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Genomics In The Journals: Apr 7, 2011

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – A pair of large genome-wide association studies appearing in Nature Genetics roughly double the number of genes associated with late-onset Alzheimer's disease.

In the first of these, members of the Alzheimer Disease Genetics Consortium from 44 American research centers did a three-stage GWAS and meta-analysis involving tens of thousands of individuals with or without Alzheimer's disease. In the process, they verified associations with several genes previously identified in the disease and found four new risk genes: MS4A, CD2AP, EPHA1, and CD33.

In a second Nature Genetics paper, researchers from Europe and the US found the same four genes — along with a fifth, ABCA7 — in their own three-stage study. Alzheimer's risk genes tend to fall in immune system, cholesterol, and lipid-related pathways, they found. But the new research also points to alterations in an endocytosis-related pathway, researchers noted, perhaps reflecting a role for endocytosis in removing excess amyloid beta protein from the brain.

"We now have four genes that implicate this very precise process and it offers a very big clue that this process is playing a strong role in the development of Alzheimer's disease," Cardiff University neuropsychiatric genetics and genomics researcher Julie Williams, who led the latter research teams, said in a statement.

Investigators from the National Institute of Diabetes, Digestive, and Kidney Diseases and the Uniformed Services University of Health Sciences reported in Nature that they have successfully used chromatin immunoprecipitation coupled with Illumina GAII sequencing to map meiotic DNA double-strand breaks across the male mouse genome. Because these sites point to places where genetic recombination events occur during meiosis, this approach led them to histone methylation marks and hotspots in the mouse genome that are particularly prone to these rearrangements.

"Our findings uncover several fundamental features of mammalian recombination hotspots and underline the power of the new recombination map for future studies of genetic recombination, genome stability, and evolution," co-corresponding author Galina Petukhova, a biologist at USU, and co-authors wrote.

In a Science Translational Medicine study, researchers from Singapore and the US used genomic breakpoint analyses with high-density comparative genomic hybridization microarrays, fluorescence in situ hybridization, PCR, and targeted sequencing to track down and verify a recurrent gene fusion in stomach cancer. By looking at 106 stomach cancer samples and dozens of gastric cancer cell lines, they identified a fusion between the chromosome 11 genes CD44 and SLC1A2 that truncates SLC1A2 but ups its activity.

"It does suggest that drugs that inhibit SLC1A2 function could be used to sensitize tumors to chemotherapy," senior author Patrick Tan, a cancer and stem cell biology researcher at Duke-NUS Graduate Medical School Singapore, said in a statement. "Such glutamate uptake inhibitors are available, and we are working very hard to test this possibility."

Meanwhile, an early online paper in Proceedings of the National Academy of Sciences by National Institute on Alcohol Abuse and Alcoholism and University of Miami researchers narrows in on some of the shared transcriptional and epigenetic changes that occur in the human hippocampus when individuals are addicted to cocaine or to alcohol — as well as alterations that seem to be drug-specific. The team used a combination of RNA sequencing and chromatin immunoprecipitation-enriched sequencing targeting histone H3 lysine 4 trimethylation to find gene expression and chromatin patterns in post-mortem hippocampal samples from eight chronic cocaine users, eight alcoholics, and eight drug-free control individuals.

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

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