Characterizing temporary hydrological regimes at a European scale

Monthly duration curves have been constructed from climate data across Europe to help address the relative frequency of ecologically critical low flow stages in temporary rivers, when flow persists only in disconnected pools in the river bed. The hydrological model is 5 based on a partitioning of precipitation to estimate water available for evapotranspiration and plant growth and for residual runoff. The duration curve for monthly flows has then been analysed to give an estimate of bankfull flow based on recurrence interval. The corresponding frequency for pools is then based on the ratio of bank full discharge to pool flow, arguing from observed ratios of cross-sectional areas at flood 10 and low flows to estimate pool flow as 0.1% of bankfull flow, and so estimate the frequency of the pool conditions that constrain survival of river-dwelling arthropods and fish. The methodology has been applied across Europe at 15 km resolution, and can equally be applied under future climatic scenarios

Improved siRNA/shRNA Functionality by Mismatched Duplex

siRNA (small interfering RNA) and shRNA (small hairpin RNA) are powerful and commonly used tools in biomedical research. Currently, siRNAs are generally designed as two 21 nt strands of RNA that include a 19 nt completely complementary part and a 2 nt overhang. However, since the si/shRNAs use the endogenous miRNA machinery for gene silencing and the miRNAs are generally 22 nt in length and contain multiple internal mismatches, we tested if the functionality can be increased by designing the si/shRNAs to mimic a miRNA structure. We systematically investigated the effect of single or multiple mismatches introduced in the passenger strand at different positions on siRNA functionality. Mismatches at certain positions could significantly increase the functionality of siRNAs and also, in some cases decreased the unwanted passenger strand functionality. The same strategy could also be used to design shRNAs. Finally, we showed that both si and miRNA structured oligos (siRNA with or without mismatches in the passenger strand) can repress targets in all individual Ago containing cells, suggesting that the Ago proteins do not differentiate between si/miRNA-based structure for silencing activity

Early loss of Crebbp confers malignant stem cell properties on lymphoid progenitors.

Loss-of-function mutations of cyclic-AMP response element binding protein, binding protein (CREBBP) are prevalent in lymphoid malignancies. However, the tumour suppressor functions of CREBBP remain unclear. We demonstrate that loss of Crebbp in murine haematopoietic stem and progenitor cells (HSPCs) leads to increased development of B-cell lymphomas. This is preceded by accumulation of hyperproliferative lymphoid progenitors with a defective DNA damage response (DDR) due to a failure to acetylate p53. We identify a premalignant lymphoma stem cell population with decreased H3K27ac, which undergoes transcriptional and genetic evolution due to the altered DDR, resulting in lymphomagenesis. Importantly, when Crebbp is lost later in lymphopoiesis, cellular abnormalities are lost and tumour generation is attenuated. We also document that CREBBP mutations may occur in HSPCs from patients with CREBBP-mutated lymphoma. These data suggest that earlier loss of Crebbp is advantageous for lymphoid transformation and inform the cellular origins and subsequent evolution of lymphoid malignancies

Reph, a Regulator of Eph Receptor Expression in the Drosophila melanogaster Optic Lobe

Receptors of the Eph family of tyrosine kinases and their Ephrin ligands are involved in developmental processes as diverse as angiogenesis, axon guidance and cell migration. However, our understanding of the Eph signaling pathway is incomplete, and could benefit from an analysis by genetic methods. To this end, we performed a genetic modifier screen for mutations that affect Eph signaling in Drosophila melanogaster. Several dozen loci were identified on the basis of their suppression or enhancement of an eye defect induced by the ectopic expression of Ephrin during development; many of these mutant loci were found to disrupt visual system development. One modifier locus, reph (regulator of eph expression), was characterized in molecular detail and found to encode a putative nuclear protein that interacts genetically with Eph signaling pathway mutations. Reph is an autonomous regulator of Eph receptor expression, required for the graded expression of Eph protein and the establishment of an optic lobe axonal topographic map. These results reveal a novel component of the regulatory pathway controlling expression of eph and identify reph as a novel factor in the developing visual system

Initial sequencing and analysis of the human genome

The human genome holds an extraordinary trove of information about human development, physiology, medicine and evolution. Here we report the results of an international collaboration to produce and make freely available a draft sequence of the human genome. We also present an initial analysis of the data, describing some of the insights that can be gleaned from the sequence.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62798/1/409860a0.pd

Variations in Stress Sensitivity and Genomic Expression in Diverse S. cerevisiae Isolates

Interactions between an organism and its environment can significantly influence phenotypic evolution. A first step toward understanding this process is to characterize phenotypic diversity within and between populations. We explored the phenotypic variation in stress sensitivity and genomic expression in a large panel of Saccharomyces strains collected from diverse environments. We measured the sensitivity of 52 strains to 14 environmental conditions, compared genomic expression in 18 strains, and identified gene copy-number variations in six of these isolates. Our results demonstrate a large degree of phenotypic variation in stress sensitivity and gene expression. Analysis of these datasets reveals relationships between strains from similar niches, suggests common and unique features of yeast habitats, and implicates genes whose variable expression is linked to stress resistance. Using a simple metric to suggest cases of selection, we found that strains collected from oak exudates are phenotypically more similar than expected based on their genetic diversity, while sake and vineyard isolates display more diverse phenotypes than expected under a neutral model. We also show that the laboratory strain S288c is phenotypically distinct from all of the other strains studied here, in terms of stress sensitivity, gene expression, Ty copy number, mitochondrial content, and gene-dosage control. These results highlight the value of understanding the genetic basis of phenotypic variation and raise caution about using laboratory strains for comparative genomics

Phenotypic Consequences of Copy Number Variation: Insights from Smith-Magenis and Potocki-Lupski Syndrome Mouse Models

The characterization of mice with different number of copies of the same genomic segment shows that structural changes influence the phenotypic outcome independently of gene dosage

Genetic diversity fuels gene discovery for tobacco and alcohol use

Tobacco and alcohol use are heritable behaviours associated with 15% and 5.3% of worldwide deaths, respectively, due largely to broad increased risk for disease and injury(1-4). These substances are used across the globe, yet genome-wide association studies have focused largely on individuals of European ancestries(5). Here we leveraged global genetic diversity across 3.4 million individuals from four major clines of global ancestry (approximately 21% non-European) to power the discovery and fine-mapping of genomic loci associated with tobacco and alcohol use, to inform function of these loci via ancestry-aware transcriptome-wide association studies, and to evaluate the genetic architecture and predictive power of polygenic risk within and across populations. We found that increases in sample size and genetic diversity improved locus identification and fine-mapping resolution, and that a large majority of the 3,823 associated variants (from 2,143 loci) showed consistent effect sizes across ancestry dimensions. However, polygenic risk scores developed in one ancestry performed poorly in others, highlighting the continued need to increase sample sizes of diverse ancestries to realize any potential benefit of polygenic prediction.Peer reviewe