The lion's share of bacteria in various environments cannot be cloned in the laboratory and thus cannot be sequenced using existing technologies. A major goal of single-cell genomics is to complement gene-centric metagenomic data with whole-genome assemblies of uncultivated organisms. Assembly of single-cell data is challenging because of highly non-uniform read coverage as well as elevated levels of sequencing errors and chimeric reads. We describe SPAdes, a new assembler for both single-cell and standard (multicell) assembly, and demonstrate that it improves on the recently released E+V-SC assembler (specialized for single-cell data) and on popular assemblers Velvet and SoapDeNovo (for multicell data). SPAdes generates single-cell assemblies, providing information about genomes of uncultivatable bacteria that vastly exceeds what may be obtained via traditional metagenomics studies. SPAdes is available online ( http://bioinf.spbau.ru/spades ). It is distributed as open source software.

SPAdes, a new genome assembly algorithm and its applications to single-cell sequencing ( 7th Annual SFAF Meeting, 2012)

The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but epigenomic studies lack a similar reference. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection so far of human epigenomes for primary cells and tissues. Here we describe the integrative analysis of 111 reference human epigenomes generated as part of the programme, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression. We establish global maps of regulatory elements, define regulatory modules of coordinated activity, and their likely activators and repressors. We show that disease- and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease. Our results demonstrate the central role of epigenomic information for understanding gene regulation, cellular differentiation and human disease.

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Integrative analysis of 111 reference human epigenomes

The Ensembl Variant Effect Predictor is a powerful toolset for the analysis, annotation, and prioritization of genomic variants in coding and non-coding regions. It provides access to an extensive collection of genomic annotation, with a variety of interfaces to suit different requirements, and simple options for configuring and extending analysis. It is open source, free to use, and supports full reproducibility of results. The Ensembl Variant Effect Predictor can simplify and accelerate variant interpretation in a wide range of study designs.

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The Ensembl Variant Effect Predictor.

The UK Biobank project is a prospective cohort study with deep genetic and phenotypic data collected on approximately 500,000 individuals from across the United Kingdom, aged between 40 and 69 at recruitment. The open resource is unique in its size and scope. A rich variety of phenotypic and health-related information is available on each participant, including biological measurements, lifestyle indicators, biomarkers in blood and urine, and imaging of the body and brain. Follow-up information is provided by linking health and medical records. Genome-wide genotype data have been collected on all participants, providing many opportunities for the discovery of new genetic associations and the genetic bases of complex traits. Here we describe the centralized analysis of the genetic data, including genotype quality, properties of population structure and relatedness of the genetic data, and efficient phasing and genotype imputation that increases the number of testable variants to around 96 million. Classical allelic variation at 11 human leukocyte antigen genes was imputed, resulting in the recovery of signals with known associations between human leukocyte antigen alleles and many diseases.

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The UK Biobank resource with deep phenotyping and genomic data

requirement in a patient receiving 6-MP. The patient was a 53-year old woman with an aortic prosthetic valve and aorto-coronary by-pass. She was on longterm OAT with acenocoumarol (mean dose 21 mg/week and mean INR=3.3) since January 1992 until August 1995. Her treatment included captopril, isosorbide trinitrate and furosemide. The level of hypocoagulability was measured every four weeks using bovine thromboplastin ISI=0.98 (Thrombotest from Nycomed, IMMUNO, Barcelona, Spain) with a mechanical coagulometer AMAX CS-90 (from Grifols-Movaco, Barcelona, Spain) assisted by a computer program (Sintromac from Grifols, Barcelona, Spain). Her dose of acenocoumarol was adjusted according to the results which were expressed as the INR as recommended by the Subcommittee of Standardization of the International Society on Thrombosis and Hemostasis. She had a mean INR = 3.37. In August 1995 she was diagnosed as having acute promyelocytic leukemia. Induction of specific treatment was excluded because of her age and cardiac disease. OAT was stopped and heparinization and all-transretinoic acid (ATRA) were started and continued until the end of September. From October 1995 she received 6-MP 100 mg daily p.o., methotrexate every two weeks i.v. and ATRA fifteen days every three months, for two years. During this time, liver damage was minimal (AST=60; ALT=70; total bilirubin = 1.2 mg/dL) and platelet count not less than 1503109/L. The level of hypocoagulability was, at that time, measured every two weeks. The dose of acenocoumarol was increased progressively from 21 mg/week when she started cytotoxic treatment to 70 mg/week in June 1996, with a mean INR=1.9. From June 1996 to November 1997, the patient maintained a mean INR=3.4 with a mean dose of 71 mg/week (see Table 1). When 6-MP was stopped, the patient continued receiving 70 mg/week for a week. At the end of this week, her INR had increased from 3 to 12. The acenocoumarol was stopped and reintroduced 24 hours later at her habitual dose (3 mg/day) without hemorrhagic complications. Although the interaction of azathioprine or 6-MP with acenocoumarol is not established, studies in rats indicate that 6-MP increases prothrombin synthesis or activation3 and decreases warfarin activity.2,5 An increase in warfarin requirements can be interpreted as a prothrombotic state in patients with disorders requiring immunomodulatory therapy.5,6 Our patient had a promyelocytic leukemia, known to cause a prothrombotic state. Our patient required a progressively increasing dose of acenocoumarol that she maintained during the remission period of the hematologic process; only when it finished, did she return to the normal requirements. In spite of the short life of acenocoumarol compared to warfarin, the increase of INR after stopping 6-MP was delayed, which suggests a metabolic interaction between 6MP and OA, possibly induction of hepatic microenzymes activity, as seen with barbiturates.5 According to the behavior of our patient, OA dosage (acenocoumarol or warfarin) should be reviewed no later than a week after ending azathioprine or 6-MP and the OA dose reduced to the amount before 6-MP treatment.

Autologousperipheral blood stem cell transplantation in a patient with multiple sclerosisand concomitant Ph+ acute leukemia.

To the Editor: Collard et al. reported a high frequency of antinuclear antibodies (ANA), 22.5% in patients with multiple sclerosis (MS) compared with healthy individuals.1 They also found a correlation between ANA occurrence and increased clinical disease activity.1 Gadolinium-enhanced MRI is a valuable tool for examining the natural history of MS, being a more sensitive measure of disease activity than clinical evaluation.2\n\nWe investigated the frequency of enhancing lesions in patients with relapsing-remitting MS (RRMS) to determine whether MRI activity was related to …

Antinuclear antibodies and MRI activity in multiple sclerosis [8] (multiple letters)

The complex biology of neurological diseases calls for collaborative efforts that may increase the success rate of clinical research. Models have been proposed, but concrete actions remain insufficient. Based on recent considerations from basic science, from science of patient input and from an analysis of scientific resources in Italy, we here explain why our country may represent an appropriate environment for such actions. Furthermore, we sketch operational framework and business model to be applied in order to accelerate, in parallel, the development of therapies in common and rare diseases.

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An “all-wheel drive” proposal to accelerate clinical research in common and rare neurological diseases

Immune-mediated damage is probably the most relevant event among those that contribute to the pathogenesis of multiple sclerosis (MS). The search for autoantigens inducing T cell responses in MS as well as in other immune-mediated, organ-specific diseases was initated as soon as efficient techniques for the isolation and expansion of antigen-specific T cell lines became available [1].

Marco Salvetti

Papers

Autologousperipheral blood stem cell transplantation in a patient with multiple sclerosisand concomitant Ph+ acute leukemia.

Antinuclear antibodies and MRI activity in multiple sclerosis [8] (multiple letters)

An “all-wheel drive” proposal to accelerate clinical research in common and rare neurological diseases

Non-Myelin Antigen Autoreactivity in Multiple Sclerosis