Many existing cohorts contain a range of relatedness between genotyped individuals, either by design or by chance. Haplotype estimation in such cohorts is a central step in many downstream analyses. ...Using genotypes from six cohorts from isolated populations and two cohorts from non-isolated populations, we have investigated the performance of different phasing methods designed for nominally 'unrelated' individuals. We find that SHAPEIT2 produces much lower switch error rates in all cohorts compared to other methods, including those designed specifically for isolated populations. In particular, when large amounts of IBD sharing is present, SHAPEIT2 infers close to perfect haplotypes. Based on these results we have developed a general strategy for phasing cohorts with any level of implicit or explicit relatedness between individuals. First SHAPEIT2 is run ignoring all explicit family information. We then apply a novel HMM method (duoHMM) to combine the SHAPEIT2 haplotypes with any family information to infer the inheritance pattern of each meiosis at all sites across each chromosome. This allows the correction of switch errors, detection of recombination events and genotyping errors. We show that the method detects numbers of recombination events that align very well with expectations based on genetic maps, and that it infers far fewer spurious recombination events than Merlin. The method can also detect genotyping errors and infer recombination events in otherwise uninformative families, such as trios and duos. The detected recombination events can be used in association scans for recombination phenotypes. The method provides a simple and unified approach to haplotype estimation, that will be of interest to researchers in the fields of human, animal and plant genetics.
The MUSASHI (MSI) family of RNA binding proteins (MSI1 and MSI2) contribute to a wide spectrum of cancers including acute myeloid leukemia. We find that the small molecule Ro 08-2750 (Ro) binds ...directly and selectively to MSI2 and competes for its RNA binding in biochemical assays. Ro treatment in mouse and human myeloid leukemia cells results in an increase in differentiation and apoptosis, inhibition of known MSI-targets, and a shared global gene expression signature similar to shRNA depletion of MSI2. Ro demonstrates in vivo inhibition of c-MYC and reduces disease burden in a murine AML leukemia model. Thus, we identify a small molecule that targets MSI's oncogenic activity. Our study provides a framework for targeting RNA binding proteins in cancer.
We have mapped sequence-directed nucleosome positioning on genomic DNA molecules using high-throughput sequencing. Chromatins, prepared by reconstitution with either chicken or frog histones, were ...separately digested to mononucleosomes using either micrococcal nuclease (MNase) or caspase-activated DNase (CAD). Both enzymes preferentially cleave internucleosomal (linker) DNA, although they do so by markedly different mechanisms. MNase has hitherto been very widely used to map nucleosomes, although concerns have been raised over its potential to introduce bias. Having identified the locations and quantified the strength of both the chicken or frog histone octamer binding sites on each DNA, the results obtained with the two enzymes were compared using a variety of criteria. Both enzymes displayed sequence specificity in their preferred cleavage sites, although the nature of this selectivity was distinct for the two enzymes. In addition, nucleosomes produced by CAD nuclease are 8–10 bp longer than those produced with MNase, with the CAD cleavage sites tending to be 4–5 bp further out from the nucleosomal dyad than the corresponding MNase cleavage sites. Despite these notable differences in cleavage behaviour, the two nucleases identified essentially equivalent patterns of nucleosome positioning sites on each of the DNAs tested, an observation that was independent of the histone type. These results indicate that biases in nucleosome positioning data collected using MNase are, under our conditions, not significant.
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► We measured nucleosome positioning using two distinct nucleases. ► CAD and MNase provided equivalent positioning profiles. ► The results were independent of DNA and histone type used to prepare chromatin. ► Our data are not consistent with the proposal that MNase provides biased nucleosome positioning measurements.
Marine pelagic ecosystems: the West Antarctic Peninsula Ducklow, Hugh W; Baker, Karen; Martinson, Douglas G ...
Philosophical transactions - Royal Society. Biological sciences,
01/2007, Letnik:
362, Številka:
1477
Journal Article
Recenzirano
Odprti dostop
The marine ecosystem of the West Antarctic Peninsula (WAP) extends from the Bellingshausen Sea to the northern tip of the peninsula and from the mostly glaciated coast across the continental shelf to ...the shelf break in the west. The glacially sculpted coastline along the peninsula is highly convoluted and characterized by deep embayments that are often interconnected by channels that facilitate transport of heat and nutrients into the shelf domain. The ecosystem is divided into three subregions, the continental slope, shelf and coastal regions, each with unique ocean dynamics, water mass and biological distributions. The WAP shelf lies within the Antarctic Sea Ice Zone (SIZ) and like other SIZs, the WAP system is very productive, supporting large stocks of marine mammals, birds and the Antarctic krill, Euphausia superba. Ecosystem dynamics is dominated by the seasonal and interannual variation in sea ice extent and retreat. The Antarctic Peninsula is one among the most rapidly warming regions on Earth, having experienced a 2°C increase in the annual mean temperature and a 6°C rise in the mean winter temperature since 1950. Delivery of heat from the Antarctic Circumpolar Current has increased significantly in the past decade, sufficient to drive to a 0.6°C warming of the upper 300 m of shelf water. In the past 50 years and continuing in the twenty-first century, the warm, moist maritime climate of the northern WAP has been migrating south, displacing the once dominant cold, dry continental Antarctic climate and causing multi-level responses in the marine ecosystem. Ecosystem responses to the regional warming include increased heat transport, decreased sea ice extent and duration, local declines in ice-dependent Adélie penguins, increase in ice-tolerant gentoo and chinstrap penguins, alterations in phytoplankton and zooplankton community composition and changes in krill recruitment, abundance and availability to predators. The climate/ecological gradients extending along the WAP and the presence of monitoring systems, field stations and long-term research programmes make the region an invaluable observatory of climate change and marine ecosystem response.
There are two very different interpretations of the prehistory of Island Southeast Asia (ISEA), with genetic evidence invoked in support of both. The “out-of-Taiwan” model proposes a major Late ...Holocene expansion of Neolithic Austronesian speakers from Taiwan. An alternative, proposing that Late Glacial/postglacial sea-level rises triggered largely autochthonous dispersals, accounts for some otherwise enigmatic genetic patterns, but fails to explain the Austronesian language dispersal. Combining mitochondrial DNA (mtDNA), Y-chromosome and genome-wide data, we performed the most comprehensive analysis of the region to date, obtaining highly consistent results across all three systems and allowing us to reconcile the models. We infer a primarily common ancestry for Taiwan/ISEA populations established before the Neolithic, but also detected clear signals of two minor Late Holocene migrations, probably representing Neolithic input from both Mainland Southeast Asia and South China, via Taiwan. This latter may therefore have mediated the Austronesian language dispersal, implying small-scale migration and language shift rather than large-scale expansion.
India is a patchwork of tribal and non-tribal populations that speak many different languages from various language families. Indo-European, spoken across northern and central India, and also in ...Pakistan and Bangladesh, has been frequently connected to the so-called "Indo-Aryan invasions" from Central Asia ~3.5 ka and the establishment of the caste system, but the extent of immigration at this time remains extremely controversial. South India, on the other hand, is dominated by Dravidian languages. India displays a high level of endogamy due to its strict social boundaries, and high genetic drift as a result of long-term isolation which, together with a very complex history, makes the genetic study of Indian populations challenging.
We have combined a detailed, high-resolution mitogenome analysis with summaries of autosomal data and Y-chromosome lineages to establish a settlement chronology for the Indian Subcontinent. Maternal lineages document the earliest settlement ~55-65 ka (thousand years ago), and major population shifts in the later Pleistocene that explain previous dating discrepancies and neutrality violation. Whilst current genome-wide analyses conflate all dispersals from Southwest and Central Asia, we were able to tease out from the mitogenome data distinct dispersal episodes dating from between the Last Glacial Maximum to the Bronze Age. Moreover, we found an extremely marked sex bias by comparing the different genetic systems.
Maternal lineages primarily reflect earlier, pre-Holocene processes, and paternal lineages predominantly episodes within the last 10 ka. In particular, genetic influx from Central Asia in the Bronze Age was strongly male-driven, consistent with the patriarchal, patrilocal and patrilineal social structure attributed to the inferred pastoralist early Indo-European society. This was part of a much wider process of Indo-European expansion, with an ultimate source in the Pontic-Caspian region, which carried closely related Y-chromosome lineages, a smaller fraction of autosomal genome-wide variation and an even smaller fraction of mitogenomes across a vast swathe of Eurasia between 5 and 3.5 ka.
Regulation of intracellular cyclic adenosine 3 ′,5 ′-monophosphate (cAMP) is integral in mediating cell growth, cell differentiation, and immune responses in hematopoietic cells. To facilitate ...studies of cAMP regulation we developed a BRET (bioluminescence resonance energy transfer) sensor for cAMP, CAMYEL (cAMP sensor using YFP-Epac-RLuc), which can quantitatively and rapidly monitor intracellular concentrations of cAMP in vivo. This sensor was used to characterize three distinct pathways for modulation of cAMP synthesis stimulated by presumed Gs-dependent receptors for isoproterenol and prostaglandin E2. Whereas two ligands, uridine 5 ′-diphosphate and complement C5a, appear to use known mechanisms for augmentation of cAMP via Gq/calcium and Gi, the action of sphingosine 1-phosphate (S1P) is novel. In these cells, S1P, a biologically active lysophospholipid, greatly enhances increases in intracellular cAMP triggered by the ligands for Gs-coupled receptors while having only a minimal effect by itself. The enhancement of cAMP by S1P is resistant to pertussis toxin and independent of intracellular calcium. Studies with RNAi and chemical perturbations demonstrate that the effect of S1P is mediated by the S1P2 receptor and the heterotrimeric G13 protein. Thus in these macrophage cells, all four major classes of G proteins can regulate intracellular cAMP.
Abstract
Time-activity budgets are fundamental to behavioural studies, allowing examination of how individuals allocate their time, and potentially energy, and how these patterns vary spatially and ...temporally and in relation to habitat, individual identity, sex, social status and levels of anthropogenic disturbance. Direct observations of animal behaviour, especially in the wild, are often limited to daylight hours; therefore, many activity budgets relate to diurnal activity only, or assumptions are made about nocturnal activity. Activity budgets have been a key component of many behavioural and energetics studies of breeding grey seals (Halichoerus grypus, Fabricius, 1791), and yet very little is known about nocturnal activity of grey seals, and a general, implicit assumption of no significant change from day to night seems to pervade the literature. Here we use a combination of high resolution digital video and thermal imaging video camera to follow known individual grey seal mothers from day into night to examine activity patterns during lactation. We show distinct differences in nocturnal activity budgets relative to diurnal activity budgets. Mothers spent significantly more time resting with a reduction of time spent in the alert and comfort move behavioural categories during nocturnal periods. It is clear that diurnal time-activity patterns of breeding female grey seals cannot be extrapolated to represent activity across a 24-hour cycle. These considerations are particularly critical in studies that aim to use time-activity budgets as proxies for energy budgets.
Exceptional sea ice conditions occurred in the West Antarctic Peninsula (WAP) region from September 2001 to February 2002, resulting from a strongly positive atmospheric pressure anomaly in the South ...Atlantic coupled with strong negative anomalies in the Bellingshausen–Amundsen and southwest Weddell Seas. This created a strong and persistent north-northwesterly flow of mild and moist air across the WAP. In situ, satellite, and NCEP–NCAR Reanalysis (NNR) data are used to examine the profound and complex impact on regional sea ice, oceanography, and biota. Extensive sea ice melt, leading to an ocean mixed layer freshening and widespread ice surface flooding, snow–ice formation, and phytoplankton growth, coincided with extreme ice deformation and dynamic thickening. Sea ice dynamics were crucial to the development of an unusually early and rapid (short) retreat season (negative ice extent anomaly). Strong winds with a dominant northerly component created an unusually compact marginal ice zone and a major increase in ice thickness by deformation and over-rafting. This led to the atypical persistence of highly compact coastal ice through summer. Ecological effects were both positive and negative, the latter including an impact on the growth rate of larval Antarctic krill and the largest recorded between-season breeding population decrease and lowest reproductive success in a 30-yr Adélie penguin demographic time series. The unusual sea ice and snow cover conditions also contributed to the formation of a major phytoplankton bloom. Unexpectedly, the initial bloom occurred within compact sea ice and could not be detected in Sea-Viewing Wide Fieldof-View Sensor (SeaWiFS) ocean color data. This analysis demonstrates that sea ice extent alone is an inadequate descriptor of the regional sea ice state/conditions, from both a climatic and ecological perspective; further information is required on thickness and dynamics/deformation.
Using high-throughput sequencing, we have mapped sequence-directed nucleosome positioning in vitro on four plasmid DNAs containing DNA fragments derived from the genomes of sheep, drosophila, human ...and yeast. Chromatins were prepared by reconstitution using chicken, frog and yeast core histones. We also assembled yeast chromatin in which histone H3 was replaced by the centromere-specific histone variant, Cse4. The positions occupied by recombinant frog and native chicken histones were found to be very similar. In contrast, nucleosomes containing the canonical yeast octamer or, in particular, the Cse4 octamer were assembled at distinct populations of locations, a property that was more apparent on particular genomic DNA fragments. The factors that may contribute to this variation in nucleosome positioning and the implications of the behavior are discussed.
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•Chromatins were formed on plasmids containing fragments of sheep, drosophila, human and yeast genomic DNAs with four types of histone octamer.•Nucleosome positioning was measured for each reconstitute.•Although similar, the binding profiles obtained with the yeast histone octamer, including one containing Cse4, were distinct from those obtained with chick or frog histones.•The difference in nucleosome positioning was best seen on AT-rich DNA substrates.
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