7 results on '"Schalkwyk, Leonard C"'
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2. Stochastic Choice of Allelic Expression in Human Neural Stem Cells.
- Author
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Jeffries, Aaron R., Perfect, Leo W., Ledderose, Julia, Schalkwyk, Leonard C., Bray, Nicholas J., Mill, Jonathan, and Price, Jack
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GENE expression ,NEURAL stem cells ,CLONING ,ALLELES ,GENOMES ,NEURODEVELOPMENTAL treatment - Abstract
Monoallelic gene expression, such as genomic imprinting, is well described. Less well-characterized are genes undergoing stochastic monoallelic expression (MA), where specific clones of cells express just one allele at a given locus. We performed genome-wide allelic expression assessment of human clonal neural stem cells derived from cerebral cortex, striatum, and spinal cord, each with differing genotypes. We assayed three separate clonal lines from each donor, distinguishing stochastic MA from genotypic effects. Roughly 2% of genes showed evidence for autosomal MA, and in about half of these, allelic expression was stochastic between different clones. Many of these loci were known neurodevelopmental genes, such as OTX2 and OLIG2. Monoallelic genes also showed increased levels of DNA methylation compared to hypomethylated biallelic loci. Identified monoallelic gene loci showed altered chromatin signatures in fetal brain, suggesting an in vivo correlate of this phenomenon. We conclude that stochastic allelic expression is prevalent in neural stem cells, providing clonal diversity to developing tissues such as the human brain. S tem C ells 2012;30:1938-1947 [ABSTRACT FROM AUTHOR]
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- 2012
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3. Allelic Skewing of DNA Methylation Is Widespread across the Genome
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Schalkwyk, Leonard C., Meaburn, Emma L., Smith, Rebecca, Dempster, Emma L., Jeffries, Aaron R., Davies, Matthew N., Plomin, Robert, and Mill, Jonathan
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DNA methylation , *GENOMES , *ALLELES , *GENOMIC imprinting , *SINGLE nucleotide polymorphisms , *MICROARRAY technology , *DNA restriction enzymes , *GENE expression - Abstract
DNA methylation is assumed to be complementary on both alleles across the genome, although there are exceptions, notably in regions subject to genomic imprinting. We present a genome-wide survey of the degree of allelic skewing of DNA methylation with the aim of identifying previously unreported differentially methylated regions (DMRs) associated primarily with genomic imprinting or DNA sequence variation acting in cis. We used SNP microarrays to quantitatively assess allele-specific DNA methylation (ASM) in amplicons covering 7.6% of the human genome following cleavage with a cocktail of methylation-sensitive restriction enzymes (MSREs). Selected findings were verified using bisulfite-mapping and gene-expression analyses, subsequently tested in a second tissue from the same individuals, and replicated in DNA obtained from 30 parent-child trios. Our approach detected clear examples of ASM in the vicinity of known imprinted loci, highlighting the validity of the method. In total, 2,704 (1.5%) of our 183,605 informative and stringently filtered SNPs demonstrate an average relative allele score (RAS) change ≥0.10 following MSRE digestion. In agreement with previous reports, the majority of ASM (∼90%) appears to be cis in nature, and several examples of tissue-specific ASM were identified. Our data show that ASM is a widespread phenomenon, with >35,000 such sites potentially occurring across the genome, and that a spectrum of ASM is likely, with heterogeneity between individuals and across tissues. These findings impact our understanding about the origin of individual phenotypic differences and have implications for genetic studies of complex disease. [ABSTRACT FROM AUTHOR]
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- 2010
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4. Utility of the pooling approach as applied to whole genome association scans with highdensity Affymetrix microarrays.
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Schosser, Alexandra, Pirlo, Katrina, Gaysina, Darya, Cohen-Woods, Sarah, Schalkwyk, Leonard C., Elkin, Amanda, Korszun, Ania, Gunasinghe, Cerisse, Gray, Joanna, Jones, Lisa, Meaburn, Emma, Farmer, Anne E., Craig, Ian W., and McGuffin, Peter
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NUCLEOTIDES ,GENETIC polymorphisms ,GENOTYPE-environment interaction ,BLOOD ,NUCLEIC acids ,GENE frequency ,POPULATION genetics ,DNA microarrays ,GENOMES - Abstract
Background: We report an attempt to extend the previously successful approach of combining SNP (single nucleotide polymorphism) microarrays and DNA pooling (SNP-MaP) employing high-density microarrays. Whereas earlier studies employed a range of Affymetrix SNP microarrays comprising from 10 K to 500 K SNPs, this most recent investigation used the 6.0 chip which displays 906,600 SNP probes and 946,000 probes for the interrogation of CNVs (copy number variations). The genotyping assay using the Affymetrix SNP 6.0 array is highly demanding on sample quality due to the small feature size, low redundancy, and lack of mismatch probes. Findings: In the first study published so far using this microarray on pooled DNA, we found that pooled cheek swab DNA could not accurately predict real allele frequencies of the samples that comprised the pools. In contrast, the allele frequency estimates using blood DNA pools were reasonable, although inferior compared to those obtained with previously employed Affymetrix microarrays. However, it might be possible to improve performance by developing improved analysis methods. Conclusions: Despite the decreasing costs of genome-wide individual genotyping, the pooling approach may have applications in very large-scale case-control association studies. In such cases, our study suggests that highquality DNA preparations and lower density platforms should be preferred. [ABSTRACT FROM AUTHOR]
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- 2010
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5. The 21st International Mammalian Genome Conference Meeting Report.
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Amos-Landgraf, James and Schalkwyk, Leonard C.
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CONFERENCES & conventions , *GENOMES , *GENOMICS , *ANIMAL genome mapping - Abstract
Information on the 21st International Mammalian Genome Conference which was held at the Kyoto Terrsa in Kyoto, Japan is presented. The conference centered on systems biology and the ability of the rat as a laboratory model. It also featured bioinformatics workshops on the latest technology such as gene ontologies for mouse genetics and genomics. The meeting also witnessed the developments in the field of mutagenesis.
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- 2008
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6. Microarrays.
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Plomin, Robert and Schalkwyk, Leonard C.
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GENETICS , *DNA microarrays , *GENOMES , *GENETIC markers , *NUCLEOTIDE sequence - Abstract
Microarrays are revolutionizing genetics by making it possible to genotype hundreds of thousands of DNA markers and to assess the expression (RNA transcripts) of all of the genes in the genome. Microarrays are slides the size of a postage stamp that contain millions of DNA sequences to which single-stranded DNA or RNA can hybridize. This miniaturization requires little DNA or RNA and makes the method fast and inexpensive; multiple assays of each target make the method highly accurate. DNA microarrays with hundreds of thousands of DNA markers have made it possible to conduct systematic scans of the entire genome to identify genetic associations with complex disorders or dimensions likely to be influenced by many genes of small effect size. RNA microarrays can provide snapshots of gene expression across all of the genes in the genome at any time in any tissue, which has far-reaching applications such as structural and functional ‘genetic neuroimaging’ and providing a biological basis for understanding environmental influence. [ABSTRACT FROM AUTHOR]
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- 2007
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7. Behavioral Characterization of Wild Derived Male Mice (Mus musculus musculus) of the PWD/Ph Inbred Strain: High Exploration Compared to C57BL/6J.
- Author
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Fernandes, Cathy, Liu, Lin, Paya-Cano, José L., Gregorová, Soňa, Forejt, Jiři, and Schalkwyk, Leonard C.
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GENOMES ,MICE behavior ,PHENOTYPES ,GENOTYPE-environment interaction ,BEHAVIOR genetics - Abstract
PWD/Ph is an inbred mouse strain derived from wild mice trapped in central Czech Republic. These mice are of the Mus musculus musculus subspecies, whose ancestors separated from those of Mus musculus domesticus about one million years ago. There is a high degree of variation in the genomic sequence and a wide range of phenotypes between PWD/Ph and standard laboratory inbred mouse strains, the genomes of which are principally Mus musculus domesticus in origin, making PWD/Ph mice an useful resource for complex trait research. As a first step in taking advantage of this resource, a preliminary characterization of the behavior of PWD/Ph mice was performed. Groups of 10 PWD/Ph and C57BL/6J male mice were tested in the open field, novel object exploration task and Morris water maze. PWD/Ph were marginally more anxious than C57BL/6J mice in the open field but subsequently displayed much higher levels of exploration and lower anxiety than C57BL/6J mice following introduction of a novel object. As C57BL/6J itself is rated as highly explorative among classical inbred strains, PWD/Ph probably represents an extreme among mouse strains for this specific behavior. PWD/Ph and C57BL/6J mice differed in their water escape training profiles in the Morris water maze, perhaps reflecting different motivational factors. However, there were no differences in overall cognitive ability (spatial learning) as both groups learned to find the hidden platform and performed equally well when the location of the platform was changed. This is the first quantification of the behavior of PWD/Ph mice and the results are promising for the potential of the consomic panel currently being generated with PWD/Ph and C57BL/6J as a tool for the molecular dissection of behavior. [ABSTRACT FROM AUTHOR]
- Published
- 2004
- Full Text
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