The Interaction of Genetic Background and Mutational Effects in Regulation of Mouse Craniofacial Shape.

Inbred genetic background significantly influences the expression of phenotypes associated with known genetic perturbations and can underlie variation in disease severity between individuals with the same mutation. However, the effect of epistatic interactions on the development of complex traits, such as craniofacial morphology, is poorly understood. Here, we investigated the effect of three inbred backgrounds (129X1/SvJ, C57BL/6J, and FVB/NJ) on the expression of craniofacial dysmorphology in mice (Mus musculus) with loss of function in three members of the Sprouty family of growth factor negative regulators (Spry1, Spry2, or Spry4) in order to explore the impact of epistatic interactions on skull morphology. We found that the interaction of inbred background and the Sprouty genotype explains as much craniofacial shape variation as the Sprouty genotype alone. The most severely affected genotypes display a relatively short and wide skull, a rounded cranial vault, and a more highly angled inferior profile. Our results suggest that the FVB background is more resilient to Sprouty loss of function than either C57 or 129, and that Spry4 loss is generally less severe than loss of Spry1 or Spry2 While the specific modifier genes responsible for these significant background effects remain unknown, our results highlight the value of intercrossing mice of multiple inbred backgrounds to identify the genes and developmental interactions that modulate the severity of craniofacial dysmorphology. Our quantitative results represent an important first step toward elucidating genetic interactions underlying variation in robustness to known genetic perturbations in mice

Self-Referential Noise and the Synthesis of Three-Dimensional Space

Generalising results from Godel and Chaitin in mathematics suggests that self-referential systems contain intrinsic randomness. We argue that this is relevant to modelling the universe and show how three-dimensional space may arise from a non-geometric order-disorder model driven by self-referential noise.Comment: Figure labels correcte

Genetics of murine craniofacial morphology: diallel analysis of the eight founders of the Collaborative Cross

Using eight inbred founder strains of the mouse Collaborative Cross (CC) project and their reciprocal F1 hybrids, we quantified variation in craniofacial morphology across mouse strains, explored genetic contributions to craniofacial variation that distinguish the founder strains, and tested whether specific or summary measures of craniofacial shape display stronger additive genetic contributions. This study thus provides critical information about phenotypic diversity among CC founder strains and about the genetic contributions to this phenotypic diversity, which is relevant to understanding the basis of variation in standard laboratory strains and natural populations. Craniofacial shape was quantified as a series of size-adjusted linear dimensions (RDs) and by principal components (PC) analysis of morphological landmarks captured from computed tomography images from 62 out of the 64 reciprocal crosses of the CC founder strains. We first identified aspects of skull morphology that vary between these phenotypically ‘normal’ founder strains and that are defining characteristics of these strains. We estimated the contributions of additive and various non-additive genetic factors to phenotypic variation using diallel analyses of a subset of these strongly differing RDs and the first 8 PCs of skull shape variation. We find little difference in the genetic contributions to RD measures and PC scores, suggesting fundamental similarities in the magnitude of genetic contributions to both specific and summary measures of craniofacial phenotypes. Our results indicate that there are stronger additive genetic effects associated with defining phenotypic characteristics of specific founder strains, suggesting these distinguishing measures are good candidates for use in genotype-phenotype association studies of CC mice. Our results add significantly to understanding of genotype-phenotype associations in the skull, which serve as a foundation for modeling the origins of medically and evolutionarily relevant variation

The host galaxies of luminous quasars

We present results of a deep HST/WFPC2 imaging study of 17 quasars at z~0.4, designed to determine the properties of their host galaxies. The sample consists of quasars with absolute magnitudes in the range -24>M_V>-28, allowing us to investigate host galaxy properties across a decade in quasar luminosity, but at a single redshift. We find that the hosts of all the RLQs, and all the RQQs with nuclear luminosities M_V<-24, are massive bulge-dominated galaxies, confirming and extending the trends deduced from our previous studies. From the best-fitting model host galaxies we have estimated spheroid and black-hole masses, and the efficiency (with respect to Eddington luminosity) with which each quasar is radiating. The largest inferred black-hole mass in our sample is \~3.10^9 M_sun, comparable to those at the centres of M87 and Cygnus A. We find no evidence for super-Eddington accretion in even the most luminous objects. We investigate the role of scatter in the black-hole:spheroid mass relation in determining the ratio of quasar to host-galaxy luminosity, by generating simulated populations of quasars lying in hosts with a Schechter mass function. Within the subsample of the highest luminosity quasars, the observed variation in nuclear-host luminosity ratio is consistent with being the result of the scatter in the black-hole:spheroid relation. Quasars with high nuclear-host ratios can be explained by sub-Eddington accretion onto black holes in the high-mass tail of the black-hole:spheroid relation. Our results imply that, owing to the Schechter cutoff, host mass should not continue to increase linearly with quasar luminosity, at the very highest luminosities. Any quasars more luminous than M_V=-27 should be found in massive elliptical hosts which at the present day would have M_V ~ -24.5.Comment: Accepted for publication in MNRAS. 18 pages; 7 figures and 17 greyscale images are reproduced here at low quality due to space limitations. High-resolution figures are available from ftp://ftp.roe.ac.uk/pub/djef/preprints/floyd2004

The WiggleZ Dark Energy Survey: the growth rate of cosmic structure since redshift z=0.9

We present precise measurements of the growth rate of cosmic structure for the redshift range 0.1 < z < 0.9, using redshift-space distortions in the galaxy power spectrum of the WiggleZ Dark Energy Survey. Our results, which have a precision of around 10% in four independent redshift bins, are well-fit by a flat LCDM cosmological model with matter density parameter Omega_m = 0.27. Our analysis hence indicates that this model provides a self-consistent description of the growth of cosmic structure through large-scale perturbations and the homogeneous cosmic expansion mapped by supernovae and baryon acoustic oscillations. We achieve robust results by systematically comparing our data with several different models of the quasi-linear growth of structure including empirical models, fitting formulae calibrated to N-body simulations, and perturbation theory techniques. We extract the first measurements of the power spectrum of the velocity divergence field, P_vv(k), as a function of redshift (under the assumption that P_gv(k) = -sqrt[P_gg(k) P_vv(k)] where g is the galaxy overdensity field), and demonstrate that the WiggleZ galaxy-mass cross-correlation is consistent with a deterministic (rather than stochastic) scale-independent bias model for WiggleZ galaxies for scales k < 0.3 h/Mpc. Measurements of the cosmic growth rate from the WiggleZ Survey and other current and future observations offer a powerful test of the physical nature of dark energy that is complementary to distance-redshift measures such as supernovae and baryon acoustic oscillations.Comment: 17 pages, 11 figures, accepted for publication by MNRA

Activation of p38 MAPK pathway in the skull abnormalities of Apert syndrome Fgfr2+P253R mice

<p>Abstract</p> <p>Background</p> <p>Apert syndrome is characterized by craniosynostosis and limb abnormalities and is primarily caused by FGFR2 +/P253R and +/S252W mutations. The former mutation is present in approximately one third whereas the latter mutation is present in two-thirds of the patients with this condition. We previously reported an inbred transgenic mouse model with the Fgfr2 +/S252W mutation on the C57BL/6J background for Apert syndrome. Here we present a mouse model for the Fgfr2+/P253R mutation.</p> <p>Results</p> <p>We generated inbred <it>Fgfr2</it>^{+/<it>P253R </it>}mice on the same C56BL/6J genetic background and analyzed their skeletal abnormalities. 3D micro-CT scans of the skulls of the <it>Fgfr2</it>^{+/<it>P253R </it>}mice revealed that the skull length was shortened with the length of the anterior cranial base significantly shorter than that of the <it>Fgfr2</it>^{+/<it>S252W </it>}mice at P0. The <it>Fgfr2</it>^{+/<it>P253R </it>}mice presented with synostosis of the coronal suture and proximate fronts with disorganized cellularity in sagittal and lambdoid sutures. Abnormal osteogenesis and proliferation were observed at the developing coronal suture and long bones of the <it>Fgfr2</it>^{+/<it>P253R </it>}mice as in the <it>Fgfr2</it>^{+/<it>S252W </it>}mice. Activation of mitogen-activated protein kinases (MAPK) was observed in the <it>Fgfr2</it>^{+/<it>P253R </it>}neurocranium with an increase in phosphorylated p38 as well as ERK1/2, whereas phosphorylated AKT and PKCα were not obviously changed as compared to those of wild-type controls. There were localized phenotypic and molecular variations among individual embryos with different mutations and among those with the same mutation.</p> <p>Conclusions</p> <p>Our <it>in vivo </it>studies demonstrated that the Fgfr2 +/P253R mutation resulted in mice with cranial features that resemble those of the <it>Fgfr2</it>^{+/<it>S252W </it>}mice and human Apert syndrome. Activated p38 in addition to the ERK1/2 signaling pathways may mediate the mutant neurocranial phenotype. Though Apert syndrome is traditionally thought to be a consistent phenotype, our results suggest localized and regional variations in the phenotypes that characterize Apert syndrome.</p

The WiggleZ Dark Energy Survey: measuring the cosmic expansion history using the Alcock-Paczynski test and distant supernovae

Astronomical observations suggest that today's Universe is dominated by a dark energy of unknown physical origin. One of the most notable consequences in many models is that dark energy should cause the expansion of the Universe to accelerate: but the expansion rate as a function of time has proven very difficult to measure directly. We present a new determination of the cosmic expansion history by combining distant supernovae observations with a geometrical analysis of large-scale galaxy clustering within the WiggleZ Dark Energy Survey, using the Alcock-Paczynski test to measure the distortion of standard spheres. Our result constitutes a robust and non-parametric measurement of the Hubble expansion rate as a function of time, which we measure with 10-15% precision in four bins within the redshift range 0.1 < z < 0.9. We demonstrate that the cosmic expansion is accelerating, in a manner independent of the parameterization of the cosmological model (although assuming cosmic homogeneity in our data analysis). Furthermore, we find that this expansion history is consistent with a cosmological-constant dark energy.Comment: 13 pages, 7 figures, accepted for publication by MNRA

The WiggleZ Dark Energy Survey: Survey Design and First Data Release

The WiggleZ Dark Energy Survey is a survey of 240,000 emission line galaxies in the distant universe, measured with the AAOmega spectrograph on the 3.9-m Anglo-Australian Telescope (AAT). The target galaxies are selected using ultraviolet photometry from the GALEX satellite, with a flux limit of NUV<22.8 mag. The redshift range containing 90% of the galaxies is 0.2<z<1.0. The primary aim of the survey is to precisely measure the scale of baryon acoustic oscillations (BAO) imprinted on the spatial distribution of these galaxies at look-back times of 4-8 Gyrs. Detailed forecasts indicate the survey will measure the BAO scale to better than 2% and the tangential and radial acoustic wave scales to approximately 3% and 5%, respectively. This paper provides a detailed description of the survey and its design, as well as the spectroscopic observations, data reduction, and redshift measurement techniques employed. It also presents an analysis of the properties of the target galaxies, including emission line diagnostics which show that they are mostly extreme starburst galaxies, and Hubble Space Telescope images, which show they contain a high fraction of interacting or distorted systems. In conjunction with this paper, we make a public data release of data for the first 100,000 galaxies measured for the project.Comment: Accepted by MNRAS; this has some figures in low resolution format. Full resolution PDF version (7MB) available at http://www.physics.uq.edu.au/people/mjd/pub/wigglez1.pdf The WiggleZ home page is at http://wigglez.swin.edu.au

Observational constraints on the curvaton model of inflation

Simple curvaton models can generate a mixture of of correlated primordial adiabatic and isocurvature perturbations. The baryon and cold dark matter isocurvature modes differ only by an observationally null mode in which the two perturbations almost exactly compensate, and therefore have proportional effects at linear order. We discuss the CMB anisotropy in general mixed models, and give a simple approximate analytic result for the large scale CMB anisotropy. Working numerically we use the latest WMAP observations and a variety of other data to constrain the curvaton model. We find that models with an isocurvature contribution are not favored relative to simple purely adiabatic models. However a significant primordial totally correlated baryon isocurvature perturbation is not ruled out. Certain classes of curvaton model are thereby ruled out, other classes predict enough non-Gaussianity to be detectable by the Planck satellite. In the appendices we review the relevant equations in the covariant formulation and give series solutions for the radiation dominated era.Comment: Minor changes and corrections to match version accepted by PR