MTR-Viewer: Identifying regions within genes under purifying selection

Advances in genomic sequencing have enormous potential to revolutionise personalised medicine, however distinguishing disease-causing from benign variants remains a challenge. The increasing number of human genome and exome sequences available has revealed areas where unfavourable variation is removed through purifying selection. Here we present the MTR-Viewer, a web-server enabling easy visualisation at the gene or variant level of the Missense Tolerance Ratio (MTR), a measure of regional intolerance to missense variation calculated using variation from 220,000 exome and genome sequences. The MTR-Viewer enables exploration of MTR calculations, using different sliding windows, for over 18,000 human protein-coding genes and 85,000 alternative transcripts. Users can also view MTR scores calculated for specific ethnicities, to enable easy exploration of regions that may be under different selective pressure. The spatial distribution of population and known disease variants is also displayed on the protein’s domain structure. Intolerant regions were found to be highly enriched for ClinVar pathogenic and COSMIC somatic missense variants (Mann-Whitney U test p < 2.2x10-16). As the MTR is not biased by known domains and protein features, it can highlight functionally important regions within genes overlooked or inaccessible by traditional methods. MTR-Viewer is freely available via a user friendly web-server at http://biosig.unimelb.edu.au/mtr-viewer/.M.S. was supported by the Australian Government Research Training Program. S.P. was supported by an NHMRC R.D. Wright Career Development Fellowship (1126877). S.P. is an employee of AstraZeneca. D.B.A. was supported by the Jack Brockhoff Foundation [JBF 4186, 2016], a Newton Fund RCUK-CONFAP Grant awarded by The Medical Research Council (MRC) [MR/M026302/1]; the National Health and Medical Research Council of Australia [APP1072476]; and the Department of Biochemistry and Molecular Biology, University of Melbourne

A Theoretical Model for the Mbh−σM_{\rm bh}-\sigma Relation for Supermassive Black Holes in Galaxies

We construct a model for the formation of black holes within galactic bulges. The initial state is a slowly rotating isothermal sphere, characterized by effective transport speed \aeff and rotation rate $\Omega$. The black hole mass is determined when the centrifugal radius of the collapse flow exceeds the capture radius of the central black hole. This model reproduces the observed correlation between black hole masses and galactic velocity dispersions, \mbh \approx 10^8 M_\odot (\sigma/200 \kms)^4, where \sigma = \sqrt{2} \aeff. This model also predicts the ratio \mrat of black hole mass to host mass: \mrat $\approx$ 0.004 (\sigma/200 \kms).Comment: 9 pages, 2 figures, submitted to Astrophysical Journal Letter

Supermassive Black Holes in Active Galactic Nuclei. I. The Consistency of Black Hole Masses in Quiescent and Active Galaxies

We report the first results of a program to measure accurate stellar velocity dispersions in the bulges of the host galaxies of active galactic nuclei (AGNs) for which accurate black hole (BH) masses have been determined via reverberation mapping. We find good agreement between BH masses obtained from reverberation mapping, and from the M(BH) - sigma relation as defined by quiescent galaxies, indicating a common relationship between active and quiescent black holes and their large-scale environments.Comment: Submitted to ApJ

Dominant Nuclear Outflow Driving Mechanisms in Powerful Radio Galaxies

In order to identify the dominant nuclear outflow mechanisms in Active Galactic Nuclei, we have undertaken deep, high resolution observations of two compact radio sources (PKS 1549-79 and PKS 1345+12) with the Advanced Camera for Surveys (ACS) aboard the Hubble Space Telescope. Not only are these targets known to have powerful emission line outflows, but they also contain all the potential drivers for the outflows: relativistic jets, quasar nuclei and starbursts. ACS allows the compact nature (<0.15") of these radio sources to be optically resolved for the first time. Through comparison with existing radio maps we have seen consistency in the nuclear position angles of both the optical emission line and radio data. There is no evidence for bi-conical emission line features on the large-scale and there is a divergance in the relative position angles of the optical and radio structure. This enables us to exclude starburst driven outflows. However, we are unable to clearly distinguish between radiative AGN wind driven outflows and outflows powered by relativistic radio jets. The small scale bi-conical features, indicative of such mechanisms could be below the resolution limit of ACS, especially if aligned close to the line of sight. In addition, there may be offsets between the radio and optical nuclei induced by heavy dust obscuration, nebular continuum or scattered light from the AGN.Comment: 9 pages, 8 figures, emulateapj, ApJ Accepte

Cosmic Microwave Background Dipole induced by double inflation

The observed CMBR dipole is generally interpreted as the consequence of the peculiar motion of the Sun with respect to the reference frame of the CMBR. This article proposes an alternative interpretation in which the observed dipole is the result of isocurvature perturbations on scales larger than the present Hubble radius. These perturbations are produced in the simplest model of double inflation, depending on three parameters. The observed dipole and quadrupole can be explained in this model, while severely constraining its parameters.Comment: Latex, 9 pages, no figure, to appear in Phys. Rev.

Correlated adiabatic and isocurvature perturbations from double inflation

It is shown that double inflation (two minimally coupled massive scalar fields) can produce correlated adiabatic and isocurvature primordial perturbations. Depending on the two relevant parameters of the model, the contributions to the primordial perturbations are computed, with special emphasis on the correlation, which can be quantitatively represented by a correlation spectrum. Finally the primordial spectra are evolved numerically to obtain the CMBR anisotropy multipole expectation values. It turns out that the existence of mixing and correlation can alter very significantly the temperature fluctuation predictions.Comment: 23 pages, 7 figures, RevTex. To appear in Phys. Rev.

Inelastic Dark Matter

Many observations suggest that much of the matter of the universe is non-baryonic. Recently, the DAMA NaI dark matter direct detection experiment reported an annual modulation in their event rate consistent with a WIMP relic. However, the Cryogenic Dark Matter Search (CDMS) Ge experiment excludes most of the region preferred by DAMA. We demonstrate that if the dark matter can only scatter by making a transition to a slightly heavier state (Delta m ~ 100kev), the experiments are no longer in conflict. Moreover, differences in the energy spectrum of nuclear recoil events could distinguish such a scenario from the standard WIMP scenario. Finally, we discuss the sneutrino as a candidate for inelastic dark matter in supersymmetric theories.Comment: 20 pages, 6 figure