41 research outputs found

    Polygenic basis and biomedical consequences of telomere length variation

    Get PDF
    Telomeres, the end fragments of chromosomes, play key roles in cellular proliferation and senescence. Here we characterize the genetic architecture of naturally occurring variation in leukocyte telomere length (LTL) and identify causal links between LTL and biomedical phenotypes in 472,174 well-characterized UK Biobank participants. We identified 197 independent sentinel variants associated with LTL at 138 genomic loci (108 new). Genetically determined differences in LTL were associated with multiple biological traits, ranging from height to bone marrow function, as well as several diseases spanning neoplastic, vascular and inflammatory pathologies. Finally, we estimated that, at the age of 40 years, people with an LTL >1 s.d. shorter than the population mean had a 2.5-year-lower life expectancy compared with the group with ≄1 s.d. longer LDL. Overall, we furnish new insights into the genetic regulation of LTL, reveal wide-ranging influences of LTL on physiological traits, diseases and longevity, and provide a powerful resource available to the global research community

    Mutations in SPATA13/ASEF2 cause primary angle closure glaucoma

    Get PDF
    Current estimates suggest 50% of glaucoma blindness worldwide is caused by primary angle-closure glaucoma (PACG) but the causative gene is not known. We used genetic linkage and whole genome sequencing to identify Spermatogenesis Associated Protein 13, SPATA13 (NM_001166271; NP_001159743, SPATA13 isoform I), also known as ASEF2 (Adenomatous polyposis coli-stimulated guanine nucleotide exchange factor 2), as the causal gene for PACG in a large seven-generation white British family showing variable expression and incomplete penetrance. The 9 bp deletion, c.1432_1440del; p.478_480del was present in all affected individuals with angle-closure disease. We show ubiquitous expression of this transcript in cell lines derived from human tissues and in iris, retina, retinal pigment and ciliary epithelia, cornea and lens. We also identified eight additional mutations in SPATA13 in a cohort of 189 unrelated PACS/PAC/PACG samples. This gene encodes a 1277 residue protein which localises to the nucleus with partial co-localisation with nuclear speckles. In cells undergoing mitosis SPATA13 isoform I becomes part of the kinetochore complex co-localising with two kinetochore markers, polo like kinase 1 (PLK-1) and centrosome-associated protein E (CENP-E). The 9 bp deletion reported in this study increases the RAC1-dependent guanine nucleotide exchange factors (GEF) activity. The increase in GEF activity was also observed in three other variants identified in this study. Taken together, our data suggest that SPATA13 is involved in the regulation of mitosis and the mutations dysregulate GEF activity affecting homeostasis in tissues where it is highly expressed, influencing PACG pathogenesis

    Polygenic basis and biomedical consequences of telomere length variation.

    Get PDF
    Funder: Health Data Research UK EU/EFPIA Innovative Medicines Initiative Joint Undertaking BigData@Heart (11607).Funder: Health Data Research UKTelomeres, the end fragments of chromosomes, play key roles in cellular proliferation and senescence. Here we characterize the genetic architecture of naturally occurring variation in leukocyte telomere length (LTL) and identify causal links between LTL and biomedical phenotypes in 472,174 well-characterized UK Biobank participants. We identified 197 independent sentinel variants associated with LTL at 138 genomic loci (108 new). Genetically determined differences in LTL were associated with multiple biological traits, ranging from height to bone marrow function, as well as several diseases spanning neoplastic, vascular and inflammatory pathologies. Finally, we estimated that, at the age of 40 years, people with an LTL >1 s.d. shorter than the population mean had a 2.5-year-lower life expectancy compared with the group with ≄1 s.d. longer LDL. Overall, we furnish new insights into the genetic regulation of LTL, reveal wide-ranging influences of LTL on physiological traits, diseases and longevity, and provide a powerful resource available to the global research community

    Historical geographies of the future: airships and the making of imperial atmospheres

    Get PDF
    This article explores the elemental encounters and imaginative geographies of empire to develop a new means of engaging with the historical geographies of the future. Futures have recently become an important topic of historical and cultural inquiry, and historical geographers have an important role to play in understanding the place of the future in the past and in interrogating the role of posited futures in shaping action in historical presents. Drawing on literature from science and technology studies, a framework is developed for engaging with the material and imaginative geographies that coalesce around practices of imagination, expectation, and prediction. This framework is then used to reconstruct efforts to develop airship travel in the British Empire in the 1920s and 1930s. At a moment of imperial anxiety, airships were hoped to tie the empire together by conveying bodies, capital, and military capacity between its furthest points. Confident projections of the colonization of global airspace were nonetheless undermined by material encounters with a vibrant, often unpredictable atmospheric environment. The article aims to spur renewed work on the historical geographies of the future, while also contributing to debates on the cultural and political geographies of the atmosphere and of atmospheric knowledge making. Key Words: atmosphere, empire, future, mobility, technology

    Avifauna recovers faster in areas less accessible to trapping in regenerating tropical forests

    Get PDF
    Tropical forest restoration stands to deliver important conservation gains, particularly in lowland Southeast Asia, which has suffered some of the world's highest rates of recent forest loss and degradation. This promise, however, depends on the extent to which biodiversity at forest restoration sites continues to be exposed to threats. A key knowledge gap concerns the extent to which biodiversity recovery in naturally regenerating tropical forests is impacted by trapping for the multi-million-dollar wildlife trade. Here, we use a repeated survey dataset to quantify rates of avian community recovery under forest regeneration, at a flagship restoration site in the lowland rainforests of Sumatra, Indonesia. We show that over a decade, forest regeneration was associated with significant abundance increases for 43.8 % of bird species. However, the apparent negative impacts of trade-driven trapping on avian populations also intensified: the proportion of species dependent on very remote forests increased from 5.4 % to 16.2 %. Moreover, the overall accessibility of the forest increased. We found that 14 % of species did not recover as fast as predicted based on the observed forest regeneration over the study period. We found trapping to disproportionately impact species targeted for trade: compared to opportunistically trapped species, twice more species showed increased abundance only in very remote forests. Our results highlight the potential for rapid avifaunal recovery in regenerating tropical forests, but also emphasize the urgency of tackling the serious threat of wildlife trade to Southeast Asia's biodiversity.We gratefully acknowledge the funding support from the joint AEC-OBC Conservation Grant (No. P1250) provided by the Oriental Bird Club and the Ecology Arboriculture Landscape, Sir Philip Reckitt Educational Trust travel grant, and European Commission’s Joint Master’s Degree Fellowship (FPA 2023 – 0224/ 532524-1-FR-2012-1-ERA MUNDUS-EMMC)
    corecore