Sex-, Diet-, and Cancer-Dependent Epistatic Effects on Complex Traits in Mice

The genetic basis of quantitative traits such as body weight and obesity is complex, with several hundred quantitative trait loci (QTLs) known to affect these and related traits in humans and mice. It also has become increasingly evident that the single-locus effects of these QTLs vary considerably depending on factors such as the sex of the individuals and their dietary environment, and we were interested to know whether this context-dependency also applies to two-locus epistatic effects of QTLs as well. We therefore conducted a genome scan to search for epistatic effects on 13 different weight and adiposity traits in an F2 population of mice (created from an original intercross of the FVB strain with M16i, a polygenic obesity model) that were fed either a control or a high-fat diet and half of which harbored a transgene (PyMT) that caused the development of metastatic mammary cancer. We used a conventional interval mapping approach with SNPs to scan all 19 autosomes, and found extensive epistasis affecting all of these traits. More importantly, we also discovered that the majority of these epistatic effects exhibited significant interactions with sex, diet, and/or presence of PyMT. Analysis of these interactions showed that many of them appeared to involve QTLs previously identified as affecting these traits, but whose single-locus effects were variously modified by two-locus epistatic effects of other QTLs depending on the sex, diet, or PyMT environment. It was concluded that this context-dependency of epistatic effects is an important component of the genetic architecture of complex traits such as those contributing to weight and obesity

Experience with multiple control groups in a large population-based case–control study on genetic and environmental risk factors

We discuss the analytic and practical considerations in a large case–control study that had two control groups; the first control group consisting of partners of patients and the second obtained by random digit dialling (RDD). As an example of the evaluation of a general lifestyle factor, we present body mass index (BMI). Both control groups had lower BMIs than the patients. The distribution in the partner controls was closer to that of the patients, likely due to similar lifestyles. A statistical approach was used to pool the results of both analyses, wherein partners were analyzed with a matched analysis, while RDDs were analyzed without matching. Even with a matched analysis, the odds ratio with partner controls remained closer to unity than with RDD controls, which is probably due to unmeasured confounders in the comparison with the random controls as well as intermediary factors. However, when studying injuries as a risk factor, the odds ratio remained higher with partner control subjects than with RRD control subjects, even after taking the matching into account. Finally we used factor V Leiden as an example of a genetic risk factor. The frequencies of factor V Leiden were identical in both control groups, indicating that for the analyses of this genetic risk factor the two control groups could be combined in a single unmatched analysis. In conclusion, the effect measures with the two control groups were in the same direction, and of the same order of magnitude. Moreover, it was not always the same control group that produced the higher or lower estimates, and a matched analysis did not remedy the differences. Our experience with the intricacies of dealing with two control groups may be useful to others when thinking about an optimal research design or the best statistical approach

Surmising synchrony of sound and sight: Factors explaining variance of audiovisual integration in hurdling, tap dancing and drumming.

Auditory and visual percepts are integrated even when they are not perfectly temporally aligned with each other, especially when the visual signal precedes the auditory signal. This window of temporal integration for asynchronous audiovisual stimuli is relatively well examined in the case of speech, while other natural action-induced sounds have been widely neglected. Here, we studied the detection of audiovisual asynchrony in three different whole-body actions with natural action-induced sounds-hurdling, tap dancing and drumming. In Study 1, we examined whether audiovisual asynchrony detection, assessed by a simultaneity judgment task, differs as a function of sound production intentionality. Based on previous findings, we expected that auditory and visual signals should be integrated over a wider temporal window for actions creating sounds intentionally (tap dancing), compared to actions creating sounds incidentally (hurdling). While percentages of perceived synchrony differed in the expected way, we identified two further factors, namely high event density and low rhythmicity, to induce higher synchrony ratings as well. Therefore, we systematically varied event density and rhythmicity in Study 2, this time using drumming stimuli to exert full control over these variables, and the same simultaneity judgment tasks. Results suggest that high event density leads to a bias to integrate rather than segregate auditory and visual signals, even at relatively large asynchronies. Rhythmicity had a similar, albeit weaker effect, when event density was low. Our findings demonstrate that shorter asynchronies and visual-first asynchronies lead to higher synchrony ratings of whole-body action, pointing to clear parallels with audiovisual integration in speech perception. Overconfidence in the naturally expected, that is, synchrony of sound and sight, was stronger for intentional (vs. incidental) sound production and for movements with high (vs. low) rhythmicity, presumably because both encourage predictive processes. In contrast, high event density appears to increase synchronicity judgments simply because it makes the detection of audiovisual asynchrony more difficult. More studies using real-life audiovisual stimuli with varying event densities and rhythmicities are needed to fully uncover the general mechanisms of audiovisual integration

Dietary Fat Alters Body Composition, Mammary Development, and Cytochrome P450 Induction after Maternal TCDD Exposure in DBA/2J Mice with Low-Responsive Aryl Hydrocarbon Receptors

BackgroundIncreased fat intake is associated with obesity and may make obese individuals uniquely susceptible to the effects of lipophilic aryl hydrocarbon receptor (AHR) ligands.ObjectivesWe investigated the consequences of high-fat diet (HFD) and AHR ligands on body composition, mammary development, and hepatic P450 expression.MethodsPregnant C57BL/6J (B6) and DBA/2J (D2) dams, respectively expressing high- or low-responsive AHR, were dosed at mid-gestation with TCDD. At parturition, mice were placed on an HFD or a low-fat diet (LFD). Body fat of progeny was measured before dosing with 7,12-dimethylbenz[a]anthracene (DMBA). Fasting blood glucose was measured, and liver and mammary glands were analyzed.ResultsMaternal TCDD exposure resulted in reduced litter size in D2 mice and, on HFD, reduced postpartum survival in B6 mice. In D2 mice, HFD increased body mass and fat in off-spring, induced precocious mammary gland development, and increased AHR expression compared with mice given an LFD. Maternal TCDD exposure increased hepatic Cyp1a1 and Cyp1b1 expression in offspring on both diets, but DMBA depressed Cyp1b1 expression only in mice fed an HFD. In D2 progeny, TCDD exposure decreased mammary terminal end bud size, and DMBA exposure decreased the number of terminal end buds. Only in D2 progeny fed HFD did perinatal TCDD increase blood glucose and the size of mammary fat pads, while decreasing both branch elongation and the number of terminal end buds.ConclusionsWe conclude that despite having a low-responsive AHR, D2 progeny fed a diet similar to that consumed by most people are susceptible to TCDD and DMBA exposure effects blood glucose levels, mammary differentiation, and hepatic Cyp1 expression

Characterization of a Be(p,xn) neutron source for fission yields measurements

We report on measurements performed at The Svedberg Laboratory (TSL) to characterize a proton-neutron converter for independent fission yield studies at the IGISOL-JYFLTRAP facility (Jyv\"askyl\"a, Finland). A 30 MeV proton beam impinged on a 5 mm water-cooled Beryllium target. Two independent experimental techniques have been used to measure the neutron spectrum: a Time of Flight (TOF) system used to estimate the high-energy contribution, and a Bonner Sphere Spectrometer able to provide precise results from thermal energies up to 20 MeV. An overlap between the energy regions covered by the two systems will permit a cross-check of the results from the different techniques. In this paper, the measurement and analysis techniques will be presented together with some preliminary results.Comment: 3 pages, 3 figures, also submitted as proceedings of the International Conference on Nuclear Data for Science and Technology 201

Electron stimulated hydroxylation of a metal supported silicate film

Water adsorption on a double-layer silicate film was studied by using infrared reflection–absorption spectroscopy, thermal desorption spectroscopy and scanning tunneling microscopy. Under vacuum conditions, small amounts of silanols (Si–OH) could only be formed upon deposition of an ice-like (amorphous solid water, ASW) film and subsequent heating to room temperature. Silanol coverage is considerably enhanced by low-energy electron irradiation of an ASW pre-covered silicate film. The degree of hydroxylation can be tuned by the irradiation parameters (beam energy, exposure) and the ASW film thickness. The results are consistent with a generally accepted picture that hydroxylation occurs through hydrolysis of siloxane (Si–O–Si) bonds in the silica network. Calculations using density functional theory show that this may happen on Si–O–Si bonds, which are either parallel (i.e., in the topmost silicate layer) or vertical to the film surface (i.e., connecting two silicate layers). In the latter case, the mechanism may additionally involve the reaction with a metal support underneath. The observed vibrational spectra are dominated by terminal silanol groups (ν(OD) band at 2763 cm−1) formed by hydrolysis of vertical Si–O–Si linkages. Film dehydroxylation fully occurs only upon heating to very high temperatures (∼1200 K) and is accompanied by substantial film restructuring, and even film dewetting upon cycling hydroxylation/dehydroxylation treatment

QTL Underlying Voluntary Exercise in Mice: Interactions with the "Mini Muscle" Locus and Sex

Exercise improves many aspects of human health, yet many people remain inactive even when exercise is prescribed. We previously created a backcross (BC) between mice selectively bred for high levels of voluntary wheel running (VWR) and fixed for “mini muscle” (MM), a recessive mutation causing ∼50% reduction in triceps surae mass. We previously showed that BC mice having the MM trait ran faster and further than mice without MM and that MM maps to chromosome 11. Here, we genotyped the BC with genome-wide single nucleotide polymorphisms to identify quantitative trait loci (QTL) controlling voluntary exercise and tissue and body mass traits and to determine whether these QTL interact with the MM locus or with sex. We detected 3 VWR QTL, representing the first voluntary exercise QTL mapped using this high running selection line, and 5 tissue mass QTL. Several interactions between trait QTL and the MM locus as well as sex were also identified. These results begin to explain the genetic architecture of VWR and further support MM as a locus having major effects, including its main effects on the muscle phenotype, its pleiotropic effects on wheel running and tissue mass traits, and through its interactions with other QTL and with sex

Study of the reaction pbar p -> phi phi from 1.1 to 2.0 GeV/c

A study has been performed of the reaction pbar p -> 4K using in-flight antiprotons from 1.1 to 2.0 GeV/c incident momentum interacting with a hydrogen jet target. The reaction is dominated by the production of a pair of phi mesons. The pbar p -> phi phi cross section rises sharply above threshold and then falls continuously as a function of increasing antiproton momentum. The overall magnitude of the cross section exceeds expectations from a simple application of the OZI rule by two orders of magnitude. In a fine scan around the xi/f_J(2230) resonance, no structure is observed. A limit is set for the double branching ratio B(xi -> pbar p) * B(xi -> phi phi) < 6e-5 for a spin 2 resonance of M = 2.235 GeV and Width = 15 MeV.Comment: 13 pages, 13 figures, 2 tables, Latex. To be published in Phys. Rev.

Physical mapping of genes in the porcine ovarian transcriptome.

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