Production of 21 Ne in depth-profiled olivine from a 54 Ma basalt sequence, Eastern Highlands (37° S), Australia

In this study we investigate the cosmogenic neon component in olivine samples from a vertical profile in order to quantify muogenic 21Ne production in this mineral. Samples were collected from an 11 m thick Eocene basalt profile in the Eastern Highlands of southeastern Australia. An eruption age of 54.15 ± 0.36 Ma (2σ) was determined from 40Ar/39Ar step-heating experiments (n = 6) on three whole-rock samples. A 36Cl profile on the section indicated an apparent steady state erosion rate of 4.7 ± 0.5 m Ma−1. The eruption age was used to calculate in situ produced radiogenic 4He and nucleogenic 3He and 21Ne concentrations in olivine. Olivine mineral separates (n = 4), extracted from the upper two metres of the studied profile, reveal cosmogenic 21Ne concentrations that attenuate exponentially with depth. However, olivine (Fo68) extracted from below 2 m does not contain discernible 21Ne aside from magmatic and nucleogenic components, with the exception of one sample that apparently contained equal proportions of nucleogenic and muogenic neon. Modelling results suggest a muogenic neon sea-level high-latitude production rate of 0.02 ± 0.04 to 0.9 ± 1.3 atoms g−1 a−1 (1σ), or <2.5% of spallogenic cosmogenic 21Ne production at Earth’s surface. These data support a key implicit assumption in the literature that accumulation of muogenic 21Ne in olivine in surface samples is likely to be negligible/minimal compared to spallogenic 21Ne

Provenance history of detrital diamond deposits, West Coast of Namaqualand, South Africa

The West Coast of Namaqualand in South Africa hosts extensive detrital diamond deposits, but considerable debate exists as to the provenance of these diamonds. Some researchers have suggested derivation of the diamonds from Cretaceous-Jurassic kimberlites (also termed Group I kimberlites) and orangeites (also termed Group II kimberlites) located on the Kaapvaal Craton. However, others favour erosion of diamonds from the ca.300 Ma Dwyka Group sediments, with older, pre-Karoo kimberlites being the original source(s). Previous work has demonstrated that 40Ar/39Ar analyses of clinopyroxene inclusions, extracted from diamonds, yield ages approaching the time(s) of source kimberlite emplacement, which can be used to constrain the provenance of placer diamond deposits. In the current study, 40Ar/39Ar analyses were conducted on clinopyroxene inclusions from two similar batches of Namaqualand detrital diamonds, yielding (maximum) ages ranging from 117.5 ± 43.6 Ma to 3684 ± 191 Ma (2σ) and 120.6 ± 15.4 Ma to 688.8 ± 4.9 Ma (2σ), respectively. The vast majority of inclusions (88%) produced ages younger than 500 Ma, indicating that most Namaqualand diamonds originated from Cretaceous-Jurassic kimberlites/orangeites, with few, if any, derived from the Dwyka tillites. The provenance of the Namaqualand diamonds from ca.115–200 Ma orangeites is consistent with Late Cretaceous paleo-drainage reconstructions, as these localities could have been sampled by the ‘paleo-Karoo’ River and transported to the West Coast via an outlet close to the current Olifants River mouth. At ca.90 Ma, this drainage system appears to have been captured by the ‘paleo-Kalahari’ River, a precursor to the modern Orange River system. This latter drainage is considered to have transported diamonds eroded from both ca.80–90 Ma kimberlites and ca.115–200 Ma orangeites to the West Coast, which were subsequently reworked along the Namibian coast, forming additional placer deposits

The Hera orebody: a complex distal (Au–Zn–Pb–Ag–Cu) skarn in the Cobar Basin of central New South Wales, Australia

The Hera Au–Pb–Zn–Ag deposit in the southeastern Cobar Basin of central New South Wales preserves calc-silicate veins and remnant sandstone/carbonate-hosted skarn within a reduced anchizonal Siluro-Devonian turbidite sequence. The skarn orebody distribution is controlled by a long-lived, basin margin fault system, that has intersected a sedimentary horizon dominated by siliciclastic turbidite, with lesser gritstone and thick sandstone intervals, and rare carbonate-bearing stratigraphy. Foliation (S1) envelopes the orebody and is crosscut by a series of late-stage east–west and north–south trending faults. Skarn at Hera displays mineralogical zonation along strike, from southern spessartine–grossular–biotite–actinolite-rich associations, to central diopside-rich–zoisite–actinolite/tremolite–grossular-bearing associations, through to the northern most tremolite–anorthite-rich (garnet-absent) association in remnant carbonate-bearing lithologies and sandstone horizons; the northern lodes also display zonation down dip to garnet present associations. High-T, prograde skarn assemblages rich in pyroxene and garnet are pervasively replaced by actinolite/tremolite–biotite-rich retrograde skarn which coincides with the main pulse of sulfide mineralization. The dominant sulfides are high-Fe–Mn sphalerite–galena–non-magnetic high-Fe pyrrhotite–chalcopyrite; pyrite, arsenopyrite; scheelite (low Mo) is locally abundant. The distribution of metals in part mimics the changing gangue mineralogy, with Au concentrated in the southern and lower northern lode systems and broadly inverse concentrations for Ag–Pb–Zn. Stable isotope data (O–H–S) from skarn amphiboles and associated sulfides are consistent with magmatic (or metamorphic) water and sulfur input during the retrograde skarn phase, while hydrosilicates and sulfides from the wall rocks display comparatively elevated δD and mixed δ34S consistent with progressive mixing or dilution of original magmatic (or metamorphic) waters within the Hera deposit by unexchanged waters typical of low latitude (tropical) meteoritic waters. High precision titanite (U–Pb) and biotite (Ar–Ar) geochronology reveals a manifold orebody commencing with high-T skarn and retrograde Pb–Zn-rich skarn formation at ≥403 Ma, Au–low-Fe sphalerite mineralization at 403.4 ± 1.1 Ma, foliation development remobilization or new mineralization at 390 ± 0.2 Ma followed by thrusting, orebody dismemberment at 384.8 ± 1.1 Ma and remobilization or new mineralization at 381.0 ± 2.2 Ma. The polymetallic nature of the Hera orebody is a result of multiple mineralization events during extension and compression and involving both magmatic and likely formational metal sources

Whole genome sequencing and imputation in isolated populations identify genetic associations with medically-relevant complex traits

Next-generation association studies can be empowered by sequence-based imputation and by studying founder populations. Here we report ∼9.5 million variants from whole-genome sequencing (WGS) of a Cretan-isolated population, and show enrichment of rare and low-frequency variants with predicted functional consequences. We use a WGS-based imputation approach utilizing 10,422 reference haplotypes to perform genome-wide association analyses and observe 17 genome-wide significant, independent signals, including replicating evidence for association at eight novel low-frequency variant signals. Two novel cardiometabolic associations are at lead variants unique to the founder population sequences: chr16:70790626 (high-density lipoprotein levels beta −1.71 (SE 0.25), P=1.57 × 10−11, effect allele frequency (EAF) 0.006); and rs145556679 (triglycerides levels beta −1.13 (SE 0.17), P=2.53 × 10−11, EAF 0.013). Our findings add empirical support to the contribution of low-frequency variants in complex traits, demonstrate the advantage of including population-specific sequences in imputation panels and exemplify the power gains afforded by population isolates

Whole-Genome Sequencing Coupled to Imputation Discovers Genetic Signals for Anthropometric Traits

Deep sequence-based imputation can enhance the discovery power of genome-wide association studies by assessing previously unexplored variation across the common-and low-frequency spectra. We applied a hybrid whole-genome sequencing (WGS) and deep imputation approach to examine the broader allelic architecture of 12 anthropometric traits associated with height, body mass, and fat distribution in up to 267,616 individuals. We report 106 genome-wide significant signals that have not been previously identified, including 9 low-frequency variants pointing to functional candidates. Of the 106 signals, 6 are in genomic regions that have not been implicated with related traits before, 28 are independent signals at previously reported regions, and 72 represent previously reported signals for a different anthropometric trait. 71% of signals reside within genes and fine mapping resolves 23 signals to one or two likely causal variants. We confirm genetic overlap between human monogenic and polygenic anthropometric traits and find signal enrichment in cis expression QTLs in relevant tissues. Our results highlight the potential of WGS strategies to enhance biologically relevant discoveries across the frequency spectrum.Peer reviewe

100,000 Genomes Pilot on Rare-Disease Diagnosis in Health Care — Preliminary Report

BACKGROUND: The U.K. 100,000 Genomes Project is in the process of investigating the role of genome sequencing in patients with undiagnosed rare diseases after usual care and the alignment of this research with health care implementation in the U.K. National Health Service. Other parts of this project focus on patients with cancer and infection. METHODS: We conducted a pilot study involving 4660 participants from 2183 families, among whom 161 disorders covering a broad spectrum of rare diseases were present. We collected data on clinical features with the use of Human Phenotype Ontology terms, undertook genome sequencing, applied automated variant prioritization on the basis of applied virtual gene panels and phenotypes, and identified novel pathogenic variants through research analysis. RESULTS: Diagnostic yields varied among family structures and were highest in family trios (both parents and a proband) and families with larger pedigrees. Diagnostic yields were much higher for disorders likely to have a monogenic cause (35%) than for disorders likely to have a complex cause (11%). Diagnostic yields for intellectual disability, hearing disorders, and vision disorders ranged from 40 to 55%. We made genetic diagnoses in 25% of the probands. A total of 14% of the diagnoses were made by means of the combination of research and automated approaches, which was critical for cases in which we found etiologic noncoding, structural, and mitochondrial genome variants and coding variants poorly covered by exome sequencing. Cohortwide burden testing across 57,000 genomes enabled the discovery of three new disease genes and 19 new associations. Of the genetic diagnoses that we made, 25% had immediate ramifications for clinical decision making for the patients or their relatives. CONCLUSIONS: Our pilot study of genome sequencing in a national health care system showed an increase in diagnostic yield across a range of rare diseases. (Funded by the National Institute for Health Research and others.)

Steroid receptor coactivator-1 modulates the function of Pomc neurons and energy homeostasis

Hypothalamic neurons expressing the anorectic peptide Pro-opiomelanocortin (Pomc) regulate food intake and body weight. Here, we show that Steroid Receptor Coactivator-1 (SRC-1) interacts with a target of leptin receptor activation, phosphorylated STAT3, to potentiate Pomc transcription. Deletion of SRC-1 in Pomc neurons in mice attenuates their depolarization by leptin, decreases Pomc expression and increases food intake leading to high-fat diet-induced obesity. In humans, fifteen rare heterozygous variants in SRC-1 found in severely obese individuals impair leptin-mediated Pomc reporter activity in cells, whilst four variants found in non-obese controls do not. In a knock-in mouse model of a loss of function human variant (SRC-1L1376P), leptin-induced depolarization of Pomc neurons and Pomc expression are significantly reduced, and food intake and body weight are increased. In summary, we demonstrate that SRC-1 modulates the function of hypothalamic Pomc neurons, and suggest that targeting SRC-1 may represent a useful therapeutic strategy for weight loss.Peer reviewe

Trans-ancestry meta-analyses identify rare and common variants associated with blood pressure and hypertension

High blood pressure is a major risk factor for cardiovascular disease and premature death. However, there is limited knowledge on specific causal genes and pathways. To better understand the genetics of blood pressure, we genotyped 242,296 rare, low-frequency and common genetic variants in up to ~192,000 individuals, and used ~155,063 samples for independent replication. We identified 31 novel blood pressure or hypertension associated genetic regions in the general population, including three rare missense variants in RBM47, COL21A1 and RRAS with larger effects (>1.5mmHg/allele) than common variants. Multiple rare, nonsense and missense variant associations were found in A2ML1 and a low-frequency nonsense variant in ENPEP was identified. Our data extend the spectrum of allelic variation underlying blood pressure traits and hypertension, provide new insights into the pathophysiology of hypertension and indicate new targets for clinical intervention

Improved imputation of low-frequency and rare variants using the UK10K haplotype reference panel

Imputing genotypes from reference panels created by whole-genome sequencing (WGS) provides a cost-effective strategy for augmenting the single-nucleotide polymorphism (SNP) content of genome-wide arrays. The UK10K Cohorts project has generated a data set of 3,781 whole genomes sequenced at low depth (average 7x), aiming to exhaustively characterize genetic variation down to 0.1% minor allele frequency in the British population. Here we demonstrate the value of this resource for improving imputation accuracy at rare and low-frequency variants in both a UK and an Italian population. We show that large increases in imputation accuracy can be achieved by re-phasing WGS reference panels after initial genotype calling. We also present a method for combining WGS panels to improve variant coverage and downstream imputation accuracy, which we illustrate by integrating 7,562 WGS haplotypes from the UK10K project with 2,184 haplotypes from the 1000 Genomes Project. Finally, we introduce a novel approximation that maintains speed without sacrificing imputation accuracy for rare variants

Формирование эмоциональной культуры как компонента инновационной культуры студентов

Homozygosity has long been associated with rare, often devastating, Mendelian disorders1 and Darwin was one of the first to recognise that inbreeding reduces evolutionary fitness2. However, the effect of the more distant parental relatedness common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity, ROH), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power3,4. Here we use ROH to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts and find statistically significant associations between summed runs of homozygosity (SROH) and four complex traits: height, forced expiratory lung volume in 1 second (FEV1), general cognitive ability (g) and educational attainment (nominal p<1 × 10−300, 2.1 × 10−6, 2.5 × 10−10, 1.8 × 10−10). In each case increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing convincing evidence for the first time that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples5,6, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein (LDL) cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection7, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been