Carolyn J. Brown

Bio: Carolyn J. Brown is an academic researcher from University of British Columbia. The author has contributed to research in topics: X-inactivation & X chromosome. The author has an hindex of 51, co-authored 139 publications receiving 12837 citations. Previous affiliations of Carolyn J. Brown include Max Planck Society & BC Cancer Research Centre.

The interleukin-2 receptor γ chain maps to Xq13.1 and is mutated in X-linked severe combined immunodeficiency, SCIDX1

Abstract: The gene encoding the gamma chain of the lymphocyte interleukin-2 receptor has been cloned and shown to be required to associate with the beta chain in order for IL-2 internalization and cell activation to occur (1). We considered this gene, IL2RG, a candidate for the X-linked form of severe combined immunodeficiency at the SCIDX1 locus, in which affected males have impaired lymphocyte development. Using fluorescence in situ hybridization and PCR amplification of somatic cell hybrid DNAs, we mapped IL2RG to human Xq13.1, a location within the SCIDX1 critical region established by linkage analysis. The 4.2 kb IL2RG gene was sequenced, and its genomic organization was elucidated. Seven of 19 transformed B-lymphocyte cell lines with independent SCIDX1 mutations had absent or minimal IL2RG mRNA. Unique point mutations were documented to be specifically associated with the disease and the carrier state in four unrelated affected males and their family members: one in a boy with no detectable IL2RG mRNA, in which the mutation ablated a splice donor site; one causing premature chain termination; and two causing distinct amino acid changes. The demonstration of impaired IL2RG mRNA expression in males with X-linked SCID and of unique point mutations in SCIDX1 pedigrees constitutes powerful evidence that the SCIDX1 gene is IL2RG. Noguchi et al. (2) have independently published IL2RG mapping to Xq13 and discovery of mutations in three affected males. The specific pathogenesis of IL2RG mutations and approaches to gene therapy can now be addressed in the X-linked form of SCID.

The human X-inactivation centre is not required for maintenance of X-chromosome inactivation.

Abstract: X-chromosome inactivation occurs early in mammalian female development to achieve dosage compensation with males. Although it is widely accepted that this inactivation requires the presence in cis of the X-inactivation centre (XIC), it is not known whether the XIC is required for the initiation, promulgation or maintenance of X inactivation. The XIST gene, which is localized within the XIC interval on both the human and mouse X chromosomes, is constitutively expressed from inactive X chromosomes, suggesting a possible role in the maintenance of X inactivation. To address whether the presence of the XIC, including the XIST gene, is continuously required for the maintenance of X-chromosome inactivation, we have analysed the transcriptional activity of a number of X-linked genes in mouse/human somatic cell hybrids retaining an intact human inactive X chromosome or derivatives of the inactive X chromosome lacking the XIC. Genes subject to X inactivation remain transcriptionally silent despite the loss of the XIC, demonstrating that the presence of the XIC is not required for the maintenance of X inactivation in somatic cells.

Silencing of the mammalian X chromosome.

Abstract: ▪ Abstract Mammalian X chromosome inactivation is one of the most striking examples of epigenetic gene regulation. Early in development one of the pair of ∼160-Mb X chromosomes is chosen to be silenced, and this silencing is then stably inherited through subsequent somatic cell divisions. Recent advances have revealed many of the chromatin changes that underlie this stable silencing of an entire chromosome. The key initiator of these changes is a functional RNA, XIST, which is transcribed from, and associates with, the inactive X chromosome, although the mechanism of association with the inactive X and recruitment of facultative heterochromatin remain to be elucidated. This review describes the unique evolutionary history and resulting genomic structure of the X chromosome as well as the current understanding of the factors and events involved in silencing an X chromosome in mammals.

Landscape of DNA methylation on the X chromosome reflects CpG density, functional chromatin state and X-chromosome inactivation

Abstract: X-chromosome inactivation (XCI) achieves dosage compensation between males and females through the silencing of the majority of genes on one of the female X chromosomes. Thus, the female X chromosomes provide a unique opportunity to study euchromatin and heterochromatin of allelic regions within the same nuclear environment. We examined the interplay of DNA methylation (DNAm) with CpG density, transcriptional activity and chromatin state at genes on the X chromosome using over 1800 female samples analysed with the Illumina Infinium Human Methylation450 BeadChip. DNAm was used to predict an inactivation status for 63 novel transcription start sites (TSSs) across 27 tissues. There was high concordance of inactivation status across tissues, with 62% of TSSs subject to XCI in all 27 tissues examined, whereas 9% escaped from XCI in all tissues, and the remainder showed variable escape from XCI between females in subsets of tissues. Inter-female and twin data supported a model of predominately cis-acting influences on inactivation status. The level of expression from the inactive X relative to the active X correlated with the amount of female promoter DNAm to a threshold of ∼30%, beyond which genes were consistently subject to inactivation. The inactive X showed lower DNAm than the active X at intragenic and intergenic regions for genes subject to XCI, but not at genes that escape from inactivation. Our categorization of genes that escape from X inactivation provides candidates for sex-specific differences in disease.

Expression of Genes from the Human Active and Inactive X Chromosomes

Abstract: X-chromosome inactivation results in the cis-limited inactivation of many, but not all, of the genes on one of the pair of X chromosomes in mammalian females. In addition to the genes from the pseudoautosomal region, which have long been anticipated to escape inactivation, genes from several other regions of the human X chromosome have now been shown to escape inactivation and to be expressed from both the active and inactive X chromosomes. The growing number of genes escaping inactivation emphasizes the need for a reliable system for assessing the inactivation status of X-linked genes. Since many features of the active or inactive X chromosome, including transcriptional activity, are maintained in rodent/human somatic-cell hybrids, such hybrids have been used to study the inactivation process and to determine the inactivation status of human X-linked genes. In order to assess the fidelity of inactivation status in such hybrids, we have examined the expression of 33 X-linked genes in eight mouse/human somatic-cell hybrids that contain either the human active (three hybrids) or inactive X (five hybrids) chromosome. Inactivation of nine of these genes had previously been demonstrated biochemically in human cells, and the expression of these genes only in hybrids retaining an active X, but not in those retaining an inactive X, confirms that expression in hybrids reflects expression in human cells. Although the majority of genes tested showed consistent patterns of expression among the active X hybrids or inactive X hybrids, surprisingly, 5 of the 33 genes showed heterogeneous expression among the hybrids, demonstrating a significantly higher rate of variability than previously reported for other genes in either human somatic cells or mouse/human somatic-cell hybrids. These data suggest that at least some X-linked genes may be under additional levels of epigenetic regulation not previously recognized and that somatic-cell hybrids may provide a useful approach for studying these chromosomal phenomena.

Initial sequencing and analysis of the human genome.

Abstract: The human genome holds an extraordinary trove of information about human development, physiology, medicine and evolution. Here we report the results of an international collaboration to produce and make freely available a draft sequence of the human genome. We also present an initial analysis of the data, describing some of the insights that can be gleaned from the sequence.

Modern Applied Statistics With S

Abstract: Thank you very much for downloading modern applied statistics with s. As you may know, people have search hundreds times for their favorite readings like this modern applied statistics with s, but end up in harmful downloads. Rather than reading a good book with a cup of coffee in the afternoon, instead they cope with some harmful virus inside their laptop. modern applied statistics with s is available in our digital library an online access to it is set as public so you can download it instantly. Our digital library saves in multiple countries, allowing you to get the most less latency time to download any of our books like this one. Kindly say, the modern applied statistics with s is universally compatible with any devices to read.

Integrative analysis of 111 reference human epigenomes

Abstract: 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.