Accelerated gene evolution and subfunctionalization in the pseudotetraploid frog Xenopus laevis

Ancient whole genome duplications have been implicated in the vertebrate and teleost radiations, and in the emergence of diverse angiosperm lineages, but the evolutionary response to such a perturbation is still poorly understood. The African clawed frog Xenopus laevis experienced a relatively recent tetraploidization {approx} 40 million years ago. Analysis of the considerable amount of EST sequence available for this species together with the genome sequence of the related diploid Xenopus tropicalis provides a unique opportunity to study the genomic response to whole genome duplication

Xenopus tropicalis egg extracts provide insight into scaling of the mitotic spindle

The African clawed frog Xenopus laevis has been instrumental to investigations of both development and cell biology, but the utility of this model organism for genetic and proteomic studies is limited by its long generation time and unsequenced pseudotetraploid genome. Xenopus tropicalis, which is a small, faster-breeding relative of X. laevis, has recently been adopted for research in developmental genetics and functional genomics, and has been chosen for genome sequencing. We show that X. tropicalis egg extracts reconstitute the fundamental cell cycle events of nuclear formation and bipolar spindle assembly around exogenously added sperm nuclei. Interestingly, X. tropicalis spindles were ∼30% shorter than X. laevis spindles, and mixing experiments revealed a dynamic, dose-dependent regulation of spindle size by cytoplasmic factors. Measurements of microtubule dynamics revealed that microtubules polymerized slower in X. tropicalis extracts compared to X. laevis, but that this difference is unlikely to account for differences in spindle size. Thus, in addition to expanding the range of developmental and cell biological experiments, the use of X. tropicalis provides novel insight into the complex mechanisms that govern spindle morphogenesis

Nucleic Acid-Sensing and Interferon-Inducible Pathways Show Differential Methylation in MZ Twins Discordant for Lupus and Overexpression in Independent Lupus Samples: Implications for Pathogenic Mechanism and Drug Targeting.

Systemic lupus erythematosus (SLE) is a chronic, multisystem, autoimmune inflammatory disease with genomic and non-genomic contributions to risk. We hypothesize that epigenetic factors are a significant contributor to SLE risk and may be informative for identifying pathogenic mechanisms and therapeutic targets. To test this hypothesis while controlling for genetic background, we performed an epigenome-wide analysis of DNA methylation in genomic DNA from whole blood in three pairs of female monozygotic (MZ) twins of European ancestry, discordant for SLE. Results were replicated on the same array in four cell types from a set of four Danish female MZ twin pairs discordant for SLE. Genes implicated by the epigenetic analyses were then evaluated in 10 independent SLE gene expression datasets from the Gene Expression Omnibus (GEO). There were 59 differentially methylated loci between unaffected and affected MZ twins in whole blood, including 11 novel loci. All but two of these loci were hypomethylated in the SLE twins relative to the unaffected twins. The genes harboring these hypomethylated loci exhibited increased expression in multiple independent datasets of SLE patients. This pattern was largely consistent regardless of disease activity, cell type, or renal tissue type. The genes proximal to CpGs exhibiting differential methylation (DM) in the SLE-discordant MZ twins and exhibiting differential expression (DE) in independent SLE GEO cohorts (DM-DE genes) clustered into two pathways: the nucleic acid-sensing pathway and the type I interferon pathway. The DM-DE genes were also informatically queried for potential gene-drug interactions, yielding a list of 41 drugs including a known SLE therapy. The DM-DE genes delineate two important biologic pathways that are not only reflective of the heterogeneity of SLE but may also correlate with distinct IFN responses that depend on the source, type, and location of nucleic acid molecules and the activated receptors in individual patients. Cell- and tissue-specific analyses will be critical to the understanding of genetic factors dysregulating the nucleic acid-sensing and IFN pathways and whether these factors could be appropriate targets for therapeutic intervention

Mapping the Asymmetric Thick Disk: III. The Kinematics and Interaction with the Galactic Bar

In the first two papers of this series, Larsen et al (2010a,b) describe our faint CCD survey in the inner Galaxy and map the over-density of Thick Disk stars in Quadrant I (Q1) to 5 kpc or more along the line of sight. The regions showing the strongest excess are above the density contours of the bar in the Galactic disk. In this third paper on the asymmetric Thick Disk, we report on radial velocities and derived metallicity parameters for over 4000 stars in Q1, above and below the plane and in Q4 above the plane. We confirm the corresponding kinematic asymmetry first reported by Parker et al. (2004), extended to greater distances and with more spatial coverage. The Thick Disk stars in Q1 have a rotational lag of 60 -- 70 km/s relative to circular rotation, and the Metal-Weak Thick Disk stars have an even greater lag of 100 km/s. Both lag their corresponding populations in Q4 by approximately 30 km/s. Interestingly, the Disk stars in Q1 also appear to participate in the rotational lag by about 30 km/s. The enhanced rotational lag for the Thick Disk in Q1 extends to 4 kpc or more from the Sun. At 3 to 4 kpc, our sight lines extend above the density contours on the near side of the bar, and as our lines of sight pass directly over the bar the rotational lag appears to decrease. This is consistent with a "gravitational wake" induced by the rotating bar in the Disk which would trap and pile up stars behind it. We conclude that a dynamical interaction with the stellar bar is the most probable explanation for the observed kinematic and spatial asymmetries

Light Curve Templates and Galactic Distribution of RR Lyrae Stars from Sloan Digital Sky Survey Stripe 82

We present an improved analysis of halo substructure traced by RR Lyrae stars in the SDSS stripe 82 region. With the addition of SDSS-II data, a revised selection method based on new ugriz light curve templates results in a sample of 483 RR Lyrae stars that is essentially free of contamination. The main result from our first study persists: the spatial distribution of halo stars at galactocentric distances 5--100 kpc is highly inhomogeneous. At least 20% of halo stars within 30 kpc from the Galactic center can be statistically associated with substructure. We present strong direct evidence, based on both RR Lyrae stars and main sequence stars, that the halo stellar number density profile significantly steepens beyond a Galactocentric distance of ~30 kpc, and a larger fraction of the stars are associated with substructure. By using a novel method that simultaneously combines data for RR Lyrae and main sequence stars, and using photometric metallicity estimates for main sequence stars derived from deep co-added u-band data, we measure the metallicity of the Sagittarius dSph tidal stream (trailing arm) towards R.A.2h-3h and Dec~0 deg to be 0.3 dex higher ([Fe/H]=-1.2) than that of surrounding halo field stars. Together with a similar result for another major halo substructure, the Monoceros stream, these results support theoretical predictions that an early forming, smooth inner halo, is metal poor compared to high surface brightness material that have been accreted onto a later-forming outer halo. The mean metallicity of stars in the outer halo that are not associated with detectable clumps may still be more metal-poor than the bulk of inner-halo stars, as has been argued from other data sets.Comment: Submitted to ApJ, 68 pages, 26 figures, supplemental material (light curves, templates, animation) can be downloaded from http://www.astro.washington.edu/bsesar/S82_RRLyr.htm

Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.

Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or  ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention

Genome-wide meta-analysis of 241,258 adults accounting for smoking behaviour identifies novel loci for obesity traits

Few genome-wide association studies (GWAS) account for environmental exposures, like smoking, potentially impacting the overall trait variance when investigating the genetic contribution to obesity-related traits. Here, we use GWAS data from 51,080 current smokers and 190,178 nonsmokers (87% European descent) to identify loci influencing BMI and central adiposity, measured as waist circumference and waist-to-hip ratio both adjusted for BMI. We identify 23 novel genetic loci, and 9 loci with convincing evidence of gene-smoking interaction (GxSMK) on obesity-related traits. We show consistent direction of effect for all identified loci and significance for 18 novel and for 5 interaction loci in an independent study sample. These loci highlight novel biological functions, including response to oxidative stress, addictive behaviour, and regulatory functions emphasizing the importance of accounting for environment in genetic analyses. Our results suggest that tobacco smoking may alter the genetic susceptibility to overall adiposity and body fat distribution.Peer reviewe

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function.

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways