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Genomics In The Journals: Oct 6, 2011

NEW YORK (GenomeWeb News) – In Nature Genetics, investigators from research institutes in Switzerland and the US describe how they used mouse embryonic stem cells as a model system to explore the effects that DNA sequences have on cytosine methylation patterns. To do this, they systematically integrated more than 50 DNA elements into the beta-globin gene locus of the mouse stem cells, gauging the resulting methylation patterns in the stem cells themselves and during differentiation. Their results suggest that one thousand base pair promoter sequences can recreate the normal methylation patterns in pluripotent cells. And, the team reported, short sequences dubbed small methylation-determining regions, or MDRs, play a key role in this process.

"[W]e show that promoter sequences of [about 1,000 base pairs] are generally sufficient to precisely recapitulate DNA methylation patterns in stem cells and to replicate the changes that occur during differentiation," senior author Dirk Schubeler, a researcher with the University of Basel and the Friedrich Miescher Institute for Biomedical Research, and co-authors wrote, adding, "DNA sequence-driven patterns rely on even smaller methylation determining regions (MDRs) that reside within promoter elements."

In another Nature Genetics study, a Baylor College of Medicine-led team provides evidence that genomic architecture is behind complex genomic rearrangements at the MECP2 and PLP1 loci in a subset of individuals with a neurodevelopmental condition called MECP2 duplication syndrome. Based on array comparative genomic hybridization, multiplex ligation-dependent probe amplification, genotyping, and other data, they concluded that a recurrent duplication-inverted triplication-duplication rearrangement found in some individuals is related to inverted repeat sequences found as far away as 300,000 bases or more from the affected loci.

By bringing together gene expression data with information on genetic loci found from genome-wide association studies, a Massachusetts research team has identified subsets of immune cells apparently contributing to pathogenic processes in systemic lupus erythematosus, Crohn's disease, and rheumatoid arthritis — findings that they describe online in the American Journal of Human Genetics. The researchers used a statistical approach to search for autoimmune disease-related expression quantitative trait loci in specific immune cell types, using information on disease-associated SNPs combined with gene expression data for 223 sorted mouse immune cells assessed through the Immunological Genome Project and 79 human tissues from the Genomics Institute of the Novartis Research Foundation's tissue atlas.

"These cell types are primary candidates for future functional studies to reveal the role of risk alleles in autoimmunity," senior author Soumya Raychaudhuri, a researcher affiliated with Brigham and Women's Hospital, the Broad Institute, and Partners HealthCare Center for Personalized Genetic Medicine, and co-authors explained. "Our approach has applications in other phenotypes, outside of autoimmunity, where many loci have been discovered and high-quality cell-type-specific gene expression is available."

Researchers from the UK and France have identified a mutation in the AKT2 gene that is involved in a rare form of hypoglycemia, a condition that's often caused by overactive insulin secretion by beta cells in the pancreas. As they report in a brief in Science Express, the investigators did whole-exome sequencing on a child who had severe, recurrent hypoglycemia and facial overgrown features, but undetectable insulin levels in his blood plasma. Analyses of the exome sequence data revealed a mutation in AKT2 that the team subsequently found in two more children with similar symptoms. Their results hint that the mutation activates AKT2, which belongs to a family of kinases downstream of insulin signaling.

Genomics In The Journals is a weekly feature pointing readers to select, recently published articles involving genomics and related research.

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