Deep short-read sequencing of chromosome 17 from the mouse strains A/J and CAST/Ei identifies significant germline variation and candidate genes that regulate liver triglyceride levels

Methods for accurate identification of nucleotide and structural variation using de novo short read sequencing of mouse chromosomes are described

Walk well:a randomised controlled trial of a walking intervention for adults with intellectual disabilities: study protocol

Background - Walking interventions have been shown to have a positive impact on physical activity (PA) levels, health and wellbeing for adult and older adult populations. There has been very little work carried out to explore the effectiveness of walking interventions for adults with intellectual disabilities. This paper will provide details of the Walk Well intervention, designed for adults with intellectual disabilities, and a randomised controlled trial (RCT) to test its effectiveness. Methods/design - This study will adopt a RCT design, with participants allocated to the walking intervention group or a waiting list control group. The intervention consists of three PA consultations (baseline, six weeks and 12 weeks) and an individualised 12 week walking programme. A range of measures will be completed by participants at baseline, post intervention (three months from baseline) and at follow up (three months post intervention and six months from baseline). All outcome measures will be collected by a researcher who will be blinded to the study groups. The primary outcome will be steps walked per day, measured using accelerometers. Secondary outcome measures will include time spent in PA per day (across various intensity levels), time spent in sedentary behaviour per day, quality of life, self-efficacy and anthropometric measures to monitor weight change. Discussion - Since there are currently no published RCTs of walking interventions for adults with intellectual disabilities, this RCT will examine if a walking intervention can successfully increase PA, health and wellbeing of adults with intellectual disabilities

Improved imputation of low-frequency and rare variants using the UK10K haplotype reference panel

Imputing genotypes from reference panels created by whole-genome sequencing (WGS) provides a cost-effective strategy for augmenting the single-nucleotide polymorphism (SNP) content of genome-wide arrays. The UK10K Cohorts project has generated a data set of 3,781 whole genomes sequenced at low depth (average 7x), aiming to exhaustively characterize genetic variation down to 0.1% minor allele frequency in the British population. Here we demonstrate the value of this resource for improving imputation accuracy at rare and low-frequency variants in both a UK and an Italian population. We show that large increases in imputation accuracy can be achieved by re-phasing WGS reference panels after initial genotype calling. We also present a method for combining WGS panels to improve variant coverage and downstream imputation accuracy, which we illustrate by integrating 7,562 WGS haplotypes from the UK10K project with 2,184 haplotypes from the 1000 Genomes Project. Finally, we introduce a novel approximation that maintains speed without sacrificing imputation accuracy for rare variants

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Mouse genomic variation and its effect on phenotypes and gene regulation

We report genome sequences of 17 inbred strains of laboratory mice and identify almost ten times more variants than previously known. We use these genomes to explore the phylogenetic history of the laboratory mouse and to examine the functional consequences of allele-specific variation on transcript abundance, revealing that at least 12% of transcripts show a significant tissue-specific expression bias. By identifying candidate functional variants at 718 quantitative trait loci we show that the molecular nature of functional variants and their position relative to genes vary according to the effect size of the locus. These sequences provide a starting point for a new era in the functional analysis of a key model organism

Whole-genome sequence-based analysis of thyroid function

Tiina Paunio on työryhmän UK10K Consortium jäsen.Normal thyroid function is essential for health, but its genetic architecture remains poorly understood. Here, for the heritable thyroid traits thyrotropin (TSH) and free thyroxine (FT4), we analyse whole-genome sequence data from the UK10K project (N = 2,287). Using additional whole-genome sequence and deeply imputed data sets, we report meta-analysis results for common variants (MAF >= 1%) associated with TSH and FT4 (N = 16,335). For TSH, we identify a novel variant in SYN2 (MAF = 23.5%, P = 6.15 x 10(-9)) and a new independent variant in PDE8B (MAF = 10.4%, P = 5.94 x 10(-14)). For FT4, we report a low-frequency variant near B4GALT6/ SLC25A52 (MAF = 3.2%, P = 1.27 x 10(-9)) tagging a rare TTR variant (MAF = 0.4%, P = 2.14 x 10(-11)). All common variants explain >= 20% of the variance in TSH and FT4. Analysis of rare variants (MAFPeer reviewe

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

Cytology and cytogenetics of Eragrostis curvula (Schrad.) Nees.

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Biology, speciation, and utilization of peanut species

Peanut, also known as groundnut (Arachis hypogaea L.), is a native new world crop. Arachis species originated in South America and are found in tropical and subtropical areas. Eighty-one species have been named (Krapovickas and Gregory, 1994; Valls and Simpson, 2005; Valls et al., 2013), including the domesticated peanut, A. hypogaea L. Species have evolved in highly diverse habitats and both annual and perennial types exist. New species are being discovered in areas that previously were very difficult to reach because of poor roads and transportation. It is likely that the genus originated in the highlands in the southwestern Mato Grosso do Sul region of Brazil close to Gran Pantanal where the most ancient species of the genus (Arachis guaranitica Chodat. and Hassl. and Arachis tuberosa Bong. Ex Benth.) are found (Gregory et al., 1980; Simpson and Faries, 2001). Subsequently, as the planalto continued to be uplifted coupled with water flow, the genus spread into the drier lowlands of South America (Gregory and Gregory, 1979; Stalker and Simpson, 1995; Simpson et al., 2001). The genus likely originated in tropical wetland areas and subsequently adapted for survival in dry environments

Biology, speciation and utilization of peanut species

Peanut, also known as groundnut (Arachis hypogaea L.), is a native new world crop. Arachis species originated in South America and are found in tropical and subtropical areas. Eighty-one species have been named (Krapovickas and Gregory, 1994; Valls and Simpson, 2005; Valls et al., 2013), including the domesticated peanut, A. hypogaea L. Species have evolved in highly diverse habitats and both annual and perennial types exist. New species are being discovered in areas that previously were very difficult to reach because of poor roads and transportation. It is likely that the genus originated in the highlands in the southwestern Mato Grosso do Sul region of Brazil close to Gran Pantanal where the most ancient species of the genus (Arachis guaranitica Chodat. and Hassl. and Arachis tuberosa Bong. Ex Benth.) are found (Gregory et al., 1980; Simpson and Faries, 2001). Subsequently, as the planalto continued to be uplifted coupled with water flow, the genus spread into the drier lowlands of South America (Gregory and Gregory, 1979; Stalker and Simpson, 1995; Simpson et al., 2001). The genus likely originated in tropical wetland areas and subsequently adapted for survival in dry environments. Species in the genus Arachis are widely distributed in South America from Northeast Brazil to southern Uruguay and from the Andean lowlands in the west to the eastern Atlantic coast, and the distribution is continuous across this region (Valls et al., 1985). Species grow in deep friable sand to thick, gummy clay and on schist rocks with virtually no soil, suggesting that species have adapted to highly diverse and harsh environments (Simpson et al., 2001). Fruiting below ground likely protected the seeds from predators and the many root adaptations (e.g., rhizomes, tuberous roots) likely helped species to adapt to new habitats. Conversely, the geocarpic fruit impeded rapid spread into new environments. Krapovickas and Gregory (1994) indicated that the most defining morphological features of the genus are underground plant parts, including the fruits, rhizomatous structures, root systems, and hypocotyls. The center of origin for the cultivated species A. hypogaea is believed to be southern Bolivia to northwestern Argentina based on the occurrence of the two progenitor species Arachis duranensis and Arachis ipaënsis, and archaeological evidence gathered in this region (Hammons, 1982; Stalker and Simpson, 1995). Simpson et al. (2001) also suggested that the eastern slopes of Cordillera may be a possible area for origin of A. hypogaea because of the favorable environment for peanut growth. Advances in the peanut genome sequence and the availability of new genomic tools will help clarify the origin and evolution of the cultivated and wild species of the genus Arachis. Wild peanut species were important as sources of food in pre-Columbian times and several taxa are still widely used as forages or for their aesthetic value as a ground cover. Arachis glabrata and Arachis pintoi are utilized for grazing and Arachis repens is used as a ground cover in residential areas and roadsides in tropical regions (Mathews et al., 2000; Hernandez-Garay et al., 2004). Two wild species (Arachis villosulicarpa Hoehne and Arachis stenosperma Krapov. and W.C. Gregory) were cultivated by indigenous people in Brazil for food and medicinal use, albeit on a limited scale (Gregory et al., 1973; Simpson et al., 2001), but only A. hypogaea is economically important today as a human food source. Importantly, many Arachis species have extremely high levels of disease and insect resistances that are not present in cultivated peanut.Fil: Stalker, H. Thomas. North Carolina State University; Estados UnidosFil: Tallury, Shyamalrau P.. Clemson University,; Estados UnidosFil: Seijo, José Guillermo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste. Instituto de Botánica del Nordeste. Universidad Nacional del Nordeste. Facultad de Ciencias Agrarias. Instituto de Botánica del Nordeste; ArgentinaFil: Leal Bertioli, Soraya C.M.. Embrapa Agroindustrial Tropical - CNPAT; Brasi