MutaGeneSys: Making Diagnostic Predictions Based on Genome-Wide Genotype Data in Association Studies

Summary: We present MutaGeneSys: a system that uses genomewide genotype data for disease prediction. Our system integrates three data sources: the International HapMap project, whole-genome marker correlation data and the Online Mendelian Inheritance in Man (OMIM) database. It accepts SNP data of individuals as query input and delivers disease susceptibility hypotheses even if the original set of typed SNPs is incomplete. Our system is scalable and flexible: it operates in real time and can be configured on the fly to produce population, technology, and confidence-specific predictions. Availability: Efforts are underway to deploy our system as part of the NCBI Reference Assembly. Meanwhile, the system may be obtained from the authors. Contact: [email protected]

Co-regulated Transcripts Associated to Cooperating eSNPs Define Bi-fan Motifs in Human Gene Networks

Associations between the level of single transcripts and single corresponding genetic variants, expression single nucleotide polymorphisms (eSNPs), have been extensively studied and reported. However, most expression traits are complex, involving the cooperative action of multiple SNPs at different loci affecting multiple genes. Finding these cooperating eSNPs by exhaustive search has proven to be statistically challenging. In this paper we utilized availability of sequencing data with transcriptional profiles in the same cohorts to identify two kinds of usual suspects: eSNPs that alter coding sequences or eSNPs within the span of transcription factors (TFs). We utilize a computational framework for considering triplets, each comprised of a SNP and two associated genes. We examine pairs of triplets with such cooperating source eSNPs that are both associated with the same pair of target genes. We characterize such quartets through their genomic, topological and functional properties. We establish that this regulatory structure of cooperating quartets is frequent in real data, but is rarely observed in permutations. eSNP sources are mostly located on different chromosomes and away from their targets. In the majority of quartets, SNPs affect the expression of the two gene targets independently of one another, suggesting a mutually independent rather than a directionally dependent effect. Furthermore, the directions in which the minor allele count of the SNP affects gene expression within quartets are consistent, so that the two source eSNPs either both have the same effect on the target genes or both affect one gene in the opposite direction to the other. Same-effect eSNPs are observed more often than expected by chance. Cooperating quartets reported here in a human system might correspond to bi-fans, a known network motif of four nodes previously described in model organisms. Overall, our analysis offers insights regarding the fine motif structure of human regulatory networks

Statistical correction of the Winner’s Curse explains replication variability in quantitative trait genome-wide association studies

Genome-wide association studies (GWAS) have identified hundreds of SNPs responsible for variation in human quantitative traits. However, genome-wide-significant associations often fail to replicate across independent cohorts, in apparent inconsistency with their apparent strong effects in discovery cohorts. This limited success of replication raises pervasive questions about the utility of the GWAS field. We identify all 332 studies of quantitative traits from the NHGRI-EBI GWAS Database with attempted replication. We find that the majority of studies provide insufficient data to evaluate replication rates. The remaining papers replicate significantly worse than expected (p < 10−14), even when adjusting for regression-to-the-mean of effect size between discovery- and replication-cohorts termed the Winner’s Curse (p < 10−16). We show this is due in part to misreporting replication cohort-size as a maximum number, rather than per-locus one. In 39 studies accurately reporting per-locus cohort-size for attempted replication of 707 loci in samples with similar ancestry, replication rate matched expectation (predicted 458, observed 457, p = 0.94). In contrast, ancestry differences between replication and discovery (13 studies, 385 loci) cause the most highly-powered decile of loci to replicate worse than expected, due to difference in linkage disequilibrium

Theory of photospheric emission from relativistic outflows

In this paper we reexamine the optical depth of ultrarelativistic spherically symmetric outflows and reevaluate the photospheric radius for each model during both the acceleration and coasting phases. It is shown that for both the wind and the shell models there are two asymptotic solutions for the optical depth during the coasting phase of the outflow. In particular we show that quite counterintuitively a geometrically thin shell may appear as a thick wind for photons propagating inside it. For this reason we introduce notions of photon thick and photon thin outflows, which appear more general and better physically motivated with respect to winds and shells. Photosphere of relativistic outflow is a dynamic surface. We study its geometry and find that the photosphere of photon thin outflow has always a convex shape, while in the photon thick one it is initially convex (there is always a photon thin layer in any outflow) and then it becomes concave asymptotically approaching the photosphere of an infinitely long wind. We find that both instantaneous and time integrated observed spectra are very close to the thermal one for photon thick outflows, in line with existing studies. It is our main finding that the photospheric emission from the photon thin outflow produces non thermal time integrated spectra, which may be described by the Band function well known in the GRB literature. We find that energetic GRBs should produce photon thin outflows with photospheric emission lasting less than one second for the total energy $E_0\leq10^{54}$ erg and baryonic loading parameter $B\leq10^{-2}$. It means that only time integrated spectra may be observed from such GRBs.Comment: Revision of the previous version, new effect is discussed. Conclusions remain unchange

Constraining Sources of Ultra High Energy Cosmic Rays Using High Energy Observations with the Fermi Satellite

We analyze the conditions that enable acceleration of particles to ultra-high energies, ~10^{20} eV (UHECRs). We show that broad band photon data recently provided by WMAP, ISOCAM, Swift and Fermi satellites, yield constraints on the ability of active galactic nuclei (AGN) to produce UHECRs. The high energy (MeV - GeV) photons are produced by Compton scattering of the emitted low energy photons and the cosmic microwave background or extra-galactic background light. The ratio of the luminosities at high and low photon energies can therefore be used as a probe of the physical conditions in the acceleration site. We find that existing data excludes core regions of nearby radio-loud AGN as possible acceleration sites of UHECR protons. However, we show that giant radio lobes are not excluded. We apply our method to Cen A, and show that acceleration of protons to ~10^{20} eV can only occur at distances >~ 100 kpc from the core.Comment: Extended discussion on former results; Accepted for publication in JCA

Variants in exons and in transcription factors affect gene expression in trans

Background: In recent years many genetic variants (eSNPs) have been reported as associated with expression of transcripts in trans. However, the causal variants and regulatory mechanisms through which they act remain mostly unknown. In this paper we follow two kinds of usual suspects: SNPs that alter coding regions or transcription factors, identifiable by sequencing data with transcriptional profiles in the same cohort. We show these interpretable genomic regions are enriched for eSNP association signals, thereby naturally defining source-target gene pairs. We map these pairs onto a protein-protein interaction (PPI) network and study their topological properties. Results: For exonic eSNP sources, we report source-target proximity and high target degree within the PPI network. These pairs are more likely to be co-expressed and the eSNPs tend to have a cis effect, modulating the expression of the source gene. In contrast, transcription factor source-target pairs are not observed to have such properties, but instead a transcription factor source tends to assemble into units of defined functional roles along with its gene targets, and to share with them the same functional cluster of the PPI network. Conclusions: Our results suggest two modes of trans regulation: transcription factor variation frequently acts via a modular regulation mechanism, with multiple targets that share a function with the transcription factor source. Notwithstanding, exon variation often acts by a local cis effect, delineating shorter paths of interacting proteins across functional clusters of the PPI network

A wind environment and Lorentz factors of tens explain gamma-ray bursts X-ray plateau

Gamma-ray bursts (GRBs) are known to have the most relativistic jets, with initial Lorentz factors in the order of a few hundreds. Many GRBs display an early X-ray light-curve plateau, which was not theoretically expected and therefore puzzled the community for many years. Here, we show that this observed signal is naturally obtained within the classical GRB "fireball" model, provided that the initial Lorentz factor is rather a few tens, and the expansion occurs into a medium-low density "wind". The range of Lorentz factors in GRB jets is thus much wider than previously thought and bridges an observational gap between mildly relativistic jets inferred in active galactic nuclei, to highly relativistic jets deduced in few extreme GRBs. Furthermore, long GRB progenitors are either not Wolf-Rayet stars, or the wind properties during the final stellar evolution phase are different than at earlier times. We discuss several testable predictions of this model.Comment: 61 pages, 24 figures, 9 tables. A final edited version will appear in Nature Communication