Integrating sequence and array data to create an improved 1000 Genomes Project haplotype reference panel

A major use of the 1000 Genomes Project (1000GP) data is genotype imputation in genome-wide association studies (GWAS). Here we develop a method to estimate haplotypes from low-coverage sequencing data that can take advantage of single-nucleotide polymorphism (SNP) microarray genotypes on the same samples. First the SNP array data are phased to build a backbone (or 'scaffold') of haplotypes across each chromosome. We then phase the sequence data 'onto' this haplotype scaffold. This approach can take advantage of relatedness between sequenced and non-sequenced samples to improve accuracy. We use this method to create a new 1000GP haplotype reference set for use by the human genetic community. Using a set of validation genotypes at SNP and bi-allelic indels we show that these haplotypes have lower genotype discordance and improved imputation performance into downstream GWAS samples, especially at low-frequency variants. © 2014 Macmillan Publishers Limited. All rights reserved

Blue Hill Ship Building

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Discovery of widespread transcription initiation at microsatellites predictable by sequence-based deep neural network

Using the Cap Analysis of Gene Expression (CAGE) technology, the FANTOM5 consortium provided one of the most comprehensive maps of transcription start sites (TSSs) in several species. Strikingly, ~72% of them could not be assigned to a specific gene and initiate at unconventional regions, outside promoters or enhancers. Here, we probe these unassigned TSSs and show that, in all species studied, a significant fraction of CAGE peaks initiate at microsatellites, also called short tandem repeats (STRs). To confirm this transcription, we develop Cap Trap RNA-seq, a technology which combines cap trapping and long read MinION sequencing. We train sequence-based deep learning models able to predict CAGE signal at STRs with high accuracy. These models unveil the importance of STR surrounding sequences not only to distinguish STR classes, but also to predict the level of transcription initiation. Importantly, genetic variants linked to human diseases are preferentially found at STRs with high transcription initiation level, supporting the biological and clinical relevance of transcription initiation at STRs. Together, our results extend the repertoire of non-coding transcription associated with DNA tandem repeats and complexify STR polymorphism

Global, regional, and national disability-adjusted life-years (DALYs) for 315 diseases and injuries and healthy life expectancy (HALE), 1990�2015: a systematic analysis for the Global Burden of Disease Study 2015

Background Healthy life expectancy (HALE) and disability-adjusted life-years (DALYs) provide summary measures of health across geographies and time that can inform assessments of epidemiological patterns and health system performance, help to prioritise investments in research and development, and monitor progress toward the Sustainable Development Goals (SDGs). We aimed to provide updated HALE and DALYs for geographies worldwide and evaluate how disease burden changes with development. Methods We used results from the Global Burden of Diseases, Injuries, and Risk Factors Study 2015 (GBD 2015) for all-cause mortality, cause-specific mortality, and non-fatal disease burden to derive HALE and DALYs by sex for 195 countries and territories from 1990 to 2015. We calculated DALYs by summing years of life lost (YLLs) and years of life lived with disability (YLDs) for each geography, age group, sex, and year. We estimated HALE using the Sullivan method, which draws from age-specific death rates and YLDs per capita. We then assessed how observed levels of DALYs and HALE differed from expected trends calculated with the Socio-demographic Index (SDI), a composite indicator constructed from measures of income per capita, average years of schooling, and total fertility rate. Findings Total global DALYs remained largely unchanged from 1990 to 2015, with decreases in communicable, neonatal, maternal, and nutritional (Group 1) disease DALYs offset by increased DALYs due to non-communicable diseases (NCDs). Much of this epidemiological transition was caused by changes in population growth and ageing, but it was accelerated by widespread improvements in SDI that also correlated strongly with the increasing importance of NCDs. Both total DALYs and age-standardised DALY rates due to most Group 1 causes significantly decreased by 2015, and although total burden climbed for the majority of NCDs, age-standardised DALY rates due to NCDs declined. Nonetheless, age-standardised DALY rates due to several high-burden NCDs (including osteoarthritis, drug use disorders, depression, diabetes, congenital birth defects, and skin, oral, and sense organ diseases) either increased or remained unchanged, leading to increases in their relative ranking in many geographies. From 2005 to 2015, HALE at birth increased by an average of 2·9 years (95 uncertainty interval 2·9�3·0) for men and 3·5 years (3·4�3·7) for women, while HALE at age 65 years improved by 0·85 years (0·78�0·92) and 1·2 years (1·1�1·3), respectively. Rising SDI was associated with consistently higher HALE and a somewhat smaller proportion of life spent with functional health loss; however, rising SDI was related to increases in total disability. Many countries and territories in central America and eastern sub-Saharan Africa had increasingly lower rates of disease burden than expected given their SDI. At the same time, a subset of geographies recorded a growing gap between observed and expected levels of DALYs, a trend driven mainly by rising burden due to war, interpersonal violence, and various NCDs. Interpretation Health is improving globally, but this means more populations are spending more time with functional health loss, an absolute expansion of morbidity. The proportion of life spent in ill health decreases somewhat with increasing SDI, a relative compression of morbidity, which supports continued efforts to elevate personal income, improve education, and limit fertility. Our analysis of DALYs and HALE and their relationship to SDI represents a robust framework on which to benchmark geography-specific health performance and SDG progress. Country-specific drivers of disease burden, particularly for causes with higher-than-expected DALYs, should inform financial and research investments, prevention efforts, health policies, and health system improvement initiatives for all countries along the development continuum. Funding Bill & Melinda Gates Foundation. © 2016 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY licens

Desfolha parcial em videiras e seus efeitos em uvas e vinhos Cabernet Sauvignon da região da Campanha do Rio Grande do Sul, Brasil Partial de foliation on vines and its effects on Cabernet Sauvignon grapes and wines from the southwest of Rio Grande do Sul, Brazil

A desfolha no vinhedo tem como principais objetivos aumentar a radiação solar e a aeração na região dos frutos, para melhorar a coloração e a maturação das uvas tintas, além de reduzir a incidência de podridões, visando, com isso, obter vinhos de qualidade superior. O principal objetivo deste trabalho foi avaliar o efeito da desfolha nos parâmetros físico-químicos das uvas e dos vinhos Cabernet Sauvignon de Dom Pedrito, região da Campanha, Rio Grande do Sul (RS). As uvas foram colhidas em março de 2008, sendo provenientes de um vinhedo comercial cultivado em espaldeira. A desfolha foi realizada na base dos ramos, somente no lado que recebe o sol da manhã, com intensidade de aproximadamente 20%, no estádio fenológico grão "ervilha". As microvinificações foram feitas com controle de temperatura, em tanques de vidro em triplicata, com oito dias de maceração. Os resultados mostraram que o tratamento com desfolha apresentou mostos com pH significativamente mais baixo e maior acidez total. As cascas das uvas e os vinhos do tratamento com desfolha apresentaram aumento significativo no teor de polifenóis totais. A desfolha também propiciou vinhos com maior intensidade de cor, antocianinas totais, extrato seco e açúcar redutor, e menor teor de nitrogênio. Nos vinhos, não foram observadas diferenças significativas entre os tratamentos para acidez total e volátil, pH, álcool, densidade, extrato seco reduzido e teor de potássio. Conclui-se que a prática da desfolha em vinhedos da região da Campanha melhora a qualidade dos vinhos.<br>The practice of partial defoliation in vineyards has as main objectives increase sunlight and ventilation for the fruit, aiming to improve color and maturity in red grapes and helping to reduce fungal diseases, which should result in better wine quality. The main aim of this research was to evaluate the effects of partial defoliation on the quality of Cabernet Sauvignon grapes and wines from Dom Pedrito, on the southwest of Rio Grande do Sul state, Brazil. The grapes were harvested in March 2008 from a commercial vineyard planted in the trellis system. The defoliation intensity was of 20% and performed only on the side of the vineyard that received the morning sun and when the berry was in the pea-size. The musts were fermented in small lots, in triplicate, with temperature control and remained on the skins for eight days. The results showed that musts of the treatment with defoliation had lower values of pH and higher total acidity. The phenolic content of grape skins and wines was significantly higher for those submitted to defoliation. The defoliation also resulted in wines with greater color intensity, anthocyanins, extract content and reducing sugar, and lower nitrogen content. In wines, there were no significant differences between treatments for total and volatile acidity, pH, alcohol, density, reducing extract and potassium content. As a conclusion, these results might suggest that partial defoliation, as it was done in this vineyard, improves wine quality