Survey of variation in human transcription factors reveals prevalent DNA binding changes

Published in final edited form as: Science. 2016 Mar 25; 351(6280): 1450–1454. Published online 2016 Mar 24. doi: 10.1126/science.aad2257Sequencing of exomes and genomes has revealed abundant genetic variation affecting the coding sequences of human transcription factors (TFs), but the consequences of such variation remain largely unexplored. We developed a computational, structure-based approach to evaluate TF variants for their impact on DNA binding activity and used universal protein-binding microarrays to assay sequence-specific DNA binding activity across 41 reference and 117 variant alleles found in individuals of diverse ancestries and families with Mendelian diseases. We found 77 variants in 28 genes that affect DNA binding affinity or specificity and identified thousands of rare alleles likely to alter the DNA binding activity of human sequence-specific TFs. Our results suggest that most individuals have unique repertoires of TF DNA binding activities, which may contribute to phenotypic variation.National Institutes of Health; NHGRI R01 HG003985; P50 HG004233; A*STAR National Science Scholarship; National Science Foundatio

Deep-coverage whole genome sequences and blood lipids among 16,324 individuals.

Large-scale deep-coverage whole-genome sequencing (WGS) is now feasible and offers potential advantages for locus discovery. We perform WGS in 16,324 participants from four ancestries at mean depth >29X and analyze genotypes with four quantitative traits-plasma total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, and triglycerides. Common variant association yields known loci except for few variants previously poorly imputed. Rare coding variant association yields known Mendelian dyslipidemia genes but rare non-coding variant association detects no signals. A high 2M-SNP LDL-C polygenic score (top 5th percentile) confers similar effect size to a monogenic mutation (~30 mg/dl higher for each); however, among those with severe hypercholesterolemia, 23% have a high polygenic score and only 2% carry a monogenic mutation. At these sample sizes and for these phenotypes, the incremental value of WGS for discovery is limited but WGS permits simultaneous assessment of monogenic and polygenic models to severe hypercholesterolemia

Geochemical Characterization of the Oman Crust-Mantle Transition Zone, OmanDP Holes CM1A and CM2B

The transition from the gabbroic oceanic crust to the residual mantle harzburgites of the Oman ophiolite has been drilled at Holes CM1A and CM2B (Wadi Tayin massif) during Phase 2 of the International Continental Scientific Drilling Program Oman Drilling Project (November 2017–January 2018). In order to unravel the formation processes of ultramafic rocks in the Wadi Tayin massif crust-mantle transition zone and deeper in the mantle sections beneath oceanic spreading centers, our study focuses on the whole rock major and trace element compositions (together with CO and HO concentrations) of these ultramafic rocks (56 dunites and 49 harzburgites). Despite extensive serpentinization and some carbonation, most of the trace element contents (REE, HFSE, Ti, Th, U) record high temperature, magmatic process-related signatures. Two major trends are observed, with good correlations between (a) Th and U, Nb and LREE on one hand, and between (b) heavy REE, Ti and Hf on the other hand. We interpret the first trend as the signature of late melt/peridotite interactions as LREE are known to be mobilized by such processes (‘‘lithospheric process’’) and the second trend as the signature of the initial mantle partial melting (‘‘asthenospheric process’’), with little or no overprint from melt/rock reaction events.This research used samples and/or data provided by the Oman Drilling Project (OmanDP). The OmanDP were funded from the International Continental Scientific Drilling Project (Kelemen, Matter, Teagle Lead PIs), the Sloan Foundation‐Deep Carbon Observatory (Grant 2014–3–01, Kelemen PI), the National Science Foundation (NSF–EAR–1516300, Kelemen lead PI), NASA–Astrobiology Institute (NNA15BB02A, Templeton PI), the German Research Foundation (DFG: KO 1723/21–1, Koepke PI), the Japanese Society for the Promotion of Science (JSPS no:16H06347, Michibayashi PI; and KAKENHI 16H02742, Takazawa PI), the European Research Council (Adv: no.669972; Jamveit PI), the Swiss National Science Foundation (SNF:20FI21_163,073, Früh–Green PI), JAMSTEC, the TAMU–JR Science Operator, and contributions from the Sultanate of Oman Ministry of Regional Municipalities and Water Resources, the Oman Public Authority of Mining, Sultan Qaboos University, CRNS–Univ. Montpellier II, Columbia University of New York, and the University of Southampton. K.W is grateful for receiving the National Science Council, Taiwan (NSC‐CDA‐107‐2628‐M‐001‐006‐MY4) and Academia Sinica, Taiwan (AS‐CDA‐107‐M01) funds. F.K.’s participation in shipboard and onsite logging was supported by The Institute of earth science Academia Sinica, Taiwan and by the research grants awarded to K. Michibayashi by the Japan Society for the Promotion of Science (Kiban‐B 16340151, Kiban‐B 19340148 and Kiban‐A 22244062)

Turbulence in the Solar Atmosphere: Manifestations and Diagnostics via Solar Image Processing

Intermittent magnetohydrodynamical turbulence is most likely at work in the magnetized solar atmosphere. As a result, an array of scaling and multi-scaling image-processing techniques can be used to measure the expected self-organization of solar magnetic fields. While these techniques advance our understanding of the physical system at work, it is unclear whether they can be used to predict solar eruptions, thus obtaining a practical significance for space weather. We address part of this problem by focusing on solar active regions and by investigating the usefulness of scaling and multi-scaling image-processing techniques in solar flare prediction. Since solar flares exhibit spatial and temporal intermittency, we suggest that they are the products of instabilities subject to a critical threshold in a turbulent magnetic configuration. The identification of this threshold in scaling and multi-scaling spectra would then contribute meaningfully to the prediction of solar flares. We find that the fractal dimension of solar magnetic fields and their multi-fractal spectrum of generalized correlation dimensions do not have significant predictive ability. The respective multi-fractal structure functions and their inertial-range scaling exponents, however, probably provide some statistical distinguishing features between flaring and non-flaring active regions. More importantly, the temporal evolution of the above scaling exponents in flaring active regions probably shows a distinct behavior starting a few hours prior to a flare and therefore this temporal behavior may be practically useful in flare prediction. The results of this study need to be validated by more comprehensive works over a large number of solar active regions.Comment: 26 pages, 7 figure

Publisher Correction: Deep coverage whole genome sequences and plasma lipoprotein(a) in individuals of European and African ancestries.

The original version of this article contained an error in the name of the author Ramachandran S. Vasan, which was incorrectly given as Vasan S. Ramachandran. This has now been corrected in both the PDF and HTML versions of the article

Deep coverage whole genome sequences and plasma lipoprotein(a) in individuals of European and African ancestries.

Lipoprotein(a), Lp(a), is a modified low-density lipoprotein particle that contains apolipoprotein(a), encoded by LPA, and is a highly heritable, causal risk factor for cardiovascular diseases that varies in concentrations across ancestries. Here, we use deep-coverage whole genome sequencing in 8392 individuals of European and African ancestry to discover and interpret both single-nucleotide variants and copy number (CN) variation associated with Lp(a). We observe that genetic determinants between Europeans and Africans have several unique determinants. The common variant rs12740374 associated with Lp(a) cholesterol is an eQTL for SORT1 and independent of LDL cholesterol. Observed associations of aggregates of rare non-coding variants are largely explained by LPA structural variation, namely the LPA kringle IV 2 (KIV2)-CN. Finally, we find that LPA risk genotypes confer greater relative risk for incident atherosclerotic cardiovascular diseases compared to directly measured Lp(a), and are significantly associated with measures of subclinical atherosclerosis in African Americans

A preliminary investigation of materialism and impulsiveness as predictors of technological addictions among young adults

Background and aims: The primary objective of the present research is to investigate the drivers of technological addiction in college students — heavy users of Information and Communication Technology (ICT). The study places cell phone and instant messaging addiction in the broader context of consumption pathologies, investigating the influence of materialism and impulsiveness on these two technologies. Clearly, cell phones serve more than just a utilitarian purpose. Cell phones are used in public and play a vital role in the lives of young adults. The accessibility of new technologies, like cell phones, which have the advantages of portability and an ever increasing array of functions, makes their over-use increasingly likely. Methods: College undergraduates (N = 191) from two U.S. universities completed a paper and pencil survey instrument during class. The questionnaire took approximately 15–20 minutes to complete and contained scales that measured materialism, impulsiveness, and mobile phone and instant messaging addiction. Results: Factor analysis supported the discriminant validity of Ehrenberg, Juckes, White and Walsh's (2008) Mobile Phone and Instant Messaging Addictive Tendencies Scale. The path model indicates that both materialism and impulsiveness impact the two addictive tendencies, and that materialism's direct impact on these addictions has a noticeably larger effect on cell phone use than instant messaging. Conclusions: The present study finds that materialism and impulsiveness drive both a dependence on cell phones and instant messaging. As Griffiths (2012) rightly warns, however, researchers must be aware that one's addiction may not simply be to the cell phone, but to a particular activity or function of the cell phone. The emergence of multi-function smart phones requires that research must dig beneath the technology being used to the activities that draw the user to the particular technology

Hubble expansion and structure formation in the "running FLRW model" of the cosmic evolution

A new class of FLRW cosmological models with time-evolving fundamental parameters should emerge naturally from a description of the expansion of the universe based on the first principles of quantum field theory and string theory. Within this general paradigm, one expects that both the gravitational Newton's coupling, G, and the cosmological term, Lambda, should not be strictly constant but appear rather as smooth functions of the Hubble rate. This scenario ("running FLRW model") predicts, in a natural way, the existence of dynamical dark energy without invoking the participation of extraneous scalar fields. In this paper, we perform a detailed study of these models in the light of the latest cosmological data, which serves to illustrate the phenomenological viability of the new dark energy paradigm as a serious alternative to the traditional scalar field approaches. By performing a joint likelihood analysis of the recent SNIa data, the CMB shift parameter, and the BAOs traced by the Sloan Digital Sky Survey, we put tight constraints on the main cosmological parameters. Furthermore, we derive the theoretically predicted dark-matter halo mass function and the corresponding redshift distribution of cluster-size halos for the "running" models studied. Despite the fact that these models closely reproduce the standard LCDM Hubble expansion, their normalization of the perturbation's power-spectrum varies, imposing, in many cases, a significantly different cluster-size halo redshift distribution. This fact indicates that it should be relatively easy to distinguish between the "running" models and the LCDM cosmology using realistic future X-ray and Sunyaev-Zeldovich cluster surveys.Comment: Version published in JCAP 08 (2011) 007: 1+41 pages, 6 Figures, 1 Table. Typos corrected. Extended discussion on the computation of the linearly extrapolated density threshold above which structures collapse in time-varying vacuum models. One appendix, a few references and one figure adde

FTO Obesity Variant Circuitry and Adipocyte Browning in Humans

Background Genomewide association studies can be used to identify disease-relevant genomic regions, but interpretation of the data is challenging. The FTO region harbors the strongest genetic association with obesity, yet the mechanistic basis of this association remains elusive. Methods We examined epigenomic data, allelic activity, motif conservation, regulator expression, and gene coexpression patterns, with the aim of dissecting the regulatory circuitry and mechanistic basis of the association between the FTO region and obesity. We validated our predictions with the use of directed perturbations in samples from patients and from mice and with endogenous CRISPR–Cas9 genome editing in samples from patients. Results Our data indicate that the FTO allele associated with obesity represses mitochondrial thermogenesis in adipocyte precursor cells in a tissue-autonomous manner. The rs1421085 T-to-C single-nucleotide variant disrupts a conserved motif for the ARID5B repressor, which leads to derepression of a potent preadipocyte enhancer and a doubling of IRX3 and IRX5 expression during early adipocyte differentiation. This results in a cell-autonomous developmental shift from energy-dissipating beige (brite) adipocytes to energy-storing white adipocytes, with a reduction in mitochondrial thermogenesis by a factor of 5, as well as an increase in lipid storage. Inhibition of Irx3 in adipose tissue in mice reduced body weight and increased energy dissipation without a change in physical activity or appetite. Knockdown of IRX3 or IRX5 in primary adipocytes from participants with the risk allele restored thermogenesis, increasing it by a factor of 7, and overexpression of these genes had the opposite effect in adipocytes from nonrisk-allele carriers. Repair of the ARID5B motif by CRISPR–Cas9 editing of rs1421085 in primary adipocytes from a patient with the risk allele restored IRX3 and IRX5 repression, activated browning expression programs, and restored thermogenesis, increasing it by a factor of 7. Conclusions Our results point to a pathway for adipocyte thermogenesis regulation involving ARID5B, rs1421085, IRX3, and IRX5, which, when manipulated, had pronounced pro-obesity and anti-obesity effects. (Funded by the German Research Center for Environmental Health and others.)National Institutes of Health (U.S.) (R01HG004037)National Institutes of Health (U.S.) (R01GM113708)National Institutes of Health (U.S.) (R01HG008155)National Institutes of Health (U.S.) (RC1HG005334