Beecroft Institute for Particle Astrophysics and Cosmology

Abstract:

The impact of inherited genetic variation on gene expression in humans is well-established. The majority of known expression quantitative trait loci (eQTLs) impact expression of local genes (cis-eQTLs). More research is needed to identify effects of genetic variation on distant genes (trans-eQTLs) and understand their biological mechanisms. One common trans-eQTLs mechanism is "mediation" by a local (cis) transcript. Thus, mediation analysis can be applied to genome-wide SNP and expression data in order to identify transcripts that are "cis-mediators" of trans-eQTLs, including those "cis-hubs" involved in regulation of many trans-genes. Identifying such mediators helps us understand regulatory networks and suggests biological mechanisms underlying trans-eQTLs, both of which are relevant for understanding susceptibility to complex diseases. The multitissue expression data from the Genotype-Tissue Expression (GTEx) program provides a unique opportunity to study cis-mediation across human tissue types. However, the presence of complex hidden confounding effects in biological systems can make mediation analyses challenging and prone to confounding bias, particularly when conducted among diverse samples. To address this problem, we propose a new method: Genomic Mediation analysis with Adaptive Confounding adjustment (GMAC). It enables the search of a very large pool of variables, and adaptively selects potential confounding variables for each mediation test. Analyses of simulated data and GTEx data demonstrate that the adaptive selection of confounders by GMAC improves the power and precision of mediation analysis. Application of GMAC to GTEx data provides new insights into the observed patterns of cis-hubs and trans-eQTL regulation across tissue types.

Abstract:

We perform a combined analysis of cosmic shear tomography, galaxy-galaxy lensing tomography, and redshift-space multipole power spectra (monopole and quadrupole) using 450 deg$^2$ of imaging data by the Kilo Degree Survey (KiDS) overlapping with two spectroscopic surveys: the 2-degree Field Lensing Survey (2dFLenS) and the Baryon Oscillation Spectroscopic Survey (BOSS). We restrict the galaxy-galaxy lensing and multipole power spectrum measurements to the overlapping regions with KiDS, and self-consistently compute the full covariance between the different observables using a large suite of $N$-body simulations. We methodically analyze different combinations of the observables, finding that galaxy-galaxy lensing measurements are particularly useful in improving the constraint on the intrinsic alignment amplitude (by 30%, positive at $3.5\sigma$ in the fiducial data analysis), while the multipole power spectra are useful in tightening the constraints along the lensing degeneracy direction (e.g. factor of two stronger matter density constraint in the fiducial analysis). The fully combined constraint on $S_8 \equiv \sigma_8 \sqrt{\Omega_{\rm m}/0.3} = 0.742 \pm 0.035$, which is an improvement by 20% compared to KiDS alone, corresponds to a $2.6\sigma$ discordance with Planck, and is not significantly affected by fitting to a more conservative set of scales. Given the tightening of the parameter space, we are unable to resolve the discordance with an extended cosmology that is simultaneously favored in a model selection sense, including the sum of neutrino masses, curvature, evolving dark energy, and modified gravity. The complementarity of our observables allows for constraints on modified gravity degrees of freedom that are not simultaneously bounded with either probe alone, and up to a factor of three improvement in the $S_8$ constraint in the extended cosmology compared to KiDS alone.

Abstract:

We measured stacked weak lensing cluster masses for a sample of 1323 galaxy clusters detected by the RedGOLD algorithm in the Canada–France–Hawaii Telescope Legacy Survey W1 and the Next Generation Virgo Cluster Survey at $0.2\lt z\lt 0.5$, in the optical richness range $10\lt \lambda \lt 70$. This is the most comprehensive lensing study of a $\sim 100 \% $ complete and $\sim 80 \% $ pure optical cluster catalog in this redshift range. We test different mass models, and our final model includes a basic halo model with a Navarro Frenk and White profile, as well as correction terms that take into account cluster miscentering, non-weak shear, the two-halo term, the contribution of the Brightest Cluster Galaxy, and an a posteriori correction for the intrinsic scatter in the mass–richness relation. With this model, we obtain a mass–richness relation of $\mathrm{log}{M}_{200}/{M}_{\odot }\,=(14.46\pm 0.02)+(1.04\pm 0.09)\mathrm{log}(\lambda /40)$ (statistical uncertainties). This result is consistent with other published lensing mass–richness relations. We give the coefficients of the scaling relations between the lensing mass and X-ray mass proxies, L X and T X, and compare them with previous results. When compared to X-ray masses and mass proxies, our results are in agreement with most previous results and simulations, and consistent with the expected deviations from self-similarity.

Abstract:

X chromosome inactivation (XCI) silences transcription from one of the two X chromosomes in female mammalian cells to balance expression dosage between XX females and XY males. XCI is, however, incomplete in humans: up to one-third of X-chromosomal genes are expressed from both the active and inactive X chromosomes (Xa and Xi, respectively) in female cells, with the degree of 'escape' from inactivation varying between genes and individuals. The extent to which XCI is shared between cells and tissues remains poorly characterized, as does the degree to which incomplete XCI manifests as detectable sex differences in gene expression and phenotypic traits. Here we describe a systematic survey of XCI, integrating over 5,500 transcriptomes from 449 individuals spanning 29 tissues from GTEx (v6p release) and 940 single-cell transcriptomes, combined with genomic sequence data. We show that XCI at 683 X-chromosomal genes is generally uniform across human tissues, but identify examples of heterogeneity between tissues, individuals and cells. We show that incomplete XCI affects at least 23% of X-chromosomal genes, identify seven genes that escape XCI with support from multiple lines of evidence and demonstrate that escape from XCI results in sex biases in gene expression, establishing incomplete XCI as a mechanism that is likely to introduce phenotypic diversity. Overall, this updated catalogue of XCI across human tissues helps to increase our understanding of the extent and impact of the incompleteness in the maintenance of XCI.