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Genomics In The Journals: Jun 21, 2012

NEW YORK (GenomeWeb News) – In a study scheduled to appear online this week in the Proceedings of the National Academy of Sciences, researchers from centers in the US, UK, Japan, and Norway report on the strategy that they used to home in on genes contributing to prostate cancer pathogenesis.

Within more than 660 prostate tumor and normal prostate tissue samples obtained from European American, African American, and Japanese men, the team looked at how allele patterns at a dozen prostate cancer-associated variants coincided with expression of more than 100 candidate genes falling within about a million bases of these risk loci. Their analysis uncovered five genes with transcription patterns showing ties to four of the prostate cancer risk variants. Two of these genes, MSMB and NCOA4, had been linked to prostate cancer pathogenesis in the past, the study authors noted, while another three genes — NUDT11, SLC22A3, and HNF1B — had not been implicated in the process previously.

Members of the St. Jude Children's Research Hospital-Washington University Pediatric Cancer Genome Project and collaborators from Australia and Canada have tracked down new mutations within various medulloblastoma subgroups — work that they describe online in Nature.

The researchers did whole-genome sequencing on 37 tumor-normal pairs to look for driver mutations in the malignant childhood brain cancer. After finding apparent medulloblastoma-associated mutations in the genomes, they went on to sequence 136 suspicious genes in 56 more medulloblastoma samples. The search uncovered recurrent mutations in dozens of new medulloblastoma genes, along with alterations that are helping to more clearly delineate the four known medulloblastoma sub-types.

Within some medulloblastoma samples from the so-called WNT-subgroup, for example, investigators found genetic glitches affecting chromatin remodeling-related genes such as SMARCA4, along with mutations in DDX3X, CDH1, and PIK3CA. On the other hand, tumors from two more difficult to treat subtypes, known as subgroups 3 and 4, harbored mutations involving histone-modifying genes and were prone to over-expression of the methylase enzyme-coding gene EZH2.

"This study provides new direction for understanding what drives these tumors and uncovers totally unexpected new drug targets," co-senior author Richard Gilbertson, director of the St. Jude Comprehensive Cancer Center, said in a statement. "There are drugs already in development against these targets aimed at treating adult cancers and other diseases."

An international team led by investigators at the University of California at Los Angeles assessed genome-wide transcriptional patterns in individuals with or without autism spectrum disorder, looking at how gene expression outlier regions in individuals with the condition relate to regions of rare copy number variation.

As they report in the American Journal of Human Genetics, the team relied on Illumina arrays to discern gene expression patterns in blood samples from 439 members of 244 families from the Simons Simplex Collection, comprised of families that include at least one child with and one child without ASD.

Researchers found that affected and unaffected children had comparable numbers of genes with especially high or low expression profiles. In the children with ASD, though, expression outliers often included transcripts for genes involved in neural and nervous system function. And in the affected children, the location of these unusually expressed genes was more apt to overlap with sites containing rare, autism-associated CNVs — a pattern that the team used to not only prioritize CNVs for further study, but also to track down new candidate CNVs that might contribute to autism.

"A gene mutation accompanied by a change in expression clues us to a hot spot on the genome and directs us where to look next," senior author Daniel Geschwind, a genetics and neurology researcher at UCLA's David Geffen School of Medicine, said in a statement. "Not all mutations will influence gene expression, but this approach improves our ability to pinpoint those that do."

A mouse study in Cell suggests that the presence of an appropriate gut microbiome is crucial for normal intestinal immune system development.

A Brigham and Women's Hospital and Harvard Medical School-led team started with germ-free mice that were missing the microbial communities that normally live in and on the animals. They then introduced gut microbes into these mice using fecal samples from either healthy humans or healthy mice.

In addition to experiments gauging the immune cell and gene expression profiles in each group of mice, the study's authors used 16S ribosomal RNA sequencing to track gut microbiomes in the animals and their offspring. Mice colonized with human gut microbes showed differences in innate and adaptive immune cell maturation in the intestine, researchers reported, including shifts in T-cell numbers that resembled those seen in mice lacking gut microbes altogether. Moreover, mice colonized with human gut microbes did not fare as well against Salmonella bacteria infection as mice with transplanted microbes from other mice.

"Human microbe-colonized mice have gut immune systems that look essentially identical to germ-free mice," Harvard microbiology and immunology researcher Dennis Kasper, the study's senior author, said in a statement. "Even though they have the same number and diversity of bacteria, their immune systems don't develop properly."

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

The Scan

Genome Sequences Reveal Range Mutations in Induced Pluripotent Stem Cells

Researchers in Nature Genetics detect somatic mutation variation across iPSCs generated from blood or skin fibroblast cell sources, along with selection for BCOR gene mutations.

Researchers Reprogram Plant Roots With Synthetic Genetic Circuit Strategy

Root gene expression was altered with the help of genetic circuits built around a series of synthetic transcriptional regulators in the Nicotiana benthamiana plant in a Science paper.

Infectious Disease Tracking Study Compares Genome Sequencing Approaches

Researchers in BMC Genomics see advantages for capture-based Illumina sequencing and amplicon-based sequencing on the Nanopore instrument, depending on the situation or samples available.

LINE-1 Linked to Premature Aging Conditions

Researchers report in Science Translational Medicine that the accumulation of LINE-1 RNA contributes to premature aging conditions and that symptoms can be improved by targeting them.