Understanding Mammalian Genetic Systems: The Challenge of Phenotyping in the Mouse

Understanding mammalian genetic systems is predicated on the determination of the relationship between genetic variation and phenotype. Several international programmes are under way to deliver mutations in every gene in the mouse genome. The challenge for mouse geneticists is to develop approaches that will provide comprehensive phenotype datasets for these mouse mutant libraries. Several factors are critical to success in this endeavour. It will be important to catalogue assay and environment and where possible to adopt standardised procedures for phenotyping tests along with common environmental conditions to ensure comparable datasets of phenotypes. Moreover, the scale of the task underlines the need to invest in technological development improving both the speed and cost of phenotyping platforms. In addition, it will be necessary to develop new informatics standards that capture the phenotype assay as well as other factors, genetic and environmental, that impinge upon phenotype outcome

Gelsolin Plays a Role in the Actin Polymerization Complex of Hair Cell Stereocilia

A complex of proteins scaffolded by the PDZ protein, whirlin, reside at the stereocilia tip and are critical for stereocilia development and elongation. We have shown that in outer hair cells (OHCs) whirlin is part of a larger complex involving the MAGUK protein, p55, and protein 4.1R. Whirlin interacts with p55 which is expressed exclusively in outer hair cells (OHC) in both the long stereocilia that make up the stereocilia bundle proper as well as surrounding shorter microvilli that will eventually regress. In erythrocytes, p55 forms a tripartite complex with protein 4.1R and glycophorin C promoting the assembly of actin filaments and the interaction of whirlin with p55 indicates that it plays a similar role in OHC stereocilia. However, the components directly involved in actin filament regulation in stereocilia are unknown. We have investigated additional components of the whirlin interactome by identifying interacting partners to p55. We show that the actin capping and severing protein, gelsolin, is a part of the whirlin complex. Gelsolin is detected in OHC where it localizes to the tips of the shorter rows but not to the longest row of stereocilia and the pattern of localisation at the apical hair cell surface is strikingly similar to p55. Like p55, gelsolin is ablated in the whirler and shaker2 mutants. Moreover, in a gelsolin mutant, stereocilia in the apex of the cochlea become long and straggly indicating defects in the regulation of stereocilia elongation. The identification of gelsolin provides for the first time a link between the whirlin scaffolding protein complex involved in stereocilia elongation and a known actin regulatory molecule

Mice with an N-Ethyl-N-Nitrosourea (ENU) Induced Tyr209Asn Mutation in Natriuretic Peptide Receptor 3 (NPR3) Provide a Model for Kyphosis Associated with Activation of the MAPK Signaling Pathway

Non-syndromic kyphosis is a common disorder that is associated with significant morbidity and has a strong genetic involvement; however, the causative genes remain to be identified, as such studies are hampered by genetic heterogeneity, small families and various modes of inheritance. To overcome these limitations, we investigated 12 week old progeny of mice treated with the chemical mutagen N-ethyl-N-nitrosourea (ENU) using phenotypic assessments including dysmorphology, radiography, and dual-energy X-ray absorptiometry. This identified a mouse with autosomal recessive kyphosis (KYLB). KYLB mice, when compared to unaffected littermates, had: thoraco-lumbar kyphosis, larger vertebrae, and increased body length and increased bone area. In addition, female KYLB mice had increases in bone mineral content and plasma alkaline phosphatase activity. Recombination mapping localized the Kylb locus to a 5.5Mb region on chromosome 15A1, which contained 51 genes, including the natriuretic peptide receptor 3 (Npr3) gene. DNA sequence analysis of Npr3 identified a missense mutation, Tyr209Asn, which introduced an N-linked glycosylation consensus sequence. Expression of wild-type NPR3 and the KYLB-associated Tyr209Asn NPR3 mutant in COS-7 cells demonstrated the mutant to be associated with abnormal N-linked glycosylation and retention in the endoplasmic reticulum that resulted in its absence from the plasma membrane. NPR3 is a decoy receptor for C-type natriuretic peptide (CNP), which also binds to NPR2 and stimulates mitogen-activated protein kinase (MAPK) signaling, thereby increasing the number and size of hypertrophic chondrocytes. Histomorphometric analysis of KYLB vertebrae and tibiae showed delayed endochondral ossification and expansion of the hypertrophic zones of the growth plates, and immunohistochemistry revealed increased p38 MAPK phosphorylation throughout the growth plates of KYLB vertebrae. Thus, we established a model of kyphosis due to a novel NPR3 mutation, in which loss of plasma membrane NPR3 expression results in increased MAPK pathway activation, causing elongation of the vertebrae and resulting in kyphosis

Koinonia

Spotlight FeaturesSovereign Stumbling: My Life Journey to Date, Larry Crabb Conversations About Racism, Jessie Brown Anxiety: A Growing Problem in College Students, Steven M. Conn Thinking TheologicallyTeaching the Truth, Michael and Stephanie Santarosa Book ReviewsKingdom Triangle: Recover the Christian Mind, Renovate the Soul, Restore the Spirit\u27s Power (by J.P. Moreland), reviewed by Steve Ivester The Soul of a Christian University: A Field Guide for Educators (edited by Stephen T. Beers), reviewed by Kyle Lantz The Outrageous Idea of Academic Faithfullness (by Donald Opitz and Derek Melleby), reviewed by Nathan Geer I Once Was Lost: What Postmodern Skeptics Taught Us About Their Path to Jesus (by Don Everts and Doug Schaupp), reviewed by Andrew D. Rowell FeaturesThe President\u27s Corner Editor\u27s Deskhttps://pillars.taylor.edu/acsd_koinonia/1012/thumbnail.jp

KOI-54: The Kepler Discovery of Tidally Excited Pulsations and Brightenings in a Highly Eccentric Binary

Kepler observations of the star HD 187091 (KIC 8112039, hereafter KOI-54) revealed a remarkable light curve exhibiting sharp periodic brightening events every 41.8 days with a superimposed set of oscillations forming a beating pattern in phase with the brightenings. Spectroscopic observations revealed that this is a binary star with a highly eccentric orbit, e = 0.83. We are able to match the Kepler light curve and radial velocities with a nearly face-on (i = 5 degrees.5) binary star model in which the brightening events are caused by tidal distortion and irradiation of nearly identical A stars during their close periastron passage. The two dominant oscillations in the light curve, responsible for the beating pattern, have frequencies that are the 91st and 90th harmonic of the orbital frequency. The power spectrum of the light curve, after removing the binary star brightening component, reveals a large number of pulsations, 30 of which have a signal-to-noise ratio greater than or similar to 7. Nearly all of these pulsations have frequencies that are either integer multiples of the orbital frequency or are tidally split multiples of the orbital frequency. This pattern of frequencies unambiguously establishes the pulsations as resonances between the dynamic tides at periastron and the free oscillation modes of one or both of the stars. KOI-54 is only the fourth star to show such a phenomenon and is by far the richest in terms of excited modes.NASA, Science Mission DirectorateNASA NNX08AR14GEuropean Research Council under the European Community 227224W.M. Keck FoundationMcDonald Observator

Kepler-4B: A Hot Neptune-Like Planet of A G0 Star Near Main-Sequence Turnoff

Early time-series photometry from NASA's Kepler spacecraft has revealed a planet transiting the star we term Kepler-4, at R.A. = 19(h)02(m)27.(s)68, delta = +50 degrees 08'08 '' 7. The planet has an orbital period of 3.213 days and shows transits with a relative depth of 0.87 x 10(-3) and a duration of about 3.95 hr. Radial velocity (RV) measurements from the Keck High Resolution Echelle Spectrometer show a reflex Doppler signal of 9.3(-1.9)(+1.1) m s(-1), consistent with a low-eccentricity orbit with the phase expected from the transits. Various tests show no evidence for any companion star near enough to affect the light curve or the RVs for this system. From a transit-based estimate of the host star's mean density, combined with analysis of high-resolution spectra, we infer that the host star is near turnoff from the main sequence, with estimated mass and radius of 1.223(-0.091)(+0.053) M(circle dot) and 1.487(-0.084)(+0.071) R(circle dot).We estimate the planet mass and radius to be {M(P), R(P)} = {24.5 +/- 3.8 M(circle plus), 3.99 +/- 0.21 R(circle plus)}. The planet's density is near 1.9 g cm(-3); it is thus slightly denser and more massive than Neptune, but about the same size.W. M. Keck FoundationNASA's Science Mission DirectorateAstronom

Kepler-7b: A Transiting Planet with Unusually Low Density

We report the discovery and confirmation of Kepler-7b, a transiting planet with unusually low density. The mass is less than half that of Jupiter, Mp = 0.43 Mj, but the radius is fifty percent larger, Rp = 1.48 Rj. The resulting density, 0.17 g/cc, is the second lowest reported so far for an extrasolar planet. The orbital period is fairly long, P = 4.886 days, and the host star is not much hotter than the Sun, Teff = 6000 K. However, it is more massive and considerably larger than the sun, Mstar = 1.35 Msun and Rstar = 1.84 Rsun, and must be near the end of its life on the Main Sequence.Comment: 19 pages, 3 figure

Latitudinal variation in ecological opportunity and intraspecific competition indicates differences in niche variability and diet specialization of Arctic marine predators

Individual specialization (IS), where individuals within populations irrespective of age, sex, and body size are either specialized or generalized in terms of resource use, has implications on ecological niches and food web structure. Niche size and degree of IS of near‐top trophic‐level marine predators have been little studied in polar regions or with latitude. We quantified the large‐scale latitudinal variation of population‐ and individual‐level niche size and IS in ringed seals (Pusa hispida) and beluga whales (Delphinapterus leucas) using stable carbon and nitrogen isotope analysis on 379 paired ringed seal liver and muscle samples and 124 paired beluga skin and muscle samples from eight locations ranging from the low to high Arctic. We characterized both within‐ and between‐individual variation in predator niche size at each location as well as accounting for spatial differences in the isotopic ranges of potential prey. Total isotopic niche width (TINW) for populations of ringed seals and beluga decreased with increasing latitude. Higher TINW values were associated with greater ecological opportunity (i.e., prey diversity) in the prey fish community which mainly consists of Capelin (Mallotus villosus) and Sand lance (Ammodytes sp.) at lower latitudes and Arctic cod (Boreogadus saida) at high latitudes. In beluga, their dietary consistency between tissues also known as the within‐individual component (WIC) increased in a near 1:1 ratio with TINW (slope = 0.84), suggesting dietary generalization, whereas the slope (0.18) of WIC relative to TINW in ringed seals indicated a high degree of individual specialization in ringed seal populations with higher TINWs. Our findings highlight the differences in TINW and level of IS for ringed seals and beluga relative to latitude as a likely response to large‐scale spatial variation in ecological opportunity, suggesting species‐specific variation in dietary plasticity to spatial differences in prey resources and environmental conditions in a rapidly changing ecosystem

A Transiting Hot Jupiter Orbiting a Metal-Rich Star

We announce the discovery of Kepler-6b, a transiting hot Jupiter orbiting a star with unusually high metallicity, [Fe/H] = +0.34 +/- 0.04. The planet's mass is about 2/3 that of Jupiter, Mp = 0.67 Mj, and the radius is thirty percent larger than that of Jupiter, Rp = 1.32 Rj, resulting in a density of 0.35 g/cc, a fairly typical value for such a planet. The orbital period is P = 3.235 days. The host star is both more massive than the Sun, Mstar = 1.21 Msun, and larger than the Sun, Rstar = 1.39 Rsun.Comment: 12 pages, 2 figures, submitted to the Astrophysical Journal Letter