A global reference for human genetic variation

The 1000 Genomes Project set out to provide a comprehensive description of common human genetic variation by applying whole-genome sequencing to a diverse set of individuals from multiple populations. Here we report completion of the project, having reconstructed the genomes of 2,504 individuals from 26 populations using a combination of low-coverage whole-genome sequencing, deep exome sequencing, and dense microarray genotyping. We characterized a broad spectrum of genetic variation, in total over 88 million variants (84.7 million single nucleotide polymorphisms (SNPs), 3.6 million short insertions/deletions (indels), and 60,000 structural variants), all phased onto high-quality haplotypes. This resource includes >99% of SNP variants with a frequency of >1% for a variety of ancestries. We describe the distribution of genetic variation across the global sample, and discuss the implications for common disease studies.We thank the many people who were generous with contributing their samples to the project: the African Caribbean in Barbados; Bengali in Bangladesh; British in England and Scotland; Chinese Dai in Xishuangbanna, China; Colombians in Medellin, Colombia; Esan in Nigeria; Finnish in Finland; Gambian in Western Division – Mandinka; Gujarati Indians in Houston, Texas, USA; Han Chinese in Beijing, China; Iberian populations in Spain; Indian Telugu in the UK; Japanese in Tokyo, Japan; Kinh in Ho Chi Minh City, Vietnam; Luhya in Webuye, Kenya; Mende in Sierra Leone; people with African ancestry in the southwest USA; people with Mexican ancestry in Los Angeles, California, USA; Peruvians in Lima, Peru; Puerto Ricans in Puerto Rico; Punjabi in Lahore, Pakistan; southern Han Chinese; Sri Lankan Tamil in the UK; Toscani in Italia; Utah residents (CEPH) with northern and western European ancestry; and Yoruba in Ibadan, Nigeria. Many thanks to the people who contributed to this project: P. Maul, T. Maul, and C. Foster; Z. Chong, X. Fan, W. Zhou, and T. Chen; N. Sengamalay, S. Ott, L. Sadzewicz, J. Liu, and L. Tallon; L. Merson; O. Folarin, D. Asogun, O. Ikpwonmosa, E. Philomena, G. Akpede, S. Okhobgenin, and O. Omoniwa; the staff of the Institute of Lassa Fever Research and Control (ILFRC), Irrua Specialist Teaching Hospital, Irrua, Edo State, Nigeria; A. Schlattl and T. Zichner; S. Lewis, E. Appelbaum, and L. Fulton; A. Yurovsky and I. Padioleau; N. Kaelin and F. Laplace; E. Drury and H. Arbery; A. Naranjo, M. Victoria Parra, and C. Duque; S. Däkel, B. Lenz, and S. Schrinner; S. Bumpstead; and C. Fletcher-Hoppe. Funding for this work was from the Wellcome Trust Core Award 090532/Z/09/Z and Senior Investigator Award 095552/Z/11/Z (P.D.), and grants WT098051 (R.D.), WT095908 and WT109497 (P.F.), WT086084/Z/08/Z and WT100956/Z/13/Z (G.M.), WT097307 (W.K.), WT0855322/Z/08/Z (R.L.), WT090770/Z/09/Z (D.K.), the Wellcome Trust Major Overseas program in Vietnam grant 089276/Z.09/Z (S.D.), the Medical Research Council UK grant G0801823 (J.L.M.), the UK Biotechnology and Biological Sciences Research Council grants BB/I02593X/1 (G.M.) and BB/I021213/1 (A.R.L.), the British Heart Foundation (C.A.A.), the Monument Trust (J.H.), the European Molecular Biology Laboratory (P.F.), the European Research Council grant 617306 (J.L.M.), the Chinese 863 Program 2012AA02A201, the National Basic Research program of China 973 program no. 2011CB809201, 2011CB809202 and 2011CB809203, Natural Science Foundation of China 31161130357, the Shenzhen Municipal Government of China grant ZYC201105170397A (J.W.), the Canadian Institutes of Health Research Operating grant 136855 and Canada Research Chair (S.G.), Banting Postdoctoral Fellowship from the Canadian Institutes of Health Research (M.K.D.), a Le Fonds de Recherche duQuébec-Santé (FRQS) research fellowship (A.H.), Genome Quebec (P.A.), the Ontario Ministry of Research and Innovation – Ontario Institute for Cancer Research Investigator Award (P.A., J.S.), the Quebec Ministry of Economic Development, Innovation, and Exports grant PSR-SIIRI-195 (P.A.), the German Federal Ministry of Education and Research (BMBF) grants 0315428A and 01GS08201 (R.H.), the Max Planck Society (H.L., G.M., R.S.), BMBF-EPITREAT grant 0316190A (R.H., M.L.), the German Research Foundation (Deutsche Forschungsgemeinschaft) Emmy Noether Grant KO4037/1-1 (J.O.K.), the Beatriu de Pinos Program grants 2006 BP-A 10144 and 2009 BP-B 00274 (M.V.), the Spanish National Institute for Health Research grant PRB2 IPT13/0001-ISCIII-SGEFI/FEDER (A.O.), Ewha Womans University (C.L.), the Japan Society for the Promotion of Science Fellowship number PE13075 (N.P.), the Louis Jeantet Foundation (E.T.D.), the Marie Curie Actions Career Integration grant 303772 (C.A.), the Swiss National Science Foundation 31003A_130342 and NCCR “Frontiers in Genetics” (E.T.D.), the University of Geneva (E.T.D., T.L., G.M.), the US National Institutes of Health National Center for Biotechnology Information (S.S.) and grants U54HG3067 (E.S.L.), U54HG3273 and U01HG5211 (R.A.G.), U54HG3079 (R.K.W., E.R.M.), R01HG2898 (S.E.D.), R01HG2385 (E.E.E.), RC2HG5552 and U01HG6513 (G.T.M., G.R.A.), U01HG5214 (A.C.), U01HG5715 (C.D.B.), U01HG5718 (M.G.), U01HG5728 (Y.X.F.), U41HG7635 (R.K.W., E.E.E., P.H.S.), U41HG7497 (C.L., M.A.B., K.C., L.D., E.E.E., M.G., J.O.K., G.T.M., S.A.M., R.E.M., J.L.S., K.Y.), R01HG4960 and R01HG5701 (B.L.B.), R01HG5214 (G.A.), R01HG6855 (S.M.), R01HG7068 (R.E.M.), R01HG7644 (R.D.H.), DP2OD6514 (P.S.), DP5OD9154 (J.K.), R01CA166661 (S.E.D.), R01CA172652 (K.C.), P01GM99568 (S.R.B.), R01GM59290 (L.B.J., M.A.B.), R01GM104390 (L.B.J., M.Y.Y.), T32GM7790 (C.D.B., A.R.M.), P01GM99568 (S.R.B.), R01HL87699 and R01HL104608 (K.C.B.), T32HL94284 (J.L.R.F.), and contracts HHSN268201100040C (A.M.R.) and HHSN272201000025C (P.S.), Harvard Medical School Eleanor and Miles Shore Fellowship (K.L.), Lundbeck Foundation Grant R170-2014-1039 (K.L.), NIJ Grant 2014-DN-BX-K089 (Y.E.), the Mary Beryl Patch Turnbull Scholar Program (K.C.B.), NSF Graduate Research Fellowship DGE-1147470 (G.D.P.), the Simons Foundation SFARI award SF51 (M.W.), and a Sloan Foundation Fellowship (R.D.H.). E.E.E. is an investigator of the Howard Hughes Medical Institute

Production of transgenic Valencia orange suspension cells to be used as donors for chromosome transfer

The method for plant transformation and antibiotic selection has been well established for several citrus varieties. Transgenic citrus suspension cells, however, have never been produced and maintained, thus, a procedure for transformation, antibiotic selection, and maintenance of transgenic suspension cells is still required. Transgenic citrus suspension cells containing the npt II gene forresistance to an aminoglycoside antibiotic would be very valuable for chromosome transfer experiments. To determine the lethal antibiotic concentration where growth inhibition of suspension cells would occur, the antibiotics kanamycin sulfate, geneticin, and paromomycin sulfate were used. Paromomycin sulfate at 50 µg/ml was found to be the best antibiotic forselection. Geneticin and kanamycin were not appropriate forselection of transgenic Valencia sweet orange suspension cells. For protoplast transformation, the electroporation parameters and incubation procedures were established. Pulses of 400, 500, and 700 V/cm were evaluated. The best electroporation settings were pulse of 500 V/cm and capacitance of 1000 µF. To secure high survival rates of the protoplasts, it was essential to add BH3 medium immediately after electroporation. Transgenic suspension cells of Valencia sweet orange containing the npt II and the ß-glucuronidase (Gus) gene were produced and maintained in 14 day subculture cycles in medium containing 50 µg/ml of paromomycin sulfate. This concentration was also very efficient for selection of transgenic Valencia embryos, since non-transgenic embryos were bleached

Predicting the risk of recurrent venous thromboembolism in patients with cancer: A prospective cohort study

The risk of recurrent venous thromboembolism (VTE) in cancer patients despite anticoagulant therapy is high. Clinical factors and pro-coagulant markers may identify high-risk patients and guide decisions about intensifying anticoagulation therapy. To evaluate whether serial measurements of pro-coagulant markers can identify patients at high risk of recurrent VTE. In this multicenter, prospective cohort study, patients with active cancer and acute deep vein thrombosis or pulmonary embolism were enrolled. Patients received standard low-molecular-weight heparin therapy and were followed for 6 months. D-dimer and soluble P-selectin levels were measured at baseline and 1, 4, 5, 12, and 24 weeks post treatment initiation. The association between recurrent VTE and a previously developed risk score, baseline values of the biomarkers, and individual relative changes from baseline were assessed. We enrolled 117 cancer patients (22% lung, 21% colorectal, 9% breast) with a mean age of 63 years; 62% had metastatic cancer. Eleven patients (9.4%) developed recurrent VTE, including two cases of fatal pulmonary embolism. VTE recurrence rates were 7.8% (95% CI, 3.1-18) in patients with a risk score of ≤0 points compared to 11% (95% CI, 5.2-20) for those with a score of ≥1 point (hazard ratio 1.3; 95% CI, 0.39-4.5). Baseline P-selectin levels but not D-dimer levels were significantly associated with a high risk of recurrence; the risk was four-fold higher in patients with elevated P-selectin levels than in those with normal levels (hazard ratio 4.0; 95% CI, 1.1-14). Changes in biomarker levels during treatment were not associated with recurrent VTE. Baseline P-selectin but not D-dimer levels predict recurrent VTE and may be a valuable addition to clinical prediction rules to select patients for more intensive therapy or closer observatio

Sono, trabalho e estudo: duração do sono em estudantes trabalhadores e não trabalhadores Sleep, work, and study: sleep duration in working and non-working students

Este estudo objetivou investigar a duração do sono e fatores associados em escolares trabalhadores e não trabalhadores. Foram coletadas informações sobre o padrão do ciclo vigília/sono de 863 adolescentes de 10 a 19 anos em escolas de São Paulo, Brasil. Análises ajustadas foram aplicadas para comparação da duração do sono entre trabalhadores e não trabalhadores. O porcentual de adolescentes trabalhadores foi de 18,4% e 52% dos jovens que trabalhavam apresentaram oito ou menos horas de sono. A prevalência de baixa duração do sono foi maior nos trabalhadores dos sexos masculino (p = 0,017) e feminino (p < 0,001). Os estudantes trabalhadores apresentaram menor duração do sono mesmo com ajuste pela classe socioeconômica (p < 0,001). Apesar de existirem mais trabalhadores no turno da noite, no modelo ajustado pelo sexo e nível socioeconômico, os estudantes trabalhadores do turno da tarde apresentaram maior prevalência de baixa duração do sono (RP = 2,53; IC95%: 1,68-4,12).<br>The aim of this study was to investigate the duration of sleep and associated factors in working and non-working students. Data were analyzed on the sleep-wake cycle in 863 teenage students in São Paulo, Brazil. Adjusted analyses were performed to compare sleep duration in working and non-working students. 18.4% of the group worked, and 52% of the working students slept eight hours or less per night. Prevalence of short sleep duration was higher in working students of both sexes (males, p = 0.017; females, p < 0.001). Working students showed short sleep duration in the analysis adjusted for socioeconomic status, but short sleep was more frequent in older adolescents (p = 0.004) and in lower (p = 0.001) and middle (p = 0.011) socioeconomic classes. Although more working students were in night school, in the model adjusted for gender and socioeconomic status, working students in afternoon courses showed higher prevalence of short sleep duration (PR = 2.53; 95%CI: 1.68-4.12)

Cerebral infarct in children aged zero to fifteen years Infarto cerebral em crianças de zero a quinze anos de idade

Cerebral infarcts in children present peculiar characteristics either due to their diversity of causes or due to the unknown nature of the causes. The etiologies of cerebral infarct were reviewed in children from zero to 15 years old, attended at a tertiary hospital, in Ribeirão Preto (Brazil), from 1990 to 1997, adopting the modified Trial of ORG 10172 in Acute Stroke Treatment (TOAST) criteria of classification; 1 - Atherosclerosis in large arteries; 2 - Cardioembolic; 3 - Occlusion of small vessels; 4 - Other etiologies; 5 - Undetermined cause. Thirty-nine children were included, 18 males and 21 females, aged 2 months to 15 years, mean age 5.67. The largest group, N=22 (56.4%), included children with ''other etiologies'', 7 of them aged under two years. The most common etiology was dehydration and septic shock leading to brain hypoperfusion and watershed infarcts. Nine (23%) children had ''Undetermined etiology'', 7 (17,9%) cardioembolic subtype and none had atherosclerosis. Laboratory improvement is needed for the large number of patients without a defined cause, and the high proportion of children with dehydration in the group with a determined cause emphasizes the need for preventive health actions among infants and children.<br>Infartos cerebrais em crianças apresentam peculiaridades, como grande variedade de causas e alta freqüência sem etiologia definida. Foram revistos os diagnósticos etiológicos em crianças de zero a 15 anos, atendidas durante o ictus e com imagens cerebrais sugestivas de infarto, entre 1990 e 1997 em hospital terciário de Ribeirão Preto (SP). Adotou-se o critério de classificação modificado do Trial of ORG 10172 in Acute Stroke Treatment (TOAST): 1 - Arterioesclerose de grandes artérias, 2 - Cardioembólico, 3 - Oclusão de pequenos vasos, 4 - Outras etiologias, 5 - Não determinada. Trinta e nove crianças foram incluídas, 18 do sexo masculino e 21 do feminino, com idade variando entre 2 meses e 15 anos e média de 5,67. O maior grupo, com 22 crianças (56,4%), foi o de ''Outras etiologias'', 7 das quais com idades entre 2 meses e um ano. A etiologia mais freqüente foi desidratação e choque séptico, levando a hipoperfusão cerebral e infarto em zonas limítrofes. Nove (23%) com etiologia não determinada constituiram o segundo grupo, 7 (17,9%) apresentaram causas cardioembólicas e nenhum caso foi registrado com arteriosclerose. Ressalta-se a necessidade de investimento laboratorial, considerando-se a alta freqüência de casos sem diagnóstico. O alto número de crianças com infarto decorrente de desidratação requer atenção para ações preventivas em saúde infantil