Relationships between estimated autozygosity and complex traits in the UK Biobank

<div><p>Inbreeding increases the risk of certain Mendelian disorders in humans but may also reduce fitness through its effects on complex traits and diseases. Such inbreeding depression is thought to occur due to increased homozygosity at causal variants that are recessive with respect to fitness. Until recently it has been difficult to amass large enough sample sizes to investigate the effects of inbreeding depression on complex traits using genome-wide single nucleotide polymorphism (SNP) data in population-based samples. Further, it is difficult to infer causation in analyses that relate degree of inbreeding to complex traits because confounding variables (e.g., education) may influence both the likelihood for parents to outbreed and offspring trait values. The present study used runs of homozygosity in genome-wide SNP data in up to 400,000 individuals in the UK Biobank to estimate the proportion of the autosome that exists in autozygous tracts—stretches of the genome which are identical due to a shared common ancestor. After multiple testing corrections and controlling for possible sociodemographic confounders, we found significant relationships in the predicted direction between estimated autozygosity and three of the 26 traits we investigated: age at first sexual intercourse, fluid intelligence, and forced expiratory volume in 1 second. Our findings corroborate those of several published studies. These results may imply that these traits have been associated with Darwinian fitness over evolutionary time. However, some of the autozygosity-trait relationships were attenuated after controlling for background sociodemographic characteristics, suggesting that alternative explanations for these associations have not been eliminated. Care needs to be taken in the design and interpretation of ROH studies in order to glean reliable information about the genetic architecture and evolutionary history of complex traits.</p></div

Quantitative Analysis of Novel Chemical and shRNA Based Methods to Increase Survival of Motor Neuron Protein Levels

Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disorder that is the leading genetic cause of infantile death. SMA is caused by homozygous deletion or mutation of the survival of motor neuron 1 gene (SMN1). The SMN2 gene is nearly identical to SMN1, however is alternatively spliced. The close relationship to SMN1 results in SMN2 being a very power genetic modifier of SMA disease severity and a target for therapies. In this study we attempt to characterize novel chemical compounds identified as potential activators of the SMN2 gene. Additionally, we sought to determine the regulatory role individual HDAC proteins use to control expression of full length protein from the SMN2 gene. We used quantitative PCR to determine the effects of novel compounds and shRNA silencing of individual HDACs on the steady state levels of a SMN2-luciferase reporter transcripts. We determined that the compounds identified in multiple reporter high throughput screens increased SMN protein levels via transcriptional activation of the SMN2 gene. Other compounds identified in the same screen functioned post-transcriptionally, possibly stabilizing the SMN protein itself by decreasing degradation. Furthermore, we determined that reduction of individual HDAC proteins was sufficient to increase SMN protein levels in a transgenic reporter system. Knockdown of class I HDAC proteins preferentially activated the reporter by increased promoter transcription. Silencing of class II HDAC proteins maintained transcriptional activity; however silencing of HDAC 5 and 6 also appeared to enhance inclusion of an alternatively spliced exon. This collective work defines a quantitative RNA based protocol to determine mechanism of SMN reporter increase in response to any chosen treatment method. Additionally, this work highlights HDAC proteins 2 and 6 as excellent investigative targets. These data are important to the basic understanding of SMN expression regulation and the refinements of current therapeutic compounds as well as the development of novel SMA therapeutics

Resonant Orbits and the High Velocity Peaks Towards the Bulge

We extract the resonant orbits from an N-body bar that is a good representation of the Milky Way, using the method recently introduced by Molloy et al. (2015). By decomposing the bar into its constituent orbit families, we show that they are intimately connected to the boxy-peanut shape of the density. We highlight the imprint due solely to resonant orbits on the kinematic landscape towards the Galactic centre. The resonant orbits are shown to have distinct kinematic features and may be used to explain the cold velocity peak seen in the APOGEE commissioning data (Nidever at al., 2012). We show that high velocity peaks are a natural consequence of the motions of stars in the 2:1 orbit family and that stars on other higher order resonances can contribute to the peaks. The locations of the peaks vary with bar angle and, with the tacit assumption that the observed peaks are due to the 2:1 family, we find that the locations of the high velocity peaks correspond to bar angles in the range 10 < theta_bar < 25 (deg). However, some important questions about the nature of the peaks remain, such as their apparent absence in other surveys of the Bulge and the deviations from symmetry between equivalent fields in the north and south. We show that the absence of a peak in surveys at higher latitudes is likely due to the combination of a less prominent peak and a lower number density of bar supporting orbits at these latitudes.Comment: 7 Figures, 1 Table, Now includes figures & discussion of higher order resonances, Minor revisions to text throughout, Conclusions unchange

Resonant Clumping and Substructure in Galactic Discs

We describe a method to extract resonant orbits from N-body simulations exploiting the fact that they close in a frame rotating with a constant pattern speed. Our method is applied to the N-body simulation of the Milky Way by Shen et al. (2010). This simulation hosts a massive bar, which drives strong resonances and persistent angular momentum exchange. Resonant orbits are found throughout the disc, both close to the bar itself and out to the very edges of the disc. Using Fourier spectrograms, we demonstrate that the bar is driving kinematic substructure even in the very outer parts of the disc. We identify two major orbit families in the outskirts of the disc that make significant contributions to the kinematic landscape, namely the m:l = 3:-2 and 1:-1 families resonating with the pattern speed of the bar. A mechanism is described that produces bimodal distributions of Galactocentric radial velocities at selected azimuths in the outer disc. It occurs as a result of the temporal coherence of particles on the 3:-2 resonant orbits, which causes them to arrive simultaneously at pericentre or apocentre. This resonant clumping, due to the in-phase motion of the particles through their epicycle, leads to both inward and outward moving groups which belong to the same orbital family and consequently produce bimodal radial velocity distributions. This is a possible explanation of the bimodal velocity distributions observed towards the Galactic anti-Centre by Liu et al. (2012). Another consequence is that transient overdensities appear and dissipate (in a symmetric fashion) on timescales equal to the their epicyclic period resulting in a periodic pulsing of the disc's surface density.Comment: 11 Figures, 1 Table. Accepted for publication in ApJ. Version 2 reflects minor changes to the text. Animation referenced in Figure 7 is available at http://hubble.shao.ac.cn/~shen/resonantclumping/DensMovie.mp

Poly(A)-binding proteins: multifunctional scaffolds for the post-transcriptional control of gene expression

Most eukaryotic mRNAs are subject to considerable post-transcriptional modification, including capping, splicing, and polyadenylation. The process of polyadenylation adds a 3' poly(A) tail and provides the mRNA with a binding site for a major class of regulatory factors, the poly(A)-binding proteins (PABPs). These highly conserved polypeptides are found only in eukaryotes; single-celled eukaryotes each have a single PABP, whereas humans have five and Arabidopis has eight. They typically bind poly(A) using one or more RNA-recognition motifs, globular domains common to numerous other eukaryotic RNA-binding proteins. Although they lack catalytic activity, PABPs have several roles in mediating gene expression. Nuclear PABPs are necessary for the synthesis of the poly(A) tail, regulating its ultimate length and stimulating maturation of the mRNA. Association with PABP is also a requirement for some mRNAs to be exported from the nucleus. In the cytoplasm, PABPs facilitate the formation of the 'closed loop' structure of the messenger ribonucleoprotein particle that is crucial for additional PABP activities that promote translation initiation and termination, recycling of ribosomes, and stability of the mRNA. Collectively, these sequential nuclear and cytoplasmic contributions comprise a cycle in which PABPs and the poly(A) tail first create and then eliminate a network of cis- acting interactions that control mRNA function

Differential regulation of the SMN2 gene by individual HDAC proteins

Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disorder that is the leading genetic cause of infantile death. SMA is caused by homozygous deletion or mutation of the survival of motor neuron 1 gene (SMN1). The SMN2 gene is nearly identical to SMN1, however is alternatively spliced. The close relationship to SMN1 results in SMN2 being a very power genetic modifier of SMA disease severity and a target for therapies. We sought to identify the regulatory role individual HDAC proteins use to control expression of full length protein from the SMN2 genes. We used quantitative PCR to determine the effects shRNA silencing of individual HDACs on the steady state levels of a SMN2-luciferase reporter transcripts. We determined that reduction of individual HDAC proteins was sufficient to increase SMN protein levels in a transgenic reporter system. Knockdown of class I HDAC proteins preferentially activated the reporter by increased promoter transcription. Silencing of class II HDAC proteins maintained transcriptional activity; however silencing of HDAC 5 and 6 also appeared to enhance inclusion of an alternatively spliced exon. This work highlights HDAC proteins 2 and 6 as excellent investigative targets. These data are important to the basic understanding of SMN expression regulation and the refinements of current therapeutic compounds as well as the development of novel SMA therapeutics

A library of infectious hepatitis C viruses with engineered mutations in the E2 gene reveals growth-adaptive mutations that modulate interactions with scavenger receptor class B type I

While natural hepatitis C virus (HCV) infection results in highly diverse quasispecies of related viruses over time, mutations accumulate more slowly in tissue culture, in part because of the inefficiency of replication in cells. To create a highly diverse population of HCV particles in cell culture and identify novel growth-enhancing mutations, we engineered a library of infectious HCV with all codons represented at most positions in the ectodomain of the E2 gene. We identified many putative growth-adaptive mutations and selected nine highly represented E2 mutants for further study: Q412R, T416R, S449P, T563V, A579R, L619T, V626S, K632T, and L644I. We evaluated these mutants for changes in particle-to-infectious-unit ratio, sensitivity to neutralizing antibody or CD81 large extracellular loop (CD81-LEL) inhibition, entry factor usage, and buoyant density profiles. Q412R, T416R, S449P, T563V, and L619T were neutralized more efficiently by anti-E2 antibodies and T416R, T563V, and L619T by CD81-LEL. Remarkably, all nine variants showed reduced dependence on scavenger receptor class B type I (SR-BI) for infection. This shift from SR-BI usage did not correlate with a change in the buoyant density profiles of the variants, suggesting an altered E2-SR-BI interaction rather than changes in the virus-associated lipoprotein-E2 interaction. Our results demonstrate that residues influencing SR-BI usage are distributed across E2 and support the development of large-scale mutagenesis studies to identify viral variants with unique functional properties. IMPORTANCE Characterizing variant viruses can reveal new information about the life cycle of HCV and the roles played by different viral genes. However, it is difficult to recapitulate high levels of diversity in the laboratory because of limitations in the HCV culture system. To overcome this limitation, we engineered a library of mutations into the E2 gene in the context of an infectious clone of the virus. We used this library of viruses to identify nine mutations that enhance the growth rate of HCV. These growth-enhancing mutations reduced the dependence on a key entry receptor, SR-BI. By generating a highly diverse library of infectious HCV, we mapped regions of the E2 protein that influence a key virus-host interaction and provide proof of principle for the generation of large-scale mutant libraries for the study of pathogens with great sequence variability

The Role of Legal Services in the Antipoverty Program

Large-scale adaptive radiations might explain the runaway success of a minority of extant vertebrate clades. This hypothesis predicts, among other things, rapid rates of morphological evolution during the early history of major groups, as lineages invade disparate ecological niches. However, few studies of adaptive radiation have included deep time data, so the links between extant diversity and major extinct radiations are unclear. The intensively studied Mesozoic dinosaur record provides a model system for such investigation, representing an ecologically diverse group that dominated terrestrial ecosystems for 170 million years. Furthermore, with 10,000 species, extant dinosaurs (birds) are the most speciose living tetrapod clade. We assembled composite trees of 614-622 Mesozoic dinosaurs/birds, and a comprehensive body mass dataset using the scaling relationship of limb bone robustness. Maximum-likelihood modelling and the node height test reveal rapid evolutionary rates and a predominance of rapid shifts among size classes in early (Triassic) dinosaurs. This indicates an early burst niche-filling pattern and contrasts with previous studies that favoured gradualistic rates. Subsequently, rates declined in most lineages, which rarely exploited new ecological niches. However, feathered maniraptoran dinosaurs (including Mesozoic birds) sustained rapid evolution from at least the Middle Jurassic, suggesting that these taxa evaded the effects of niche saturation. This indicates that a long evolutionary history of continuing ecological innovation paved the way for a second great radiation of dinosaurs, in birds. We therefore demonstrate links between the predominantly extinct deep time adaptive radiation of non-avian dinosaurs and the phenomenal diversification of birds, via continuing rapid rates of evolution along the phylogenetic stem lineage. This raises the possibility that the uneven distribution of biodiversity results not just from large-scale extrapolation of the process of adaptive radiation in a few extant clades, but also from the maintenance of evolvability on vast time scales across the history of life, in key lineages

Higgs Messengers

We explore the consequences of the Higgs fields acting as messengers of supersymmetry breaking. The hidden-sector paradigm in the gauge mediation framework is relaxed by allowing two types of gauge-invariant, renormalizable operators that are typically discarded: direct coupling between the Higgses and supersymmetry breaking singlets, and Higgs-messenger mixing terms. The most important phenomenological consequence is a flavor-dependent shift in sfermion masses. This is from a one-loop contribution, which we compute for a general set of weak doublet messengers. We also study a couple of explicit models in detail, finding that precision electroweak constraints can be satisfied with a spectrum significantly different from that of gauge mediation.Comment: 20 pages, 5 figure

Physical characteristics and non-keplerian orbital motion of "propeller" moons embedded in Saturn's rings

We report the discovery of several large "propeller" moons in the outer part of Saturn's A ring, objects large enough to be followed over the 5-year duration of the Cassini mission. These are the first objects ever discovered that can be tracked as individual moons, but do not orbit in empty space. We infer sizes up to 1--2 km for the unseen moonlets at the center of the propeller-shaped structures, though many structural and photometric properties of propeller structures remain unclear. Finally, we demonstrate that some propellers undergo sustained non-keplerian orbit motion. (Note: This arXiv version of the paper contains supplementary tables that were left out of the ApJL version due to lack of space).Comment: 9 pages, 4 figures; Published in ApJ