Nonadditive Genetic Effects in Animal Behavior

Heritabilities, commonly used to predict evolutionary potential, are notoriously low for behaviors. Apart from strong contributions of environmental variance in reducing heritabilities, the additive genetic components can be very low, especially when they are camouflaged by nonadditive genetic effects. We first report the heritabilities of courtship traits in founder‐flush and control populations of the housefly (Musca domestica L.). We estimated the heritability of each male and female display through the regression of the courtships involving daughters and sons (with randomly selected mates) onto the “midparental” courtship values of their parents. Overall, the average heritability was significantly higher for the parent‐daughter assays than for the parent‐son assays. We attributed the low (even negative) heritabilities to genotype‐by‐environment interactions whereby the male’s behavior is influenced by the “environment” of his mating partner’s preferences for the display, generating epistasis through indirect genetic effects. Moreover, bottlenecked lines had up to 800% of the heritability of the controls, suggesting “conversion” of additive genetic variance from nonadditive components. Second, we used line‐cross assays on separate populations that had been selected for divergence in mating behavior to identify dominance and epistasis through heterosis and outbreeding depression in courtship. Finally, our literature review confirms the prevalence of such low heritabilities (i.e., a conservative mean of 0.38) and nonadditive genetics in other behavioral repertoires (64% of the studies). We conclude that animal behavior is especially prone to the gamut of quantitative genetic complexities that can result in negative heritabilities, negative selection responses, inbreeding depression, conversion, heterosis, and outbreeding depression

Die Rolle von Cytohesinen als zytoplasmatischer EGFR-Aktivator in Adenokarzinomen der Lunge

In der Behandlung fortgeschrittener – insbesondere solider – Tumorentitäten hat sich im letzten Jahrzehnt eine entscheidende Entwicklung weg von Standard-Radio-Chemotherapie-Regimen hin zu einer personalisierten Medizin, die auf die genetischen Eigenschaften der einzelnen Tumorzelle ausgerichtet ist, abgezeichnet. Im Rahmen der aktuellen Forschung bei Bronchialkarzinomen spielen hierbei u.a. Wachstumsfaktor-rezeptoren eine bedeutende Rolle. Gemeinsam mit den Arbeitsgruppen von Prof. Dr. Michael Famulok, LIMES-Institut der Universität Bonn, und Dr. Roland Ullrich, Max Planck Institut an der medizinischen Fakultät der Universität Köln, konnten Cytohesine erstmalig als regulativ wirkende zytoplasmatische Aktivatoren des EGFR ermittelt werden, die die Rezeptoraktivierung durch eine direkte Wechselwirkung mit der zytoplasmatischen Domäne von dimerisierten EGF-Rezeptoren erhöhen und damit eine Konformationsneuanordnung – je nach dem jeweiligen Bedarf der einzelnen Zelle – erleichtern. Mittels immunhistochemischer Färbungen von Adenokarzinomzellen der Lunge konnten in meiner Arbeit die zuvor in vitro gewonnenen Ergebnisse bestätigt werden: Die Tumorzellen zeigten eine Überexpression von ARNO/Cytohesin-1; des Weiteren korrelierten diese erhöhten Expressionsraten mit einer gesteigerten Autophos-phorylierung des EGFR (pEGFR). Schließlich zeigte sich bei der immunhistochemischen Anfärbung mit Antikörpern, die gegen pAkt und pp42/pp44 gerichtet sind, dass die durch die Überexpression von ARNO/Cytohesin-1 vermittelte Aktivitätssteigerung des pEGFR auch über zwei der wichtigsten Signaltransduktionskaskaden fortgeleitet wird. Um zu demonstrieren, dass dabei pEGFR und ARNO/Cytohesin-1 auf denselben Zellen kolokalisiert sind, wurde zusätzlich eine Doppelimmunfluoreszenz-Färbung von Adenokarzinomzellen der Lunge, durchgeführt. Im Folgenden konnte im Mausmodel demonstriert werden, dass sich ARNO/Cytohesin-1 durch SecinH3, einen GEF-Antagonist gegen Cytohesine, inhibieren lässt. Hierzu wurde in Zellkulturen die Zelllinie PC9 expandiert, die athymischen männlichen Nacktmäusen subkutan injiziert wurde. Eine Hälfte der Mäuse wurde durch intraperitoneale Injektionen mit SecinH3 behandelt. Mittels FLT-PET-Bildgebung wurden die Tumorgrößen der therapierten und nicht-therapierten Mäuse verglichen; hier zeigte sich nach der Behandlung mit SecinH3 eine deutliche Verkleinerung der jeweiligen Tumore. Bei einer posttherapeutischen Analyse des Ki-67-Proliferationsindexes ließ sich eine reduzierte Wachstumsrate der Tumorzellen nachweisen. Schlussendlich ließ sich mittels der TUNEL-Methode zur Detektion von apoptotischen Tumorzellen ebenfalls ein Therapieansprechen auf SecinH3 demonstrieren. Unsere Ergebnisse belegen, dass Cytohesine eine neuartige Substanzklasse intrazellulärer EGFR-Aktivatoren darstellen, die bei einer Überexpression zu einer unkontrollierten Signalwirkung des EGFR führen können. In Zukunft könnten sie eine große pathophysiologische Bedeutung als neue Angriffsziele bei der Behandlung der EGFR-abhängigen Tumorzellen mit zielgerichteten Therapeutika, die nicht auf den Rezeptor selbst, sondern auf seine Aktivatoren gerichtet sind, besitzen

Role of IKK/NF-κB Signaling in Extinction of Conditioned Place Aversion Memory in Rats

The inhibitor κB protein kinase/nuclear factor κB (IKK/NF-κB) signaling pathway is critical for synaptic plasticity. However, the role of IKK/NF-κB in drug withdrawal-associated conditioned place aversion (CPA) memory is unknown. Here, we showed that inhibition of IKK/NF-κB by sulphasalazine (SSZ; 10 mM, i.c.v.) selectively blocked the extinction but not acquisition or expression of morphine-induced CPA in rats. The blockade of CPA extinction induced by SSZ was abolished by sodium butyrate, an inhibitor of histone deacetylase. Thus, the IKK/NF-κB signaling pathway might play a critical role in the extinction of morphine-induced CPA in rats and might be a potential pharmacotherapy target for opiate addiction

A Test of Speciation via Sexual Selection on Female Preferences

Sexual selection for divergent female preferences has been proposed to stimulate speciation. We tested this basic model by selecting for divergence in the courtship repertoire of the house fly Musca domestica L. Specifically, we subjected replicate strains to artificial selection for differentiation along the first two principal components of the phenotypic intercorrelation structure of five courtship traits. Highly significant differentiation in courtship repertoire resulted, and the magnitude of the selection response was highest along the first principal component (representing the ‘size’, or general intensity, of courtship). Videotaped matings of the crosses between divergent lines (i.e. males of one strain mating with females from a different line) showed that the selection responses in the intensities of male performances were due to shifts in female preferences. In particular, the males were able to accommodate the demands of ‘foreign’ females (as well as their own) in the no-choice situation (i.e. only one male and one female per mating chamber). In contrast to this plasticity of the males, the females were consistent in their differential resistance responses, regardless of the type of male involved in the courtship. Multiple-choice mate choice tests revealed significant reproductive isolation among some lines, although the effect was asymmetrical. The patterns of nonrandom mating were largely due to females from more genetically healthy lines (i.e. with overall high mating propensity) discriminating against males from populations with more inbreeding depression. We suggest that the inability to achieve true (symmetrical) reproductive isolation could have been due to low evolutionary potential in the ‘shape’ of courtship, as defined by the second principal component. Copyright 2002 The Association for the Study of Animal Behaviour. Published by Elsevier Science Ltd. All rights reserved

Reversed Selection Responses in Small Populations of the Housefly (\u3ci\u3eMusca domestica\u3c/i\u3e L.)

We compared the efficacy of artificial and natural selection processes in purging the genetic load of perpetually small populations. We subjected replicate lines of the housefly (Musca domestica L.), recently derived from the wild, to artificial selection for increased mating propensity (i.e., the proportion of male-female pairs initiating copulation within 30 min) in efforts to cull out the inbreeding depression effects of long-term small population size (as determined by a selection protocol for increased assortative mating). We also maintained parallel non-selection lines for assessing the spontaneous purge of genetic load due to inbreeding alone. We thus evaluated the fitness of artificially and \u27Cynaturally\u27 purging populations held at census sizes of 40 individuals over the course of 18 generations. We found that the artificially selected lines had significant increases in mating propensity (up to 46% higher from the beginning of the protocol) followed by reversed selection responses back to the initial levels, resulting in non-significant heritabilities. Nevertheless, the \u27naturally\u27 selected lines had significantly lower fitness overall (a 28% reduction from the beginning of the protocol), although lower effective population sizes could have contributed to this effect. We conclude that artificial selection bolstered fitness, but only in the short-term, because the inadvertent fixation of extant genetic load later resulted in pleiotropic fitness declines. Still, the short-term advantage of the selection protocol likely contributed to the success of the speciation experiment since our recently-derived housefly populations are particularly vulnerable to inbreeding depression effects on mating behavior

Testing Alternative Methods for Purging Genetic Load Using the Housefly (\u3ci\u3eMusca domestica\u3c/i\u3e L.)

When a population faces long-term inbreeding, artificial selection, in principle, can enhance natural selection processes for purging the exposed genetic load. However, strong purge pressures might actually decrease fitness through the inadvertent fixation of deleterious alleles and allelic combinations. We tested lines of the housefly (Musca domestica L.) for the effectiveness of artificial selection to promote the adaptation to small population size. Specifically, replicate populations were held at average census sizes of 54 for nine generations or 30 for 14 generations while being subjected to artificial selection pressure for increased fitness in overall mating propensity (i.e., the proportion of virgin male–female pairs initiating copulation within 30 min), while also undergoing selection to create differences among lines in multivariate components of courtship performance. In the 14-generation experiment, a subset of the lines were derived from a founder-flush population (i.e., derived from three male–female pairs). In both experiments, we also maintained parallel non-selection lines to assess the potential for natural purging through serial inbreeding alone. Sub-populations derived from a stock newly derived from the wild responded to artificial selection for increased mating propensity, but only in the short-term, with eventual rebounds back to the original levels. Serial inbreeding in these lines simply reduced mating propensity. In sub-populations derived from the same base population, but 36 generations later, both artificial selection and serial inbreeding increased mating propensity, but mainly to restore the level found upon establishment in the laboratory. Founder-flush lines responded as well as the non-bottlenecked controls, so we base our major conclusions on the comparisons between fresh-caught and long-term laboratory stocks. We suggest that the effectiveness of the alternative purge protocols depended upon the amount of genetic load already exposed, such that prolonged periods of relaxed or altered selection pressures of the laboratory rendered a population more responsive to purging protocols

Genetic tools for studying adaptation and the evolution of behavior

The rapid expansion of genomic and molecular genetic techniques in model organisms, and the application of these techniques to organisms that are less well studied genetically, make it possible to understand the genetic control of many behavioral phenotypes. However, many behavioral ecologists are uncertain about the value of including a genetic component in their studies. In this article, we review how genetic analyses of behavior are central to topics ranging from understanding past selection and predicting future evolution to explaining the neural and hormonal control of behavior. Furthermore, we review both new and old techniques for studying evolutionary behavior genetics and highlight how the choice of approach depends on both the question and the organism. Topics discussed include genetic architecture, detecting the past history of selection, and genotype-by-environment interactions. We show how these questions are being addressed with techniques including statistical genetics, QTL analyses, transgenic analyses, and microarrays. Many of the techniques were first applied to the behavior of genetic model organisms such as laboratory mice and flies. Two recent developments serve to expand the relevance of such studies to behavioral ecology. The first is to use model organisms for studies of the genetic basis of evolutionarily relevant behavior and the second is to apply methods developed in model genetic systems to species that have not previously been examined genetically. These conceptual advances, along with the rapid diversification of genetic tools and the recognition of widespread genetic homology, suggest a bright outlook for evolutionary genetic studies. This review provides access to tools through references to the recent literature and shows the great promise for evolutionary behavioral genetics.</p

Cytohesins are cytoplasmic ErbB receptor activators

Signaling by ErbB receptors requires the activation of their cytoplasmic kinase domains, which is initiated by ligand binding to the receptor ectodomains. Cytoplasmic factors contributing to the activation are unknown. Here we identify members of the cytohesin protein family as such factors. Cytohesin inhibition decreased ErbB receptor autophosphorylation and signaling, whereas cytohesin overexpression stimulated receptor activation. Monitoring epidermal growth factor receptor (EGFR) conformation by anisotropy microscopy together with cell-free reconstitution of cytohesin-dependent receptor autophosphorylation indicate that cytohesins facilitate conformational rearrangements in the intracellular domains of dimerized receptors. Consistent with cytohesins playing a prominent role in ErbB receptor signaling, we found that cytohesin overexpression correlated with EGF signaling pathway activation in human lung adenocarcinomas. Chemical inhibition of cytohesins resulted in reduced proliferation of EGFR-dependent lung cancer cells in vitro and in vivo. Our results establish cytohesins as cytoplasmic conformational activators of ErbB receptors that are of pathophysiological relevance