Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Genes Regulated by HPV 16 E6 and High Expression of NFX1-123 in Cervical Cancers

Purpose High-risk human papillomaviruses (HR HPV) cause cervical cancer, and in these cancers, HPV type 16 is the most common HR type. The HR viral oncogenes E6 and E7 partner with cellular proteins to drive cancer and modulate immune pathways; previously, we demonstrated in keratinocytes that HPV 16 E6 and high expression of the endogenous host protein partner NFX1-123 led to the increased expression of multiple genes, including Notch1, secretory leukocyte peptidase inhibitor (SLPI), and retinoic acid early transcript 1G (RAET1G). The present study was conducted to determine if NFX1-123 was highly expressed in cervical cancer and if genes increased by NFX1-123 and 16E6 in keratinocytes were also increased in cervical cancers. Materials and Methods The Cancer Genome Atlas (TCGA) database and The Human Protein Atlas database were used to compare relative mRNA and protein gene expression, respectively, in the normal cervix and cervical cancers. Formalin-fixed paraffin-embedded (FFPE) normal cervix and HPV 16 positive cervical cancer samples were analyzed for relative protein expression by immunohistochemical staining. Protein expression of a subset of regulated genes was quantified by Western blot of HPV positive and negative cell lines. Results Immunohistochemical staining of HPV 16 positive cervical dysplasias and cancers revealed high NFX1-123, Ki67, and Notch1 expression. NFX1 and NFX1L1 mRNA levels were increased in cervical cancers compared to normal cervix in the TCGA database. Fourteen genes previously identified as upregulated in keratinocytes with 16E6 and overexpressed NFX1-123 also had high mRNA expression and selected genes had high protein expression in cervical cancers and cell lines. Conclusion In cervical cancer, NFX1-123 is highly expressed, and 16E6 and NFX1-123 together alter the expression of a wide set of genes. The involvement of these genes in cell proliferation, differentiation, invasion, and metastasis provides further insight into potential ways that HR HPVs promote cancer initiation and maintenance

Glacial geomorphology of the Ahuriri River valley, central Southern Alps, New Zealand

No description supplie

Cosmogenic 10Be constraints on deglacial snowline rise in the Southern Alps, New Zealand

Geochronological dating of glacial landforms, such as terminal and lateral moraines, is useful for determining the extent and timing of past glaciation and for reconstructing the magnitude and rate of past climate changes. In the Southern Alps of New Zealand, well-dated glacial geomorphological records constrain the last glacial cycle across much of the Waitaki River basin (e.g. Ōhau, Pukaki, Tekapo) but its southern sector such as the Ahuriri River valley remains comparatively unconstrained. Recently, there has been debate on the scale and rapidity of mountain glacier retreat during the last glacial termination, particularly the 20–17 ka period in New Zealand. Missing from this debate is well-constrained equilibrium-line altitude (ELA) and associated temperature reconstructions, particularly over the period around 17 ka, which can help us to develop a more complete picture of how past temperature changes drove glacier retreat. Here we report the first glacial chronology dataset from the Last Glacial Maximum (LGM) and subsequent deglaciation from the Ahuriri River valley, Southern Alps, New Zealand (44°23′54″S, 169°39′48″E) based on 38 beryllium-10 (10Be) surface-exposure ages from terminal moraine systems and glaciated bedrock situated at the lower and middle sections of the valley. Our results show that the former Ahuriri Glacier reached its maximum extent at 19.8 ± 0.3 ka, which coincides with the global Last Glacial Maximum. By 16.7 ± 0.3 ka, the glacier had retreat ∼18 km up-valley suggesting at least ∼43% glacier-length loss relative to its full LGM extent. This deglaciation was accompanied by the formation of a shallow proglacial lake. Using the accumulation area ratio (AAR) method, we estimate that the ELA was lower than present by ∼880 m (∼1120 m a.s.l.) at 19.8 ± 0.3 ka, and ∼770 m lower (∼1230 m a.s.l.) at 16.7 ± 0.3 ka. Applying an estimate for temperature lapse rate, this ELA anomaly implies that local air temperature was 5 ± 1 °C colder than present (1981–2010) at 19.8 ± 0.3 ka, while it was 4.4 ± 0.9 °C colder at 16.7 ± 0.3 ka, assuming no change in precipitation. The substantial glacier retreat in response to a relatively small accompanying increases in ELA (110 m) and temperature (0.6 °C) may have been a result of the high glacier-length sensitivity of this glacier system due to its low gradient of former ice surface. Our low warming estimate differs markedly from other deglaciation studies, specifically from Rakaia River valley, which reports a much larger temperature increase at the onset of the last deglaciation. This precisely-dated moraine record along with reconstructed ELA as proxies for atmospheric conditions, provides new insight into post LGM glacier behaviour and climate conditions in New Zealand

Varia

La rubrique Varia regroupe tous les articles qui ne font pas partie d'un dossier thématique. Ces articles peuvent cependant être soit entièrement indépendants, soit réagir à ou compléter un dossier thématique paru précédemment. Pour cette rubrique, les contributions acceptées par le comité de lecture de la revue sont publiées tout au long de l'année, sans périodicité fixe

NQO1 protects obese mice through improvements in glucose and lipid metabolism

Chronic nutrient excess leads to metabolic disorders and insulin resistance. Activation of stress-responsive pathways via Nrf2 activation contributes to energy metabolism regulation. Here, inducible activation of Nrf2 in mice and transgenesis of the Nrf2 target, NQO1, conferred protection from diet-induced metabolic defects through preservation of glucose homeostasis, insulin sensitivity, and lipid handling with improved physiological outcomes. NQO1-RNA interaction mediated the association with and inhibition of the translational machinery in skeletal muscle of NQO1 transgenic mice. NQO1-Tg mice on high-fat diet had lower adipose tissue macrophages and enhanced expression of lipogenic enzymes coincident with reduction in circulating and hepatic lipids. Metabolomics data revealed a systemic metabolic signature of improved glucose handling, cellular redox, and NAD+ metabolism while label-free quantitative mass spectrometry in skeletal muscle uncovered a distinct diet- and genotype-dependent acetylation pattern of SIRT3 targets across the core of intermediary metabolism. Thus, under nutritional excess, NQO1 transgenesis preserves healthful benefits.The work was funded, in part, by the Intramural Research Program of the National Institutes of Health/NIA and by grants #5R01CA206155 and R01ES031263 (S.B.), R01 DK109964 (D.R., K.F., R.d.C.)

Evaluation of Second-Generation Sequencing of 19 Dilated Cardiomyopathy Genes for Clinical Applications

Medical sequencing for diseases with locus and allelic heterogeneities has been limited by the high cost and low throughput of traditional sequencing technologies. “Second-generation” sequencing (SGS) technologies allow the parallel processing of a large number of genes and, therefore, offer great promise for medical sequencing; however, their use in clinical laboratories is still in its infancy. Our laboratory offers clinical resequencing for dilated cardiomyopathy (DCM) using an array-based platform that interrogates 19 of more than 30 genes known to cause DCM. We explored both the feasibility and cost effectiveness of using PCR amplification followed by SGS technology for sequencing these 19 genes in a set of five samples enriched for known sequence alterations (109 unique substitutions and 27 insertions and deletions). While the analytical sensitivity for substitutions was comparable to that of the DCM array (98%), SGS technology performed better than the DCM array for insertions and deletions (90.6% versus 58%). Overall, SGS performed substantially better than did the current array-based testing platform; however, the operational cost and projected turnaround time do not meet our current standards. Therefore, efficient capture methods and/or sample pooling strategies that shorten the turnaround time and decrease reagent and labor costs are needed before implementing this platform into routine clinical applications