Cis-Acting Polymorphisms Affect Complex Traits through Modifications of MicroRNA Regulation Pathways

Genome-wide association studies (GWAS) have become an effective tool to map genes and regions contributing to multifactorial human diseases and traits. A comparably small number of variants identified by GWAS are known to have a direct effect on protein structure whereas the majority of variants is thought to exert their moderate influences on the phenotype through regulatory changes in mRNA expression. MicroRNAs (miRNAs) have been identified as powerful posttranscriptional regulators of mRNAs. Binding to their target sites, which are mostly located within the 3′-untranslated region (3′-UTR) of mRNA transcripts, they modulate mRNA expression and stability. Until today almost all human mRNA transcripts are known to harbor at least one miRNA target site with an average of over 20 miRNA target sites per transcript. Among 5,101 GWAS-identified sentinel single nucleotide polymorphisms (SNPs) that correspond to 18,884 SNPs in linkage disequilibrium (LD) with the sentinels () we identified a significant overrepresentation of SNPs that affect the 3′-UTR of genes (OR = 2.33, 95% CI = 2.12–2.57, ). This effect was even stronger considering all SNPs in one LD bin a single signal (OR = 4.27, 95% CI = 3.84–4.74, ). Based on crosslinking immunoprecipitation data we identified four mechanisms affecting miRNA regulation by 3′-UTR mutations: (i) deletion or (ii) creation of miRNA recognition elements within validated RNA-induced silencing complex binding sites, (iii) alteration of 3′-UTR splicing leading to a loss of binding sites, and (iv) change of binding affinity due to modifications of 3′-UTR folding. We annotated 53 SNPs of a total of 288 trait-associated 3′-UTR SNPs as mediating at least one of these mechanisms. Using a qualitative systems biology approach, we demonstrate how our findings can be used to support biological interpretation of GWAS results as well as to provide new experimentally testable hypotheses

The Higgs sector of the munuSSM and collider physics

The $\mu\nu$SSM is a supersymmetric standard model that accounts for light neutrino masses and solves the $\mu$ problem of the MSSM by simply using right-handed neutrino superfields. Since this mechanism breaks R-parity, a peculiar structure for the mass matrices is generated. The neutral Higgses are mixed with the right- and left-handed sneutrinos producing 8$\times$8 neutral scalar mass matrices. We analyse the Higgs sector of the $\mu\nu$SSM in detail, with special emphasis in possible signals at colliders. After studying in general the decays of the Higges, we focus on those processes that are genuine of the $\mu\nu$SSM, and could serve to distinguish it from other supersymmetric models. In particular, we present viable benchmark points for LHC searches. For example, we find decays of a MSSM-like Higgs into two lightest neutralinos, with the latter decaying inside the detector leading to displaced vertices, and producing final states with 4 and 8 $b$-jets plus missing energy. Final states with leptons and missing energy are also found.Comment: Final version to appear in JHEP. The discussion on signals at colliders, expanded. 33 pages, 8 figures and 9 table

Completeness and consistency of renormalisation group flows

We study different renormalisation group flows for scale dependent effective actions, including exact and proper-time renormalisation group flows. These flows have a simple one loop structure. They differ in their dependence on the full field-dependent propagator, which is linear for exact flows. We investigate the inherent approximations of flows with a non-linear dependence on the propagator. We check explicitly that standard perturbation theory is not reproduced. We explain the origin of the discrepancy by providing links to exact flows both in closed expressions and in given approximations. We show that proper-time flows are approximations to Callan-Symanzik flows. Within a background field formalism, we provide a generalised proper-time flow, which is exact. Implications of these findings are discussed.Comment: 33 pages, 15 figures, revtex, typos corrected, to be published in Phys.Rev.

Rare variants in LRRK1 and Parkinson's disease

Approximately 20 % of individuals with Parkinson's disease (PD) report a positive family history. Yet, a large portion of causal and disease-modifying variants is still unknown. We used exome sequencing in two affected individuals from a family with late-onset PD to identify 15 potentially causal variants. Segregation analysis and frequency assessment in 862 PD cases and 1,014 ethnically matched controls highlighted variants in EEF1D and LRRK1 as the best candidates. Mutation screening of the coding regions of these genes in 862 cases and 1,014 controls revealed several novel non-synonymous variants in both genes in cases and controls. An in silico multi-model bioinformatics analysis was used to prioritize identified variants in LRRK1 for functional follow- up. However, protein expression, subcellular localization, and cell viability were not affected by the identified variants. Although it has yet to be proven conclusively that variants in LRRK1 are indeed causative of PD, our data strengthen a possible role for LRRK1 in addition to LRRK2 in the genetic underpinnings of PD but, at the same time, highlight the difficulties encountered in the study of rare variants identified by next-generation sequencing in diseases with autosomal dominant or complex patterns of inheritance

Gamma-ray detection from gravitino dark matter decay in the μν\mu\nuSSM

The $\mu\nu$SSM provides a solution to the $\mu$-problem of the MSSM and explains the origin of neutrino masses by simply using right-handed neutrino superfields. Given that R-parity is broken in this model, the gravitino is a natural candidate for dark matter since its lifetime becomes much longer than the age of the Universe. We consider the implications of gravitino dark matter in the $\mu\nu$SSM, analyzing in particular the prospects for detecting gamma rays from decaying gravitinos. If the gravitino explains the whole dark matter component, a gravitino mass larger than 20 GeV is disfavored by the isotropic diffuse photon background measurements. On the other hand, a gravitino with a mass range between 0.1-20 GeV gives rise to a signal that might be observed by the FERMI satellite. In this way important regions of the parameter space of the $\mu\nu$SSM can be checked.Comment: Final version to appear in JCAP, 13 pages, 3 figure

Combined fit to the spectrum and composition data measured by the Pierre Auger Observatory including magnetic horizon effects

The measurements by the Pierre Auger Observatory of the energy spectrum and mass composition of cosmic rays can be interpreted assuming the presence of two extragalactic source populations, one dominating the flux at energies above a few EeV and the other below. To fit the data ignoring magnetic field effects, the high-energy population needs to accelerate a mixture of nuclei with very hard spectra, at odds with the approximate E$^{-2}$ shape expected from diffusive shock acceleration. The presence of turbulent extragalactic magnetic fields in the region between the closest sources and the Earth can significantly modify the observed CR spectrum with respect to that emitted by the sources, reducing the flux of low-rigidity particles that reach the Earth. We here take into account this magnetic horizon effect in the combined fit of the spectrum and shower depth distributions, exploring the possibility that a spectrum for the high-energy population sources with a shape closer to E$^{-2}$ be able to explain the observations

Studies of the mass composition of cosmic rays and proton-proton interaction cross-sections at ultra-high energies with the Pierre Auger Observatory

In this work, we present an estimate of the cosmic-ray mass composition from the distributions of the depth of the shower maximum (Xmax) measured by the fluorescence detector of the Pierre Auger Observatory. We discuss the sensitivity of the mass composition measurements to the uncertainties in the properties of the hadronic interactions, particularly in the predictions of the particle interaction cross-sections. For this purpose, we adjust the fractions of cosmic-ray mass groups to fit the data with Xmax distributions from air shower simulations. We modify the proton-proton cross-sections at ultra-high energies, and the corresponding air shower simulations with rescaled nucleus-air cross-sections are obtained via Glauber theory. We compare the energy-dependent composition of ultra-high-energy cosmic rays obtained for the different extrapolations of the proton-proton cross-sections from low-energy accelerator data

Study of downward Terrestrial Gamma-ray Flashes with the surface detector of the Pierre Auger Observatory

The surface detector (SD) of the Pierre Auger Observatory, consisting of 1660 water-Cherenkov detectors (WCDs), covers 3000 km2 in the Argentinian pampa. Thanks to the high efficiency of WCDs in detecting gamma rays, it represents a unique instrument for studying downward Terrestrial Gamma-ray Flashes (TGFs) over a large area. Peculiar events, likely related to downward TGFs, were detected at the Auger Observatory. Their experimental signature and time evolution are very different from those of a shower produced by an ultrahigh-energy cosmic ray. They happen in coincidence with low thunderclouds and lightning, and their large deposited energy at the ground is compatible with that of a standard downward TGF with the source a few kilometers above the ground. A new trigger algorithm to increase the TGF-like event statistics was installed in the whole array. The study of the performance of the new trigger system during the lightning season is ongoing and will provide a handle to develop improved algorithms to implement in the Auger upgraded electronic boards. The available data sample, even if small, can give important clues about the TGF production models, in particular, the shape of WCD signals. Moreover, the SD allows us to observe more than one point in the TGF beam, providing information on the emission angle