens and identify 20 genes predicted with high confidence to be GWAS targets that promote cancer by driving proliferation or modulating the DNA damage response in breast cells. We validate the regulation of a subset of these genes by breast cancer risk variants. Conclusions: We demonstrate that phenotypic CRISPR screens can accurately pinpoint the gene target of a risk locus. In addition to defining gene targets of risk loci associated with increased breast cancer risk, we provide a platform for identifying gene targets and phenotypes mediated by risk variants.Natasha K. Tuano, Jonathan Beesley, Murray Manning, Wei Shi, Laura Perlaza, Jimenez, Luis F. Malaver, Ortega, Jacob M. Paynter, Debra Black, Andrew Civitarese, Karen McCue, Aaron Hatzipantelis, Kristine Hillman, Susanne Kaufmann, Haran Sivakumaran, Jose M. Polo, Roger R. Reddel, Vimla Band, Juliet D. French, Stacey L. Edwards, David R. Powell, Georgia Chenevix, Trench, and Joseph Rosenblu

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

Axially symmetric continuum mechanical model for the oscillon

The oscillon is a highly localized dynamical phenomenon occurring in a thin horizontal layer of granular material, which rests on a rigid plate oscillating in the vertical direction. The geometry is axially symmetric and physically resembles a splash of liquid due to a falling drop, except that it continually perpetuates itself and does not generate a spreading wave, as is the case for a liquid splash. The oscillon moves from “peak” to “crater” and “crater” to “peak” such that the time from “peak” to “peak” or “crater” to “crater” is twice the period of the oscillating plate. The physics of granular phenomena is not properly understood, and there is no continuum mechanical theory of granular materials which is widely accepted as accurately describing their behaviour. Here for a free-flowing (cohesion-less) granular material, under axially symmetric conditions, we present a partial continuum mechanical analysis assuming the Coulomb–Mohr yield function and non-dilatant double-shearing theory. We examine small perturbations superimposed upon a purely vertical vibration, and make the assumption that throughout the motion, the lower surface of the layer remains in contact with the rigid metal plate. We show how the temporal dependence, which decouples from the spatial structure, is governed by Mathieu’s equation for the physically relevant case of the rigid plate oscillating sinusoidally, and therefore stability is determined by certain key parameters. We explore a variety of possible forms for spatial dependence. The present axially symmetric analysis complements that presented by the authors for plane strain conditions, and we find, quite remarkably, that apart from constants, both flows are governed by similar fourth-order systems of ordinary differential equations. This means that for both plane strain and axially symmetry, analogous pattern forming conditions can operate.</p

The underlying return-generating factors for REIT returns: an application of independent component analysis

Multi-factor approaches to analysis of real estate returns have, since the pioneering work of Chan, Hendershott and Sanders (1990), emphasised a macro-variables approach in preference to the latent factor approach that formed the original basis of the arbitrage pricing theory. With increasing use of high frequency data and trading strategies and with a growing emphasis on the risks of extreme events, the macro-variable procedure has some deficiencies. This paper explores a third way, with the use of an alternative to the standard principal components approach – independent components analysis (ICA). ICA seeks higher moment independence and maximises in relation to a chosen risk parameter. We apply an ICA based on kurtosis maximisation to weekly US REIT data using a kurtosis maximising algorithm. The results show that ICA is successful in capturing the kurtosis characteristics of REIT returns, offering possibilities for the development of risk management strategies that are sensitive to extreme events and tail distributions