Gene-SCOUT: identifying genes with similar continuous trait fingerprints from phenome-wide association analyses

Large-scale phenome-wide association studies performed using densely-phenotyped cohorts such as the UK Biobank (UKB), reveal many statistically robust gene-phenotype relationships for both clinical and continuous traits. Here, we present Gene-SCOUT, a tool used to identify genes with similar continuous trait fingerprints to a gene of interest. A fingerprint reflects the continuous traits identified to be statistically associated with a gene of interest based on multiple underlying rare variant genetic architectures. Similarities between genes are evaluated by the cosine similarity measure, to capture concordant effect directionality, elucidating clusters of genes in a high dimensional space. The underlying gene-biomarker population-scale association statistics were obtained from a gene-level rare variant collapsing analysis performed on over 1500 continuous traits using 394 692 UKB participant exomes, with additional metabolomic trait associations provided through Nightingale Health''s recent study of 121 394 of these participants. We demonstrate that gene similarity estimates from Gene-SCOUT provide stronger enrichments for clinical traits compared to existing methods. Furthermore, we provide a fully interactive web-resource (http://genescout.public.cgr.astrazeneca.com) to explore the pre-calculated exome-wide similarities. This resource enables a user to examine the biological relevance of the most similar genes for Gene Ontology (GO) enrichment and UKB clinical trait enrichment statistics, as well as a detailed breakdown of the traits underpinning a given fingerprint.     

Differences in locomotor behavior correspond to different patterns of morphological selection in two species of waterfall-climbing gobiid fishes

Behavior plays an important role in mediating relationships between morphology and performance in animals and, thus, can influence how selection operates. However, to what extent can the use of specific behaviors be associated with particular types of selection on morphological traits? Laboratory selection analyses on waterfall-climbing gobiid fishes were performed to investigate how behavioral variations in locomotion can affect patterns of linear and nonlinear morphological selection. Species from sister genera (Sicyopterus stimpsoni and Sicydium punctatum) that use different climbing behaviors were exposed to similar artificial waterfalls to simulate a controlled selective regime involving the climbing of a nearly vertical slope against flowing water. Juvenile S. stimpsoni “inch up” waterfalls by alternate attachment of oral and pelvic suckers with little axial or fin movement, leading to straightforward expectations that climbing selection should favor morphologies that improve drag reduction and substrate adhesion. In contrast, juvenile S. punctatum climb using substantial axial and fin movements, complicating expectations for selection patterns and potentially promoting correlational selection. Comparisons of directional, quadratic and correlational selection coefficients for various morphological traits and trait interactions indicated that these species showed different selection patterns that generally fit these predictions. Both directional and correlational selection patterns were different between the species, and on average were stronger in S. punctatum compared to S. stimpsoni. Stronger selection in S. punctatum may be related to its climbing style that requires more integrated movement of the fins and body axis than S. stimpsoni, promoting dynamic interactions among body regions within a complicated hydrodynamic environment.     

MASSUGU2 encodes Aux/IAA19, an auxin-regulated protein that functions together with the transcriptional activator NPH4/ARF7 to regulate differential growth responses of hypocotyl and formation of lateral roots in Arabidopsis thaliana

We have isolated a dominant, auxin-insensitive mutant of Arabidopsis thaliana, massugu2 (msg2), that displays neither hypocotyl gravitropism nor phototropism, fails to maintain an apical hook as an etiolated seedling, and is defective in lateral root formation. Yet other aspects of growth and development of msg2 plants are almost normal. These characteristics of msg2 are similar to those of another auxin-insensitive mutant, non-phototropic hypocotyl4 (nph4), which is a loss-of-function mutant of AUXIN RESPONSE FACTOR7 (ARF7) (Harper et al., 2000). Map-based cloning of the MSG2 locus reveals that all four mutant alleles result in amino acid substitutions in the conserved domain II of an Auxin/Indole-3-Acetic Acid protein, IAA19. Interestingly, auxin inducibility of MSG2/IAA19 gene expression is reduced by 65% in nph4/arf7. Moreover, MSG2/IAA19 protein binds to the C-terminal domain of NPH4/ARF7 in a Saccharomyces cerevisiae (yeast) two-hybrid assay and to the whole latter protein in vitro by pull-down assay. These results suggest that MSG2/IAA19 and NPH4/ARF7 may constitute a negative feedback loop to regulate differential growth responses of hypocotyls and lateral root formation.     

Calcium-permeable AMPA receptor plasticity is mediated by subunit-specific interactions with PICK1 and NSF

A recently described form of synaptic plasticity results in dynamic changes in the calcium permeability of synaptic AMPA receptors. Since the AMPA receptor GluR2 subunit confers calcium permeability, this plasticity is thought to occur through the dynamic exchange of synaptic GluR2-lacking and GluR2-containing receptors. To investigate the molecular mechanisms underlying this calcium-permeable AMPA receptor plasticity (CARP), we examined whether AMPA receptor exchange was mediated by subunit-specific protein-protein interactions. We found that two GluR2-interacting proteins, the PDZ domain-containing Protein interacting with C kinase (PICK1) and N-ethylmaleimide sensitive fusion protein (NSF), are specifically required for CARP. Furthermore, PICK1, but not NSF, regulates the formation of extrasynaptic plasma membrane pools of GluR2-containing receptors that may be laterally mobilized into synapses during CARP. These results demonstrate that PICK1 and NSF dynamically regulate the synaptic delivery of GluR2-containing receptors during CARP and thus regulate the calcium permeability of AMPA receptors at excitatory synapses.     

Unsaturated fatty acids induce non-canonical autophagy

To obtain mechanistic insights into the cross talk between lipolysis and autophagy, two key metabolic responses to starvation, we screened the autophagy-inducing potential of a panel of fatty acids in human cancer cells. Both saturated and unsaturated fatty acids such as palmitate and oleate, respectively, triggered autophagy, but the underlying molecular mechanisms differed. Oleate, but not palmitate, stimulated an autophagic response that required an intact Golgi apparatus. Conversely, autophagy triggered by palmitate, but not oleate, required AMPK, PKR and JNK1 and involved the activation of the BECN1/PIK3C3 lipid kinase complex. Accordingly, the downregulation of BECN1 and PIK3C3 abolished palmitate-induced, but not oleate-induced, autophagy in human cancer cells. Moreover, Becn1^+/− mice as well as yeast cells and nematodes lacking the ortholog of human BECN1 mounted an autophagic response to oleate, but not palmitate. Thus, unsaturated fatty acids induce a non-canonical, phylogenetically conserved, autophagic response that in mammalian cells relies on the Golgi apparatus.     

A model for cystic endometrial hyperplasia/pyometra complex in the bitch

The objective of this study was to develop a reliable model for the study of the cystic endometrial hyperplasia and pyometra complex (CEH/P) in the bitch. Greyhound bitches (n = 15) were ovariectomised and allocated into three groups (Group 1, n = 5; Group 2, n = 5; Group 3, n = 10, including 5 used from Group 1). Simulated proestrus, estrus and diestrus were induced by treatment with estradiol benzoate and megestrol acetate. The duration of cervical opening during estrus was determined by the intra-vaginal infusion of radio-opaque medium and subsequent radiography of the uterus (Group 1). One milliliter of a culture of Escherichia coli (with five uro-pathogenic virulence factors as identified by PCR: pap, sfa, hlyA, cnf1 and fim) was inoculated intra-vaginally daily throughout the simulated estrus (Group 2). One milliliter of the culture (n = 6) or sterile Luria-Bertani broth (n = 4) was introduced directly into the uterus on simulated diestrus Days 8 or 12 (Group 3). Necropsies were performed 12 and 7-14 days after the inoculation (Groups 2 and 3). The cervix remained open throughout the duration of simulated estrus (5-6 days) in four out of five bitches, and for a shorter duration (3 days of a 6-day estrus period) in one bitch (Group 1). CEH/P was induced by inoculation of bacteria into the uterus (10/10 bitches) but not into the vagina (0/5 bitches), (P = 0.003). A model for the study of CEH/P has been validated.