Phenotype-based genetic association studies (PGAS) - towards understanding the contribution of common genetic variants to schizophrenia subphenotypes

Neuropsychiatric diseases ranging from schizophrenia to affective disorders and autism are heritable, highly complex and heterogeneous conditions, diagnosed purely clinically, with no supporting biomarkers or neuroimaging criteria. Relying on these “umbrella diagnoses”, genetic analyses, including genome-wide association studies (GWAS), were undertaken but failed to provide insight into the biological basis of these disorders. “Risk genotypes” of unknown significance with low odds ratios of mostly <1.2 were extracted and confirmed by including ever increasing numbers of individuals in large multicenter efforts. Facing these results, we have to hypothesize that thousands of genetic constellations in highly variable combinations with environmental co-factors can cause the individual disorder in the sense of a final common pathway. This would explain why the prevalence of mental diseases is so high and why mutations, including copy number variations, with a higher effect size than SNPs, constitute only a small part of variance. Elucidating the contribution of normal genetic variation to (disease) phenotypes, and so re-defining disease entities, will be extremely labor-intense but crucial. We have termed this approach PGAS (“phenotype-based genetic association studies”). Ultimate goal is the definition of biological subgroups of mental diseases. For that purpose, the GRAS (Göttingen Research Association for Schizophrenia) data collection was initiated in 2005. With >3000 phenotypical data points per patient, it comprises the world-wide largest currently available schizophrenia database (N > 1200), combining genome-wide SNP coverage and deep phenotyping under highly standardized conditions. First PGAS results on normal genetic variants, relevant for e.g., cognition or catatonia, demonstrated proof-of-concept. Presently, an autistic subphenotype of schizophrenia is being defined where an unfortunate accumulation of normal genotypes, so-called pro-autistic variants of synaptic genes, explains part of the phenotypical variance. Deep phenotyping and comprehensive clinical data sets, however, are expensive and it may take years before PGAS will complement conventional GWAS approaches in psychiatric genetics

A myofibrillar protein of insect muscle related to vertebrate titin connects Z band and A band: Purification and molecular characterization of invertebrate mini-titin.

We show that myofibrils of insect flight and leg muscle contain a doublet of polypeptides with apparent molecular weights of 700K (K = 10(3) Mr) (Hmp I) and 600K (Hmp II), respectively. In Locusta migratoria high ionic strength extraction solubilizes only Hmp II, which is readily purified in native form. It probably reflects a proteolytic derivative of the non-extractable Hmp I. On the basis of its viscosity radius and sedimentation coefficient, Hmp II has a molecular weight of 600K and seems to consist of a single polypeptide chain. The highly asymmetric structure of the molecule is confirmed by rotary shadowing. The flexible rods have a uniform diameter of 3–4 nm and an average length of 260 nm. Polyclonal antibodies show cross-reactivity between Hmp II and its putative precursor Hmp I. We discuss the similarities and differences between the larger titin I/titin II of vertebrate sarcomeric muscle and the smaller Hmp I/Hmp II of invertebrate muscle and conclude that the latter may reflect a mini-titin. In line with the smaller length, immunoelectron microscopy locates the insect mini-titin to the I band and a very short portion of the A band only, while vertebrate titin is known to connect the Z band to the M band. Mini-titin has also been purified from several other insects including Drosophila. Immunofluorescence microscopy on frozen sections shows that mini-titin is present in the sarcomeric muscles of various species from different invertebrate phyla. These include Annelida, Nematomorpha, Plathelmintha, Nemertea and Nematoda like Ascaris lumbricoides and Caenorhabditis elegans. This wide-spread occurrence of invertebrate mini-titin is confirmed by immunoblotting experiments

Brain energy metabolism: conserved functions of glycolytic glial cells

The discovery in mammals that axons are metabolically supported by myelinating glial cells explains why neurons can extend meters in length. In this issue, Volkenhoff et al. (2015) show that, in Drosophila, the transfer of lactate from the glial to the neuronal compartment is conserved in evolution, independent of body size

Investigation of the relation between local diffusivity and local inherent structures in the Kob-Andersen Lennard-Jones model

We analyze one thousand independent equilibrium trajectories of a system of 155 Lennard Jones particles to separate in a model-free approach the role of temperature and the role of the explored potential energy landscape basin depth in the particle dynamics. We show that the diffusion coefficient $D$ can be estimated as a sum over over contributions of the sampled basins, establishing a connection between thermodynamics and dynamics in the potential energy landscape framework. We provide evidence that the observed non-linearity in the relation between local diffusion and basin depth is responsible for the peculiar dynamic behavior observed in supercooled states and provide an interpretation for the presence of dynamic heterogeneities.Comment: minor text changes, references adde

Distinct mechanisms of Drosophila CRYPTOCHROME-mediated light-evoked membrane depolarization and in vivo clock resetting.

Drosophila CRYPTOCHROME (dCRY) mediates electrophysiological depolarization and circadian clock resetting in response to blue or ultraviolet (UV) light. These light-evoked biological responses operate at different timescales and possibly through different mechanisms. Whether electron transfer down a conserved chain of tryptophan residues underlies biological responses following dCRY light activation has been controversial. To examine these issues in in vivo and in ex vivo whole-brain preparations, we generated transgenic flies expressing tryptophan mutant dCRYs in the conserved electron transfer chain and then measured neuronal electrophysiological phototransduction and behavioral responses to light. Electrophysiological-evoked potential analysis shows that dCRY mediates UV and blue-light-evoked depolarizations that are long lasting, persisting for nearly a minute. Surprisingly, dCRY appears to mediate red-light-evoked depolarization in wild-type flies, absent in both cry-null flies, and following acute treatment with the flavin-specific inhibitor diphenyleneiodonium in wild-type flies. This suggests a previously unsuspected functional signaling role for a neutral semiquinone flavin state (FADH•) for dCRY. The W420 tryptophan residue located closest to the FAD-dCRY interaction site is critical for blue- and UV-light-evoked electrophysiological responses, while other tryptophan residues within electron transfer distance to W420 do not appear to be required for light-evoked electrophysiological responses. Mutation of the dCRY tryptophan residue W342, more distant from the FAD interaction site, mimics the cry-null behavioral light response to constant light exposure. These data indicate that light-evoked dCRY electrical depolarization and clock resetting are mediated by distinct mechanisms

Repetitive titin epitopes with a 42 nm spacing coincide in relative position with known A band striations also identified by major myosin-associated proteins. An immunoelectron-microscopical study on myofibrils.

A direct titin-thick filament interaction in certain regions of the A band is suggested by results using four new monoclonal antibodies specific for titin in immunoelectron microscopy. Antibodies T30, T31 and T32 identify quasi-repeats in the titin molecule characterized by a 42–43 nm repeat spacing. These stripes seem to coincide with striations established by others on negatively stained cryosections of the A band. Antibodies T30 and T32 recognize epitopes matching five or two of the seven striations per half sacromere known to harbor both the myosin-associated C-protein and an 86K (K = 10(3) Mr) protein. Antibody T31 labels two stripes in the P zone, which correspond to the two positions where decoration is seen with 86K protein, but not with C-protein. The single titin epitope defined by antibody T33 is located 55 nm prior to the center of the M band. This position seems to coincide with the M7 striation defined by others on negatively stained A bands. The T33 epitope position proves that the titin molecule, which is known to be anchored at the Z line, also penetrates into the complex architecture of the M band. The titin epitopes described here enable us to begin to correlate known ultrastructural aspects of the interior part of the A band with the disposition of the titin molecule in the sarcomere. They raise the question of whether there is a regular interaction pattern between titin and the thick filaments

Monte Carlo Simulations of Globular Cluster Evolution - II. Mass Spectra, Stellar Evolution and Lifetimes in the Galaxy

We study the dynamical evolution of globular clusters using our new 2-D Monte Carlo code, and we calculate the lifetimes of clusters in the Galactic environment. We include the effects of a mass spectrum, mass loss in the Galactic tidal field, and stellar evolution. We consider initial King models containing N = 10^5 - 3x10^5 stars, and follow the evolution up to core collapse, or disruption, whichever occurs first. We find that the lifetimes of our models are significantly longer than those obtained using 1-D Fokker-Planck (F-P) methods. We also find that our results are in very good agreement with recent 2-D F-P calculations, for a wide range of initial conditions. Our results show that the direct mass loss due to stellar evolution can significantly accelerate the mass loss through the tidal boundary, causing most clusters with a low initial central concentration (Wo <~ 3) to disrupt quickly in the Galactic tidal field. Only clusters born with high initial central concentrations (Wo >~ 7) or steep initial mass functions are likely to survive to the present and undergo core collapse. We also study the orbital characteristics of escaping stars, and find that the velocity distribution of escaping stars in collapsing clusters looks significantly different from the distribution in disrupting clusters. We calculate the lifetime of a cluster on an eccentric orbit in the Galaxy, such that it fills its Roche lobe only at perigalacticon. We find that such an orbit can extend the lifetime by at most a factor of a few compared to a circular orbit in which the cluster fills its Roche lobe at all times.Comment: 32 pages, including 10 figures, to appear in ApJ, minor corrections onl