The Genome of the Netherlands: Design, and project goals

Within the Netherlands a national network of biobanks has been established (Biobanking and Biomolecular Research Infrastructure-Netherlands (BBMRI-NL)) as a national node of the European BBMRI. One of the aims of BBMRI-NL is to enrich biobanks with different types of molecular and phenotype data. Here, we describe the Genome of the Netherlands (GoNL), one of the projects within BBMRI-NL. GoNL is a whole-genome-sequencing project in a representative sample consisting of 250 trio-families from all provinces in the Netherlands, which aims to characterize DNA sequence variation in the Dutch population. The parent-offspring trios include adult individuals ranging in age from 19 to 87 years (mean=53 years; SD=16 years) from birth cohorts 1910-1994. Sequencing was done on blood-derived DNA from uncultured cells and accomplished coverage was 14-15x. The family-based design represents a unique resource to assess the frequency of regional variants, accurately reconstruct haplotypes by family-based phasing, characterize short indels and complex structural variants, and establish the rate of de novo mutational events. GoNL will also serve as a reference panel for imputation in the available genome-wide association studies in Dutch and other cohorts to refine association signals and uncover population-specific variants. GoNL will create a catalog of human genetic variation in this sample that is uniquely characterized with respect to micro-geographic location and a wide range of phenotypes. The resource will be made available to the research and medical community to guide the interpretation of sequencing projects. The present paper summarizes the global characteristics of the project

Skewed X-inactivation is common in the general female population

X-inactivation is a well-established dosage compensation mechanism ensuring that X-chromosomal genes are expressed at comparable levels in males and females. Skewed X-inactivation is often explained by negative selection of one of the alleles. We demonstrate that imbalanced expression of the paternal and maternal X-chromosomes is common in the general population and that the random nature of the X-inactivation mechanism can be sufficient to explain the imbalance. To this end, we analyzed blood-derived RNA and whole-genome sequencing data from 79 female children and their parents from the Genome of the Netherlands project. We calculated the median ratio of the paternal over total counts at all X-chromosomal heterozygous single-nucleotide variants with coverage ≥10. We identified two individuals where the same X-chromosome was inactivated in all cells. Imbalanced expression of the two X-chromosomes (ratios ≤0.35 or ≥0.65) was observed in nearly 50% of the population. The empirically observed skewing is explained by a theoretical model where X-inactivation takes place in an embryonic stage in which eight cells give rise to the hematopoietic compartment. Genes escaping X-inactivation are expressed from both alleles and therefore demonstrate less skewing than inactivated genes. Using this characteristic, we identified three novel escapee genes (SSR4, REPS2, and SEPT6), but did not find support for many previously reported escapee genes in blood. Our collective data suggest that skewed X-inactivation is common in the general population. This may contribute to manifestation of symptoms in carriers of recessive X-linked disorders. We recommend that X-inactivation results should not be used lightly in the interpretation of X-linked variants

Avaliação estatística da variação da velocidade de propagação de ondas de ultra-som na madeira em presença de defeitos Statistical evaluation of the ultrasonic wave velocity variation in defective wood

Os métodos visuais para a detecção de defeitos na madeira, ainda que de grande utilidade, podem ser falhos e exigem a utilização de mão-de-obra relativamente bem treinada. Muitas vezes, a presença de nós, rachaduras ou, ainda, regiões com medula no interior de uma peça serrada, podem ser imperceptíveis na avaliação visual. Um dos grandes avanços obtidos nos últimos anos na caracterização de materiais, tanto do ponto de vista mecânico quanto da qualidade, é a aplicação de técnicas que utilizam a propagação de ondas, destacando-se, dentre elas, o ultra-som. O objetivo deste trabalho é avaliar, estatisticamente, a possibilidade de se utilizar o método do ultra-som na detecção de defeitos em peças de madeira serrada. Para isto, foram utilizadas 180 peças de dimensões nominais: 0,027 m de espessura; 0,10 m de largura e 0,25 m de comprimento, retiradas de vigas de Pinus sp obtidas em serraria da cidade de Campinas. As peças foram ensaiadas na umidade de equilíbrio ao ar. Para a realização dos ensaios utilizou-se o equipamento de emissão de ondas de ultra-som marca Steinkamp BP-7 com transdutores de 45 kHz. Inicialmente foi realizada uma análise visual das peças e, posteriormente, a determinação da velocidade de propagação das ondas nas mesmas peças. Com os resultados, realizou-se uma análise exploratória das variáveis e obteve-se um modelo de regressão logística visando verificar a relação entre a presença ou não de defeitos e a velocidade de propagação da onda do ultra-som na madeira. Os resultados demonstram uma forte relação entre a velocidade de propagação da onda de ultra-som e os defeitos detectados pela análise visual<br>Visual methods to detect wood defects, although of great utility, can lead to inaccurate results and demand a specialist to carry it out. The presence of knots, cracks or pith regions inside a sawed piece can be imperceptible in the visual evaluation. One of the greatest progress obtained in the last years in the characterization of materials - not only to determine its mechanical properties but also its quality - is the application of acoustic techniques like the ultrasound. The objective of this study is to evaluate, by statistical analysis, the sensibility of the ultrasonic method for detection of defects in pieces of sawed wood. For the trail, 180 pieces of Pinus sp. with 0.027 m of thickness, 0.10 m of width and 0.25 of length were used. These pieces tested under air dried condition (approximately 12% moisture content), were obtained at a saw mill in Campinas. The velocity of ultrasonic waves was measured by Steinkamp BP-7 ultrasound equipment with 45 kHz transducers. Initially the pieces were analyzed by visual method and later the velocity of ultrasonic waves through the wood pieces was measured. An exploratory analysis of the variables was done and a logistic regression model was obtained. The objective was to verify the relationship for the presence or absence of defects in the wood and the velocity of ultrasonic wave propagation. The results demonstrate a strong relationship between the ultrasonic wave propagation and the defects detected by the visual analysi

Rituximab for Multirelapsing, Steroid-Dependent or Steroid-Resistant, Minimal-Change Nephropathy – a Report of Nine Adult Cases

Photograph of the interior of the Oklahoma Governor's Mansion, during Henry Bellmon's administration